2018 Physical Activity Guidelines Advisory Committee Scientific Report

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1 2018 Physical Activity Guidelines Advisory Committee Scientific Report To the Secretary of Health and Human Services

2 The findings of this report are those of the 2018 Physical Activity Guidelines Advisory Committee. They do not necessarily reflect the views of the Office of Disease Prevention and Health Promotion or the U.S. Department of Health and Human Services. Suggested citation: 2018 Physical Activity Guidelines Advisory Committee. 2018 Physical Activity Guidelines Advisory Committee Scientific Report . Washington, DC: U.S. Department of Health and Human Services, 2018.

3 Office of the Secretar y DEPARTMENT SERVICES OF HEALTH & HUMAN ant Secretary for Hea Office of the Assist lth Washington, DC 20201 Alex Azar The Honorable Services of Health Secretary and Human 200 Independence Avenue, S.W. D.C. 20201 Washington, Secretary Azar, Dear 2018 Physical Activity Guidelines Advisory Committee, On behalf of to the entire we are very pleased the Physical Activity Guidelines Advisory Committee Scientific Report. submit 2018 with reviewing the scientific literature on physical activity and health. The Our Committee was charged Physical Activity Guidelines Advisory Committee Scientific Report provides a detailed 2018 of summary the disease and health promotion benefits of a more physically active America that is firmly prevention by the latest scientific It builds on and significantly expands the scientific evidence established evidence. Physical in the first Guidelines Advisory Committee Report, 2008. The Committee summarized Activity the 2008 Scientific Report to be an excellent document judged it as the foundation for the and used the expansion of knowledge about the relationships between however, that current It is clear, report. activity and health during the past 10 years has provided evidence of even more health physical benefits, demonstrated greater flexibility about how to achieve those benefits, and shown that a more physically active American can be facilitated in a wide variety of ways. population Report demonstrates the full age spectrum, regular physical activity provides a The Scientific that, across of benefits sleep better, and perform daily tasks more easily. The report variety that help us feel better, that some benefits happen immediately. A single bout of moderate-to-vigorous also demonstrates physical activity that night's sleep, reduce anxiety symptoms, improve cognition, reduce can improve pressure, sensitivity insulin blood on the day that it is performed. Most of these and improve of moderate-to-vigorous physical become even larger with the regular performance improvements activity. The newly documented health benefits also include reduced risk of excessive weight gain in adults, children, improved cognitive function and a reduced risk of dementia; and women; and pregnant risk of cancer of the bladder, endometrium, esophagus, kidney, lung, and stomach. The report reduced In for the first time, activity-related health benefits for children ages 3 to 5 years. physical demonstrates, a chronic disease or condition such as addition, for the large number of adults who already have osteoarthritis, or type 2 diabetes, a reduced risk of developing a new chronic condition hypertension, and reduced risk of progression of the condition they already have, plus improvements in quality of life and physical function. U.S. Public Health Service

4 Given Americans' of participation in physical activity and high prevalence of chronic diseases low rates disabilities, this report timely. It provides the necessary foundation for the and associated is particularly the 2008 Activity Guidelines fo r Americans. Strong federal guidelines, to revise Physical Department on physical activity should be an essential component policies, and programs of any comprehensive prevention promotion strategy for Americans. Included and health report is a summary of disease in this physical activity promotion interventions that hold promise for improving the nation's evidence-based activity physical levels. of the entire Committee, we thank you for the opportunity to support the prevention On behalf of the Department. Over the Committee members and consultants priorities the past 20 months, exceptionally extensive scientific review that made this report worked long and hard to conduct the Despite this task being added possible. busy schedules, they met tight deadlines, provided to their usual insight one another, and unselfishly worked to develop a consensus report. Thus, and education to we wish to thank you for assembling a Committee of outstanding professionals who are knowledgeable, dedicated, and highly productive. Committee members are committed to the broad dissemination of this report and the ensuing Please do not hesitate to contact us or any of the Committee guidelines. if we can be of further members service. that this report to emphasize not have been completed without the outstanding It is important could of all the HHS staff who assisted us throughout the entire process. We are very grateful support for their substantial throughout the process. Their excellent logistical and management support in all assistance of the Committee's work was essential. Special recognition goes to Lieutenant Commander aspects Katrina Piercy of the Office of Disease Prevention and Health Promotion and Captain Richard Troiano of the National Cancer to the coordination, and ultimate completion, Institute for their tireless dedication This report of this project. benefits from the expert editing provided by Anne Brown Rodgers, greatly who helped us present information that is useful and readable, and from the rigorous literature review work by Bonny Bloodgood at ICF. overseen Sincerely, Abby C. King, PhD Co-Chair, 2018 Physical Activity Guidelines Advisory Committee Departments of Health Research & Policy and Medicine, School of Medicine, Stanford University Kenneth E. Powell, MD, MPH Co-Chair, 2018 Physical Activity Guidelines Advisory Committee Retired, Atlanta, Georgia

5 2018 Physical Activity Guidelines Advisory Committee Scientific Report February 2018

6 Table of Contents TABLE OF CONTENTS i ... ... Membership Lists .. A-1 ... Executive Summary Part A. . B-1 . Part B. Introduction ... C-1 ... .. Part C. Background and Key Physical Activity Concepts D-1 ... . Part D. Integrating the Evidence E-1 Systematic Review Literature Search Methodology ... . Part E. Part F. The Science Base New Issues in Defining Physical Activity Part F. Chapter 1. ... Physical Activity Behaviors: Steps, Bouts, and High Intensity Training -1 F1 ... Part F. Chapter 2. Sedentary Behavior -1 F2 Physical Activity and Selected Health Outcomes Part F. Chapter 3. Brain Health ... F3 -1 Part F. Chapter 4. Cancer Prevention ... F4 -1 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight -1 F5 ... Gain Part F. Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident F6 -1 Cardiovascular Disease ...

7 Table of Contents Physical Activity Considerations for Selected Populations ... Part F. Chapter 7. Youth -1 F7 Part F. Chapter 8. Women Who are Pregnant or Postpartum ... -1 F8 ... Part F. Chapter 9. Older Adults -1 F9 ... Part F. Chapter 10. Individuals with Chronic Conditions F10-1 Promoting Physical Activity Promoting Regular Physical Activity ... Part F. Chapter 11. F11-1 G-1 Needs for Future Research ... Part G. Part H. Appendices Appendix H-1. Glossary of Terms ... H1 -1 Appendix H-2. Subcommittee and Work Group Assignments ... H2 -1 Appendix H-3. ... Biographical Sketches of the Committee Members H3 -1 Appendix H-4. Public Comment Process ... H4 -1

8 Membership Lists MEMBERSHIP LISTS Table of Contents Physical Activity Guidelines Advisory Committee ... ... ... i Consultants to Subcommittees or Work Groups ... ... ... iv Outside Experts vi ... U.S. Department of Health and Human Services Staff ... viii Literature Review Staff ... x Technical Assistance to the Subcommittees ... xi PHYSICAL ACTI IDELINES ADVISORY COMMITTEE VITY GU -Chairs Co Abby C. King, PhD, FACSM, FSBM Department of Health Research & Policy Stanford Prevention Research Center, Department of Medicine School of Medicine Stanford University Stanford, CA Ken neth E. Powell, MD, MPH, FACSM, FACP Emeritus Georgia Department of Human Resources (Retired) Centers for Disease Control and Prevention (Retired) Atlanta, GA Members David Buchner, MD, MPH, FACSM Department of Kinesiology and Community Health University of Illinois at Urbana-Champaign Champaign, IL D Wayne Campbell, Ph Department of Nutrition Science Department of Health and Kinesiology Purdue University West Lafayette, IN 2018 Physical Activity Guidelines Advisory Committee Scientific Report i

9 Membership Lists Loretta DiPietro, PhD, MPH, FACSM ent of Exercise and Nutrition Sciences Departm Milken Institute School of Public Health The George Washington University Washington, DC Kirk I. Erickson, PhD epartment of Psychology D Department of Geriatric Medicine University of Pittsburgh Pittsburgh, PA , PhD Charles H. Hillman Department of Psychology Department of Physical Therapy, Movement, and Rehabilitation Sciences Northeastern University Boston, MA John M. Jakic ic, PhD, FACSM, FTOS Department of Health and Physical Activity Physical Activity and Weight Management Research Center University of Pittsburgh Pittsburgh, PA Kathleen F. Janz, EdD, FACSM Department of Health and Human Physiology Department of Epidemiology University of Iowa Iowa City, IA k, PhD, FACSM Peter T. Katzmarzy Pennington Biomedical Research Center Baton Rouge, LA CSM, FACC, FAHA William E. Kraus, MD, FA Department of Medicine School of Medicine Duke University Durham, NC Richard F. Macko, MD D epartments of Neurology and Medicine, Geriatrics School of Medicine University of Maryland Baltimore, MD 2018 Physical Activity Guidelines Advisory Committee Scientific Report ii

10 Membership Lists David X. Marquez, PhD, FACSM, FSBM, FGSA Department of Kinesiology and Nutrition University of Illinois at Chicago Chicago, IL Anne McTiernan, MD, PhD, FACSM, FTOS, FACE Fred Hutchinson Cancer Research Center School of Medicine School of Public Health University of Washington Seattle, WA Russell R. Pate, PhD, FACSM Department of Exercise Science School of Public Health University of South Carolina Columbia, SC Linda S. Pescatello, PhD, FACSM, FAHA Department of Kinesiology College of Agriculture, Health and Natural Resources University of Connecticut Storrs, CT Melicia C. Whitt-Glover, PhD, FACSM Gramercy Research Group Winston-Salem State University Winston-Salem, NC 2018 Physical Activity Guidelines Advisory Committee Scientific Report iii

11 Membership Lists CONSULTANTS TO SUBCOMMITTEES OR WORK GROUPS These individuals provided expertise on a specific topic or question throughout the course of the work of a Subcommittee or Work Group. Brain Health Subcommittee David E. Conroy, PhD The Pennsylvania State University University Park, PA Steven J. Petruzzello, PhD University of Illinois at Urbana-Champaign Urbana, IL Cancer-Primary Prevention Subcommittee Christine M. Friedenreich, PhD University of Calgary Alberta, Canada Cardiometabolic Health and Weight Management Subcommittee Ronald J. Sigal, MD, MPH University of Calgary Alberta, Canada Exposure Subcommittee William L. Haskell, PhD Stanford University Stanford, CA Individuals with Chronic Conditions Subcommittee Virginia Byers Kraus, MD, PhD Duke University School of Medicine Durham, NC Christine M. Friedenreich, PhD University of Calgary Alberta, Canada Ronald J. Sigal, MD, MPH University of Calgary Alberta, Canada Ronald J. Sigal, MD, MPH University of Calgary Alberta, Canada 2018 Physical Activity Guidelines Advisory Committee Scientific Report iv

12 Membership Lists Promotion of Physical Activity Subcommittee Matthew P. Buman, PhD Arizona State University Phoenix, AZ Melissa A. Napolitano, PhD The George Washington University DC Washington, Physical Fitness Work Group William L. Haskell, PhD Stanford University Stanford, CA Pregnancy and Postpartum Work Group Kelly Evenson, PhD, MS University of North Carolina – Chapel Hill Chapel Hill, NC 2018 Physical Activity Guidelines Advisory Committee Scientific Report v

13 Membership Lists OUTSIDE EXPERTS These individuals provided information or a presentation to the full Committee, a Subcommittee, or a Work Group on a specific topic or question at one meeting. Full Committee Janet E. Fulton, PhD Centers for Disease Control and Prevention Atlanta, GA William L. Haskell, PhD Stanford University Stanford, CA Richard P. Troiano, PhD National Institutes of Health Bethesda, MD Exposure Subcommittee Wendy M. Kohrt, PhD University of Colorado Denver Aurora, CO Heather McKay, PhD University of British Columbia Vancouver, BC Pedro Saint-Maurice, PhD F. National Cancer Institute Bethesda, MD Individuals with Chronic Conditions Subcommittee Alison N. Cernich, Ph.D. Eunice Kennedy Shriver National Institute for Child Health and Human Development Bethesda, MD 2018 Physical Activity Guidelines Advisory Committee Scientific Report vi

14 Membership Lists Pregnancy and Postpartum Work Group James Pivarnik, PhD Michigan State University East Lansing, MI Lisa Chasan-Tabor, ScD University of Massachusetts Amherst, MA Young Adult Transition Work Group Katherine Brooke-Wavell, BSc, MSc, PhD Loughborough University Loughborough, UK Jonathan Tobias, BA, MBBS, PhD, MD University of Bristol Bristol, UK vii 2018 Physical Activity Guidelines Advisory Committee Scientific Report

15 Membership Lists U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES STAFF Co -Executive Secretaries Richard D. Olson, MD, MPH Director, Division of Prevention Science Office of Disease Prevention and Health Promotion Designated Federal Officer to the Physical Activity Guidelines Advisory Committee Ka -C trina L. Piercy, PhD, RD, ACSM- EP Lieutenant Commander, U.S. Public Health Service Physical Activity and Nutrition Advisor Office of Disease Prevention and Health Promotion Alternate Designated Federal Officer to the Physical Activity Guidelines Advisory Committee Rachel M. Ballard, MD, MPH Director, Prevention Research Coordination Office of Disease Prevention National Institutes of Health Janet E. Fulton, PhD Chief, Physical Activity and Health Branch Division of Nutrition, Physical Activity, and Obesity Centers for Disease Control and Prevention Deborah A. Galuska, MPH, PhD Associate Director of Science Division of Nutrition, Physical Activity, and Obesity Centers for Disease Control and Prevention Shellie Y. Pfohl, MS (through September 2016) Executive Director President’s Council on Fitness, Sports & Nutrition Richard P. Troiano, PhD Captain, U.S. Public Health Service Program Director, Division of Cancer Control and Population Sciences National Cancer Institute National Institutes of Health Lead Management Staff Stephanie M. George, PhD, MPH, MA Office of Disease Prevention National Institutes of Health Alison Vaux-Bjerke, MPH Office of Disease Prevention and Health Promotion 2018 Physical Activity Guidelines Advisory Committee Scientific Report viii

16 Membership Lists Management Support Staff Emily Bhutiani, MS (July 2016-June 2017) National Cancer Institute National Institutes of Health Eric Hyde, MPH (from July 2017) Division of Nutrition, Physical Activity, and Obesity Centers for Disease Control and Prevention Kate Olscamp, MPH (from September 2017) President’s Council on Fitness, Sports & Nutrition Sarah Prowitt, MPH (July 2016-June 2017) Office of Disease Prevention and Health Promotion Julia Quam, MSPH, RDN (from August 2017) Office of Disease Prevention and Health Promotion Kyle Sprow, MPH, CSCS (from September 2017) National Cancer Institute National Institutes of Health Data Assistance Staff Susan A Carlson, PhD, MPH Division of Nutrition, Physical Activity, and Obesity Centers for Disease Control and Prevention Geoffrey Whitfield, PhD, Med Division of Nutrition, Physical Activity, and Obesity Centers for Disease Control and Prevention Technical Writer/Editor Anne Brown Rodgers 2018 Physical Activity Guidelines Advisory Committee Scientific Report ix

17 Membership Lists LITERATURE REVIEW STAFF ICF Leadership Team Audie Atienza, PhD Bonny Bloodgood, MA Sondra Dietz, MPH, MA Isabela Lucas, PhD Mary Schwarz Bethany Tennant, PhD Andrea Torres, PhD Librarians Michelle Cawley, MLS, MS (ICF) Nicole Vetter, MLS (ICF) Nancy Terry, MLS (National Institutes of Health) Abstractors Matthew Beerse, MS Natalie Eichner, M Ed Diego Ferreira, MS Janice Hassett Vick, PhD Akilah Heggs, MA Evan Hilberg, MS, MPH Afton Seeley, MS Chelsea Smith, MS Cheng Kun Wen, MPH Christie Zunker, PhD Additional Support Zoe Donnell, MA Ashley Phillips Jillian Pugatch, MPH Revathi Muralidharan Shweta Satyan, MS Ashley Schaad, MA Emily Reinas 2018 Physical Activity Guidelines Advisory Committee Scientific Report x

18 Membership Lists TECHNICAL ASSISTAN CE TO THE SUBCOMMITTEES Aging Subcommittee Tim Hughes, The George Washington University Brain Health Subcommittee George Grove Jr, University of Pittsburgh Jamie Cohen, University of Pittsburgh Chelsea Stillman, PhD, University of Pittsburgh Cardiometabolic and Weight Management Subcommittee Katherine Collins, MS, University of Pittsburgh Exposure Subcommittee David Bartlett, PhD, Duke University School of Medicine Joyce Sizemore, Duke University Individuals with Chronic Conditions Subcommittee Andrew Hua, PhD, University of Illinois at Urbana-Champaign Promotion of Physical Activity Subcommittee Ben Chrisinger, PhD, Stanford University Youth Subcommittee Janna Borden, University of South Carolina Michaela Schenkelberg, University of South Carolina Other Support: Darlyne Esparza, Stanford University (Assistant to Dr. Abby King) Jessica Goyette-Blankenship, Purdue University (Assistant to Dr. Wayne Campbell) Susanne DeSantis (The George Washington University) 2018 Physical Activity Guidelines Advisory Committee Scientific Report xi

19 Part A. Executive Summary PART A . EXECUTIVE SUMMARY Table of Contents Introduction ... A-1 Major Findings ... A-2 ... blic Health Impact A-6 Pu ... A-7 The Future INTRODUCTION The 2018 P hysical Activity Guidelines Advisory Committee Scientific Report abundantly demonstrates that physical activity is a “best buy” for public health. The report provides a detailed summary of the disease prevention and health promotion benefits of a more physically active America that is firmly established by the latest scientific evidence. It builds on and significantly expands the scientific evidence summarized in the first The Committee . Physical Activity Guidelines Advisory Committee Report, 2008 judged the 2008 Scientific Report to be an excellent document and used it as the foundation for the current report. It is clear, however, that the expansion of knowledge about the relationships between physical activity and health during the past 10 years has provided evidence of even more health benefits, demonstrated greater flexibility about how to achieve those benefits, and shown that a more physically active American population can be facilitated in a wide variety of ways. The 17 members of the 2018 Physical Activity Guidelines Advisory Committee were appointed in June 2016 and sworn into duty in July 2016. The Committee was instructed to examine the scientific literature, especially articles published in the 10 years since the publication of the 2008 Scientific Report, and to confirm, expand, or modify the recommendations in th at report. The Committee conduct ed detailed searches of the scientific literature, evaluat ed and discussed at length the quality of the ed ev idence, and develop conclusions based on the evidence as a whole. The quantity and quality of the report reflects this careful and diligent process. 2018 Physical Activity Guidelines Advisory Committee Scientific Report A-1

20 Part A. Executive Summary MAJOR FINDINGS Physically active individuals sleep better, feel better, and function better. The 2018 Scientific Report demonstrates that, in addition to disease prevention benefits, regular physical activity provides a variety of benefits that help individuals sleep better, feel better, and perform daily tasks more easily. • Strong evidence demonstrates that moderate- to-vigorous physical activity improves the quality of sleep. It does so by reducing the length of time it takes to go to sleep and reducing the time one is awake after going to sleep and before arising in the morning. It also can increase the time in deep sleep and reduce daytime sleepiness. • Single episodes of physical activity promote acute improvements in executive function for a period of time. Executive function includes the processes of the brain that help organize daily activities and plan for the future. Tasks such as one’s ability to plan and organize, self -monitor and inhibit or facilitate behaviors, initiate tasks, and control emotions all are part of executive function. Physical activity also improves other components of cognition, including memory, processing speed, attention, and academic performance. • Regular physical activity not only reduces the risk of clinical depression but reduces depressive e symptoms among people both with and without clinical depression. Physical activity can reduc the severity of those symptoms whether one has only a few or many. • Regular physical activity reduces symptoms of anxiety, including both chronic levels of anxiety as well as the acute feelings of anxiety felt by many individuals from time to time. • Strong evidence also demonstrates that perceived quality of life is improved by regular physical activity. • Physical activity improves physical function among individuals of all ages, enabling them to conduct their daily lives with energy and without undue fatigue. This is true for older adults, for whom improved physical function not only reduces risk of falls and fall-related injuries but contributes to their ability to maintain independence. It is also true for young and middle-aged adults, as improved physical function is manifested in the ability to more easily accomplish the tasks of daily living, such as climbing stairs or carrying groceries. Some benefits happen immediately. A single bout of moderate- to-vigorous physical activity will reduce blood pressure, improve insulin sensitivity, improve sleep, reduce anxiety symptoms, and improve cognition on the day that it is performed. Most of these improvements become even larger with the A-2 2018 Physical Activity Guidelines Advisory Committee Scientific Report

21 Part A. Executive Summary to-vigorous physical activity. Other benefits, such as disease risk regular performance of moderate- reduction and physical function, accrue within days to weeks after adopting a new physical activity routine. Physical activity reduces the risk of a large number of diseases and conditions. The past 10 years have greatly expanded the list of diseases and conditions for which greater amounts of physical activity reduce the risk. Some of the major results include: • Strong evidence demonstrates that greater volumes of moderate- to-vigorous physical activity are associated with preventing or minimizing excessive weight gain in adults, maintaining weight within a healthy range, and preventi ng obesity. This is important because losing weight is difficult and costly. • Strong evidence demonstrates that higher amounts of physical activity are associated with a reduced risk of excessive increases in body weight and adiposity in children ages 3 to 17 years. • Strong evidence also demonstrates that more physically active women are less likely to gain excessive weight during pregnancy. They also are less likely to develop gestational diabetes or develop postpartum depression than their less active peers. Maternal and child health has been, appropriately, a priority in the United States for generations. These findings indicate that physical activity is an important tool in the maintenance of maternal health, and affects a key time period when establishing lifelong healthy behaviors can be beneficial to women and their children alike. • Strong evidence demonstrates that greater volumes of physical activity reduce the risk of dementia and improve other aspects of cognitive function. Given the high and rising prevalence of older Americans and the expense and heartache of caring for individuals with dementia, the value of preventing dementia is high. • For the first time, the 2018 Scientific Report demonstrates that regular physical activity provides health benefits to children as young as ages 3 to 5 years. The 2008 Committee was unable to reach a conclusion about this young age group because of insufficient information . A substantial increase in evidence since then has allowed the 2018 Committee to conclude that, in addition to the reduced risk of excessive gains in body weight and adiposity, regular physical activity improves bone health in this young age group. These findings call attention to the importance of establishing healthy physical activity behaviors at an early age. • For older adults, strong evidence demonstrates a reduced risk of falls and fall-related injuries. A-3 2018 Physical Activity Guidelines Advisory Committee Scientific Report

22 Part A. Executive Summary • to-vigorous physical activity reduced the The 2008 Committee concluded that regular moderate- ed that list to include a reduced risk risk of breast and colon cancer. The 2018 Committee expand for cancers of the bladder, endometrium, esophagus, kidney, lung, and stomach. • A large portion of the general population already has a chronic disease or condition. The 2018 Committee has concluded that, for many of these individuals, regular physical activity can reduce the risk of developing a new chronic condition, reduce the risk of progression of the condition they already have, and improve their quality of life and physical function. The conditions examined by the Committee included some of the most prevalent, including osteoarthritis, hypertension, and type 2 diabetes. The benefits of physical activity can be achieved in a variety of ways . The public health target range suggested in the 2008 Scientific Report was 500 to 1,000 MET-minutes of moderate- to-vigorous physical activity ( or 150 to 300 minutes per week of moderate-intensity physical activity) . The 2018 Committee concurs with this target range. Unfortunately, half the U.S. adult population does not currently attain this level of physical activity to-vigorous . Thirty percent of the population reports doing no moderate- physical activity. Thus, for a large segment of the population, major improvements in health are available from modest increases in regular physical activity. The 2008 Committee report ed that inactive individuals can achieve substantial health gains by increasing their activity level even if they do not reach the target range. Since 2008, substantially more information in the scientific literature documents the value of reducing inactivity even if the 150- to 300- mi nute weekly target range is not achieved. Here is a brief review of the major findings. For individuals who perform no or little moderate- to-vigorous physical activity, replacing • sedentary behavior with light-intensity physical activity reduces the risk of all-cause mortality, cardiovascular disease incidence and mortality, and the incidence of type 2 diabetes. Before this report, evidence that light-intensity physical activity could provide health benefits had not been clearly stated. • Individuals who perform no or little moderate- to-vigorous physical activity, no matter how much time they spend in sedentary behavior, can reduce their health risks by gradually adding some or more moderate-intensity physical activity. For individuals whose amount of moderate-to • -vigorous physical activity is below the current public health target range of 150 to 300 minutes of moderate-intensity physical activity, even A-4 2018 Physical Activity Guidelines Advisory Committee Scientific Report

23 Part A. Executive Summary small increases in moderate-intensity physical activity provide health benefits. There is no threshold that must be exceeded before benefits begin to occur. • For individuals whose physical activity is below the current public health target range, greater benefits can be achieved by reducing sedentary behavior, increasing moderate-intensity physical activity, or combinations of both. • For any given increase in moderate- to-vigorous physical activity, the relative gain in benefits is greater for individuals who are below the current public health target range than for individuals already within the physical activity target range. For individuals below the target range, substantial reductions in risk are available with relative ly small increases in moderate-intensity physical activity. • Individuals already within the physical activity target range can gain more benefits by doing more moderate- to-vigorous physical activity. Individuals within the target range already have substantial benefits from their current volume of physical activity. • Bouts, or episodes, of moderate- to-vigorous physical activity of any duration may be included in the daily accumulated total volume of physical activity. The 2008 Physical Activity Guidelines for Americans to-vigorous physical activity in bouts of 10 recommended accumulating moderate- minutes or more. Research now shows that any amount of moderate- to-vigorous physical activity counts toward meeting the target range . Previously, insufficient evidence was available to support the value of bouts less than 10 minutes in duration. The 2018 Committee was able to conclude that bouts of any length contribute to the health benefits associated with the accumulated volume of physical activity. Efforts to promote physical activity can be effective. The 2008 Scientific Report included no information about methods of promoting and facilitating healthy levels of physical activity. The 2018 Scientific Report includes a summary of major findings from the large body of scientific literature about promoti ng physical activity through different interventions. • Strong evidence demonstrates that individual-level interventions can increase the volume of physical activity performed by youth and by adults, especially when the interventions are based on behavioral change theories and techniques. • School-based, especially multi-component, programs and community-wide physical activity programs can be effective. A-5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

24 Part A. Executive Summary • Environmental and policy changes that improve access to places where people can be physically active, modify the built environment to better support physical activity behaviors (including physically active transport), and that, in general, make it easier for people to be physically active can be effective. • Information and communication technologies, including wearable activity monitors, telephone and smartphone programs and applications, computer-tailored print interventions, and the Internet, can be used to enable self-monitoring, deliver messages, and provide support, all of which are helpful in promoti ng regular physical activity. PUBLIC HEALTH IMPACT The public health impact of insufficient physical activity and the potential gains from even small population-wide increases are substantial. Information contained in this report indicates that, in addition to a reduced risk of death, greater amounts of regular moderate- to-vigorous physical activity reduce the risk of many of the most common and expensive diseases or conditions in the United States. Heart disease, stroke, hypertension, type 2 diabetes, dementia, depression, postpartum depression, excessive weight gain, falls with injuries among the elderly, and breast, colon, endometrial, esophageal, kidney, stomach, and lung cancer are all less common among individuals who are or become more physically active. In addition, this report provides evidence that for some of these conditions, individuals who are or become more physically active, relative to their peers with the same condition, have a reduced risk of mortality, reduced risk of developing other chronic diseases or conditions, and reduced risk of progression of the disease they already have . They also have improved physical function and better quality of life. Each of these conditions alone adds substantially to annual direct and indirect medical costs in the United States. Even small increases in regular moderate- to-vigorous physical activity, especially if made by the least physically active individuals, would appreciably reduce the nation’s direct and indirect medical costs. Quantification of the costs attributable to insufficient physical activity was beyond the scope of this Committee. It is clear, however, that the cost reductions would be large by any standards. More difficult to quantify, but equally as important, are the benefits associated with how individuals feel every day and the energy and vitality they have to carry out their daily lives. Placing dollar estimates on improved cognition across the full life span, better quality of life, fewer symptoms of depression and anxiety, enhanced quality of sleep, and improved physical function is difficult. In addition, monetizing 2018 Physical Activity Guidelines Advisory Committee Scientific Report A-6

25 Part A. Executive Summary these benefits likely cannot adequately describe the intangible societal benefits that derive from a happier and more energetic population. THE FUTURE The field of physical activity and public health has matured markedly in the past 10 years, and it will continue to develop at a rapid pace . Using the existing extensive scientific foundation and aided by recent technological advances, increases in knowledge about the relationships between physical activity and a wide variety of health and quality of life outcomes will surely continue. The Committee has described current evidence and recent gains in knowledge, but recognizes that in the near future, the field will generate more information about the benefits of physical activity and the types and volumes that provide those benefits. In addition, gains in the area of physical activity promotion are accumulating rapidly . Transferring this new knowledge into public health practice has the potential to improve the health of the American public to an unprecedented level. At the same time, the Committee recognized that important gaps in knowledge still remain. It prepared a substantial list of topic-specific research recommendations. Six overarching recommendations are provided here. Determine the independent and interactive effects of physical activity and sedentary behavior • on multiple health outcomes in youth, adults, and older adults. Determine the role and contribution of light-intensity physical activity alone or in combination • with moderate- to-vigorous physical activity to health outcomes . • Identify effective intervention strategies for increasing physical activity through actions in multiple settings in youth, adults, and older adults. Determine how the effectiveness of interventions differs by sex, age, race, ethnicity, socioeconomic status, and other factors. • Strengthen the understanding of dose-response relationships between physical activity and multiple health outcomes in youth, adults, and older adults, and especially during the life transitions between these categories . • Expand knowledge of the extent to which the relationships between physical activity and health outcomes are modified by demographic factors, including sex and race/ethnicity. • Develop instrumentation and data collection systems that will enhance physical activity surveillance systems in the United States. A-7 2018 Physical Activity Guidelines Advisory Committee Scientific Report

26 Part B. Introduction PART B. INTRODUCTION Table of Contents Setting the Stage ... B-1 ... B-2 The Physical Activity Guidelines Advisory Committee B-3 Charge to the Committee ... Committee Processes ... B-4 Committee Meetings B-4 ... ... B-4 Public Comments d Work Process ... B-5 Committee Organization an Approaches to Reviewing the Evidence ... B-6 B-6 Report Structure ... Contents and ... B-7 Organization of the Scientific Report References ... B-8 AGE SETTING THE ST In 2008, the U.S. Department of Health and Human Services (HHS) released the first edition of 1 the Physical Activity Guidelines for Americans . The Guidelines provides science-based advice on how physical activity can help promote health and reduce the risk of chronic disease. The Guidelines serves as the benchmark and primary, authoritative voice of the federal government for providing science- based guidance on physical activity, fitness, and health for Americans. It provides a foundation for federal recommendations and education for physical activity programs for Americans, including those at risk of chronic disease. The Guidelines were developed using information from a Physical Activity Guidelines Advisory 3 2 similar to the expert committees formed for the Dietary Guidelines for Americans Committee, process. This committee mechanism was recognized as an effective approach to obtain a comprehensive and systematic review of the science, which contributes to successful federal implementation as well as broad public acceptance of the Guidelines. B-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

27 Part B. Introduction In 2013, five years after the Guidelines was released, HHS developed the Physical Activity Guidelines 4 . Midcourse Report: Strategies to Increase Physical Activity Among Youth This report built on the 2008 1 Guidelines by focusing on strategies to help youth achieve the recommended 60 minutes of daily physical activity in a variety of settings, including school, preschool and childcare, community, family and home, and primary care. 1 The 2008 Guideline was developed because of strong evidence that regular physical activity promotes s health and reduces risk of many chronic diseases, including heart disease, diabetes, and several cancers. This evidence base continues to grow; thus, in December 2015 HHS began the process of developing the second edition of the Physical Activity Guidelines by calling for nominations to the 2018 Physical Activity Guidelines Advisory Committee. THE PHYSICAL ACTIVITY GUIDELINES ADVISORY COMMITTEE The 2018 Physical Activity Guidelines Advisory Commit s formed to provide wa tee (Committee) independent advice and recommendations based on current scientific evidence for use by the federal government in developing the second edition of the Physical Activity Guidelines for Americans . Nominations for nationally recognized experts in the field of physical activity and health were sought from the public through a Federal Register notice published on December 18, 2015. Criteria for Committee members included knowledge about current scientific research in human physical activity; familiarity with the purpose, communication, and application of federal physical activity guidelines; and demonstrated interest in the public’s health and well -being through their research and/or educational endeavors. Expertise was sought in specific specialty areas related to physical activity and health promotion or disease prevention, including but not limited to: health promotion and chronic disease prevention; bone, joint, and muscle health and performance; obesity and weight management; physical activity and risk of musculoskeletal injury; physical activity and cognition; physical activity within specific settings, such as preschool or childcare, schools (e.g., activity breaks, physical education), the community, or built environment; physical activity dose-response; sedentary behavior; behavior change; systematic reviews; and special populations, including children, older adults, individuals with disabilities, and women who are pregnant or postpartum . B-2 2018 Physical Activity Guidelines Advisory Committee Scientific Report

28 Part B. Introduction To ensure that recommendations of the Committee took into account the needs of the diverse groups served by HHS, membership was sought to include, to the extent practicable, a diverse group of men and women with representation from various geographic locations, racial and ethnic groups, and individuals with disabilities. Equal opportunity practices, in line with HHS policies, were followed in all membership appointments to the Committee. Appointments were made without discrimination on the basis of age, race and ethnicity, gender, sexual orientation, disability, or cultural, religious, or socioeconomic status. Individuals were appointed to serve as members of the Committee to represent balanced viewpoints of the scientific evidence and not to represent the viewpoints of any specific group. Members of the Committee were classified as Special Government Employees during their term of appointment, and as such were subject to the ethical standards of conduct for all federal employees. The Committee served without pay and worked under the regulations of the Federal Advisory Committee Act, known as FACA (Public Law 92-463 (5 U.S.C. Appendix 2, the Federal Advisory Committee Act of 1972), as amended). The Secretary of HHS appointed 17 individuals for membership to the Committee in June 2016. The selected individuals are highly respected by their peers for their depth and breadth of scientific knowledge of the relationship between physical activity and health in all relevant areas of the current Physical Activity Guidelines. Biographical sketches of the Committee members are presented in Part H. Appendix 3. Biographical sketches. CHARGE TO THE COMMITTEE The Committee was established for the single, time-limited task of reviewing the 2008 Physical Activity and developing physical activity and related health recommendations in this Guidelines for Americans Scientific Report to the Secretary of HHS. The Committee’ s charge, which was described in the Committee’s charter, is as follows: The Committee, whose duties are time-limited and solely advisory in nature, will: Examine the first edition of the Physical Activity Guidelines for Americans and determine topics • for which new scientific evidence is likely to be available that may reconfirm or inform revisions to the current guidance or suggest new guidance. 2018 Physical Activity Guidelines Advisory Committee Scientific Report B-3

29 Part B. Introduction • Place its primary focus on the systematic review and analysis of the evidence published since the last Committee deliberations. • Place its primary emphasis on the development of physical activity recommendations for the general population in the United States and for specific subgroups of the population where warranted by a public health need. Prepare and submit to the Secretary of HHS a scientific advisory report of technical • recommendations with rationales to inform the development of the second edition of the Physical Activity Guidelines for Americans. The Committee is responsible for providing authorship for this scientific report; however, responsibilities do not include translating the recommendations into policy, developing a draft of the policy, or making recommendations for implementation, including communication and outreach strategies. • Disband upon the submittal of the Committee’s rec ommendations via the scientific advisory report to the Secretary of HHS. Complete all work within the two-year charter time frame. • COMMITTEE PROCESSES The Committee operated under the regulations of the Federal Advisory Committee Act as outlined in its arter which was filed with Congress on June 1, 2016. This process ensures independent review in an ch open public manner, with opportunities for public participation. Committee Meetings The Committee held five public meetings over the course of 16 months. Meetings were held in July and October 2016, and March, July, and October 2017. The members met in person on the campus of the National Institutes of Health in Bethesda, Maryland, for each meeting. All meetings were publicly available live by videocast. In addition, the public was invited to attend the Committee’s first two meetings in person. All meetings were announced through a Federal Register notice. Meeting summaries, presentations, archived recordings of all of the meetings, and other Committee related materials a re available at https://health.gov/paguidelines . Public Comments Oral comments from the public were presented at the second public meeting, and written comments were accepted throughout the tenure of the Committee. Written comments were shared with the 2018 Physical Activity Guidelines Advisory Committee Scientific Report B-4

30 Part B. Introduction Committee members as they were received. These comments are available for review at . The public comments process is described in Appendix 4. Public https://health.gov/paguidelines Part H. Comments . Committee Organization and Work Process During its first public meeting, the Committee decided that the work of reviewing the science would be best achieved by establishing subcommittees, each of which would review and interpret the literature for specific health outcomes and/or populations and summarize their findings as a chapter in the report. The Subcommittees, composed of Committee members and consultants, communicated by email and conference calls and met during public Committee meetings. Each Subcommittee was responsible for presenting to the full Committee its literature review process, grade and conclusion statement for each question, and research recommendations. During the public meetings, the Subcommittees responded to questions and made changes as indicated. The conclusions in this report represent the consensus of the entire Committee. The Committee formed nine subcommittees: Aging, Brain Health, Cancer – Primary Prevention, Cardiometabolic Health and Prevention of Weight Gain, Exposure, Individuals with Chronic Conditions, Promotion of Physical Activity, Sedentary Behavior, and Youth. After its first public meeting, the Committee formed three Work Groups to consider additional topics: Physical Fitness, Youth to Adult Transition, and Pregnancy and Postpartum. The Subcommittee and Work Group organization are . Each Committee detailed in P Appendix 2. PAGAC Subcommittee and Work Group Assignments art H. member served on at least two Subcommittees, with the exception of the Co-Chairs, one of whom was a rticipated in all of the other Subcommittees and Work Co -Chair pa Subcommittee chair. The other Groups. To assist in the review process, Subcommittee chairs identified consultants to fill knowledge gaps in one or more specific areas (see consultant list in Membership List ). Consultants participated in Subcommittee discussions and decisions, but were not considered Committee members . Similar to Committee members, they completed ethics training and went through a federal review and clearance process. In addition, outside experts (see list in Membership List ) provided information or a presentation to Subcommittees or Work Groups on a specific topic or question at one meeting . A Designated Federal Officer (DFO) and Alternate DFO from the Office of Disease Prevention and Health Promotion (ODPHP) supported the Committee members. ODPHP served as the administrative lead for B-5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

31 Part B. Introduction this project. The DFO and Alternate DFO also served as two of the seven -Executive Secretaries , who Co represented the various agencies responsible for federal physical activity policy and programs. These agencies include ODPHP, the Centers for Disease Control and Prevention (C ), the National Institutes DC of Health (NIH), and the President’s Council on Fitness, Sports & Nutrition ( PCFSN) . Each Subcommittee was supported by a federal staff liaison trained in the Federal Advisory Committee Act management and a systematic review liaison from the literature review team. Approaches to Reviewing the Evidence The Committee used the state- of-the-art methodology — systematic reviews — to address its 38 research questions and 104 subquestions. These reviews are publicly available on https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx . Part E. Systematic Review Literature Search Methodology of this report details the process used by the Committee to evaluate the scientific evidence. This section also describes the grading rubric the Committee used to . Each Subcommittee drafted a chapter that grade the level of evidence available to answer its questions summarizes and synthesizes the results of its review and includes the evidence grades and conclusion statements for each question (see Part F. The Science Base ). Research recommendations to address gaps that could advance knowledge related to the question posed and inform future federal physical activity guidance, as well as other policies and programs, are included at the end of each chapter and in Part G. Needs for Future Research . At least two Committee members who were not members of the drafting Subcommittee and federal staff liaisons reviewed each chapter. Report Structure Reflecting the Subcommittee and Work Group structure, the bulk of the report consists of 11 science- based chapters that summarize the evidence assessed and evaluated by the Committee. Ten chapters correspond to the work of the nine Subcommittees —the Exposure Subcommittee’s findings are split into two chapters — and one chapter covers the work of the Pregnancy and Postpartum Work Group. In addition to summarizing the evidence relating physical activity to individual health outcomes, one of the Committee’s major goals was to integrate the scientific information on the relationship between physical activity and health and to summarize it in a manner that could be used effectively by HHS to develop the Physical Activity Guidelines and related statements. This information is contained in Part D. . Integrating the Evidence B-6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

32 Part B. Introduction CONTENTS AND ORGANIZATION OF THE SCIENTIFIC REPORT a Membership List of the Physical Activity Guidelines Advisory Committee The report starts with members, consultants, and federal staff to acknowledge the individuals involved in the development of this report. There are four major components in the report. The first component provides essential background and synthesis information and includes: • Part A. Executive Summary provides an executive summary of the entire report. • Part B. Introduction provides a brief background on the rationale for updating the Physical Activity Guidelines for Americans and an explanation of the Committee’s formation, structure, and process to develop its report. • Part C. Background and Key Physical Activity Concepts explains the concepts and terminology that provide the foundation for the report’s content and framing, including those relating to physical activity, sedentary behavior, dimensions of physical activity, physical fitness, and measurement. • synthesizes the Committee's findings about the relation of Part D. Integrating the Evidence physical activity to a broad array of health outcomes. Part E. Systematic Review Literature Search Methodology explains the process used to • systematically review the literature review questions. The second component, Part F. The Science Base , includes 11 chapters organized into four sections that review and summarize the scientific literature relating physical activity to individual health-related outcomes and populations: New Issues in Defining Physical Activity • Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Chapter 2. Sedentary Behavior • Physical Activity and Selected Health Outcomes Chapter 3. Brain Health • • Chapter 4. Cancer Prevention • Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease • Physical Activity Considerations for Selected Populations B-7 2018 Physical Activity Guidelines Advisory Committee Scientific Report

33 Part B. Introduction • Chapter 7. Youth Chapter 8. Women Who are Pregnant • or Postpartum Ch apter 9. Older Adults • • Chapter 10. Individuals with Chronic Conditions Promoting Physical Activity • Chapter 11. Promoting Regular Physical Activity The third component, Part G . Needs for Future Research provides the Committee 's collective recommendations about key areas of research that could address gaps they encountered and further enhance the science base on physical activity and health. The fourth component, Part H. Appendices , includes 1) glossary of terms, 2) list of Subcommittee and Work Group assignments, 3) biographical sketches of Committee members, and 4) description of the public comment process with a link to the public comment database. REFERENCES . U.S. Department of Health and Human Services. 1. 2008 Physical Activity Guidelines for Americans Washington, DC: U.S. Department of Health and Human Services; 2008. . Published 2008. Accessed September 22, 2017. https://health.gov/paguidelines/guidelines 2. Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee Repo rt, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. https://health.gov/paguidelines/guidelines/report.aspx . Published 2008. Accessed September 22, 2017. – 3. U.S. Department of Health and Human Services; U.S. Department of Agriculture. 2015 2020 Dietary . Published . 8th ed. http://health.gov/dietaryguidelines/2015/guidelines Guidelines for Americans December 2015. Accessed January 11, 2018. ncil 4.Physical Activity Guidelines for Americans Midcourse Report Subcommittee of the President’s Cou on Fitness, Sports & Nutrition. Physic al Activity Guidelines for Americans Midcourse Report: Strategies to Increase Physical Activity Among Youth . Washington, DC: U.S. Department of Health and Human . Published 2013. Accessed September 22, Services, 2013. https://health.gov/paguidelines/midcourse 2017. B-8 2018 Physical Activity Guidelines Advisory Committee Scientific Report

34 Part C. Background and Key Physical Activity Concepts PART C Y . BACKGROUND AND KEY PHYSICAL ACTIVIT CONCEPTS Table of Contents . C-1 ... Historical Perspective Physical Activity Terms and Dimensions C-3 ... Core Terms ... C-3 Types of Physical Activity ... C-4 Domains of Physical Activity C-5 ... Body Position ... C-6 Absolute and Relative Intensity ... C-7 Dose, Volume, and Dose-response for Aerobic Activities ... ... C-9 C-11 Measuring Physical Activity ... Occupational Categories C-12 ... onnaires ... C-12 Questi Devices ... C-12 Monitoring Physical Activity ... C-13 C-18 Physical Fitness ... Physical Activity Across the Life Course C-22 ... Safety During Physical Activity ... C-24 Promotion of Physical Activity ... C-26 References ... C-27 HISTORICAL PER SPECTIVE The field of physical activity and public health has been developing at a rapid pace during the past – exercise science and epidemiologic several decades. During the 1950s and 1960s, two scientific areas C-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

35 Part C. Background and Key Physical Activity Concepts – converged in an effort to understand and address the heart disease epidemic. In the United science States, the percentage of all deaths caused by heart disease had risen from 8 to 10 percent in the early 1 By the late 1980s, scientific evidence had clearly shown percent by 19 60. 1900s to slightly less than 40 2 that regularly performed moderate- to-vigorous physical activity reduced the risk of heart disease. 3 Evidence of other health benefits soon followed. This 2018 Physical Activity Guidelines Advisory adds to the lengthening list of health benefits of regular physical activity. Committee Scientific Report Less well recognized has been a third area of influence beyond exercise science and epidemiologic science. In 1974, the Canadian government published a report titled A New Perspective on the Health of 4 Canadians . More commonly referred to as “The Lalonde Report,” after the Canadian Minister of Health and Welfare, the report made a clear distinction between the clinical health care system and the arena of disease prevention and health promotion. Within disease prevention and health promotion, it called attention to the importance of “lifestyle ” including physical activity. The Canadian report was followed , by the U.S. report, Healthy People: The Surgeon General’s Report on Health Promotion and Disease 5 , which had a similar message. Prevention These documents called attention to the important impact of lifestyle behaviors on the risk of disease, an observation that is now well accepted. Also widely recognized is the fact that individual behaviors, including physical activity behaviors, are determined not solely by individual choice but by social and cultural factors as well as environmental impediments or opportunities. Thus, while exercise science and epidemiologic science remain central to the field of physical activity and public health, the field now includes an array of other scientific disciplines. Behavioral science, clinical science, recreation science, transportation science, city planning, political science, and other disciplines are now recognized to be essential for the proper study and practice of physical activity and public health. The widening range of scientific fields currently contributing to this topic reflects the recognition that physical activity is embedded and intricately connected to every aspect of daily life. No longer viewed 6 ” physical activity is recognized as only as distinct and prolonged bouts of “vigorous physical exercise , encompassing the accumulation of movement occurring throughout the day, regardless of location, type, or purpose. This broader view of physical activity complicates the study, understanding, and . The purpose of this chapter is to provide a brief discussion of discussion of this key health behavior 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-2

36 Part C. Background and Key Physical Activity Concepts physical activity-related terminology and issues that may help readers understand the concepts, evidence, and interpretations that are presented elsewhere in th is report. 7 The Physical Activity Guidelines Advisory Committee Report, 2008 and the 2008 Physical Activity 8 demonstrated that the importance and value of physical activity and public Guidelines for Americans health had been recognized at the highest level of government. The 2018 Scientific Report is further evidence of the importance of physical activity to the national interest. PHYSICAL ACTIVITY TERMS AND DIMENSIONS As the field has matured and the complexity of physical activity has become more apparent, applying clear definitions and descriptions of relevant concepts and issues has become increasingly important. In this document, the Committee has endeavored to use the most appropriate terms for the physical activity behaviors and concepts being discussed. Core Terms 9 Physical activity is bodily movement produced by skeletal muscles that results in energy expenditure. The term, physical activity, does not require or imply any specific aspect or quality of movement. The he term “physical activity” has been term encompasses all types, intensities, and domains. Although t used often as a short-hand description for moderate- to-vigorous-intensity forms of physical activity, given current interest and discussions about physical activity of intensities less than moderate-intensity (i.e., <3 METs, see description below), the term “physical activity” should be used when discussin g the full range of intensities. More specific descriptors such as sedentary behavior, light, moderate, vigorous , or moderate- to-vigorous should be used when talking about a specific range of intensities. Exercise is physical activity that is planned, structured, repetitive, and designed to improve or maintain 9 physical fitness, physical performance, or health. Exercise, like physical activity, encompasses all to- intensities. The word exercise, like the term physical activity, has been used often to mean moderate- vigorous-intensity physical activity. However, it is preferable to specify the intensity when discussing or describing exercise. C-3 2018 Physical Activity Guidelines Advisory Committee Scientific Report

37 Part C. Background and Key Physical Activity Concepts is any waking behavior characterized by an energy expenditure 1.5 or fewer METs Sedentary behavior 10 while sitting, reclining, or lying. Most office work, driving a car, and sitting while watching television are examples of sedentary behaviors. Non-exercise physical activity is a phrase that encompasses all physical activity that is not exercise. It has been used to mean various types and intensities of physical activity, mostly light intensity physical activity. Given its ambiguity, however, clearer descriptions of the physical activity behavior of interest are preferable. Types of Physical Activity Specific Types of Activity A common way of describing physical activity type is to specify the activity under discussion. Walking, bicycling, tai chi, bocce ball, gardening, and vacuuming are examples of specific activities . Activity by Predominant Physiologic Effect Aerobic Physical Activity Aerobic physical activity includes forms of activity that are intense enough and performed long enough an individual’s cardiorespiratory fitness. Aerobic activities such as walking, to maintain or improve basketball, soccer, or dancing, commonly require the use of large muscle groups. The connection between aerobic activities such as these and cardiorespiratory fitness is sufficiently close that the term “ aerobic capacity ” is considered equivalent to cardiorespiratory fitness. Technically, aerobic physical activity includes any activity that could be maintained using only oxygen-supported metabolic energy pathways and could be continued for more than a few minutes. However, since the publication of 11 both common and scientific usage, “aerobic” activity has come to mean physical in 1969 in Aerobics activity that would be expected to maintain or improve cardiorespiratory fitness or aerobic capacity. Anaerobic Physical Activity Anaerobic physical activity refers to high-intensity activity that exceeds the capacity of the cardiovascular system to provide oxygen to muscle cells for the usual oxygen consuming metabolic pathways. Anaerobic activity can be maintained for only about 2 to 3 minutes. Sprinting and power lifting are examples of anaerobic physical activity. 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-4

38 Part C. Background and Key Physical Activity Concepts Muscle-strengthening Activities Muscle-strengthening activities maintain or improve muscular strength (how much resistance can be overcome), endurance (how many times or for how long resistance can be overcome), or power (how fast can the resistance be overcome) . Muscle-strengthening activities include everyday behaviors, such as carrying heavy groceries, shoveling snow, lifting children, or climbing stairs, as well as the use of exercise equipme nt, such as weight machines, free weights, or elastic bands. Bone-strengthening Activities Bone-strengthening activities are movements that create impact and muscle-loading forces on bone. These forces stress the bone, which adapts by modifying its structure (shape) or mass (mineral content), thereby increasing its resistance to fracture. Jumping, hopping, skipping, and dancing are activities that are good for bone strengthening, as are muscle-strengthening activities. Balance Training Balance training activities are movements that safely challenge postural control. If practiced regularly, they improve the ability to resist intrinsic or environmental forces that cause falls whether walking, standing, or sitting. Standing on one foot, walking heel- to-toe, the balance walk, and using a wobble 12, 13 board are examples of balance training activities. Flexibility Training Flexibility training, also called stretching, improves the range and ease of movement around a joint. Dynamic stretching, such as the movements of tai chi, qigong, and yoga, and static stretching are examples of flexibility training. Yoga, Tai Chi, and Qigong These activities, whose origins lie outside of Western culture, typically combine muscle-strengthening, balance training, light-intensity aerobic activity, and flexibility in one package. Some variations of yoga, tai chi, and qigong emphasize relaxation, meditation, or spirituality as well. As a result, are sometimes “mind referred to as - body” activities. Domains of Physical Activity As noted above, physical activity occurs throughout the day, for a variety of purposes, and in many types of settings. Occupational forms of physical activity were the focus of most of the initial epidemiologic 14, 15 studies on physical activity and health. ivity As occupations requiring high levels of physical act 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-5

39 Part C. Background and Key Physical Activity Concepts 17 16, Most of the declined, the research focus shifted to leisure-time or recreational physical activity. research findings summarized for this report are based on studies of leisure-time physical activities. For many individuals, physical activity during leisure-time is more easily modified than during other domains and includes the majority of moderate- to-vigorous intensity activities. Nevertheless, physical activity can and does occur throughout all portions of the day, and, with few exceptions, the health-enhancing value of physical activity is independent of the purpose for performing it. As a result, n on -leisure forms of physical activity, such as transport-related physical activities like cycling to work, are now recognized as options for physical activity promotion. There are many ways of grouping physical activity. One popular method categorizes physical activity into four domains, as follows: • Occupational physical activity is performed while one is working. Stocking shelves in a store, delivering packages in an office, preparing or serving food in restaurant, or carrying tools in a garage are examples of occupational physical activity. is performed in order to get from one place to another. Walking • Transportation physical activity or bicycling to and from work, school, transportation hubs, or a shopping center are examples. Household physical activity is done in or around one’s home. It includes household tasks such • as cooking, cleaning, home repair, yardwork, or gardening. • Leisure-time physical activity is performed at one’s discretion when one is not working, transporting to a different location, and not doing household chores. Sports or exercise, going for a walk, and playing games (hopscotch, basketball) are examples of leisure-time physical activity. Bod y Position The rising interest and recognized importance of low energy expenditure activities call attention to body position during physical activity. Physical activity occurs in any body position. Some positions, notably, lying, reclining, and sitting, facilitate less bodily movement and energy expenditure than do standing or ambulating. Recently developed motion sensors can measure low levels of physical activity more accurately than previously possible and have enabled research in this area. Given the large amount of awake time that is spent sitting, much of the research has focused upon sitting. To promote standard terminology and improve communication, researchers have collaborated in the development of a 10 proposed set of definitions for research in this area. The definition of sedentary behavior, “any waking C-6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

40 Part C. Background and Key Physical Activity Concepts behavior characterized by an energy expenditure equivalents (METs), while in a sitting, ≤1.5 metabolic ” is used throughout this reclining or lying posture, report. Absolute and Relative Intensity Absolute Intensity Absolute intensity is the rate of energy expenditure required to perform any physical activity. It can be measured in METs, kilocalories, joules, or oxygen consumption. The most commonly mentioned unit in this report is the MET. One MET is the rate of energy expenditure while sitting at rest, which, for most people approximates an oxygen uptake of 3.5 milliliters per kilogram per minute. The energy expenditure of other activities is expressed in multiples of METs. For example, for the average adult, . sitting and reading requires about 1.3 METs. Strolling or walking slowly requires about 2.0 METs Walking at about 3.0 miles per hour requires about 3.3 METs, and running at 5 miles per hour requires f energy expenditure for a substantial number of activities has been The average rate o about 8.3 METs. 18 19 document ed for the general adult population and for children and youth ages 6 to 18. commonly have been divided into 4 categories. Absolute rates of energy expenditure • Vigorous-intensity activity requires 6.0 or greater METs; examples include walking very fast (4.5 to 5 mph), running, carrying heavy groceries or other loads upstairs, shoveling snow by hand, sh mower, or participating in an aerobics class. Adults generally mowing grass with a hand- pu 20 spend less than 1 percent of waking time in vigorous activity (Figure C-1). • requires 3.0 to less than 6.0 METs; examples include walking briskly Moderate-intensity activity or with purpose (3 to 4 mph), mopping or vacuuming, or raking a yard. • Light-intensity activity requires 1.6 to less than 3.0 METs; examples include walking at a slow or leisurely pace (2 mph or less), cooking activities, or standing while scanning groceries as a cashier. • Physical activity requiring 1.0 to 1.5 METs have, in the past, been referred to as “sedentary activity .” Almost all these physical activities are included in the term “sedentary behavior,” defined earlier to be any waking behavior characterized by an energy expenditure 1.5 or fewer 10 METs while sitting, reclining, or lying . The one common activity with an energy expenditure of 1.5 METs not included within sedentary behavior is standing quietly. Continued use of the term “sedentary activity” is sure to be confusing, especially because standing is the only behavior within it not covered by “sedentary behavior.” In this report, the Committee has simply used the 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-7

41 Part C. Background and Key Physical Activity Concepts word standing whenever necessary. These low-intensity physical activity behaviors are very common. Accelerometer-based estimates indicate that adults in the United States spend more than 50 percent of their waking time in physical activities requiring an estimated 1.0 to 1.5 METs 21 (Figure C-1). Figure C-1. Proportion of Time-awake at Different Categories of Accelerometer Counts for U.S. Adults, by Sex and Age Group, 2003-2004 Note: *= Some researchers categorize counts in this range as light-intensity, others as moderate-intensity. 20 22 Source: Adapted from data found in Matthew, 2005, and Troiano et al., 2008. Relative Intensity For the general young to middle-aged adult population, the terms used to describe the rate of energy expenditure – light, moderate, vigorous – adequately represent the perceived level of effort to perform an activity. Older individuals, those with certain physical impairments, or individuals who have been very inactive may have a lower aerobic capacity and, as a result, may perceive the activity to be relatively 23 more difficult to perform, thereby creating a mismatch between the word used to describe the absolute rate of energy expenditure and the individual ’ s perceived level of effort. Relative intensity refers to the ease or difficulty with which an individual performs any given physical activity. It has a physiologic basis and can be described using physiologic parameters, such as percent of 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-8

42 Part C. Background and Key Physical Activity Concepts aerobic capacity (VO max) or percent of maximal heart rate . Relative intensity can also be measured 2 with tools that assess an individual’s perception about how difficult it is to perform an activity. A variety of tools have been developed to help individuals self-regulate the relative intensity of their aerobic physical activity. For ease of use in non-clinical settings, the sing-talk test is the simplest. During light- intensity activities most people are able to sing, during moderate-intensity they can talk but not sing, 24 Also simple to use is a and during vigorous activities, even talking is difficult. 10 -point scale, originally 8 designed as a communication tool, where 0 is sitting and 10 is the greatest effort possible. Moderate- intensity physical activity is about half way (five or six points), with vigorous higher (seven or eight). In general, a n individual’s subjective assessment of how hard he or she is working corresponds well with laboratory-based assessments of capacity. The contrast between absolute and relative intensities can be highlighted by noting that the focus of e individual’s level of effort absolute intensity is the activity, whereas the focus of relative intensity is th during the activity. Observational population-based studies typically determine what an individual has . Experimental studies done and estimate the energy required to do it, so the measurement is absolute typically use relative intensity in prescribing a program of physical activity to ensure the desired level of effort is appropriate for the individual. Dose, Volume, and Dose-response for Aerobic Activities Dose Dose of aerobic physical activity is the type and amount of reported or prescribed physical activity. Physical activity may be prescribed for improving health, rehabilitation, training, or research. As device s to measure physical activity become more common and functional in both research and popular use, modifications in the components and summary descriptors of dose are likely. The components of dose for aerobic physical activity are the frequency, duration, and intensity of the physical activity: Frequency is usually counted as sessions or bouts of moderate- to-vigorous physical activity per • day or per week. • Duration is the length of time for each session or bout. • Intensity is the rate of energy expended during the physical activity session or bout, usually in . METs C-9 2018 Physical Activity Guidelines Advisory Committee Scientific Report

43 Part C. Background and Key Physical Activity Concepts Dose is commonly calculated for a specific period of time, such as per day or per week, and, for aerobic activity, has been limited to moderate- to-vigorous physical activity because those are the intensities known to provide benefits. Increasingly, the acronym FITT, standing for frequency, intensity , time (duration), and type of activity (e.g., aerobic, muscle-strengthening) has been used to describe physical 25 activity dose. Volume Volume is the quantification of the dose of activity accumulated over a specified length of time. Volume is usually expressed in MET-minutes or MET-hours per day or week. It is calculated by multiplying the physical activity frequency and duration by the MET values corresponding to that physical activity. For activities, such as walking or running, where a rate of energy expenditure at any given speed is a fixed amount, volume is sometimes simplified to minutes or hours of the activity, such as minutes per week of walking . Kilocalories per day or per week is used is used less frequently. As the use of personal devices (see Devices, below) to measure physical activity has increased, volume is sometimes expressed as activity counts or step counts during a set period of time. Steps are easily counted. Step counts are easily understood by individuals and the media. They are a useful prescription tool for health care providers and trainers. Step counts blend well with public health messages encouraging the use of stairs rather than elevators, walking in airports rather than taking the train or shuttle, or parking at a distance from the final destination. Step counts include light- as well as moderate- and vigorous-intensity physical activity. As a result, the number of steps that would be equivalent to 150 to 300 minutes per week of moderate- to-vigorous physical activity varies from 26, 27 t may be less than the commonly suggested 10,000 steps. individual to individual and i Regardless, step counts are simple to use, can be tailored to meet individual needs, and appear to be useful for 8 monitoring progress toward personal goals. Dose-response Dose-response is the relationship between the dose or volume of physical activity and the magnitude of ch ange, if any, in the health outcome or physiologic change. A graduated response — small dose with small response, large dose with large response — is evidence of the truth of the relationship. For ordinal data, a dose-response relationship requires at least three levels of exposure, in this case three volumes of physical activity (Figure C-2). For data collected as a continuous variable, differing shapes of the relationship can be examined. The shape of a dose response curve adds importantly to the 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-10

44 Part C. Background and Key Physical Activity Concepts understanding of the relationship. For example, in Figure C-2, the shape indicates that the majority of the reduction in mortality risk among individuals with type 2 diabetes is achieved by moving from “no activity” to “some activity”, and that meeting the Guidelines confers addition al benefits. Figure C-2. Risk of Cardiovascular Mortality Among People with Type 2 Diabetes by Dose of Physical Activity 28 Source: Adapted from data found in Sadarangani et al., 2014. MEASURING PHYSICAL ACTIVITY Measuring physical activity with reasonable accuracy and acceptable cost is vital to the understanding of the relationship between physical activity and health. Because of the complexity of physical activity, it may be the most difficult aspect of the study and promotion of physical activity. measuring Over time, the preferred method of measuring physical activity behavior has changed. Early epidemiologic studies commonly relied upon job categories to categorize workers into higher or lower levels of physical activity. As mechanization reduced the number of jobs requiring substantial amounts of physical activity, questionnaires to assess primarily leisure-time physical activity became the ominant method. Recently, technological advances have made possible the development of devices pred 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-11

45 Part C. Background and Key Physical Activity Concepts to assess bodily movement. The accuracy of devices has improved and the cost has declined such that ferred measurement tool epidemiologic stud ies . devices are now the pre in many C Occupational ategories Estimates of the energy requirements for various job categories provided an inexpensive and simple method of dividing individuals into higher and lower physical activity categories. Only employed individuals , mostly men, were included and the method assumes all workers in the same category expend about the same energy on the job. The decline in physically demanding jobs has made job categories a less useful measurement too l than they were 60 to 70 years ago. Nevertheless, the method provided persuasive evidence that individuals who were more physically active had lower rates of cardiovascular disease than did the co - workers who had less physically demanding jobs. ir naires Question Information for questionnaires usually comes from individual s reporting on their own physical activity behavior. It may also come from proxy reporters, such as parents of young children, or observers watching the physical activity of others. S evera l general categories of questionnaires have been developed, as have large numbers of specific questionnaires within each category. Global questionnaires strive to place individuals into physical activity categories using one or more questions. Quantitative history questionnaires use more questions to inquire about participation in specific activities or activities vigorous intensity. moderate nother Physical activity diaries are a of specific intensity, almost always - - to form of questionnaire recent que stionnaires have begun to inquire about sedentary or sitting Many . - to - vigorous physical behaviors but, for the most part, questionnaires have focused upon moderate activity because those activities are most easily remembered. Questionnaires generally do a n adequ ate job of ranking individuals from high to low physical activity volumes. They are less accurate determining performed. Questionnaires are capable of the actual volume of moderate - to - vigorous physical activity determining Individuals can also and the domains for those activities. the specific activities performed relative intensity of their activities . The use of the I nternet to administer questionnaires and report the has to collate the responses d reduce the burden on both respondent s and researcher s. Devices and their accuracy of devices to measure physical movement have been improving rapidly The types and cost has steadily declined Formerly, devices were one of two general types: pedometers, devices that . 12 visory Committee Scientific Report C - 2018 Physical Activity Guidelines Ad

46 Part C. Background and Key Physical Activity Concepts counted steps, and accelerometers, devices that measured truncal or limb movement. With current technology, accelerometers are now available as smart phone apps and components of wrist watches. They have become more accurate at assessing upper body as well as lower body movements and some are waterproof, enabling the assessment of water activities. Many of these systems use a variety of sensor systems.” sensors and technologies and are referred to as “multi - They measure steps, often are paired with global positioning systems providing estimates of speed and distance, and some include heart rate monitors, making estimates of relative as well as absolute energy expenditure possible. The advances in measurement of bodily movement, especially light-intensity physical activities, will continue to improve knowledge and understanding of the relationship between physical activity and health. MONITORING PHYSICAL ACTIVITY Monitoring the status of selected health indicators is a vital function of public health agencies and a . Public health agencies now monitor, in critical factor in the allocation of public health resources addition to causes of death, disease incidence and prevalence, and the prevalence of important health- related behaviors, such as physical activity. They now also recognize the importance of monitoring factors that facilitate or impede physical activity, such as policies and environments. As indicated in the previous section, physical activity is difficult to measure and monitor precisely. Until recently, public health monitoring systems used only self-report instruments. Device-measured physical activity monitoring systems are becoming more available, and already provide useful supplements to existing national systems. The increasing use and capacity of devices that measure physical activity is likely to both enable and require flexibility and change in public health physical activity monitoring systems in the near future. This section provides examples of useful information provided by public health monitoring systems. One simple and important use of monitoring data is to describe the proportion of individuals performing different amounts of physical activity (Figure C-3). About half of the U.S. adult population reports that they accumulate less than the target range of 150 to 300 minutes of leisure-time moderate-intensity equivalent physical activity each week. Nearly one-third are classified as “inactive,” meaning that they report doing less than 10 minutes of moderate- to-vigorous physical activity. Because the benefits for several important health outcomes, such as cardiovascular disease, type 2 diabetes, and all-cause mortality, accrue rapidly at the lower end of the physical activity range, facilitating more physical activity 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-13

47 Part C. Background and Key Physical Activity Concepts among the individuals who are inactive would be expected to produce substantial reductions in morbidity and mortality. Figure C-3. Distribution of Self-Reported Volume of Moderate- to-Vigorous Physical Activity, 150 Minutes per Week Increments, U.S. Adults, 2015 29 Source: Adapted from data found in the National Health Interview Survey, 2015. Another important use of monitoring data is to identify population subgroups who stand to benefit the most from increasing their physical activity level (Figure C-4). The proportion of adults in or above the target range differ substantially and systematically across age groups, income groups, and by disability status. Similar information is available for high school students (Figure C-5). 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-14

48 Part C. Background and Key Physical Activity Concepts Figure C-4. Percentage Adults within or above Target Range for Moderate- to-Vigorous Physical Activity by Population Subgroup, 2015 Legend: W=White, B=Black, H=Hispanic, A=Asian. Note: Estimates are age-adjusted using the year 2000 standard population. 29 Source: Adapted from data found in the National Health Interview Survey, 2015. C-15 2018 Physical Activity Guidelines Advisory Committee Scientific Report

49 Part C. Background and Key Physical Activity Concepts Figure C-5. Percentage of High School Students Meeting Aerobic Target Range, 2013 Legend: NH-W=Non-Hispanic White, NH-B=Non-Hispanic Black, H=Hispanic, A=Asian, AN&AI=Alaska Native and American Indian. 30 Source: Adapted from data found in the Youth Risk Behavior Survey, 2013. In addition to information about the current prevalence of physical activity behaviors overall and among subgroups, public health monitoring systems also provide information about changes, if any, over time (Figure C-6). National estimates of changes in prevalence over time provide information about the overall impact of the multiple factors that influence physical activity behaviors. Data from the National Health Interview Survey suggest that from 1998 through 2015 the prevalence of individuals who report to-vigorous physical activity has declined from about 40 percent to 30 doing no leisure-time moderate- 29 29 percent. The decline has occurred for both women and men. 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-16

50 Part C. Background and Key Physical Activity Concepts Figure C- 6. Prevalence of Adults Who Engage in No Leisure-time Moderate- to-Vigorous Physical Activity, by Sex and Year, 1998 to 2015 Note: Estimates are age-adjusted using the year 2000 standard population. 29 Source: Adapted from data found in the National Health Interview Survey, 1998-2015. In addition to monitoring the prevalence of physical activity among population subgroups and over time, current surveillance systems are beginning to monitor the prevalence of policies and environmental characteristics that facilitate regular physical activity participation. For example, the number of states with clear physical education curriculum policies in elementary, middle, and high schools has slowly 31 risen between 2006 and 2012 (Figure C-7). 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-17

51 Part C. Background and Key Physical Activity Concepts Figure C-7. Percentage of States with a Clear Physical Education Policy, by Level of School, School Years 2006-2007 to 2011-2012 31 Source: Adapted from data found in Institute of Medicine, 2013. PHYSICAL FITNESS Physical fitness is a physiologic attribute determining a person’s ability to perform muscle-powered for example, to walk, run, work. A fundamental manifestation of this attribute is the ability to move — climb stairs, and lift heavy objects. As a result, physical fitness is an important factor in the ability of . individuals to perform routine daily activities and an important issue from a public health perspective Physical fitness has been defined as “the ability to carry out daily tasks with vigor and alertness, without 32 undue fatigue, and with ample energy to enjoy leisure-time pursuits an d respond to emergencies.” The concept of physical fitness typically has been operationalized as a multicomponent construct including cardiorespiratory endurance (aerobic power), musculoskeletal fitness, flexibility, balance, and s to this speed of movement (see Table C-1) . For the purposes of this report, to the term “fitness” refer general sense. 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-18

52 Part C. Background and Key Physical Activity Concepts Table C-1. Components of Physical Fitness The ability to perform large-muscle, whole-body exercise at Cardiorespiratory Endurance erate to high intensities for extended periods of time. mod The integrated function of muscle strength, muscle endurance, and Musculoskeletal Fitness muscle power to enable performance of work. The range of motion available at a joint or group of joints. Flexibility The ability to maintain equilibrium while moving or while Balance stationary. Speed The ability to move the body quickly. A large volume of research has focused on the relationship between physical activity and health . The findings of that research, summarized elsewhere throughout this report, identify multiple health . In addition, a substantial body benefits associated with maintaining greater amounts of physical activity cardiorespiratory fitness and, in — of research has examined the relationship between physical fitness some cases, musculoskeletal fitness . The findings show that greater physical and health outcomes — fitness is associated with reduced all-cause mortality, cardiovascular disease mortality, and risk of 33 To date, the majority of this information has developing a wide range of non-communicable diseases. 33 been acquired in men, but some data now indicate that these relationships also exist in women. Thus, compelling scientific evidence indicat es that both physical activity and physical fitness provide important health benefits . In addition, it is clear that physical activity and physical fitness are positively 34 correlated, and it is well documented that increases in the amounts and intensities of physical activity typically produce increases in physical fitness, particularly in those who are less physically active at 35 baseline. Accordingly, it is reasonable to question the independence of the relationships between physical activity and physical fitness with health outcomes . In some epidemiological studies it has been possible to examine, independently, the associations of both physical activity and fitness on th e 36 This research shows that physical activity behavior accounts for only a incidence of disease outcomes. 37 portion of the impact of physical fitness on health. Similarly, the impact of physical activity on health is 37 partially explained by its effect on physical fitness. The available evidence suggests that physical activity and physical fitness interact in their effects on a variety of health outcomes. Given that both physical activity and physical fitness are complex 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-19

53 Part C. Background and Key Physical Activity Concepts . Figure C- multicomponent concepts, it is likely that they interact in a variety of ways to influence health 8 is a simple conceptual framework for observational studies. Figure C-9 is a simple conceptual 39 38, mework for intervention studies. fra Both are intended to stimulate thought, discussion, and research into the mechanisms of greatest importance to the field of physical activity and public health. The models will be improved by future investigations . Figure C-8. The Role of Physical Fitness along Various Pathways between Physical Activity and Health Outcomes, Observational Studies Physical fitness may serve as an intermediate variable along the pathway between Pathway A: • physical activity and health outcomes. Synonyms for intermediate variable include contingent 40 variable, intervening (causal) variable, and mediator variable. Intermediate variables lie along the pathway between the exposure and outcome of interest. In this case, physical activity induces changes in physical fitness and physical fitness causes changes in the health outcome. • Pathway B: Physical fitness may serve as an effect modifier. Synonyms for effect modifier 40 include moderator variable or antecedent moderator. Effect modifiers operate outside of the causal chain to influence the effect of the exposure variable on the outcome. If, in an observational study, the participants are stratified according a component of physical fitness and the beneficial effect of a greater volume of physical activity compared to a lower volume differs between strata of physical fitness, then physical fitness is an effect modifier. C-20 2018 Physical Activity Guidelines Advisory Committee Scientific Report

54 Part C. Background and Key Physical Activity Concepts • Pathway C: Physical activity may be associated with health outcomes through pathways that do not involve physical fitness. • Pathway D: Physical fitness may be considered as an outcome itself. Individuals who are more to carry out daily tasks with vigor and alertness, without undue physically fit are better able “ fatigue, and with ample energy to enjoy leisure time pursuits and to meet unforeseen emergencies”— in other words, the definition of fitness suggested above. Figure C-9. The Role of Physical Fitness along Various Pathways between Physical Activity and Health Outcomes, Intervention Studies • Pathway A: This pathway represents the potential moderating influence of initial physical Baseline physical fitness can exert an fitness on interventions to increase physical activity. important influence on responses to interventions aimed at increasing physical activity. For example, individuals with low baseline fitness may not respond behaviorally as well as 41 , or individuals with high baseline fitness to interventions emphasizing vigorous physical activity may require a more gradual increase in intensity to achieve comparable effects. me Pathway B: This pathway represents the potential diating influence of changes in physical • fitness on the health effects derived from physical activity increases. With an increase in physical activity, a change in physical fitness can mediate some of the resultant health effects, such that the health effects accrue directly in relation to the increases in fitness. In theory, for some health outcomes, an increase in physical activity may produce change in a health outcome only if physical fitness is increased. Pathway C: • Physical activity may be associated with health outcomes through pathways that do not involve changes in physical fitness. 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-21

55 Part C. Background and Key Physical Activity Concepts • Pathway D: An increase in physical fitness represents an important health outcome in its own right. Although physical activity is the primary exposure of public health concern, physical fitness is an appropriate addition to the list of outcomes important to public health. For many years, physical fitness has been used as an appropriate public health outcome for children and youth, and physical function has been recognized as an important health outcome for older adults. Missing has been the recognition that improved physical fitness is important in the everyday lives of young and middle-aged adults, as well. Depending upon the physical activity regimen and population, physical fitness can change relatively 42 quickly in response to an increase in physical activity. As such changes are typically readily detected by individuals who have increased their physical activity, physical fitness can serve as an important source of positive reinforcement for individuals who have adopted a higher level of activity . It is important to physical fitness is affected by both note that, like many other physiologic characteristics, a n individual’s genetic factors and behavior. Accordingly, it is to be expected that the extent to which physical fitness is enhanced by an increase in physical activity varies from individual to individual. PHYSICAL ACTIVITY ACROSS THE LIFE COURSE Physical activity capacity, preferences, and needs vary substantially across the life course. This creates a tension between the ne ed for public health guidelines to be simple and the need to properly account for the variation among age groups. Current practice is to divide the population into three primary age- — groups — youth, adults, and older adults with several subcategories for the youth group (Table C-2). The break between youth and adults represents the transition from secondary school to higher education or full-time work; the break between adults and older adults is less clear-cut but generally centers on retirement. These breaks represent significant changes in social and environmental factors that influence physical activity participation and are, therefore, important in understanding and designing successful physical activity promotion strategies. These breaks also represent changes in the health outcomes associated with physical activity. Specifically, the youth guidelines are designed to ensure healthy growth and development , the adult guidelines primarily address disease prevention, and the older adult guidelines center on slowing the loss of function due to aging. The differences in these three paradigms (growth and development, disease prevention, maintenance of function) are reflected 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-22

56 Part C. Background and Key Physical Activity Concepts in the differences in recommended volumes and types of health-related physical activity across the life course. Table C-2. Age Groups in National Physical Activity Guidelines or Recommendations from Five Developed Nations United Canada United States Australia Germany Kingdom Age Group (2011 and 43 46 8 (2016) (2014) (2008) 45 47 44, 2017) (2011) <5 years not 0-3 years walking 0-5 years 0-4 years 6-17 years 4 -6 years Children and 5-11 years 5-12 years <5 years adolescents 6-11 years walking 13-17 years 12-17 years 12-18 years 5-18 years 18-64 years 19-64 years 18-65 years Adults 18-64 years 18-64 years Older 65+ years Older adults 65+ years 65+ years 65+ years Australians Legend: <=less than, +=more than. 10) suggests that The normal decline in maximal aerobic capacity across the life course (Figure C- guidelines set for the “average” adult my not be challenging enough for the youngest adults and too challenging for many older adults. The 2008 Physical Guidelines for Americans acknowledged this problem for older adults and modified the older adult guidelines to emphasize relative rather than 8 absolute intensity to guide the level of effort. The 2018 Advisory Committee recognized that similar adjustments might be appropriate for younger adults, namely that intensity for younger adults should be relative to their aerobic capacity. This would mean a higher absolute intensity and perhaps a higher accumulated volume than for middle-aged and older-adults. In addition, the Committee recognized that the health outcomes influenced by physical activity during young adulthood shared features with the growth and development needs of younger individuals and the disease prevention needs of middle-aged and older adults. As examples, the brain is not fully developed and the skeleton not fully mineralized until well into the third decade, and maintenance of normal blood pressure and body weight is important for younger as well as older adults. After discussion and preliminary research examining physical activity and health outcomes during young adulthood, the Committee felt the issue to be important but set it aside because the available literature did not appear to be strong enough to either confirm or support a change to the current approach. For the present, the age groups used by the 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-23

57 Part C. Background and Key Physical Activity Concepts 8 Committee are the same as in the 2008 Physical Activity Guidelines for Americans , the guidelines from 48 other countries (Table C-2), as well as Healthy People data. . Maximal Oxygen Uptake in METs, by Age Group Figure C- 10 Legend: METmax=maximal oxygen uptake. 49 to for age s 16 Source: Adapted from data in Pate et al., 2006 19 and American College of Sports Medicine 50 (ACSM) for all other age groups. SAFETY DURING PHYSICAL ACTIVITY At the start of their deliberations, the Committee recognized the importance of physical activity-related adverse events. Although the benefits of regular physical activity outweigh the inherent risk of adverse events, adverse events can happen and, though usually not severe, they are an impediment to continued and more widespread participation in regular physical activity. The Committee judged the basic principles and messages of the chapter on adverse events in the Physical Activity Guidelines 7 Advisory Committee Report, 2008 to still apply in 2018. Rather than prepare a chapter that would duplicate the material in the prior report, each subcommittee looked for information about adverse events uncovered by their searches and, when appropriate, included the information in their chapters. Older Adults (See, for example, Part F. Chapter 9. ). Included here is a brief summary of the material 7 Ad visory Report. about adverse events from the 2008 7 The 2008 Advisory Report concluded that the benefits of physical activity outweigh the risks. It acknowledged a wide range of types of physical activity-associated adverse events, including musculoskeletal injuries, cardiac events, heat injuries, and infectious diseases. All types were addressed 7 noted that but the focus was on the prevention of musculoskeletal injuries. The 2008 Scientific Report 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-24

58 Part C. Background and Key Physical Activity Concepts physical activity-related musculoskeletal injuries are directly related to the type of activity, the volume of physical activity performed, and the rate of progression or change in volume of physical activity. Type of activity is important because the risk of musculoskeletal injury is directly related to the force and frequency of contact or collisions with other people, the ground, or other objects. Activities are commonly divided into four categories: Collision (e.g., football, ice hockey), contact (e.g., basketball, soccer), limited-contact (e.g., baseball, ultimate frisbee), and non-contact (e.g., running, swimming). “Activities with fewer and less forceful contact with other people or objects have appreciably lower injury rates than do collision or contact sports. Walking for exercise, gardening or yard work, bicycling or exercise cycling, dancing, swimming, and golf, already popular in the United States, are activities with 7 t he lowest injury rates.” The risk of injury is directly related to a person’s usual dose or volume of physical activity. Dose is determined by the frequency, duration, and intensity of the activity (see the section on “ Dose, Volume, and Dose-response for Aerobic Activities, above). Runners, for example, who run 40 miles per week are ” more likely to be injured than those who run 15 miles per week. 7 The risk of injury is directly related to the rate of progression or change in volume of physical activity. Military recruits, for example, are commonly prescribed a specific type and volume of exercise. The type may change and the volume may increase over time, but all recruits are expected to do the same type and volume. Recruits who, before enrollment in the military, were doing lesser amounts of physical activity, incur more injuries than do recruits who had been doing greater amounts. Students in physical education classes and participants in aerobic dance classes have similar experiences; those who were less active before the classes are more likely to have a class-related injury than are those who were more active. A few experimental studies have assigned different doses of physical activity to groups of individuals with similar baseline physical activity practices. Injury rates are higher among those assigned the higher volumes. “The findings in military recruits, students, and runners are consistent with the two major principles of exercise training programs: 1) overload and adaptation, and 2) specificity of response. The overload and adaptation principle states that function is improved when tissues (e.g., muscles) and organs (e.g., heart) are exposed to an overload (i.e., a stimulus greater than usual) and provided time to recover and adapt. Repeated exposures to a tolerable overload are followed by adaptation of the tissues and organs to the new load and improvements in performance and function. Too large an overload or insufficient C-25 2018 Physical Activity Guidelines Advisory Committee Scientific Report

59 Part C. Background and Key Physical Activity Concepts time for adaptation, however, leads to injury and malfunction. The principle of specificity states that the adaptation and improved function is limited to the tissues and organs that have been overloaded. 7 Training the muscles of the legs, for example, does not improve strength in the arms and shoulders .” 7 The 2008 Advisory Report noted that research determining the safest rate of change for individuals at differing habitual levels of physical activity is not available. That observation remains today. The 2008 Advisory Report did conclude, however, that “a dding a small and comfortable amount of walking, such as 5 to 15 minutes 2 to 3 times per week, to one’s usual daily acti vities has a low risk of musculoskeletal injury and no known risk of sudden severe cardiac events. Frequency and duration of aerobic activity should be increased before intensity. Increases in activity level may be made as often as weekly among youth, whereas monthly is more appropriate for older or unfit adults. Attainment of the desired level of 7 .” activity may require a year or more, especially for elderly, obese, or habitually sedentary individuals For more information about other aspects of physical activity-related adverse events, such as sudden adverse cardiac events, the value of proper equipment and safe environments, please see Part G. 7 in the 2008 Scientific Report. Section 10: Adverse Events PROMOTION OF PHYSICAL ACTIVITY The public health importance of developing approaches and programs to increase participation by the to-vigorous physical activity grew from two observations. First was general public in regular moderate- the evidence that regular physical activity reduced the incidence and mortality of cardiovascular disease, the leading cause of death in the United States. Second was the recognition that mechanization at to-vigorous physical activity. worksites was reducing the prevalence of jobs requiring much moderate- Over the past 30 to 35 years, the field of health education and promotion has advanced considerably in its knowledge about the complex factors that underlie physical activity behaviors and the approaches most likely to increase population levels of physical activity. Major theories and conceptual frameworks 51 52 that have been instrumental in this progress include the Health Belief Model, Social Cognitive Theory, 53 54 the Transtheoretical Model, and applications of a Social Ecological framework. The application of such theoretical models and conceptual frameworks to the study of health behavior change, including 55 : physical activity behavior change, has led to several general conclusions, which include the following C-26 2018 Physical Activity Guidelines Advisory Committee Scientific Report

60 Part C. Background and Key Physical Activity Concepts • Physical and social environmental influences are important determinants of health behavior change. • Behavior change is a process rather than an event, with factors that influence behavior changing over time. There is a difference between behavioral intention and action. • • Changing behavior initially and maintaining behavior change over longer periods of time are often two different challenges that may be governed by different factors. Given that less than half of U.S. adults and high school aged youth perform moderate- to-vigorous physical activity within the public health target range (see earlier information in this chapter), the he 2018 Scientific Report includes, for promotion of physical activity has high public health importance. T the first time, a review of the recent evidence pertaining to physical activity promotion. Given the complexity and breadth of the physical activity promotion literature, a Social Ecological framework was applied in reviewing the evidence base in this area (see Part F. Chapter 11 . Promoting Regular Physical Activity ). The literature was divided into the following levels of intervention and impact: the individual, community settings, environmental and policy approaches, and information and communication technology approaches. These different levels are defined further in the chapter. In addition, interventions aimed specifically at reducing sedentary behavior were reviewed. REFERENCES 1. Centers for Disease Control and Prevention. 98 . Leading causes of death, 1900-19 https://www.cdc.gov/nchs/data/dvs/lead1900_98.pdf . Accessed January 15, 2018. 2. Powell KE, Thompson PD, Caspersen CJ, Kendrick JS. Physical activity and the incidence of coronary heart disease. Annu Rev Public Health . 19 87;8:253-287. doi.10.1146/annurev.pu.08.050187.001345. 3. U.S. Department of Health and Human Services. Physical activity and health: a report of the Surgeon General . Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1996. . Accessed January 30, 2018. https://www.cdc.gov/nccdphp/sgr/pdf/sgrfull.pdf 4. Lalonde M. A New Perspective On The Health Of Canadians. A Working Document. Ottawa: Government of Canada; 1974. http: //www.phac-aspc.gc.ca/ph-sp/pdf/perspect-eng.pdf. Accessed January 4, 2018. 5. U.S. Department of Health, Education, and Welfare. Healthy people: The Surgeon General's r eport on . Washington, DC: U.S. Department of Health, Education, and health promotion and disease prevention C-27 2018 Physical Activity Guidelines Advisory Committee Scientific Report

61 Part C. Background and Key Physical Activity Concepts Welfare; Public Health Service; 1979. . Accessed https://profiles.nlm.nih.gov/ps/access/NNBBGK.pdf January 30, 2018. 6. U.S. Department of Health and Human Services. Promoting health/preventing disease: objectives for tion . Washington, DC: U.S. Department of Health and Human Services, Public Health Service; the na 1980. Physical Activity Guidelines Advisory Committee 7. Physical Activity Guidelines Advisory Committee. Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. https://health.gov/paguidelines/guidelines/report.aspx . Published 2008. Accessed January 4, 2018. 8. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Ame ricans . Washington, DC: U.S. Department of Health and Human Services; 2008. 9. Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. . 1985;100(2):126-131. Public Health Rep 10. Tremblay MS, Aubert S, Barnes JD, et al. Sedentary Behavior Research Network (SBRN) – Terminology Consensus Project process and outcome. Int J Behav Nutr Phys A ct . 2017;14:75. doi:10.1186/s12966-017-0525- 8. 11 . Cooper KH. Aerobics. Philadelphia, PA: Bantam Books; 1969. 12 . National Institute on Aging. Your everyday guide from the National Institute on Aging at NIH: exercise & physical activity . Publication No. 09-4258. 2009:64-69. https://go4life.nia.nih.gov/sites/default/files/nia_exercise_and_physical_activity.pdf . Accessed January 30, 2018. 13. Lesinski M, Hortobágyi T, Muehlbauer T, Gollhofer A, Granacher U. Effects of balance training on balance performance in healthy older adults: a systematic review and meta-analysis. . Sports Med 2015;45(12):1721-1738. doi:10.1007/s40279-015-0375- y. 14. Morris JN, Heady JA, Raffle PA, Roberts CG, Parks JW. Coronary heart-disease and physical activity of work. Lancet . 1953;265(6796):1111-1120. Paffenbarger RS, Hale WE. Work activity and coronary heart mortality. N Engl J Med . 15. 1975;292(11):545-550. doi:10.1056/NEJM197503132921101. 16. Morris JN, Everitt MG, Pollard R, Chave SP, Semmence AM. Vigorous exercise in leisure-time: protection against coronary heart disease. Lancet . 1980;2(8206):1207-1210. 17. Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in college alumni. . 1978;108(3):161-175. Am J Epidemiol 18 . Ainsworth BE, Haskell WL, Herrmann SD, Meckes N, Bassett DR Jr, Tudor-Locke C. Compendium of physical activities: a second update of codes and MET values. Med Sci Sports Exerc . 2011;43(8):1575- 1581. doi:10.1249/MSS.0b013e31821ece12. 19 . Butte NF, Watson KB, Ridley K, et al. A youth compendium of physical activities: activity codes and metabolic intensities. Med Sci Sports Exerc . Sept 2017. doi:578 10.1249/MSS.0000000000001430. 20. Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M. Physical activity in the United ports Exerc States measured by accelerometer. Med Sci S . 2008;40(1):181-188. doi:10.1249/mss.0b013e31815a51b3. C-28 2018 Physical Activity Guidelines Advisory Committee Scientific Report

62 Part C. Background and Key Physical Activity Concepts 21. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors in the – Am J Epidemiol . 2008;167(7):875-881. doi:10.1093/aje/kwm390. United States, 2003 2004. 22. Matthews CE. Calibration of accelerometer output for adults. Med Sci Sports Exerc . 2005;37(suppl 11):S512-S522. 23 .American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription. 9th illiams & Wilkins; 2014. ed. Baltimore, MD: Lippincott W 24. Persinger R, Foster C, Gibson M, Fater DC, Porcari JP. Consistency of the talk test for exercise prescription. Med Sci Sports Exerc . 2004;36(9):1632-1636. 25 .American College of Sports Medicine. ACSM’s Guidelines for Exercise Testing and Prescription. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2009. 26 . Harrington DM, Tudor-Locke C, Champagne CM, et al. Step-based translation of physical activity guidelines in the Lower Mississippi Delta. Appl Physiol Nutr Metab . 2011;36(4):583-585. doi:10.1139/h11-053. 27. Tudor-Locke C, Leonardi C, Johnson WD, Katzmarzyk PT, Church TS. Accelerometer steps/day translation of moderate- to-vigorous activity. Prev Med . 2011;53(1-2):31-33. doi:10.1016/j.ypmed.2011.01.014. 28 . Sadarangani KP, Hamer M, Mindell JS, Coombs NA, Stamatakis E. Physical activity and risk of all- cause and cardiovascular disease mortality in diabetic adults from Great Britain: pooled analysis of 10 population-based cohorts. Diabetes Care . 2014;37(4):10. 29 . Centers for Disease Control and Prevention, National Center for Health Statistics. National Health 2015: 2015 data release. Interview Survey (NHIS), 1997 – https://www.cdc.gov/nchs/nhis/nhis_2015_data_release.htm . Updated November 3, 2017. Accessed January 11, 2018. 30. — United States, 2013. Morb Kann L, Kinchen S, Shanklin SL, et al. Youth risk behavior surveillance . 2014;63(4):1-47. https://www.cdc.gov/mmwr/pdf/ss/ss6304.pdf . Accessed January Mortal Wkly Rep 30, 2018. 31 . Institute of Medicine. Educating the Student Body: Taking P hysical Activity and Physical Education to School . Kohl HW, Cook HD, eds. Washington, DC: The National Academies Press; 2013:74. doi:10.17226/18314. 32 . Centers for Disease Control and Prevention. Physical fitness. In CDC Glossary of Terms . https://www.cdc.gov/physicalactivity/basics/glossary/index.htm . Accessed January 30, 2018. 33 . Ross R, Blair SN, Arena R, et al. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientifi c statement fom the American Heart Association. Circulation . 2016;134(24):e653-e699. doi:10.1161/CIR.0000000000000461. 34. Jackson AS, Sui X, Hébert JR, Church TS, Blair SN. Role of lifestyle and aging on the longitudinal change in cardiorespiratory fitness. Arch Intern Med . 2009;169(19):1781-1787. doi:10.1001/archinternmed.2009.312. 35 . Garber CE, Blissmer B, Deschenes MR, et al.; American College of Sports Medicine. American College of Sports Medicine position stand: Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. 2011;43(7):1334-1359. doi:10.1249/MSS.0b013e318213fefb. C-29 2018 Physical Activity Guidelines Advisory Committee Scientific Report

63 Part C. Background and Key Physical Activity Concepts 36. Lee DC, Sui X, Artero EG, et al. Long-term effects of changes in cardiorespiratory fitness and body mass index on all-cause and cardiovascular disease mortality in men: the Aerobics Center Longitudinal 490. doi:10.1161/CIRCULATIONAHA.111.038422. Study. . 2011;124(23):2483-2 Circulation 37. DeFina LF, Haskell WL, Willis BL, et al. Physical activity versus cardiorespiratory fitness: two (partly) Prog Cardiovasc Dis . 2015;57(4):324-329. distinct components of cardiovascular health? doi:10.1016/j.pcad.2014.09.008. 38. Kraemer HC, Kiernan M, Essex M, Kupfer DJ. How and why criteria defining moderators and mediators differ between the Baron & Kenny and MacArthur approaches. Health Psychol . 2008;27(2 37/0278-6133.27.2(Suppl.).S101. suppl):S101-S108. doi:10.10 39. Kraemer HC, Frank E, Kupfer DJ. Moderators of treatment outcomes: clinical, research, and policy importance. . 2006;296(10):1286-1289. doi:10.1001/jama.296.10.1286. JAMA 40. Last JM, ed. A Dictionary of Epidemiology . 4th ed. New York, NY: Oxford University Press; 2001. 41. King AC, Kiernan M, Oman RF, Kraemer HC, Hull M, Ahn D. Can we identify who will adhere to long- term physical activity? Signal detection methodology as a potential aid to clinical decision making. Health Psychol . 1997;16(4):380-389. 42 . Hickson RC, Hagberg JM, Ehsani AA, Holloszy JO. Time course of the adaptive responses of aerobic Sports Exerc . 1981;13(1):17- 20. power and heart rate to training. Med Sci 43 . Australia Department of Health. Australia's physical activity and sedentary behaviour guidelines; www.health.gov.au/internet/main/publishing.nsf/content/health-pubhlth-strateg-phys-act- 2014. guidelines#npa05 . Accessed January 10, 2018. 44. Tremblay MS, Warburton D, Janssen I, et al. New Canadian physical activity guidelines. Appl Physiol Nutr Metab . Feb 2011;36. 45. Tremblay MS, Chaput JP, Adamo KB, et al. Canadian 24-hour movement guidelines for the early years (0-4 years): an integration of physical activity, sedentary behavior, and sleep. BMC Pub Health . 2017;17(suppl 5):874. doi:10.1186/s12889-017-4859- 6. 46 . Rutten A, Pfeifer K, eds. National recommendations for physical activity and physical activity promotion. Erlanger, GER: Florida At lantic University Press; 2016. https://www.sport.fau.de/files/2015/05/National-Recommendations-for-Physical-Activity-a nd-Physical- Activity-Promotion.pdf . Accessed January 10, 2018. 47. Department of Health, Physical Activity, Health Improvement and Protection (Scottish Government). Start active, stay active. a report on physical activity for health from the four home coun tries’ chief medical officers; 2011. https://www.sportengland.org/media/2928/dh_128210.pdf . Accessed January 10, 2018. 48 . U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion. HealthyPeople.gov. https:// www.healthypeople.gov . Accessed January 26, 2018. 49. Pate RR, Wang CY, Dowda M, Farrell SW, O'Neill JR. Cardiorespiratory fitness levels among U.S. youth 12 to 19 years of age: findings from the 1999-2002 National Health and Nutrition Examination Survey. Arch Pediatr Adolesc Med . 2006;160(10):1005-1012. doi:10.1001/archpedi.160.10.1005. 50 .American College of Sports Medicine. ACSM’s Guidelines for E xercise Testing and Prescription. 7th re, MD: Lippincott Williams & Wilkins; 2006. ed. Baltimo C-30 2018 Physical Activity Guidelines Advisory Committee Scientific Report

64 Part C. Background and Key Physical Activity Concepts 51 . Rosenstock IM, Strecher VJ, Becker MH. Social learning theory and the health belief model. Health 183. 5 – Edu Q . 1988;15(2):17 . 2001;52:1-26. 52 . Bandura A. Social cognitive theory: an agentic perspective. Ann Rev Psychol doi:10.1146/annurev.psych.52.1.1. Med Sci Sports Marcus BH, Simkin LR. The transtheoretical model: applications to exercise behavior. 53. Exerc . 1994;26(11):1400-1404. 54 . Sallis JF, Owen N. Ecological models of health behavior. In: Glanz K, Rimer BK, Lewis FM, eds. Health behavior and health education: theory, research, and practice, third edition. San Francisco, CA: Jossey- Bass; 2002. 55 . Glanz K, Bishop DB. The role of behavioral science theory in development and implementation of Annu Rev Public Health public health interventions. . 2010;31:399-418. doi:10.1146/annurev.publhealth.012809.103604. 2018 Physical Activity Guidelines Advisory Committee Scientific Report C-31

65 Part D. Integrating the Evidence PART D. INTEGRATING THE EVIDENCE Table of Contents Introduction D-1 ... ... D-4 Overall Benefits What does current scientific evid ence reveal about the relationship between moderate- Question 1. to-vigorous physical activity and risk of developing a variety of chronic diseases and other conditions? ... D-4 Question 2. Does current evidence indicate that people who habitually perform greater amounts of moderate- to-vigorous physical activity feel better and sleep better? ... D-6 Question 3. Does the evidence indicate that people who are more physically active are better able to perform everyday tasks without undue fatigue? ... D-7 ysical activity accrue? ... D-7 Question 4. How soon do the benefits of ph Question 5. What does the evidence ind icate about the public health target range, or “dose,” of moderate- to-vigorous physical activity that is likely to provide many of the health benefits listed in Table 1? D-8 ... Question 6. What does the evidence ind to-vigorous physical icate about the benefits of moderate- activity below or above the target range? ... D-9 Question 7. What does current evidence indicate about the importance of the intensity, duration, and frequency of moderate- to-vigorous physical activity that comprise the weekly target volume of physical activity? ... D- 10 e demonstrate about the relationship between Question 8. What does current scientific evidenc ... D- sedentary behavior and the risk of developing various chronic diseases or conditions? 12 Question 9. What does current scientific evid ence indicate about how the risks of sedentary behavior and the benefits of moderate- to-vigorous physical activity interact to determine overall risk or benefit? ... D- 12 Question 10. How do different types of ph ysical activity contribute to health outcomes? ... D- 14 Question 11. What does the scientific evidence indicate about the association between walking and D- 16 health benefits? ... D-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

66 Part D. Integrating the Evidence Brain Health D- 17 ... te- Question 12. Is there evidence that modera to-vigorous physical activity influences brain-related health outcomes? ... D- 17 ... D- Youth 19 dicate health and fitness benefits from physical activity for Question 13. Does current evidence in children and youth? ... D- 19 Question 14. What does the evidence ind icate about the type and dose of physical activity most likely to produce these health benefits among children?... D- 19 Older Adults D- 20 ... Question 1 5. Is there evidence that the target range for moderate- to-vigorous physical activity should differ for older adults? ... D- 20 Question 16. Is there evidence of health b enefits o f particular importance for older adults? ... D- 21 Selected Common Chronic Condition s ... D- 21 Question 17. Does the evidence indicate that habitual moderate- to-vigorous physical activity provides preventive health benefits to individuals with some common chronic conditions? 21 D- ... Pregnancy ... D- 23 idence regarding t he benefits or risks of light- to-moderate intensity physical Question 18. Is there ev ... D- 23 activity during pregnancy and the postpartum period? Weight Status ... D- 24 Question 19 onstrate that moderate- to-vigorous physical activity contributes . Does the evidence dem to preventing or minimizing excessive weight gain? ... D- 24 Question 20. Does moderate- to- vig orous physical activity provide health benefits for people with overweight or obesity even if their weight status remains the same? ... D- 24 Influence of Race or Ethnicity, and Socioeconomic Status on Health Outcomes ... D- 25 Question 21. Is there evidence that th e volume of moderate- to-vigorous physical activity associated with health benefits differs by race or ethnicity, or socioeconomic status? ... D- 25 25 D- Adverse Events ... 2018 Physical Activity Guidelines Advisory Committee Scientific Report D-2

67 Part D. Integrating the Evidence Question 22. What does the scientific evidence indicate about the pattern of physical activity that is s? ... 25 most likely to produce the fewest adverse medical events while providing benefit D- Question 23. What does the scientific evidenc e say about actions that can be taken to reduce the risk of injury during physical activity? D- 26 ... Question 24. Is there evidence regarding who should see a physician or have a medical examination before increasing the amount or intensity of physical activity they perform? ... D- 27 Promotion of Physical Activity ... ... D -27 ive for promoting regular physical activity participation? D- Question 25. What interventions are effect 27 29 D- Question 26. What interventions are effective for reducing sedentary behavior? ... References D- 30 ... INTRODUCTION This chapter , Part D . Integrating the Evidence , is the final step in the development of this report. Part F. contains the findings from the S The Science Base ubcommittees’ reviews of the scientific literature about the relationships between physical activity and selected health outcomes or conditions, about the importance of physical activity for selected age groups or populations, about the types of physical activity that influence health outcomes, and about the promotion of physical activity . Each chapter in Part F provides a review of the scientific literature on one or more specific topics. The conclusions of each chapter were discussed and approved at the public meetings over the course of the Committee’s deliberations. The purpose of this chapter is to summarize findings from the various chapters in Part F that share a similar feature, such as improved health or reduced risk of disease, a common population group, such as youth or older adults, or that pertain to the types and amounts of physical activity associated with the observed benefits. The chapter uses a question-and-answer format to address questions typically raised by the public, policy makers, and health and fitness professionals. D-3 2018 Physical Activity Guidelines Advisory Committee Scientific Report

68 Part D. Integrating the Evidence OVERALL BENEFITS Question 1. What does current scientific evidence reveal about the relationship between moderate- to-vigorous physical activity and risk of developing a variet y of chronic diseases and other conditions? Current evidence from large numbers of peer-reviewed scientific articles expands the previously documented health benefits that accrue to more physically active individuals when compared to less 1 to-vigorous physical physically activity individuals (Table D- 1). Notably, a greater volume of moderate- activity is associated with a reduced risk of excessive weight gain for both the general population and for pregnant women. Regular moderate- to-vigorous physical activity also reduces feelings of anxiety and depression, and improves sleep and quality of life. A single episode provides temporary improvement s in cognitive function. Current evidence demonstrates that even young children, ages 3 to 5 years, have greater bone strength and a healthier weight status if they are more physically active. Among older adults, regularly performed physical activity reduces the risk of dementia, improves physical function ) and reduces the risk of falling and the risk of injur y if a fall does (the ability to accomplish routine tasks re physical activity reduces the risk of cancers of the occur . Current evidence also demonstrates that mo um bladder, breast, colon, endometri , esophagus (adenocarcinoma), kidney, stomach, and lung. For people with colorectal cancer, women with breast cancer, and men with prostate cancer, greater amounts of physical activity are associated with reduced risk of mortality from the original type of cancer; for people with colorectal cancer or women with breast cancer, greater amounts of physical activity are associated with reduced risk of all-cause mortality. Physical activity-related benefits also have been demonstrated for the large number of individuals who already have one or more chronic conditions, such as osteoarthritis, hypertension, type 2 diabetes, dementia, multiple sclerosis, spinal cord injury, stroke, Parkinson ’s disease, schizophrenia, attention deficit hyperactivity disorder, and recent hip fracture. Individuals considered to be frail also benefit from regular physical activity . 2018 Physical Activity Guidelines Advisory Committee Scientific Report D-4

69 Part D. Integrating the Evidence Table D-1. Physical Activity-Related Health Benefits for the General Population and Selected Populations Documented by the 2018 Physical Activity Guidelines Advisory Committee Children ge Improved bone health and weight status 3 to <6 Years of A ge 6 to 17 years of a Improved cognitive function (ages 6to 13 years) Improved cardiorespiratory and muscular fitness Improved bone health Improved cardiovascular risk factor status Improved weight status or adiposity Fewer symptoms of depression Adults, all ages All Lower risk -cause mortality Cardiometabolic conditions Lower cardiovascular incidence and mortality (including heart disease and stroke) Lower incidence of hypertension Lower incidence of type 2 diabetes Cancer Lower incidence of bladder, breast, colon, endometri um , us , kidney, stomach, and lung cancers esophag Brain health risk of dementia Reduced Improved cognitive function Improved cognitive function following bouts of aerobic activity Improved quality of life Improved sleep Reduced feelings of anxiety and depression in healthy people and in people with existing clinical syndromes Reduced incidence of depression Weight status Reduced risk of excessive weight gain Weight loss and the prevention of weight regain following initial weight loss when a sufficient dose of moderate- to-vigorous physical activity is attained An additive effect on weight loss when combined with moderate dietary restriction Older Adults Falls Reduced incidence of falls Reduced incidence of fall-related injuries Physical function Improved physical function in older adults with and without frailty Women who are Pregnant or Postpartum Reduced risk of excessive weight gain During pregnancy Reduced risk of gestational diabetes No risk to fetus from moderate-intensity physical activity Reduced risk of postpartum depression During postpartum D-5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

70 Part D. Integrating the Evidence Individuals with Pre-Existing Medical Conditions Breast cancer Reduced risk of all-cause and breast cancer mortality Colorectal cancer Reduced risk of all-cause and colorectal cancer mortality Prostate cancer Reduced risk of prostate cancer mortality Decreased pain Osteoarthritis Improved function and quality of life Reduced risk of progression of cardiovascular disease Hypertension Reduced risk of increased blood pressure over time Type 2 diabetes Reduced risk of cardiovascular mortality Reduced progression of disease indicators: hemoglobin A1c, blood pressure, blood lipids, and body mass index Multiple sclerosis Improved walking Improved physical fitness Dementia Improved cognition Improved cognition Some conditions with impaired executive function (attention deficit hyperactivity disorder, schizophrenia, osis, Parkinson’s multiple scler nd stroke) disease, a are those added in 2018; benefits in normal font are those noted in the 2008 Scientific Note: Benefits in bold font 1 Report. Only outcomes with strong or moderate evidence of effect are included in the table. Question 2. Does current evidence indicate that people who habitual ly perform to-vigorous physical activity feel better and sleep greater amounts of moderate- better? ). Part F. Chapter 3. Brain Health People who are more physically active feel better and sleep better (see In addition to reductions in risk for a variety of chronic health diseases and conditions, strong evidence demonstrates that more physically active people consistently report better quality of life, reduced anxiety, and reduced feelings of depression. The improved feelings have been observed in both observational cohort studies and experimental trials. Strong evidence also demonstrates that people who are more physically active sleep better. Laboratory assessments of sleep using polysomnography demonstrate that greater volumes of moderate- to-vigorous physical activity are associated with reduced sleep latency (taking less time to fall asleep), improved sleep efficiency (higher percentage of time in bed actually sleeping), improved sleep quality, and more deep sleep. Research using to- standardized self-reported assessments of sleep demonstrate that a greater volume of moderate- vigorous physical activity is associated with significantly less daytime sleepiness, better sleep quality, and a reduced frequency of use of medication to aid sleep. These improvements in sleep are reported 2018 Physical Activity Guidelines Advisory Committee Scientific Report D-6

71 Part D. Integrating the Evidence by nic insomnia as well as by people without diagnosed sleep disorders . Evidence also people with chro , in general, the number of hours before bed time at which the activity is performed does indicates that performed m ore than 8 hours before bedtime, 3 not matter; benefits are equivalent for bouts of activity 8 hours before, and less than 3 hours before bedtime. to Question 3. Does the evidence indicate that people who are more physically active are better able to perform everyday tasks without undue fatigue? People who are m ore physically active are better able to perform everyday tasks without undue fatigue. I ncreased amounts of moderate - to - vigorous physical activity are associated with improved cardiorespiratory and muscular fitness and improved physical function of all ages . ( For more for adults details, see Part C . Background and Key Physical Activity Concepts ) . Climbing stairs, carrying heavy packages, performing household chores, and carrying out other daily tasks are all accomplished more easily by individuals who are m ore physically active because of a higher capacity to perform work. More Among . higher cardiorespiratory and muscular fitness physically active children and adolescents have older adults, both observational and experimental studies demonstrate that amounts of physical greater slowing of age - related loss of physical activity are associated with improved physical function and faster gait speed, better balance, function. The improvements include improved ability to get up from a seated position, and greater ab ility to carry out activities of daily living , such as bathing, dressing, physical toileting, and eating. At all ages, for a given amount of physical activity, t he relative gains in en physical fitness and physical function are greatest for individuals who have not be active. ly Question 4. How soon do the benefits accrue? of physical activity - to vigorous physical activity, commonly Some benefits occur immediately after a session of moderate - referred to as the “last bout effect.” Reduced feelings of anxiety, improved sleep, and improved cognitive function are examples of benefits that can occur after a single episode of moderate - to - vigorous physical activity. If participation in physical activity becomes regular, reductions in routine (baseline) feelings of a nxiety occur, the last bout effect on deep sleep becomes more pronounced, and components of executive function continue to improve. Executive function includes the processes of the brain that help organize daily activities and plan for the future. Tasks su ch as the ability to plan and and control emotions all are part of ; organize ; monitor, inhibit, or facilitate behaviors ; initiate tasks executive function. - 2018 Physical Activity Guidelines Advisory Committee Scientific Report D 7

72 Part D. Integrating the Evidence to-vigorous The cardiometabolic profile also shows improvements soon after an episode of moderate- physical activity. Blood pressure is reduced, and insulin sensitivity is increased. These cardiometabolic benefits persist for hours to days after the last bout. They also may be sufficient to lower the blood pressure of people with pre-hypertension and hypertension into normal ranges for a major portion of the day. Other benefits, such as reduced risk of cardiovascular disease (CVD) , diabetes, falls, and fall-related injuries among older adults, and improved physical function accrue as the physiologic adaptations to greater physical activity transpire. Improved cardiorespiratory and muscular fitness and biomarkers of disease risk start to accrue within days, and for a given amount of physical activity, maximize after a few months. Additional benefits accrue if physical activity volume is further increased. The reductions in risk apply every day and at all ages, including young adults, even though their risk for chronic disease is lower than for middle-aged and older adults. Question 5 . What does the evidence indicate about the public health target range, or “dose,” of moderate- to-vigorous physical activity that is likely to provide many of the health benefits listed in Table 1? Current evidence continues to indicate that the majority of potential benefit or risk reduction is achieved by people who perform in the range of 500 to 1,000 MET-minutes per week of aerobic physical activity . Because MET-minutes is a unit of measure unfamiliar to most people, the target range has been commonly expressed as 150 to 300 minutes of moderate-intensity physical activity per week. Because vigorous-intensity physical activities (6 or more METs) require roughly twice the energy expenditure of moderate-intensity activities (3 to less than 6 METs), the time required to perform 500 to 1,000 MET- minutes of vigorous-intensity physical activity is roughly half that for moderate-intensity physical activity. As a result, about 75 to 150 minutes of vigorous-intensity physical activity per week is considered within the target range. Combinations of moderate- and vigorous-intensity activity that sum to within 500 to 1,000 MET-minutes per week are also in the target range . As an example, most healthy adults walking at about 3 miles per hour for 150 minutes during a week, or about a total of 7.5 miles, will expend about 500 MET-minutes of energy; if they walk for 300 minutes, or about 15 miles, they will expend about 1,000 MET-minutes of energy. Fewer minutes are needed to be in the target range for more vigorous activities. For example, running at 5 miles per hour would require about 60 minutes to reach 500 MET-minutes per week, or 120 minutes to reach 1,000 MET-minutes per week. D-8 2018 Physical Activity Guidelines Advisory Committee Scientific Report

73 Part D. Integrating the Evidence to- Question 6. What does the evidence indicate about the benefits of moderate- vigorous physical activity below or above the target range? People do not need to reach the low er end of the 150 to 300-minute target range to benefit from regular physical activity. Individuals who exceed the target range usually achieve even greater health benefits. For example, the line in Figure D-1 displays a typical dose-response curve for moderate- to- vigorous physical activity and the relative risk of all-cause mortality. The dose-response curve indicates no lower threshold and a steep early decline in relative risk. It also suggests some additional reduction in risk at volumes of physical activity above the current target range. In addition, the bars on the figure . display the percentage of adults reporting different amounts of moderate- to-vigorous physical activity The population distribution of self-reported moderate- to-vigorous physical activity indicates that about modestly increasing their moderate- half of the adult population could reduce their risk substantially by to-vigorous physical activity. The shape of the dose-response curves for cardiovascular disease incidence and mortality, and for the incidence of type 2 diabetes are similar to the shape of the dose-response curve for all-cause mortality depicted in Figure D-1. The evidence is currently insufficient to depict dose-response curves for other health outcomes listed in Table D-1, such as reduction in risk of dementia, several cancer sites, or excessive weight gain. D-9 2018 Physical Activity Guidelines Advisory Committee Scientific Report

74 Part D. Integrating the Evidence Figure D- 1. Risk of All-Cause Mortality and Self-Reported Physical Activity, by Minutes of Moderate- to-Vigorous Physical Activity per Week Note: *Includes all adults reporting greater than 1800 minutes per week of moderate- to-vigorous physical activity. 3 2 Ad apted from data found in Arem et al., 2015 and National Center for Health Statistics, 2015. Source: Question 7. What does current evidence indicate about the importance of the to-vigorous physical activity that intensity, duration, and frequency of moderate- comprise the weekly target volume of physical activity? Intensity The Committee did not specifically examine the relative value of different levels of intensity of physical activity, such as moderate- versus vigorous-intensity physical activity. Volume is accumulated more quickly when performing activities at greater intensity, reducing the number of minutes required to reach a desired volume. Greater intensity also brings greater levels of cardiorespiratory fitness, but also has greater risk of injury, especially if one is unaccustomed to vigorous physical activity. Greater intensity is inversely associated with pleasure during moderate- so to-vigorous physical activity, displeasure is higher during vigorous- than during moderate-intensity activity. This unpleasant affective . For public experience dissipates soon after the episode of moderate- to-vigorous physical activity ends health purposes, total volume of physical activity is a more important target than the specific intensity at which it is accumulated. 2018 Physical Activity Guidelines Advisory Committee Scientific Report D- 10

75 Part D. Integrating the Evidence High intensity interval training (HIIT), sometimes called sprint interval training, has been a recent topic of discussion in both lay and scientific publications. HIIT consists of short periods of high intensity anaerobic exercise, commonly less than 1 minute, alternating with short periods of less intense recovery. The length of time spent at high intensity and recovery intensity varies among regimens, as does the total duration of a training session. Current evidence indicates that HIIT is an efficient method for increasing cardiorespiratory fitness, providing equal fitness benefits with about half the energy expenditure when compared with continuous moderate- to-vigorous intensity exercise. There may also be some benefits on insulin-mediated glucose control . The unpleasant affective response associated with increased intensity is greatest above the lactate and ventilatory thresholds. Current information is insufficient about other potential health benefits, the risks of adverse events, and the long-term sustainability of HIIT training regimens. Please see Question 9 for a broader consideration of the issue of intensity. Duration a more important The total volume of accumulated moderate- to-vigorous physical activity is Physical determinant of health benefits than the duration of the episodes that comprise the total. The 1 Activity Guidelines Advisory Committee Report, 2008, accepted prior conclusions that bouts as short as 10 minutes added benefit and should be included in the accumulated total. At the time, evidence was not reviewed to determine if bouts shorter than 10 minutes also contributed, largely because the available data collection systems could not accurately collect information about the multiple short bouts of moderate- to-vigorous physical activity scattered throughout normal daily activity. The evidence from recent observational studies of cardiometabolic risk factors using device-measured physical activity indicates that bouts of moderate- to-vigorous physical activity of any duration contribute to the total volume of physical activity that determines benefit. These findings do not support the previous recommendation that only bouts of 10 or more minutes provide health benefits. Frequency Total volume of moderate- to-vigorous physical activity is more important than the number of days per week on which individuals perform the activity. For benefits derived from single episodes, such as reduced anxiety, improved sleep and executive function, blood pressure reductions, and improved insulin sensitivity, regular participation throughout the week would likely be more beneficial. A limited amount of evidence suggests that individuals who accumulate all or almost all of their weekly moderate- 2018 Physical Activity Guidelines Advisory Committee Scientific Report D- 11

76 Part D. Integrating the Evidence to-vigorous physical activity on 1 or 2 days per week experience reductions in all-cause and cardiovascular mortality commensurate with individuals who accumulate an equivalent total volume on 3 or more days per week. If time for moderate- to-vigorous physical activity is available only 1 or 2 days per week, doing it on those days is better than not doing it. Question 8 . What does current scientific evidence demonstrate about the relationship between sedentary behavior and the risk of developing various chronic diseases or conditions? Scientific evidence demonstrates that more time spent in sedentary behavior is related to greater all- cause mortality, CVD mortality and incidence, type 2 diabetes incidence, and the incidence of colon, endometrial, and lung cancer. Evidence is insufficient to determine whether breaks in sedentary behavior reduce the risk. For inactive adults, replacing sedentary behavior with light-intensity physical activities is likely to produce some health benefits. Among all adults, replacing sedentary behavior with higher intensity (moderate- to-vigorous) physical activities may produce even greater benefits. Question 9. What does current scientific evidence indicate about how the risks of to-vigorous physical activity sedentary behavior and the benefits of moderate- interact to determine overall risk or benefit? Evidence indicates that the volume of moderate- to-vigorous physical activity affects the level of risk of all-cause mortality and cardiovascular disease mortality associated with sedentary behavior time. The Committee developed a “heat map” depicting the risk of all-cause mortality associated with variou s combinations of sitting time and moderate- to-vigorous physical activity using regression techniques to interpolate the hazard ratios between four levels of sitting time and four levels of moderate- to-vigorous 4 physical activity (Figure D-2). In the heat map, red represents high er risk of all-cause mortality, and green represents lower risk. The greatest risk of mortality is borne by individuals wh o sit the most and who do the least moderate- to- vigorous physical activity (the upper left corner of the heat map). The lowest risk of mortality is achieved to-vigorous physical activity (lower right by individuals who sit the least and do the most moderate- corner of the heat map). 2018 Physical Activity Guidelines Advisory Committee Scientific Report D- 12

77 Part D. Integrating the Evidence Figure D- 2. Relationship Among Moderate- to-Vigorous Physical Activity, Sitting Time, and Risk of All- Cause Mortality 4 Source: Adapted from data found in Ekelund et al., 2016. At the greatest time spent sitting (the top row), the risk of all-cause mortality begins to decrease (color to-vigorous physical activity. At the greatest becomes orange) even with small additions of moderate- to-vigorous physical activity, the risk is low even for those who sit the most . The volume of moderate- 37 best currently available estimate of this volume is about to 38 MET-hours per week, equal to about 80 to 90 minutes per day of moderate-intensity activities, such as walking or yard work at a moderate level of effort, or 40 to 45 minutes per day of vigorous-intensity activities, such as running at 4 to 5 miles or vigorous dancing. per hour, bicycling at 10 or more miles per hour, climbing hills with 20-pound pack, D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 13

78 Part D. Integrating the Evidence At the lowest volume of moderate - to - vigorous physical activity (the ordinate) , the risk of all - cause increases . This suggests that for individuals who do not perform increases mortality as time spent sitting - intensity physical activities - vigorous physical activity, replacing sitting time with light - any moderate , to walking at 2 miles per hour, dusting or polishing furniture , or easy gardening , reduces the risk of such as all - cause mortality. Although the risk of all - cause mortality is reduced as the time spent in sedentary behavior is reduced, even the individuals who sit th elevated risk if they perform no e least have an High volumes of moderate - moderate vigorous physical activity. to - to - vigorous physical activity appear - to remove the risk of all - cause mortality associated with high volumes of sitting . V ery low time spent si - to - vigorous physical activity. tting reduces but does not eliminate the risk of no moderate T he heat map demonstrates that many combinations of less sitting time and more moderate - to - - D Figure is based on 2 vigorous physical activity are associated with reduced risk of all - cause mortality . firm cause and cardiovascular mortality, outcomes with well - established dose - response - evidence for all - to - vigorous physical activity. The dose - response relationships with sedentary behavior and moderate arious combinations of s for v - sedentary behavior and moderate relationship to - vigorous physical activity with other health outcomes are unknown. A similar pattern seems likely, but other patterns may emerge as additional research on other outcomes is conducted . health Question 10 . How do different types of physical activity contribute to outcomes? Aerobic ctivity A - to - vigorous Although other types of physical activity contribute to positive health outcomes, moderate D - 1. Aerobic activity leads to aerobic activity is associated with nearly all the benefits listed in Table improved cardiorespiratory fitness (VO ax m ) wi th an increase in the capacity and efficiency of the 2 cardiorespiratory system to transport oxygen to skeletal muscles and for muscles to use this oxygen . Cardiorespiratory fitness also is associated with improvements in biomarkers for CVD and type 2 diabet es (e.g., atherogenic lipoprotein profile, blood pressure, insulin sensitivity) in adults and older adults with and without these diseases. Although generally not considered muscle - strengthening behavior, aerobic activity leads to improved strength and end urance of the major muscle groups used to The high impact of some aerobic activities, perform the chosen behavior , such as running or swimming. such as running or playing tennis, and the strong muscular forces of others, such as rowing or wrestling, improv e bone health. - 2018 Physical Activity Guidelines Advisory Committee Scientific Report D 14

79 Part D. Integrating the Evidence Muscle trengthening S - strengthening activities involve contracting muscles against resistance. Greater muscular Muscle strength is associated with greater ease performing daily tasks for people of all ages , and provides reductions in blood pr . Muscle - strengthening activities for older essure equivalent to aerobic activities are adults, often in combination with balance training, associated not only with improved physical function but also with reduced risk of falls and reduced risk of injury du - strengthening e to falls. Muscle activities themselves result in can help maintain lean body mass during a program of weight loss, but by little weight loss. Muscle s are strengthened according to the exercise science principles of overload, adaptation, and Overload specificity. resistance slightly greater than usual is applied. If applied on a indicates that a regular basis and the overload is not too large, the muscl es adapt to the new load and become stronger. The improvements in strength are to the muscles to which the overload has been applied. specific Most evidence supports a muscle - strengthening program with the following characteristics: progressive muscle stre ngthening exercises that target all major muscle groups (legs, hips, back, abdomen, chest, three to , days per week. To enhance muscle nonconsecutive shoulders, arms) performed on two to vol itional fatigue . One set of 8 to 8 to 12 repetitions of each exercise should be performed strength, effective is at increasing muscular strength ; limited evidence suggests that 2 or 3 sets 12 repetitions is more effective. The most commonly prescribed methods for increasing muscular strength, endurance, and power ups) or specific types of equipment, including weight involve calisthenics ( e.g., push - ups, sit - ups, chin - machines, free weights, resistance bands, and similar devices. Essentially all types of aerobic activity, such as walking, swimming, or sporting activities c ontribute to the strength of the involved muscles, as , do many household activities such as raking leaves, vacuuming, carrying laundry baskets, or lifting heavy packages. The improvements or maintenance of muscular strength are specific to the muscles used during the activity, so a variety of activities is necessary to achieve balanced muscular strength. Bone S trengthening Bone - strengthening activities reduce the risk of osteoporosis and fractures. Bone - strengthening activities involve significant impact or muscular force s , both of which apply stress to bone, which adapts ing, and running provide significant Activities such as hopping, jumping, skipp by increasing its strength. Standing on one’s toes and suddenly dropping to one’s heels also pr impact forces. ovides helpful impact 15 D - 2018 Physical Activity Guidelines Advisory Committee Scientific Report

80 Part D. Integrating the Evidence forces. - ups, all of which require quick and strong Activities such as dancing, stair climbing, or push muscle contractions, provide significant muscle forces. T raining Balance Balance training helps maintain a steady posture against anticipated or unanticipated perturbations - strengthening activities , with sessions while walking or standing. It is commonly combined with muscle k, for the prevention of falls and fall injuries among older adults. Examples of about 3 times per wee - training activities include standing on one foot, walking heel balance to toe, and using a wobble board . - Flexibility T raining ( S tretching) Dynamic and static stretching improve the range and ease of movement around joints. Flexibility nt of multi physical activity programs but has not been training is a common compone component studied by itself, precluding assessment of its independent benefits, if any, on health. If joint sufficiently and impedes the performance of daily activities, flexibil ity training can increase range flexibility is limited of motion, thereby facilitating activities such as getting dressed or getting into and out of cars. Yoga, Tai Chi, Qi g ong These forms of physical activity are potentially beneficial because they typically combine muscle strengthening, balance training, light - intensity aerobic activity, and flexibility in one package. Yoga, tai include components that the forms ome of . S chi, and qigong each have several forms or styles of activity purposeful combination of emphasize ion , and /or spiritual thinking. The meditat relaxation, mindfulness, mental and physical components, sometimes referred to as “mind - body” activity, may provide mental or physical health benefits but prevents an assessment of the contribution of either component b y itself. Question 1 . What does the scientific evidence indicate about the association 1 between walking and health benefits? Walking, the most commonly performed aerobic activity, is associated with the wide range of benefits listed in Table - D 1. Although some medical conditions or disabilities prevent individuals from walking, for most people walking is normal and frequent component of everyday life. Walking is one of the a safest and most readily accessible physical activities. Adding 5 to 10 minutes of w alking to one’s usual daily physical activities and increasing the time and then intensity (speed) slowly over several weeks or Daily step count is an months is an excellent way to becom more physically active. e ot h er way to devices (e.g., pedometers, Modern technological a final goal. smart monitor gradual increases toward - 2018 Physical Activity Guidelines Advisory Committee Scientific Report D 16

81 Part D. Integrating the Evidence phones, activity trackers ) can help individuals monitor their daily step counts to en sure that they are progressing at a safe and steady pace to meet their goals. BRAIN HEALTH Question 12. Is there evidence that moderate- to-vigorous physical activity influences brain-related health outcomes? Moderate- to-vigorous physical activity positively influences several brain-related health outcomes, including cognition, anxiety, depression, sleep, and quality of life (Table D-2) . Tools enabling assessments of the brain’s structure and function are progressing rapidly and have enabled much to be learned in the past decade, with more new knowledge expected in the next several years. Current to-vigorous physical activity on various evidence indicates a beneficial effect of regular moderate- components of cognition. The evidence is strongest for a reduced risk of dementia and improved executive function. Single episodes of physical activity promote acute improvements in executive function for a brief period of time. Executive function includes the processes of the brain that help organize daily activities and plan for the future. Tasks such as one’s ability to plan and organize, self - monitor and inhibit or facilitate behaviors, initiate tasks, and control emotions all are part of executive function. Physical activity also improves other components of cognition, including memory, processing speed, attention, and academic performance. Strong evidence demonstrates that moderate- to-vigorous physical activity reduces the risk of developing major depression. It also reduces the symptoms of depression among individuals with and without clinical levels of depression. Similarly, moderate- to-vigorous physical activity reduces general feelings of anxiety (trait anxiety) among individuals with and without anxiety disorders. Acute episodes of moderate- to-vigorous physical activity also can reduce immediate feelings of anxiety (state anxiety). perceptions of one’s quality of life and improves a Moderate- to-vigorous physical activity also can raise variety of sleep outcomes among the general population as well as for individuals with symptoms of insomnia or sleep apnea. D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 17

82 Part D. Integrating the Evidence 2. Summary of Conclusion Statements Regarding Strength* of the Evidence for Relationships Table D- Between Physical Activity and Cognition, Depression, Anxiety, Affect, Quality of Life, and Sleep Strength of Population Benefit Outcome Evidence General population and children 5 Cognition Moderate Improved cognition to 13 years of age: habitual Reduced risk of dementia Strong moderate- to-vigorous physical activity Improved performance on academic Moderate achievement tests Improved neuropsychological Moderate performance (executive function, processing speed, memory) Improved cognition (executive General population and children 5 Strong to 13 years of age: acute episodes function, attention, academic to-vigorous physical of moderate- performance, memory, crystalized activity intelligence, processing speed) Individuals with dementia and Moderate Improved cognition some other conditions that affect cognition (attention deficit hyperactivity disorder, schizophrenia, multiple sclerosis, Parkinson’s disease, stroke) Improved quality of life Quality of life Adults, ages 18 years and older Strong Individuals with schizophrenia Improved quality of life Moderate Depressed Strong Reduced risk of depression Adults, ages 18 years and older mood and Strong Fewer depressive symptoms for depression individuals with and without major depression Dose-related reduction in depressive Strong symptoms (i.e., present at low levels, increases with greater frequency, intensity, volume) Anxiety Adults, ages 18 years and older: Reduced state anxiety Strong Acute episodes of moderate- to- vigorous physical activity Adults, ages 18 years and older: Reduced trait anxiety for individuals Strong habitual moderate- to-vigorous with and without anxiety disorders physical activity D- 18 2018 Physical Activity Guidelines Advisory Committee Scientific Report

83 Part D. Integrating the Evidence Strength of Population Benefit Outcome Evidence Strong Adolescents through middle-aged In experimental studies, direct Affect relationship between feelings of adults negative affect and intensity of moderate- to-vigorous physical activity Adults, ages 18 years and older: Sleep Improved sleep outcomes Strong to- acute and habitual moderate- Size of benefit directly related to Moderate vigorous physical activity duration of episode Individuals with symptoms of Improved sleep outcomes with Moderate to- greater amounts of moderate- insomnia or sleep apnea vigorous physical activity Note: “Strength of the evidence” refers to the strength of the evidence that a relationship exists and not to the size of the effect of the relationship. Only populations and outcomes with strong or moderate evidence of effect are included in the table. YOUTH Question 13. Does current evidence indicate health and fitness benefits from physical activity for children and youth? In 2008, insufficient evidence was available to comment on the impact of physical activity on the health of children younger than age 6 years. New evidence has emerged since then, and now, strong evidence indicates that greater volumes of physical activity among children ages 3 through 5 years are associated with a reduced risk of excessive weight gain and favorable indicators of bone health. Among older children and youth through high school age, the evidence continues to demonstrate that moderate- to-vigorous physical activity improves cardiovascular and muscular fitness, bone health, weight status, and cardiometabolic risk factor status. For children ages 5 through 13, the evidence to-vigorous physical activity improve cognition, indicates that both acute bouts and regular moderate- including memory, processing speed, attention, and academic performance. Information on the effect on cognition for younger children and adolescents is not yet sufficient. Question 14. What does the evidence indicate about the type and dose of physical activity most likely to produce these health benefits among children? For children 3 through 5 years, little information is available currently on the type or volume of activity ht status. Until such information becomes available, a prudent most likely to be associated with weig 19 D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report

84 Part D. Integrating the Evidence target would be for all children to achieve the current median estimated volume o f three hours per day of physical activity at intensities that include light, moderate, and vigorous physical activity. The type of physical activity associated with bone health consists of high-impact, dynamic, short duration exercise, such as hopping, skipping, jumping, tumbling; the volume of such activity needed is not currently known. For school-aged children, sufficient evidence indicates health benefits accrue with 60 minutes per day of moderate- to-vigorous physical activity. Because different benefits derive from different types of activity, the 60 minutes will be most healthful if different types of activity are performed. Vigorous-intensity physical activity will enhance cardiovascular health. A variety of play, games, exercise, sports, or chores can strengthen major muscle groups, and activities with high-impact forces, such as hopping, skipping, Physical and jumping, will improve bone strength. These findings are consistent with the findings in the Activity Guidelines Advisory Committee Report, 2008, and the recommendations in the 2008 Physical Activity Guidelines for Americans stating that within the 60 minutes of daily physical activity, children d vigorous intensity and adolescents should engage in muscle-strengthening, bone-strengthening, an 1, 5 physical activities at least three days per week. OLDER ADULTS Question 15. Is there evidence that the target range for moderate- to-vigorous physical activity should differ for older adults? The target range of 150 to 300 minutes per week of moderate relative intensity activities remains an appropriate target for older adults. However, because older adults expend more energy than younger adults for the same task, such as walking, and because aerobic capacity declines with age , relative intensity is a better guide for beneficial activity for older adults than estimates of absolute intensity developed for young and middle-aged adults. The use of relative intensity rather than absolute intensity been very inactive and who have a low as a guide to level of effort applies also to individuals who ha ve aerobic capacity as a result . Activities performed at a moderate relative intensity are commonly ibed as being “somewhat hard.” , for descr ity Concepts (S ee Part C. Background and Key Physical Activ more information about absolute and relative intensity of physical activity and ratings of perceived (relative) exertion. For both older and younger individuals, some activity is better than none, and appreciable benefits accrue from regular physical activity at levels below the target range. D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 20

85 Part D. Integrating the Evidence Question 16. Is there evidence of health benefits of particular importance for older adults? Strong evidence demonstrates that physically active older adults are less likely to experience falls, less likely to be seriously injured if they do fall, and more likely to maintain independence and functional ability compared to those who are inactive . Strong evidence also demonstrates that physically active older adults have a lower risk of dementia, better perceived quality of life, and reduced symptoms of anxiety and depression. Experimental trials have demonstrated that even individuals with frailty and ag with Parkinson ’s disease can improve their physical function, thus minimizing and delaying ing-related declines. Aerobic, muscle-strengthening, and multicomponent physical activity programs all demonstrate benefits. The improvements appear to be somewhat greater with activity programs that include specific muscle strengthening and balance training activities. SELECTED COMMON CHRONIC CONDITIONS to-vigorous Question 17. Does the evidence indicate that habitual moderate- physical activity provides preventive health benefits to individuals with some common chronic conditions? The benefits of habitual physical activity likely vary from condition to condition, but for several prevalent diseases or conditions studied by the Committee, one or more health benefits were evident (Table D-3). For example, for people with colorectal cancer, women with breast cancer, and men with prostate cancer, greater amounts of physical activity are associated with reduced risk of mortality from the original type of cancer; for people with colorectal cancer or women with breast cancer, greater amounts of physical activity are associated with reduced risk of all-cause mortality. Habitual physical activity also . Adults with reduces the risk of mortality from CVD among people with hypertension or type 2 diabetes osteoarthritis who are more physically active experience less pain, improved physical function, and better quality of life relative to less active adults with osteoarthritis . Similarly, more physically active ’s individuals who have Parkinson disease, multiple sclerosis, spinal cord injury, stroke, recent hip fracture, and frailty have better physical function, including walking ability, relative to less active adults are with the same condition. For individuals with some of these conditions, muscle strength and balance improved as well (Table D-3). Except for the mortality outcomes, evidence regarding the type of physical activity associated with these reductions often comes from intervention studies in which the physical activity exposure was a multicomponent program including aerobic activity (commonly walking), D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 21

86 Part D. Integrating the Evidence strength, and balance training. These findings emphasize that preventive effects of physical activity are relevant and important for both healthy adults and for adults with chronic conditions. Indeed, for adults with conditions where physical activity is recommended for its therapeutic effects, the evidence indicates that physical activity typically provides both therapeutic and preventive benefits. Table D-3. Evidence of Health Benefits from Habitual Physical Activity Among People with One of Several Common Chronic Diseases or Conditions RISK REDUCTION OUTCOMES INVESTIGATED FOR SURVIVORS OF THREE COMMON CANCERS Risk of Developing Recurrence of Primary Disease or Risk of Cancer-specific Risk of All-cause Mortality Mortality Condition Cancer or New Type of Cancer Breast cancer Reduced Reduced IE Reduced IE Colorectal cancer Reduced Reduced IE IE Prostate cancer RISK REDUCTION OR HEALTH IMPROVEMENT INVESTIGATED FOR SELECTED COMMON CONDITIONS Disease or Risk of Quality of Progression of Cognition Physical Function Life Mortality Condition Disease No evidence of Less pain, improved quality of life, progression of and improved physical function IE Osteoarthritis osteoarthritis up - among people with hip or knee to 10,000 steps osteoarthritis per day Reduced Reduced IE IE cardiovascular progression of Hypertension - mortality blood pressure Improved HbA1c, BP, BMI, and lipids Reduced cardiovascular IE Type 2 diabetes IE - IE for neuropathy, mortality nephropathy, retinopathy, foot sores Improved Multiple Improved IE IE walking, strength, IE sclerosis cognition fitness Improved - IE Spinal cord injury IE IE walking, wheelchair skills 22 D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report

87 Part D. Integrating the Evidence RISK REDUCTION OR HEALTH IMPROVEMENT INVESTIGATED FOR SELECTED COMMON CONDITIONS Risk of Quality of Disease or Progression of Physical Function Cognition Life Mortality Disease Condition Intellectual IE - IE IE IE disabilities Improved Parkinson’s Improved - walking, strength, - - disease cognition balance Improved - - Improved walking - Stroke cognition Improved Recent hip walking, balance, - - - - activities of daily fracture living Improved walking, balance, Frailty - - - - activities of daily living Improved - Dementia - - - cognition Improved Improved - Schizophrenia - - quality of life cognition Attention deficit Improved - hyperactivity - - - cognition disorder Legend: IE=Insufficient evidence found in systematic reviews and meta-analyses to reach a conclusion, -=question , HbA1c=hemoglobin A1c, BP=blood pressure, BMI=body mass did not address this outcome for this condition index. PREGN ANCY Question 18 . Is there evidence regarding the benefits or risks of light- to-moderate intensity physical activity during pregnancy and the postpartum period? Strong evidence demonstrates that more physically active women with a normally progressing pregnancy have a reduced risk for excessive weight gain, gestational diabetes, and postpartum depression relative to their less physically active counterparts. The amount of physical activity in most of to moderate- intensity physical the experimental trials included in the evidence consisted of light- activity accumulating to about 120 to 150 minutes per week. Insufficient information about the adoption of vigorous-intensity physical activity during pregnancy was available to reach a conclusion 2018 Physical Activity Guidelines Advisory Committee Scientific Report 23 D-

88 Part D. Integrating the Evidence about its benefits or risks during pregnancy and the postpartum period. The 2008 Advisory Committee reported that women who habitually performed vigorous-intensity physical activity prior to pregnancy could continue as long as “they remain asymptomatic and maintain open communication with their 1 alth care providers. he The 2018 Committee concurs . The 2018 Committee did not perform specific literature searches to investigate the association between physical activity and specific benefits or risks related to labor and delivery, date of delivery, weight status of the newborn, or other outcomes . Physical Activity Guidelines Advisory However, the conclusions and information provided in the 5 1 Committee Report, 2008 2008 Physical Activity Guidelines for Americans consistent with are and the the information provided on these topics in the articles included in the specific searches performed by the Committee. WEIGHT STATUS Question 19. Does the evidence demonstrate that moderate- to-vigorous physical ng or minimizing excessive weight gain? activity contributes to preventi to-vigorous physical activity are Strong evidence demonstrates that greater volumes of moderate- ng or minimizing excessive weight gain in adults, being ab le to maintain weight associated with preventi within a healthy range of body mass index, and preventi ng obesity. The 2018 Advisory Committee did not examine literature addressing the association between physical activity and weight loss or the 1 prevention of weight regain following initial weight loss . The 2008 Advisory Committee, however, did address these important issues and concluded that when a sufficient dose of moderate- to-vigorous physical activity is attained, it will result in weight loss and the prevention of weight regain following initial weight loss . The 2008 Advisory Committee also reported that physical activity has an additive effect on weight loss when combined with moderate dietary restriction compared to moderate dietary 1 restriction alone. Question 20. Does moderate- to-vigorous physical activity provide health benefits for people with overweight or obesity even if their weight status remains the same? Strong evidence demonstrates that physically active adults with overweight or obesity experience benefits generally similar to those with normal body weight. Regardless of weight status, the relative reduction in risk of all-cause mortality, incidence and mortality of cardiovascular disease, and incidence 2018 Physical Activity Guidelines Advisory Committee Scientific Report D- 24

89 Part D. Integrating the Evidence of type 2 diabetes are essentially equivalent. For endometrial cancer, the risk reduction is greater for individuals with overweight of obesity than for individuals with normal weight status. Adults with overweight or obesity are more responsive than adults with normal weight to high intensity interval training ’s effects on improving insulin sensitivity, blood pressure, and body composition. INFLUENCE OF RACE OR ETHNICITY, AND SOCIOECONOMIC STATUS ON HEALTH OUTCOMES Question 21. Is there evidence that the volume of moderate- to-vigorous physical activity associated with health benefits differs by race or ethnicity, or socioeconomic status? Race or Ethnicity The 2008 Committee reported that “ based on the currently available scientific evidence, the dose of physical activity that provides various favorable health and fitness outcomes appears to be similar for 1 The 2018 Committee concurs. In the studies used to address adults of various races and ethnicities. ” the questions asked by the 2018 Committee, the effect of race or ethnicity was uncommonly reported and, when it was, the studies showed little evidence of effect modification by race or ethnicity on the relationship between moderate- to-vigorous physical activity and health outcomes. Socioeconomic Status Information o n the effect of socioeconomic status on the relationship between modera te-to-vigorous physical activity was even more sparse than for race or ethnicity, and, therefore, this Committee was . unable to state any conclusions about the role, if any, of socioeconomic status ADVERSE EVENTS Que . What does the scientific evidence indicate about the pattern of stion 22 physical activity that is most likely to produce the fewest adverse medical events while providing benefits? The 2018 Committee determined that the basic principles and messages in the Physical Activity still Guidelines Advisory Committee Report, 2008 and the 2008 Physical Activity Guidelines for Americans 1, 5 The information in those reports indicates that activities with fewer and less forceful contact apply. D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 25

90 Part D. Integrating the Evidence with other people or objects have appreciably lower rates of musculoskeletal injuries than do collision or contact sports. Walking for exercise, gardening or yard work, bicycling or exercise cycling, dancing, swimming, and golf are popular activities in the United States, and they are associated with the lowest injury rates. Risk of musculoskeletal injury during activity increases with the total volume of activity (e.g., MET-hours per week). Intensity, frequency, and duration of activity all contribute to the risk of musculoskeletal injuries, but their relative contributions are unknown. Sudden cardiac adverse events are rare, are associated with relatively vigorous physical activity, and are inversely associated with the volume of regularly performed vigorous physical activity. The limited data available for medical risks during moderate-intensity activity indicate that the risks are very low for activities like walking and that the health benefits from such activity outweigh the risks. Question 23. What does the scientific evidence say about actions that can be taken to reduce the risk of injury during physical activity? 2008 Physical Information in the Physical Activity Guidelines Advisory Committee Report, 2008, and the Activity Guidelines indicates that injuries are more likely when people are much more physically active 1, 5 than they are accustomed to. The key point to remember is that when individuals do more activity than usual, the risk of injury is related to the size of the increase. Gradual progression, a series of small increments in physical activity each followed by a period of adaptation, is associated with less risk of musculoskeletal injuries than an abrupt increase to the same final level. Although the safest method of increasing one's physical activity has not been empirically established, for individuals who have been performing little or no moderate- to-vigorous physical activity, adding a small and comfortable amount of light- to moderate-intensity activity, such as walking an additional 5 to 15 minutes 2 to 3 times per week, has a low risk of musculoskeletal injury and no known risk of sudden severe cardiac events. Frequency and duration should be increased before raising the intensity. The risk of adverse events is also reduced by using proper equipment, such as helmets, eyewear or goggles, elbow or knee pads; choosing safe environments, such as those with good lighting, smooth surfaces, and away from traffic; following rules and policies; and making sensible choices, such as avoiding extreme heat or cold. Warming up before and cooling down after exercise are commonly recommended to prevent injuries and adverse cardiac events. Limited evidence does suggest that various combinations of warm up, muscle-strengthening, conditioning, and stretching are associated with lower rates of musculoskeletal 2018 Physical Activity Guidelines Advisory Committee Scientific Report D- 26

91 Part D. Integrating the Evidence injuries. Also based on limited evidence, careful warming up and cooling down are standard practice in cardiac rehabilitation programs. Guidelines typically recommend 10 to 20 minutes of stretching and progressive warm up activity before the main activity session and 10 to 20 minutes of gradually diminishing activity at the end. Question 24. Is there evidence regarding who should see a physician or have a medical examination before increasing the amount or intensity of physical activity they perform? Physical Activity Guidelines Advisory Committee, 2008 The 2008 Physical Activity Guidelines for , and the Americans noted, and the 2018 Physical Activity Guidelines Advisory Committee agrees, that the protective value of a medical consultation for persons with or without chronic diseases who are 1, 5 No evidence is available to interested in increasing their physical activity level is not established. indicate that people who consult with their medical provider receive more benefits and suffer fewer adverse events than people who do not. Also unknown is whether official recommendations to seek medical advice before augmenting one's regular physical activity practices reduce participation in regular moderate physical activity by implying that being active may be less safe and provide fewe r benefits than being inactive. PROMOTION OF PHYSICAL ACTIVITY Question 25. What interventions are effective for promoting regular physical activity participation? The extensive body of evidence in the physical activity promotion field shows that interventions at different levels of impact, including at the individual, community, environment and policy, and information and communication technology levels, can promote increased participation in regular physical activity (Table D-4). For example, at the individual level of impact, interventions that include behavior change theories and techniques as well as interventions specifically targeted at youth and at older adults have demonstrated success in promoting regular physical activity . At the level of community settings, multi-component school interventions and those that have successfully revised the structure of physical education classes are effective in promoting increased school-based physical on physical activity in children and adolescents. At the level of environment and policy, the evidence activity promotion among children and adults supports the utility of built environment characteristics D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 27

92 Part D. Integrating the Evidence and infrastructure that support active transportation, indoor and outdoor facilities for physical activity, and access to such facilities. At the level of information and communication technologies, the types of technologies that have been found consistently to promote regular physical activity among adults include wearable activity monitors, telephone-assisted interventions, internet-delivered interventions that include educational components, text-messaging programs, and computer-tailored print interventions. Among children and adolescents, information and communication technologies interventions involving systematically developed smartphone applications have been found to be effective . Table D- 4. Summary of Conclusion Statements Regarding Strength* of the Evidence that Varying Types of Interventions Increase the Amount of Physical Activity Among Those Who Are Exposed to the Intervention Level Type of Intervention Strength of Evidence Strong Older adults Individual Strong: Especially when family is included or Youth intervention delivered during school Behavior change theories and techniques Strong Peer led Moderate Community-based School-based Strong: Multiple components Strong: Revised physical education classes Community wide Moderate: If intervention has intensive contact with majority of population over time Strong Point- of-decision prompts Environmental and Policy Built environment and infrastructure that Moderate promotes active transportation Moderate Community design that supports physical activity, including active transportation Moderate Access to indoor or outdoor facilities D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 28

93 Part D. Integrating the Evidence Level Type of Intervention Strength of Evidence Wearable activity monitors Information and Strong: General adult population Communications (accelerometers and pedometers) Moderate: Individuals who are overweight Technologies or obese Telephone-assisted Strong Web-based or internet-delivered, with Strong: General adult population educational component Strong Computer-tailored print interventions Mobile phone programs Strong: Smart phone applications, children and adolescents Moderate: Text messaging, general population Type of Intervention to Reduce Strength of Evidence Level Sedentary Behavior Community-based Youth, primarily school-based Moderate interventions Moderate Worksite interventions Note: “Strength of the evidence” refers to the strength of the evidence that a relationship exists and not to the size of the effect of the relationship. Question 26. What interventions are effective for reducing sedentary behavior? Current evidence indicates that several types of interventions can be effective in reducing sedentary behavior in different age groups. For youth, evidence suggests that school-based interventions targeting reductions in television viewing and other screen-time activities can have a positive impact on reducing sedentary behavior. Among adults working primarily while seated, interventions targeting sedentary activities have resulted in reduced sedentary behavior at the workplace. Effective interventions have included those aimed at physical modifications to work stations (e.g., sit-stand workstations) in combination with educational and behavioral support . D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report 29

94 Part D. Integrating the Evidence REFERENCES 1. Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee Repo rt, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. https://health.gov/paguidelines/guidelines/report.aspx . Published 2008. Accessed September 22, 2017. 2. Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relation ship. JAMA Intern M ed . 2015;175(6):959-967. doi:10.1001/jamainternmed.2015.0533. 3. Centers for Disease Control and Prevention, National Center for Health Statistics. National Health 2015: 2015 data release. – Interview Survey (NHIS), 1997 . Updated November 3, 2017. Accessed https://www.cdc.gov/nchs/nhis/nhis_2015_data_release.htm January 11, 2018. 4. Ekelund U, Steene-Johannessen J, Brown WJ. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonized meta-analysis of data from more than 1 million men and women. Lancet 1. . 2016;388:1302-1310. doi:10.1016/S0140-6736(16)30370- 5. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans . Washington, DC: U.S. Department of Health and Human Services; 2008. . Published 2008. Accessed September 22, 2017. https://health.gov/paguidelines/guidelines 30 D- 2018 Physical Activity Guidelines Advisory Committee Scientific Report

95 Part E. Systematic Review Literature Search Methodology PART E. SYSTEMATIC REVIEW LITERATURE SEARCH METHODOLOGY Table of Contents Overview ... E-1 ... Systematic Review Process E-5 iew Questions ... E-5 Step 1: Develop Systematic Rev Step 2: Develop Systematic Rev iew Strategy ... E-6 Step 3: Search, Screen, and Select Evidence to Review E-8 ... Risk of Bias ... E- 12 Step 4: Abstract Data and Assess Quality and -14 Step 5: Describe the Evidence... E Step 6: Complete Evidence Por tfolios and Draft Scientific Report ... E- 15 E- 16 PAGAC Evidence Assessment Tools ... Standard Abstraction Items – /Pooled Analyses/Reports ... E- 16 SR/MA — E- 17 ... Standard Abstraction Items Original Research SR, MA, and Pooled Analyses Quality Ass Instrument ... E- 19 essment Using Tailored AMSTAR ExBP Existing Reports Quality Assessment Ins trument ... E- 19 Original Research Bias Assessment using Adapted Nutrition Evidence Library Bias Assessment Tool ... E- 20 Instrument References ... E- 22 OVERVIEW n of the Office of Disease Prevention and Health Promotion (ODPHP), the National Under the directio Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the President’s Council on Fitness, Sports and Nutrition (PCFSN), ICF (a contractor), herein referred to as the literature review team, was responsible for supporting the 2018 Physical Activity Guidelines Advisory Committee in reviewing the scientific literature used to support the development of its report. E-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

96 Part E. Systematic Review Literature Search Methodology literature review team used a methodology informed by best practices for systematic reviews (SRs) The 1 culture’s (USDA) Nutrition Evidence Library (NEL), developed by the United States Department of Agri 2 3 the Agency for Healthcare Research and Quality (AHRQ), the Cochrane Collaboration, and the Health 4 and Medicine Division of the National Academies of Sciences, Engineering, and Medicine SR standards to review, evaluate, and synthesize published, peer-reviewed physical activity research. The literature -driven methodology was designed to maximize transparency, minimize review team’s rigorous, protocol bias, and ensure the SRs conducted by the Committee were relevant, timely, and of high quality. Using 5 this evidence-based approach enabled compliance with the Data Quality Act, which states that federal agencies must ensure the quality, objectivity, utility, and integrity of the information used to form federal guidance. Strict quality control processes were implemented throughout the Committee’s process to ensure transparency, integrity, reproducibility, and research excellence in design, implementation, and synthesis of the SRs. a federal leadership The 2018 Scientific Report process was led by the Committee, with support from team. All work completed by the literature review team was under the direction and review of the i Committee members. The literature review team comprised several groups: A training and quality control team that developed an abstraction tool and accompanying • gui de, developed and implemented training and quality control protocols, and abstraction ensured overall quality and integrity of the Committee’s SRs, • SR liaisons, who managed the literature review t eam’s workflow for their designated Subcommittee(s) and/or Work Group, Librarians, who reviewed search strategies, confirmed search results, and retrieved full text • articles, • A triage team that participated in a 5-hour triage training before conducting title and abstract triage of original articles, existing reports, SRs, meta-analyses (MAs), and pooled analyses identified through the literature searches, and • Abstractors, who participated in a three-phase, five-week virtual training before abstracting data from original articles, existing reports, SRs, MAs, and pooled analyses . They also assessed i All literature review team staff were required to disclose potential conflicts of interest or professional bias before working on this team. No conflicts of interest or bias were identified. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-2

97 Part E. Systematic Review Literature Search Methodology bias of original articles and assessed the quality of existing reports, SRs, MAs, and pooled analyses. A six-step process was used to develop the Scientific Report: • Step 1: Develop systematic review questions • Step 2: Develop systematic review strategy • Step 3: Search, screen, and select evidence to review for each question trac t data and assess the quality and risk of bias of the research • Step 4 : Abs Step 5: Describe the evidence • • Step 6: Complete evidence portfolios and draft Scientific Report Figure E-1 provides a visual representation of this process. The model displays the six overarching steps and the associated tasks within each step. It also shows that at any given time, multiple SRs were being executed. For each SR, Steps 2 through 6 were completed sequentially. Throughout the life of the Committee Subcommittees presented the status of their work at in-person public meetings for review and approval by the full Committee. The responsible parties for each task (full Committee, ii Subcommittee, and/or literature review team ) are included in the model. ii Because federal staff served in an support role, specific tasks were not assigned to them. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-3

98 Part E. Systematic Review Literature Search Methodology Figure E-1. 2018 Physical Activity Guidelines Advisory Committee Process Model 2018 Physical Activity Guidelines Advisory Committee Process The Physical Activity Guidelines Advisory Committee (PAGAC) developed a Scientific Report summarizing systematic reviews relating physical activity to health outcomes. The PAGAC worked in nine Subcommittees. The Literature Review Team worked under the direction of the PAGAC. Subcommittees presented their work for ongoing review and approval at public meetings. Ongoing public meetings of the full PAGAC where Subcommittees presented the status of their work and the full PAGAC provided review and approval. DEVELOP Develop Prioritize Develop Questions Topics Questions SYSTEMATIC REVIEW 1 (SR) QUESTIONS Literature Subcommittee Subcommittee PAGAC PAGAC PAGAC Review Team SRX SR1 SR2 SYSTEMATIC REVIEW PROCESS DEVELOP Develop Tailor Develop Develop Inclusion/Exclusion SYSTEMATIC Search Strategy Abstraction Form Analytical Framework 2 Criteria REVIEW STRATEGY Literature Literature Literature Literature Subcommittee Subcommittee Subcommittee Review Team Review Team Review Team Review Team Screen Search and Screen Select SEARCH, SCREEN, Search for High-Quality Existing Reviews Original Research, Evidence Existing Reviews 3 AND SELECT and Reports and Reports if Needed for Review TO REVIEW EVIDENCE Literature Literature Literature Subcommittee Subcommittee Subcommittee Review Team Review Team Review Team ABSTRACT DATA Abstract Assess Quality and Risk of Bias Data 4 AND ASSESS QUALITY OF BIAS AND RISK Literature Literature Review Team Review Team Review and Approve Draft DESCRIBE Components of Components of 5 Evidence Portfolio Evidence Portfolio THE Literature Subcommittee EVIDENCE Review Team Cross-Review Draft Complete Review and Approve COMPLETE other Subcommittee Scientific Report Evidence Portfolios Scientific Report 6 Report Chapters Chapters EVIDENCE PORTFOLIOS Subcommittee Subcommittee Subcommittee AND DRAFT REPORT PAGAC PAGAC PAGAC PAGAC 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-4

99 Part E. Systematic Review Literature Search Methodology SYSTEMATIC REVIEW PROCESS Step 1: Develop Systematic Review Questions In 2014, a federal planning group led by ODPHP, NIH, CDC, and PCFSN organized a potential scope and state of the science meeting with experts from around the country to gather information on whether 6 sufficient new evidence was available to update the 2008 Physical Activity Guidelines for Americans. 7 e Physical Activity Guidelines Advisory Committee Report, 2008, Based on th and a summary of areas of rapidly developing science, the group identified a number of key areas with new research available : youth younger than age 6 years, older adults, brain health across the life span, dose-response, and sedentary behavior. In early 2016, the literature review team conducted a scoping exercise to determine 7 the amount of literature published on topics included in the 2008 Scientific Report since the completion of th at report. The Committee used the list of key topics from 2014, the summary of the scoping exercise, and their expertise to determine the final list of topics to examine. At the ir first public meeting, the Committee decided on topics and formed Subcommittees. The Subcommittee members then developed and refined clearly focused SR questions and subquestions within each topic, which were used to systematically search the existing literature. The development of . the SR questions took place during Subcommittee calls SR Questions Prioritize After formulating a list of SR questions, Subcommittee members ranked the questions based on the following: • Potential for greatest public health impact • Potential to inform public health policy and/or programs • Existence of mature scientific evidence • Potential generalizability ir The SR questions and their prioritization were reviewed and revised by the full Committee during the second public meeting. Any refinements to the questions or questions developed after the second public meeting were presented to leaders of all the Subcommittees for their review and approval. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-5

100 Part E. Systematic Review Literature Search Methodology Step 2: Develop Systematic Review Strategy Develop Analytical Frameworks The Subcommittees developed an analytical framework for each of their SR questions. Analytical frameworks are a visual representation of the search that provided the foundation for each search strategy. The frameworks were used throughout the process to clearly define key variables and terms, help determine the inclusion and exclusion criteria, inform the development of the literature search strategy, and control the scope. For each question, Subcommittee members were asked to develop the components of the analytical framework using the PICO (Population, Intervention or Exposure, Comparison, and Outcomes) method. The analytical frameworks specified the criteria for the types of population (participants), types of interventions (and comparisons), and the types of outcomes of interest. The frameworks were discussed and refined during Subcommittee calls. In some cases, these discussions resulted in refinements to the SR questions. The development of the analytical framework was often done in conjunction with the next step in the process (developing the inclusion and exclusion criteria). Develop Inclusion and Exclusion Criteria SR liaisons developed a template to draft inclusion and exclusion criteria for each search to determine whether studies were eligible to be included in the SR and ensure that the evidence being considered in the SRs was relevant to the U.S. population. The template was shared with Subcommittee members for review, feedback, and approval . To promote consistency, all the SRs included four basic criteria, with addition al criteria used as appropriate. The four constant criteria were: • Publication language: Studies had to be published with full text in English. Publication status: Studies had to be published in peer-reviewed journals or a high-quality • report identified by the Committee. • Research type: Studies had to be existing SRs, MA s, pooled analyses, reports, or original research, determined to have appropriate suitability and quality by the Committee. ◦ Existing reviews, including SRs, MAs, and pooled analyses, were considered if they met the inclusion criteria for the SR question; no priority was given to the selection of any specific type of review. • Study subjects: Studies had to include human subjects E-6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

101 Part E. Systematic Review Literature Search Methodology As appropriate, Subcommittee members considered additional criteria to identify the optimal evidence to answer each of their SR questions. These criteria related to the following: • Age of study subjects • Health status of study subjects • Comparison groups included or excluded • Date of publication • Study design • Intervention/exposure • Outcome Develop Search Strategies A search strategy was created to identify peer-review literature for each SR conducted. Each search strategy included the following items: • Search terms • Boolean logic used to combine search terms • Databases searched • Limits: Search date range, languages searched, types of articles included (e.g., peer-reviewed articles, database-specific filters) The search strategy also recorded the date(s) the searches were conducted and the number of articles identified with each search. Three databases (PubMed®, CINAHL, and Cochrane) were used for each SR. These databases were identified because they represented comprehensive repositories of citations, abstracts, and full articles in fields relevant to the Committee’s SRs. The SR liaisons and librarians (from both ICF and the National Institutes of Health Library), and Subcommittee members worked together in an iterative process to develop each strategy. A list of core physical activity search terms was developed and shared with the Committee. Each Subcommittee could add or remove physical activity terms, as appropriate for each of their SR questions. Core terms were: "Aerobic activities," “Aerobic activity," "Cardiovascular activities," "Cardiovascular activity," "Endurance activities," "Endurance activity," "Exercise," "Physical activities," "Physical activity," "Physical conditioning,” "Resistance training," "Sedentary lifestyle," "Strength training," "Walking," and 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-7

102 Part E. Systematic Review Literature Search Methodology “Sedentary.” Population - and/or health outcome-specific search terms were developed for each SR question. As appropriate, population- or health outcome-specific search terms (e. g., cancer, all-cause mortality) were shared among the SR liaisons for consistency across Subcommittee s. Once the search terms were approved by the Subcommittee members, the SR liaisons conducted a draft et an estimate of how many results (articles) were identified using the search strategy. If the search to g number of results seemed unreasonable or inaccurate to the Subcommittee members based on their ed expertise, the SR liaisons work wi th Subcommittee members to refine the search strategy to ensure that it adequately captured articles that addressed the SR question. If the Subcommittee members considered the number of results to be reasonable and accurate, the SR liaisons shared the list of articles identified through the search for Subcommittee review, feedback, and approval. The analytical framework, inclusion and exclusion criteria, and search strategy for each SR question can be found in the question-specific evidence portfolios, and can be accessed at www.health.gov/paguidelines . Step 3: Search, Screen, and Select Evidence to Review Searching, screening, and selecting scientific literature was an iterative process that sought to objectively identify the most complete and relevant body of evidence to answer each SR question. Working from the analytical frameworks, search strategies, and inclusion and exclusion criteria, the SR liaisons searched, screened, and selected the scientific literature in a systematic way to provide transparent evidence for each Subcommittee’s deliberations. Identify Sources of Evidence to Answer SR Questions Each SR question was answered using: • Existing reviews and/or reports, • Original research (de novo SR),or • A combination of both existing reviews and/or reports and original research. For each SR, existing reviews and reports were searched and screened fir st. These documents are valuable sources of summarized evidence that were used to prevent duplication of effort and promote efficient time and resource management. The decision to use existing reviews and/or reports, original research, or a combination of both existing reviews and/or reports and original research was made by 2018 Physical Activity Guidelines Advisory Committee Scientific Report E-8

103 Part E. Systematic Review Literature Search Methodology Subcommittee members for each SR after their review of the initial search results or the title, abstract, or full-text triage results. Search for High-Quality Existing Reviews Existing reviews were identified by using the search strategy, which specifically was restricted to identify only publications that we re SRs, MAs, and pooled analyses. Two librarians independently reviewed the ns search strategies carried out by the SR liaiso to ensure quality and comprehensiveness, providing recommendations as needed . The librarians also duplicated each search to identify any errors in searching procedures and reviewed documentation of each search strategy. After completing each search, duplicates were removed, resulting in a set of articles for triage. The list of articles identified for triage was shared with Subcommittee members, who provided review, feedback, and approval . Search for High-Quality Existing Reports iii The SR liaisons conducted a search of nine resources and websites using the search terms “physical activity, ” “exercise , ” and “sedentary” to identify and gather high -quality existing reports with potential relevance to SR questions that were not identified through the search for high-quality existing reviews . The search resulted in 1,277 titles that were reviewed for relevance independently by two SR liaisons , po s. When discrepancies were identified, a third SR resulting in a pool of 195 tentially relevant report liaison review the titles to help reach consensus. ed The SR liaisons reviewed the list of report titles and descriptions and shared with their Subcommittee(s) any they thought might be relevant. If the Subcommittee members agreed that an existing report was relevant to a SR question, the report moved to triage. Search for Original Research Articles If the Subcommittee determined that a complete (de novo) SR or partial (supplement al de novo) SR was necessary because, for example, of a lack of relevant existing reviews, SR liaisons developed a strategy for a complete or partial search that was specifically tailored to the Subcommittee ’s needs for iii Resources and websites searched to identify high-quality reports included: AHRQ Evidence Reports: http://www.guideline.gov/resources/ahrq-evidence-reports.aspx; Campbell Collaboration Library of Systematic Reviews: http://www.campbellcollaboration.org/lib/ ; Cochrane Library: Accessed through NIH Library ; Grey Literature Report: http://www.greylit.org/ ; Health and Medicine Division : http://www.nationalacademies.org/hmd/Reports.aspx ; National Guideline Clearinghouse: http://www.guideline.gov ; NICE: http://www.evidence.nhs.uk/ ; Rand Corporation: Accessed through . http://www.who.int/gho/publications/en/ NIH Library; and World Health Organization: E-9 2018 Physical Activity Guidelines Advisory Committee Scientific Report

104 Part E. Systematic Review Literature Search Methodology Subcommittee review. SR liaisons then implemented the approved search strategy. Librarians reviewed the search strategies to ensure quality and comprehensive nature, and the searches were duplicated to identify any errors in searching procedures. After completing the search, duplicates were removed, resulting in the set of articles for triage. The list of articles identified for triage was shared with Subcommittee members, who provided review, feedback, and approval. Triage Articles Once the literature search was complete, all article titles and abstracts were independently screened, or triaged by two members of the triage team, by one triage team member and one Subcommittee member, or by two or more Subcommittee members. When discrepancies were identified, an additional screener review ed the titles or abstracts to help reach consensus. • Title and abstract triage: Two screeners independently reviewed each article’s title, then ’s abstract, to determine whether it met the criteria for inclusion reviewed each remaining article in the review. The list of articles identified and the triage results were shared with Subcommittee members. Subcommittee members were asked to provide review, feedback, and approval. The triage process was conducted and recorded in the online database developed for the Committee, which record ed all triage and abstraction data. • Full -t ext triage: Full text was retrieved for the remaining articles after title and abstract triage and shared with Subcommittee members. Subcommittee members conducted triage on the full- text articles and excluded articles that did not meet the inclusion criteria. In addition, during the abstraction process, abstractors identified any concerns about inclusion, which the SR liaison brought to Subcommittee members for review and final decision. Any changes to the initial triage determinations based on full-text review were updated in the online database. SR liaisons shared the final list of included and excluded articles with the associated rationale for exclusion with Subcommittee members for their review. Conduct Supplemental Searching Activities Subcommittee members and federal support staff were encouraged to share additional articles that may have contributed to the evidence after the search strategy was executed. Subcommittee members and staff identified these articles through their expertise and familiarity with the literature or through hand searching of included article reference lists. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 10

105 Part E. Systematic Review Literature Search Methodology If an article was identified that met the inclusion criteria (i.e., was published during the time • frame searched and used existing search terms or reasonable variations of the included search terms) but had not been captured by the search strategy, it went through article triage. • If an article was identified that had not been captured by the search strategy and did not meet the time frame requirement, opened” to allow the article and other the search could be “re - relevant articles published since the search was conducted into the potential body of evidence for consideration. Before re-opening the search, Subcommittee members had to confirm that the article would meet the inclusion criteria, provide evidence that it would alter the conclusion statement and/or the evidence grade, and request approval from the leaders of all the Subcommittees. Determine Sources of Evidence After reviewing the full text of all the included existing reviews and reports, the Subcommittee members decided whether these sources of evidence could be used to answer the SR question in full, in part, or not at all. • could be used to answer the SR question in full, the If the existing reviews and reports selected literature review team proceeded to Step 4: Abstract Data and Assess Quality and Risk of Bias. • If the existing reviews and reports selected could be used to answer the SR question in part (i.e., in combination with a de novo SR), the literature review team proceeded to Step 4 for the selected existing reviews and reports. Concurrently, the Subcommittee members discussed which components of the SR question were not addressed by the selected existing reviews and/or reports . SR liaisons developed and implemented a search strategy to answer the Search for Original Research Articles remaining components of the question, as described in the section. The revised search strategy was shared with the Subcommittee members for feedback and approval before implementation. • If none of the existing reviews and reports could be used to answer the SR question (or if no were identified by the search strategy), the SR liaison existing reviews and/or reports implemented a search strategy to search for original research articles. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 11

106 Part E. Systematic Review Literature Search Methodology Data and Assess Quality and Risk of Bias : Abstract Step 4 An objective data abstraction approach was used to present and summarize the characteristics of studies that addressed a SR question. The goals of data abstraction were to accurately identify and concisely describe the key elements of each study, while capturing consistent information from each article across the whole body of evidence. Abstractors were hired, trained, and certified to perform all abstracting duties, and strict quality control procedures were used throughout the abstraction process. Conduc t Abstraction Training and Quality Control Abstractor candidates participated in a three-phase, five-week virtual training that culminated in a certification process. All abstractors were certified before abstracting articles for the Committee. The training was supported by an abstractor training manual that contained detailed instructions, definitions, reporting instructions, response options, and examples (including screen shots of the online database), as well as annotated versions of the articles used in the training. In addition to initial training - on sessions, the training and quality control team provided group retraining and recalibration and one- one consultation and training to abstractors. On an ongoing basis, the training and quality control team provided feedback and developed guidance documents (e.g., FAQs) based on frequently asked questions and common errors. Two abstractors (referred to as a “pair”) independently conducted all data abstraction tasks. Abstractors were assigned batches of articles to review in the online database. After both abstractors completed the batch, the pair reviewed their entries, discussed discrepancies, and reached agreement: • When abstractors were able to settle discrepancies, the online database was updated to reflec t the decision . • When needed, the abstractors contacted a training and quality control team member to discuss their disagreements or gain clarification. A training and quality control team member conducted an independent review of the specific data elements where discrepancies existed and provided guidance. After a decision was reached by abstractors, the online database was updated to reflect the decision. Concurrent with abstraction, the training and quality control team independently abstracted data for 12.5 percent (at a minimum) of existing reviews, reports, and original research and then compared their entries with those of the abstractor pair to identify discrepancies. A higher percentage of articles were reviewed by the training and quality control team when abstractors moved from abstracting SRs, MAs, 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 12

107 Part E. Systematic Review Literature Search Methodology pooled analyses, or reports to abstracting original articles and when new research questions required changes in the abstraction form. Abstract Data Data were entered into an online database using standard abstraction items, one for existing reviews and reports and another for original research ( Standard Abstraction Items – SR, MA, Pooled Analyses, and and Reports — Original Research ). The forms were modeled after similar Standard Abstraction Items forms used for the 2008 Advisory Committee and the Guide to Community Preventive Services SRs, and were tailored for each SR based on input from Subcommittee members. The pair of abstractors independently read and reviewed each article, abstracted key information, and entered it into the online databa se, which was prepopulated with basic information about the article (e.g., citation, abstract). After all quality control processes were conducted, complete abstraction data were used to populate individual article evidence summary tables. iv Assess Quality for Existing SRs, MAs, and Pooled Analyses In addition to abstracting key information from SRs, MAs, and pooled analyses, the pair of abstractors independently assessed each existing review’s quality. Quality for each SR, MA, or pooled analysis was 8 . a modified version of “A Measurement Tool to Assess AMSTAR , assessed using AMSTAR Ex BP BP Ex 9 . was used to assess the methodological quality of SRs and MAs , Systematic Reviews” (AMSTAR) AMSTAR is an adaptation of AMSTAR that focus es on MAs that examine the effects of exercise BP Ex training on blood pressure. The training and quality control team made additional revisions to adapt , and Pooled Analysis Quality Assessment Using Tailored for the Committee ( SR , MA AMSTAR Ex BP AMSTARExBP Instrument ). The adaptation made by the training and quality control team for the 10 Committee was based on a methodology improvement publication for AMSTAR. The main revisions clarified reporting instructions for scoring quality items in different types of reviews and were not ed to modify the tool itself. The results of the SR, MA, and pooled analysis quality assessment intend were used to develop quality assessment charts and were shared with Subcommittee members for review. iv If authors of a publication conducted an SR followed by an MA , the study was classified as an MA. If authors referred to a study as a pooled analysis, the publication was classified as pooled analysis, independently of being accompanied by a SR or not. Publications that consisted only of SRs , for which the authors did not also conduct a meta-analysis, were classified as an SR. Subcommittee members classified existing reviews as SRs, MAs, or pooled analyses consistent with abstractions and the evidence portfolio. E- 13 2018 Physical Activity Guidelines Advisory Committee Scientific Report

108 Part E. Systematic Review Literature Search Methodology Assess Quality for Existing Reports In addition to abstracting key information from existing reports, pairs of abstractors also independently assessed each report’s quality. The literature review team developed, with feedback from the USDA NEL, a set of questions that assessed the integrity and appropriateness of the methodology, recommendations, and references in existing reports ( Existing Reports Quality Assessment Instrument ). reports’ quality assessment The results of each were used to develop quality assessment charts and were shared with Subcommittee members for review. Assess the Risk of Bias for Original Research In addition to abstracting key information from each original research article, pairs of abstractors assessed each study’s risk of bias. Risk of bias, or internal validity, was assessed for each original study 11 using an adapted version of the USDA NEL Bias Assessment Tool (BAT). The NEL BAT uses a domain- based evaluation to help determine whether any systematic error exists that could either over- or underestimate the study results. Selection, performance, detection, and attrition bias are addressed in the NEL BAT. The NEL BAT is tailored by study design, with different sets of questions applying to randomized controlled trials (RCTs) (14 questions), non-randomized controlled trials (14 questions), and observational studies (12 questions). To adapt the NEL BAT for the Committee, the training and quality control team made minor revisions to expand the reporting instructions to facilitate decision making and provide examples relevant to the Committee’s topics, questions, and study designs ( Original Research Bias Assessment using Adapted Nutrition Evidence Library Bias Assessment Tool Instrument ). The results of studies’ risk of bias assessment s were used to develop the risk of bias summary charts and were shared with Subcommittee members for review. Step 5: Describe the Evidence To facilitate the Committee’s review and analysis of the evidence, the literature review team prepared evidence portfolios for each SR question. For transparency, the evidence portfolios documented the full process followed for each of the SRs, including the sources of evidence, conclusions, evidence grades, description of evidence, populations analyzed, individual evidence summary tables, risk of bias and quality assessment charts, search strategy, literature tree, references, and rationale for exclusion of . After the SR liaison compiled the evidence portfolios, all articles excluded at abstract or full-text triage 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 14

109 Part E. Systematic Review Literature Search Methodology evidence portfolios and reference lists were edited and reviewed for consistency. SR liaisons submitted evidence portfolios to the corresponding Subcommittee for review, feedback, and approval . This step was often done concurrently with Step 6: Complete Evidence Portfolio and Draft Advisory Committee Scientific Report. The evidence portfolio for each SR question can be accessed at www.health.gov/paguidelines . Step 6 : Complete Evidence Portfolios and Draft Scientific Report Develop Conclusion Statements Subcommittee members reviewed and deliberated on the body of evidence (i.e., included existing reviews, original research articles included in existing reviews, and/or included original research) to develop conclusion statements that answer ed each of their SR questions and any subquestions. Conclusion statement s were tightly associated with the evidence, focused on general agreement among the studies around the independent variable(s) and outcome(s), and acknowledged areas of ed . The conclusion statement(s) reflected only the disagreement or limitations, where they exist evidence reviewed and not information Subcommittee members might have known from another source. Grade the Evidence Along with the SR evidence portfolios, the Committee members were given a rubric, the 2018 Physical Activity Guidelines Advisory Committee Grading Criteria (Table E-1), to guide the ir assessment and grading of the strength of the evidence supporting each conclusion statement. The rubric was adapted 12 from the USDA NEL Conclusion Statement Evaluation Criteria rubric and revised slightly by Committee members to reflect the specific characteristics of physical activity literature. Grading the strength of the evidence was based on applicability of the populations, exposures, and outcomes studied; generalizability to the population of interest; risk of bias and study limitations; quantity and consistency of findings across studies; and magnitude and precision of effect. Subcommittees presented their conclusion statements and strength of evidence grades to the full Committee during public meetings for deliberation and approval. When necessary, Subcommittee ed members revis the conclusion statements and grades. Any changes to conclusion statements and strength of evidence grades had to be re-presented to the full Committee during public meetings. E- 15 2018 Physical Activity Guidelines Advisory Committee Scientific Report

110 Part E. Systematic Review Literature Search Methodology Develop Narrative Summary and Research Recommendations After the Subcommittee members developed a conclusion statement and grade for a SR question and any SR subquestions, they developed a narrative summary of their analysis and research recommendations related to the question. The summary included a review and synthesis of the evidence, rationale for evidence grades, and limitations. The research recommendations listed key areas where additional research could enhance the evidence base by addressing gaps identified in the existing research, advancing the field of physical activity research, and informing future editions of the Physical Activity Guidelines. Draft the PAGAC Scientific Report Subcommittee members drafted a summary for each SR question using the body of evidence. The SR question summaries were compiled into the Committee’s Scientific Report. PAGAC EVIDENCE ASSESSMENT TOOLS v Standard Abstraction Items – SR/MA/Pooled Analyses/Reports Summary of Individual SR/MA/Pooled Analysis/Report • Type of Review/Source ◦ Systematic Review/Meta-Analysis/Pooled-Analysis • Total Number of Studies ◦ Report • Report Organization/Sponsor Report Type • • Purpose of the Review/Report • Author Stated Funding Source • Exposure Definition ◦ Measures Steps? ◦ Measures Bouts? High Intensity Interval Training (HIIT)? ◦ vi • Timeframe v All items ending with a question mark have yes/no responses. vi Records the years covered in the search of the SR, MA, or report. If authors searched from the earliest date ” available in a database (e.g., from the database ’s inception) it was abstracted as “inception to end date of search. E- 16 2018 Physical Activity Guidelines Advisory Committee Scientific Report

111 Part E. Systematic Review Literature Search Methodology • Description of Outcomes Measures Change in Fitness? ◦ Report’s Conclusions • vii Study Population Sex • Race/Ethnicity • • Age • Socioeconomic Status • Population Density • Weight Status • Disability Status • Pregnancy Status • Cancer • Chronic Condition • Other viii Standard Abstraction Items— Original Research Study Overview • Purpos e • Study Design • to supplementary material or previous publications for detailed methods? Do the authors refer • Country • Author Stated Fund ing Source • Author Stated Sample Power Sample Size - Initial • Final Sample Size • • Attrition ( %) • Was the study an intervention? • Type of Intervention ◦ Provision of Information/Education ◦ Behavio ral ◦ Environmental ◦ Policy/Legislation/Regulation ◦ Laboratory-based ◦ Technology ◦ Other vii All populations analyzed a nd presented in the data related to the outcome of interest are recorded. viii All items ending with a question mark have yes/no responses. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 17

112 Part E. Systematic Review Literature Search Methodology • Physical Activity Exposure Assessment Self-reported ◦ Device-measured ◦ ◦ Direct Observation Other ◦ Measures Steps? ◦ ◦ Measures Bouts? • Outcomes and Measurement ◦ Measures Change in Fitness? ◦ Addresses Adverse Events? ix Study Population • Sex • Race/Ethnicity • Age • Socioeconomic Status • Population Density/Urbanicity • Weight Status Disability Status • • Pregnancy Status Cancer • • Chronic Condition • Other Intervention Components Length of Overall Physical Activity Intervention • Frequency of Physical Activity • • Intensity of Physical Activity • Duration of Physical Activity • Physical Activity Type ◦ Cardiorespiratory ◦ Strength ◦ Balance ◦ Flexibility ◦ Active Play, Free Play, or Outdoor Play ◦ Other • High Intensity Interval Training (HIIT)? Was Intention to Treat Analysis Conducted? • ix All populations analyzed/presented in the data related to the outcome of interest are recorded. E- 18 2018 Physical Activity Guidelines Advisory Committee Scientific Report

113 Part E. Systematic Review Literature Search Methodology SR, MA, and Pooled Analyses Quality Assessment Using Tailored AMSTAR ExBP Instrument Were the review questions and inclusion and exclusion criteria clearly delineated prior to • executing the search strategy? Were the population variables defined and considered in the methods? • Was a comprehensive literature search performed? • • Was there duplicate study selection and data extraction? • Was the search strategy clearly described? • Was relevant grey literature included in the review? • Was a list of studies (included and excluded) provided? • Were the characteristics of the included studies provided? • Was Frequency, Intensity, Time, and Type (FITT) defined for each study and examined in relation to the outcome effect sizes? • Was the scientific quality (risk of bias) of the included studies assessed and documented? • Did results depend on study quality, either overall, or in interaction with moderators? • Was the scientific quality of the included studies used appropriately in formulating conclusions? • Were the data appropriately synthesized in a qualitative manner and if applicable, was heterogeneity assessed? • Was the effect size index chosen justified, statistically? • Was individual-level meta-analysis used? • Were practical recommendations clearly addressed? • Was the likelihood of publication bias assessed? • Was the conflict of interest disclosed? Existing Reports Quality Assessment Instrument • Were the review questions and inclusion and exclusion criteria clearly delineated prior to executing the search strategy? • Did the inclusion criteria permit grey literature? • Was a comprehensive literature search performed? • Was the scientific quality of the included source assessed and documented? • Are limitations reported and discussed? • Are the conclusions substantiated by and logically connected to the evidence and findings presented? • Was there a clear list of practical recommendations provided for future research or work on the topic? • Are the recommendations relevant to the purpose of the report and supported by the evidence, findings, and conclusions? • Were the potential conflicts of interest among report funders, authors, expert, or stakeholders assessed and explained? • Was a reference list or a bibliography for the cited literature provided? E- 19 2018 Physical Activity Guidelines Advisory Committee Scientific Report

114 Part E. Systematic Review Literature Search Methodology Original Research Bias Assessment using Adapted Nutrition Evidence Library x Bias Assessment Tool Instrument • Were the inclusion and exclusion criteria similar across study groups? • Was the strategy for recruiting or allocating participants similar across study groups? • Was the allocation sequence randomly generated? • Was the group allocation concealed (so that assignments could not be predicted)? • Was distribution of health status, demographics, and other critical confounding factors similar across study groups at baseline? If not, does the analysis control for baseline differences between groups? • Did the investigators account for important variations in the execution of the study from the proposed protocol or research plan? • Was adherence to the study protocols similar across study groups? • Did the investigators account for the impact of unintended or unplanned concurrent interventions or exposures that were differentially experienced by study groups and might bias results? Were participants blinded to their intervention or exposure status? • • Were investigators blinded to the intervention or exposure status of participants? Were outcome assessors blinded to the intervention or exposure status of participants? • Were valid and reliable measures used consistently across all study groups to assess inclusion • and exclusion criteria, interventions and exposures, outcomes, participant health benefits and harms, and confounding? • Was the length of follow-up similar across study groups? • In cases of high or differential loss to follow-up, was the impact assessed (e.g., through sensitivity analysis or other adjustment method)? • Were other sources of bias taken into account in the design and/or analysis of the study (e.g., through matching, stratification, interaction terms, multivariate analysis, or other statistical adjustment such as instrumental variables)? Were the statistical methods used to assess the primary outcomes adequate? • x Item relevance depended on the study design reported. 2018 Physical Activity Guidelines Advisory Committee Scientific Report E- 20

115 Part E. Systematic Review Literature Search Methodology Table E- 1. 2018 Physical Activity Guidelines Advisory Committee Grading Criteria Strong Moderate Limited Not Assignable Criteria Study Applicability Some of the study Most of study All of the study populations, populations, populations, populations, exposures, and exposures, or exposures, and exposures, and outcomes are outcomes, are outcomes relate outcomes relate directly related to directly related to to the question to the question the question the question indirectly indirectly Generalizability Studied Minor doubts Serious doubts Highly unlikely (to the U.S. population, about about that the studied population of exposure, and generalizability generalizability population, interest) outcomes are free due to narrow or exposure, and/or from serious different study outcomes are doubts about population, generalizable to generalizability exposure, or the U.S. outcomes studied population Serious design Studies are of Risk of bias or k Studies of wea Studies are of strong design; design OR study limitations strong design with flaws, bias, or minor execution inconclusive (as determined by free from methodological findings due to NEL BAT and/or problems across methodological design flaws, bias, AMSTAR concerns, bias, concerns OR the body of ) ExBP or execution studies of weaker and execution evidence problems problems study design Quantity and A moderate Findings are too Few studies have Many studies Consistency (of n been published disparate to number of studies have bee published and the have been the results across synthesize OR with some inconsistency in published with single small study results are highly the available studies) some unconfirmed by consistent in direction or size of effect direction and inconsistency in other studies approximate size direction or size of effect of effect The magnitude Magnitude and The magnitude The magnitude Magnitude and and precision of precision of effect and precision of and precision of precision of effect the estimated the estimated cannot be the estimated effect provide effect provide determined effect provide confidence in the some but not a lot considerable of confidence in accuracy of the confidence in the findings the accuracy of accuracy of the the findings findings E- 21 2018 Physical Activity Guidelines Advisory Committee Scientific Report

116 Part E. Systematic Review Literature Search Methodology REFERENCES U.S Department of Agriculture (USDA). Nutrition evidence library about. USDA website. 1. — https://www.cnpp.usda.gov/nutrition-evidence-library-about . Accessed January 16, 2018. Agency for Healthcare Research and Quality. 2. Methods Guide for Effectiveness and Comparative Effectiveness Reviews . Rockville, MD: Agency for Healthcare Research and Quality; 2014. AHRQ Publication No. 10(14)-EHC063-EF. https://effectivehealthcare.ahrq.gov/topics/cer-methods- guide/overview . Accessed January 16, 2018. 3. Higgins JP, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions . Version 5.1.0. The Cochrane Collaboration; 2011. . Updated March 2011. Accessed http://handbook-5-1.cochrane.org January 16, 2018. 4. Institute of Medicine. Finding what works in health care: standards for systematic reviews. March 2011. http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2011/Finding-What- Works- in-Health- Care -Standards-for-Systematic- Reviews/Standards%20for%20Systematic%20Review%202010%20Insert.pdf . Accessed January 16, 2018. 5. Federal Trade Commission. Data Quality Act. Section 515 of the Treasury and General Government Appropriations Act for FY 2001, Pub. L. No. 106 – 554. . 2008 Physical Activity Guidelines for Americans 6. U.S Department of Health and Human Services. Washington, DC: U.S Department of Health and Human Services; 2008. . Published 2008. Accessed September 22, 2017. https://health.gov/paguidelines/guidelines 7. Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee Repo rt, 2008 . Washington, DC: U.S Department of Health and Human Services; 2008. https://health.gov/paguidelines/guidelines/report.aspx . Published 2008. Accessed January 4, 2018. 8. Johnson BT, MacDonald HV, Bruneau ML Jr, et al. Methodological quality of meta-analyses on the blood pressure response to exer cise: a review. J Hypertens . 2014;32(4):706-723. doi:10.1097/HJH.0000000000000097. 9. Shea BJ, Grimshaw JM, Wells GA, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol . Feb 2007;7:10. doi:10.1186/1471-2288-7- 10. 10 . Burda BU, Holmer HK, Norris SL. Limitations of A Measurement Tool to Assess Systematic Reviews (AMSTAR) and suggestions for improvement. Syst Rev . April 2016;5:58. doi:10.1186/s13643-016-0237- 1. 11. Office of Disease Prevention and Health Promotion. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Washington, DC: U.S Department of Health and Human Services; 2015. https://health.gov/dietaryguidelines/2015-scientific-report/05-methodology.asp . Accessed January 4, 2018. 12. Office of Disease Prevention and Health Promotion. Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Table C.2, NEL Grading Rubric. Washington, DC: U.S Department of Health an d Human Services; 2015. https://health.gov/dietaryguidelines/2015-scientific-report/05- methodology.asp#table-anchor-c.2 . Accessed January 10, 2018. E- 22 2018 Physical Activity Guidelines Advisory Committee Scientific Report

117 Part F. The Science Base New Issues in Defining Physical Activity Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training • Part F. Chapter 2. Sedentary Behavior • Physical Activity and Selected Health Outcomes • Part F. Chapter 3. Brain Health • Part F. Chapter 4. Cancer Prevention • Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain • Part F. Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Physical Activity Considerations for Selected Populations • Part F. Chapter 7. Youth • Part F. Chapter 8. Women Who are Pregnant or Postpartum • Part F. Chapter 9. Older Adults • Part F. Chapter 10. Individuals with Chronic Conditions Promoting Physical Activity • Part F. Chapter 11. Promoting Regular Physical Activity

118 New Issues in Defining Physical Activity • Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training • Part F. Chapter 2. Sedentary Behavior

119 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training . PHYSICAL ACTIVITY BEHAVIORS: PART F. CHAPTER 1 STEPS, BOUTS, AND HIGH INTENSITY TRAINING Table of Contents ... Introduction -1 F1 Review of the Science ... F1 -4 Overview of Questions Addressed ... F1 -4 Data Sources and Process Used to Answer Questions F1 -4 ... Question 1. What is the relationship between step count per day and all-cause and cardiovascular disease mortality and (2) incidence for cardiovascular disease events and risk of type 2 diabetes? . F1 -4 Question 2. What is the relationship between bout duration of physical activity and health outcomes? ... F1 -8 Question 3. What is the relationship between high intensity interval training (HIIT) and reduction in -16 F1 cardiometabolic risk? ... -21 F1 Needs for Future Research ... ... References 23 INTRODUCTION 1 Physical Activity Guidelines Advisory Committee Report, 2008 at moderate- demonstrated th The to- vigorous physical activity is associated with a wide range of health benefits. Most of the literature on which the conclusions were based used survey and questionnaire data, where physical activity exposures were assessed using self-reported estimates of time spent in aerobic continuous moderate- to-vigorous physical activity accumulated in bouts of at least 10 minutes . In the 2008 Scientific Report, all other physical activity — sedentary behavior, light-intensity physical activity, and bouts of moderate- to-vigorous intensity physical activity of less than 10 minutes duration —was considered “baseline” physical activity. The physical activity that counted toward health benefits — moderate- to-vigorous was on top of baseline physical activity. — physical activity in bouts of 10 minutes or more F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -1

120 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training 1 The conclusions of the 2008 Scientific Report were solidly based on the existing scientific information, and the findings and conclusions of the 2018 Physical Activity Guidelines Advisory Committee Report mostly extend the range of beneficial outcomes described in the 2008 Scientific Report . However, 10 additional years of scientific inquiry, aided by substantial advances in measuring physical activity, have improved and refined the understanding of the types of physical activity that influence health outcomes. These include topics such as: — • Are there simpler metrics — such as step counts for estimating the volume of health-promoting behavior? contribute to bouts less than 10 minutes in duration • Do short episodes of activity — — accumulated beneficial physical activity, such as parking distant from the entrance to a place of work (as suggested in most public health statements about physical activity); walking into the coffee shop instead of using the drive-through; getting up from chairs at work to walk around the office; getting up from the couch during the breaks in a TV program to do a chore; climbing a flight of stairs? • How does the newly popularized high intensity interval training (HIIT) mode of exercise fit into health recommendations? What, if any, is the value of light-intensity physical activity? • At any given volume of moderate- to-vigorous physical activity, does the composition of baseline • physical activity influence health outcomes? The Committee considered it important to address these questions and anticipate the ones that might arise following the publication of the 2018 Scientific Report by investigating the current data and further research needs of three particularly relevant issues: the role of daily step counts in the assessment of daily accumulated physical activity across all intensity levels, including light-intensity activity; the impact on health benefits of moderate- to-vigorous physical activity in bouts lasting less than 10 minutes; and the effect of and contribution of HIIT to the prescribed amount of weekly moderate- to-vigorous physical activity, and whether HIIT is associated with cardiometabolic health benefits. 2 All the dose-response data used to develop the physical activity targets for the 2008 Guidelines were developed using epidemiologic data from longitudinal cohort studies with the condition as the outcome to-vigorous physical activity and moderate- as the exposure. One well-accepted limitation of reported data is the inability to incorporate light-intensity physical activity . With the advent of devices to F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -2

121 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training objectively measure physical activity of community-dwelling individuals during daily life activities in addition to exercise, it is becoming increasing clear that light-intensity physical activity contributes to 3 favorable health benefits, independent of those provided by moderate- to-vigorous physical activity. 1 several developments have occurred in the means by which physical Since the 2008 Scientific Report, activity and exercise are measured, quantified, and prescribed to individuals seeking exercise-associated health benefits . The proliferation and popularity of smart phones and other wearable devices containing accelerometers have facilitated the measurement of daily steps counts (see . Part F. Chapter 11 Promoting Regular Physical Activity . Current consumer devices have three- for additional details) dimensional accelerometers, which permit assessments of step cadence; this permits the assessment of physical activity as light intensity or as moderate- to-vigorous physical activity . It is now possible to assess the contribution of light-intensity physical activity to total step counts and, therefore, to better estimate total energy expenditure (see Part C. Background and Key Concepts for additional details). to-vigorous physical activity, the Because step counts incorporate both light-intensity and moderate- Subc ommittee considered it important to better understand how the measurement of steps might fit into the assessment of daily or weekly physical activity exposures and its relationship to health outcomes. to-vigorous physical activity in episodes The persistence of the seeming need to accumulate moderate- (bouts) of at least 10 minutes, which dat es to the physical activity recommendations from the Centers 4 for Disease Control and Prevention and the American College of Sports Medicine, has provided a barrier 10 minutes might contribute to the accumulation of to research investigating how episodes of less than the recommended moderate- to-vigorous physical activity. In addition, it creates dissonance with our car in the parking lot ” “move more, sit less , ” and “park y “take the stairs recommendations such as , further from your place of work, which can incorporate more physical activity into an individual’s ” lifestyle but typically take less than 10 minutes to execute. Therefore, the Subcommittee considered it important to examine data regarding whether accumulated episodes of less than 10 minutes have health benefits and whether those benefits are similar to those of accumulated episodes of greater than 10 minutes. Since the 2008 Scientific Report, high intensity interval training (HIIT) has become a popular research topic . The media also presents HIIT as an alternative means by which individuals can achieve health to-vigorous physical activity benefits similar to those of classical continuous moderate- . Some have F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -3

122 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training suggested that HIIT may be a better alternative than traditional amounts of exercise because it consumes less overall time per week and might be more attractive as a long-term strategy by which to achieve the health benefits of regular physical activity . The Subc ommittee considered it important to examine scientific evidence regarding the use of HIIT for health benefits, the sustainability of HIIT programs, and the rate of adverse events relative to classical continuous aerobic training. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses three major questions and related subquestions. 1. What is the relationship between step count per day and (1) all-cause and cardiovascular disease mortality, and (2) incidence of cardiovascular disease events and type 2 diabetes? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? 2. What is the relationship between bout duration of physical activity and health outcomes? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? a) What is the relationship between high intensity interval training and reduction in cardiometabolic 3. risk? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) Data Sources and Process Used to Answer Questions One search and triage process was conducted for existing reviews (systematic reviews, meta-analyses, pooled analyses, and reports) for all three questions. The Exposure Subcommittee determined that systematic reviews, meta-analyses, and pooled analyses provided sufficient literature to answer Question 3. The existing reviews did not provide sufficient evidence to answer Questions 1 and 2. Separate de novo searches for original research were conducted for Questions 1 and 2. For complete details on the systematic literature review process, see Systematic Review Literature Search Part E. Methodology . Question 1 . What is the relationship between step count per day and all-cause and cardiovascular disease mortality and (2) incidence for cardiovascular disease events and risk of type 2 diabetes? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, or socio-economic status, and weight status? F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -4

123 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Original research articles Source of evidence: Conclusion Statements Insufficient evidence is available to determine whether a relationship exists between step counts per . PAGAC Grade: Not assignable. day and all-cause and cardiovascular disease mortality Limited evidence suggests that step count per day is associated with reduced incidence of cardiovascular disease events and risk of type 2 diabetes. PAGAC Grade: Limited. Limited evidence suggests a dose-response relationship between the measure of steps per day and PAGAC Grade: Limited. cardiovascular disease events and type 2 diabetes risk. Insufficient evidence is available to determine whether the relationship between the measure of steps per day and cardiovascular disease events and type 2 diabetes risk is influenced by age, sex, race/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Not assignable. Review of the Evidence The committee reviewed evidence from nine manuscripts that reported on five original research 9- 12 5-8 four used a prospective design, studies. Of the nine reports, four used a cross-sectional design, and one used a randomized controlled design where control and intervention groups were compared, as 13 The Navigator study, a well as pooled, to examine steps per day in relationship to insulin resistance. multicenter trial of 9,306 individuals with impaired glucose recruited from 40 countries, provided four manuscripts (three longitudinal and one cross-sectional). All four Navigator papers examined health outcomes after pooling intervention and control groups. Therefore, the Navigator study design was 5 , 12 9, 11 considered cross-sectional or longitudinal prospective. Participants in all nine reviewed studies were middle-age or older . Males and females, multiple races and ethnicities, a continuum of body sizes, and diverse geographical areas were represented, supporting the generalizability of conclusions. Cross-sectional studies cannot control for bi-directional relationships, i.e., the outcome causing the . Because it is likely that individuals with exposure as well as the exposure causing the outcome undiagnosed disease may take fewer steps per day than healthy individuals, the reviewed cross- sectional studies were used only to understand usual step counts per day across sample populations. F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -5

124 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training 10, , 13 12 metabolic The longitudinal studies reported health outcomes that included blood glucose levels, 9 syndrome, and a composite of CVD incidence, which included cardiovascular death, non-fatal 11 myocardial infarction, or non-fatal stroke. The baseline number of steps per day varied across studies but the median was approximately 5,000 13 steps per day. One report showed that 80 percent of the steps taken in a day were of light-intensity physical activity. Samples of older adults accumulated fewer daily steps than did younger middle-aged 10 adults. An Australian sample of Tasmanian adults (mean age at baseline 50 years) accumulated nearly twice as many daily steps at baseline as other samples (approximately 10,000, whereas most study baseline steps per day were approximately 5,000). Evidence on the Overall Relationship No study was found that examined the relationship between step counts per day and all-cause or cardiovascular mortality. Therefore, the Subcommittee was unable to draw a conclusion about this relationship . Several longitudinal studies examined the relationship between step counts per day and disease incidence or risk. One study examined cardiovascular disease events, defined as cardiovascular death, 11 non-fatal myocardial infarction, or non-fatal stroke. The other four longitudinal studies addressed type 9, 10 13 , 12, 2 diabetes risk. 11 Yates et al provided evidence of the benefit of increasing steps per day to reduce cardiovascular event incidence as well as the effect of baseline step count on subsequent cardiovascular disease events. This study included more than 45,000 person-years of follow-up in which 531 cardiovascular events occurred. Change in steps per day and baseline steps were positively associated with reduced risk for cardiovascular disease events. 12 13 9 10 focused on markers of type 2 diabetes Huffman et al, Yates et al Ponsonby et al, Herzig et al, and risk . Following a 3-month intervention in which 78 participants who already had an abnormal glucose profile participated in 3 days a week of supervised walking or usual physical activity, step count per day 13 for intervention and control groups were pooled. This measure was not associated with improved 9 glucose profiles. analyzed Navigator data and showed an incremental reduction in the 6- Huffman et al 12 year metabolic syndrome score with baseline step count . Also using Navigator data, Yates et al reported previous steps per day to be weakly and negatively associated with 2-hour glucose levels after 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1 -6

125 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training 10 followed 458 adults with a adjustment for glucose levels in the preceding 3 years. Ponsonby et al normal glucose profile and showed that higher steps per day at baseline were associated with a lower incidence risk for dysglycemia (impaired fasting glucose or impaired glucose tolerance) after 5 years. 11 a yearly 2,000 steps per day increase resulted in an 8 percent yearly Dose-response: In Yates et al reduction in cardiovascular event rate in individuals with impaired glucose tolerance. In addition, baseline level of steps per day was inversely associated with cardiovascular event incidence. Specifically, at baseline each 2,000 steps per day increment was associated with a 10 percent lower cardiovascular event rate (Figure F1-1). Figure F1-1. Association Between Change in Daily Step Count and Cardiovascular Events in Individuals with Impaired Glucose Tolerance 11 Source: Reprinted with permission from Elsevier (The Lancet, Yates et al., 2014, 383, 1059-1066). 9 Huffman et al also analyzed Navigator data and showed for every incremental 2,000 step increase in baseline steps per day a 0.29 percent reduction in the 6-year metabolic syndrome score was expected. 10 estimated that for any average daily step count, an additional 2,000 steps would be Ponsonby et al . associated with a 25 percent reduction in developing incident dysglycemia over the succeeding 5 years F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -7

126 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training 9, 11 the relationship between step count per day and health outcome Similar to the Navigator studies, 10 appeared linear in Ponsonby et al. Evidence on Specific Factors 11 Demographic factors and weight status: The difference in risk reduction reported in Yates et al was not affected by weight status, sex, age, geographical region, or level of baseline steps per day. Despite these findings, the evidence on these factors was not sufficient enough for the Subcommittee to draw a conclusion about any relationship. Negative associations between steps and metabolic syndrome score 9 10 Huffman et al reported in were independent of weight status . Ponsonby et al reported associations that were also independent of weight status when examining steps per day and dysglycemia. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: edition/report/supplementary-material.aspx for the Evidence Portfolio. Public Health Impact Steps are a basic unit of locomotion and as such, provide an easy- to-understand metric of ambulation — an important component of physical activity. Measuring step counts has been shown to motivate diverse samples of individuals to increase physical activity levels (see Part F. Chapter 11. Promoting Regular Physical Activity for more details). Increasingly, the self-assessment of steps can be accomplished through device-based, readily obtainable technology such as pedometers, smartphones, and physical activity trackers. Unlike the measure of moderate- to-vigorous physical activity minutes per week, the metric of step counts per day provides a comparable measure to how caloric intake in most dietary guidance is standardized, i.e., per day. As a result, steps per day would provide a useful tool for researchers and the public to address a variety of health and physical activity issues. In addition, steps can be at light-, moderate-, and vigorous-intensity levels, providing a range of exertion choice to promote walking at all ages and for all levels of fitness. For these reasons, the measure of steps per day has the potential to significantly improve the translation of research findings into public health recommendations, policies, and programs. Question 2. What is the relationship between bout duration of physical activity and health outcomes? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? a) Original research articles Source of evidence: F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -8

127 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Conclusion Statements Moderate evidence indicates that bouts of any length of moderate- to-vigorous physical activity contribute to the health benefits associated with accumulated volume of physical activity . PAGAC Grade: Moderate. Insufficient evidence is available to determine whether the relationship between physical activity accumulated in bouts with a duration of less than 10 minutes and health outcomes varies by age, sex, race/ethnicity, or socioeconomic status. PAGAC Grade: Not assignable. Historical Context Physical activity recommendations have traditionally focused on moderate- to-vigorous physical activity performed in a continuous manner. The historical perspective of these recommendations was 14 Surgeon General’s summarized in the U.S. In 1995, the Centers Report on Physical Activity and Health. for Disease Control and Prevention and the American College of Sports Medicine provided the first contemporary recognition of the recommendation for moderate- to-vigorous physical activity to be “accumulated” in order to achieve a specific threshold of daily physical activity that, in turn, could result 4 ed that “intermittent bouts of physical activity, This recommendation stat in health and fitness benefits. as short as 8 to 10 minutes, totaling 30 minutes or more on most days provided beneficial health and , and the 2008 Guidelines continued to support this fitness effects.” This resulted in a new paradigm recommendation for adults , stating that “aerobic activity should be performed in episodes of at least 10 2 . minutes” However, free-living physical activity is also performed in episodes typically less than 10 minutes in duration; these shorter episodes of physical activity also may have health-related benefits . ommittee was interested in examining the available scientific literature to determine Subc Thus, the whether physical activity episodes of less than 10 minutes in duration have health-related benefits; or, alternatively, if the benefits are only realized when the duration of physical activity episodes is at least 10 minutes. Review of the Evidence To answer this question, the Subcommittee reviewed evidence from 25 manuscripts that reported on 23 15- 39 original research studies. e Two pairs of these studies report ed on different outcomes from the sam 18- -27 , 38 16- 19 , 36 , 35 , 31 21 , 25 , 30 Of the 23 studies, 11 used a cross-section studies. 2 used a prospective al design, 17 22 , 37 15- 34 , 23 , 24 , 28 , 29 , 32 , 33, 38 and 1 used a non-randomized design. 9 used a randomized design, design, F1 2018 Physical Activity Guidelines Advisory Committee Scientific Report -9

128 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training These studies reported on either one or numerous outcomes. A variety of health outcomes were 16, , 20 , 23 -25 , 27 -35 , 37 , 38 15- 18 23, 24 , 29 , 31 , 32 , 37 , blood pressure, covered, including body weight or body composition, 30 16 , 19 , 22 , 23 , 27 , 31 -33 , 38 , 39 38 16, 23 , 26 , 30 , 38 21, metabolic syndrome, inflammato blood lipids, ry glucose or insulin, 31, 38 36 or a composite of CVD risk. biomarkers, 21, 25- 27 , 30 18- , 35, 36 , 38 , 31 and The duration of intermittent bouts also varied across studies. Cross-sectional 22, 37 reported on bouts of physical activity that prospective studies were less than 10 minutes, whereas 34 15- , 23 , 24 , 28 , 29 , 39 17 , 32- randomized studies reported only on intermittent bouts that were at least 10 minutes. Evidence on the Overall Relationship As reported in 11 manuscripts, 10 of the 23 unique studies examined used randomized designs that only , 28 , 39 34 , 32- , 29 15- 17 , 23 , 24 included bouts of physical activity that were at least 10 minutes in duration. These studies demonstrated that intermittent bouts resulted in similar or enhanced effects when compared to 15- continuous bouts of physical activity of longer duration for outcomes of weight and body composition, 17 , 23, 24 , 28 , 29 , 32 -34 , 39 , 23 16, 23, 24 , 29 , 32 16 16 , 23, 32 , 33 , 39 or glucose or insulin. blood lipids, blood pressure, However, these studies do not provide information to evaluate bouts of physical activity of less than 10 minutes in duration. Evidence of overall health benefits resulting from bouts of physical activity less than 10 minutes in 31 , 38 , 36 , 35 , 30, 18- 21 , 25- 27 duration is provided primarily by studies that used a cross-sectional design, with a 22, 37 few studies using a prospective design (Table F1-1). This evidence supports that physical activity accumulated in bouts less than 10 minutes in duration is associated with body mass index (BMI) or body 26 , 38 , 31 19, , 30 , 38 25 , 30 18, , 35 , 37 , 38 31, 37 , 27 20, 19, 22 , 27 , 31 , 38 , 31 ic control, glycem fatness, blood lipids, blood pressure, 36 21, 30 31, 38 inflammatory markers, ore. am Cardiovascular Disease Risk Sc metabolic syndrome, or Framingh F1 -10 2018 Physical Activity Guidelines Advisory Committee Scientific Report

129 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Table F1-1. Summary of the Association Between Physical Activity Bout Duration and Health Outcomes from Prospective and Cross-Sectional Studies that Included Bouts of Less than 10-minute Duration Study Type Sample Citation Size 2-hour insulin during a glucose tolerance test Composition Visceral Adiposity Blood Pressure Total Cholesterol HDL Cholesterol LDL Cholesterol Triglycerides Fasting Glucose Fasting Insulin HbA1c Weight BMI Percent Body Fat, Body CRP Framingham CVD Risk Score Metabolic Syndrome Both >10 Prospective 2076 White et al., 37 2015 Prospective 67 >10 Di Blasio et al., 22 2014 Both Both Both Both Both Both Both Both Cross-Sectional 6321 Both Loprinzi and 31 Cardinal, 2013 <10 <10 <10 <10 Cross-Sectional <10 >10 <10 <10 5668 Wolff-Hughes et 38 al., 2015 Cross-Sectional <10 5302 Gay et al., 26 2016 Cross-Sectional Both 4511 Fan et al., 25 2013 >10 3250 Cross-Sectional >10 Strath et al., 35 2008 Both Both Both 2109 Cross-Sectional Both Glazer et al., 27 2013 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1 -11

130 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Citation Study Type Sample Size glucose tolerance test 2-hour insulin during a Framingham CVD Risk Percent Body Fat, Body Visceral Adiposity Blood Pressure Total Cholesterol HDL Cholesterol LDL Cholesterol Triglycerides Fasting Glucose Fasting Insulin BMI Weight HbA1c Metabolic Syndrome CRP Composition Score 1-5, 1398 Cross-Sectional Vasankari et al., 36 6-10, 2017 11- 15, 20- 120 min 1119 Cross-Sectional 1-9, Clarke and 21 4-9, Janssen, 2014 7- 9 min Both Both 1009 Cross-Sectional Both Both Jefferis et al., 30 2016 298 Both Both <10 Cross-Sectional Cameron et al., 20 2017 >3 42 Cross-Sectional Ayabe et al., 18 min 2013 >3 >32 42 Cross-Sectional Ayabe et al., 19 sec min 2012 Legend: BMI=body mass index, HDL=high-density lipoprotein, LDL=low-density lipoprotein, CRP=C-reactive protein, and Both=both bouts of greater than or equal to 10 minutes versus less than 10 minutes in duration showed an association. Note: Values shown indicate the duration of physical activity bouts at which a significant association was shown with selected health outcomes. Empty cells indicate the outcome was not reported. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1 -12

131 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training 37 Obesity . One cohort study examined incidence of obesity. This study reported that physical activity accumulated in bouts of at least 10 minutes in duration was associated with lower incidence of obesity, whereas physical activity accumulated in less than 10 minutes was not associated with lower incidence of obesity. For cross-sectional studies that examined BMI, two favored physical activity accumulated in 31, bouts of at least 10 minutes compared to physical activity accumulated in bouts less than 10 minutes, 20 38 and three did not report a one favored physical activity accumulated in less than 10 minute bouts, difference between physical activity accumulated in bouts less than 10 minutes versus bouts of at least 25, 27 , 30 10 minutes. Of the seven cross-sectional studies that examined measures of body fatness, one 35 favored physical activity accumulated in bouts of at least 10 minutes, one reported that the association between total volume of physical activity was more strongly associated with cardiometabolic health 38 than physical activity accumulated in bouts of at least 10 minutes, and five studies showed no difference between physical activity accumulated in bouts of at least 10 minutes versus physical activity , 30 , 31 18, 20 , 27 not accumulated in bouts of at least 10 minutes. Resting Blood Pressure. For resting blood pressure, the Subcommittee reviewed one cohort study and 37 two cross-sectional studies. The cohort study demonstrated that physical activity in bouts of either at least 10 minutes or less than 10 minutes in duration was associated with lower incidence of hypertension. Both cross-sectional studies showed that physical activity accumulated in bouts less than 31, 38 10 minutes was associated with lower resting blood pressure. Total Cholesterol . One cross-sectional study showed that physical activity accumulated in bouts of at 31 least 10 minutes or less than 10 minutes in duration was associated with lower total cholesterol. The one cross-sectional study that examined low-density lipoprotein (LDL) cholesterol showed that both sical activity accumulated in bouts of at least 10 minutes in duration and in less than 10 minutes in phy 31 duration were inversely associated with LDL cholesterol. HDL-cholesterol. For high-density lipoprotein (HDL) cholesterol, the one prospective study, which was only 14 weeks in duration, reported that physical activity accumulated in bouts of at least 10 minutes in duration predicted increase in HDL, whereas when the threshold was reduced to include bouts of at 22 least 5 minutes this pattern of physical activity was not predictive of increase in HDL. Of the four cross- sectional studies reviewed, two showed similar associations between HDL and physical activity 27, 31 accumulated in bouts of at least 10 minutes and less than 10 minutes, one showed that physical 19 and one showed activity accumulated in bouts as short as 32 seconds was associated with higher HDL, -13 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

132 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training physical activity accumulated in bouts less than 10 minutes was more strongly associated with HDL than 38 physical activity accumulated in at least 10 minutes. Triglycerides. Three cross-sectional studies examined the association between physical activity and triglycerides. Two of these studies showed similar associations between triglycerides and physical 27, 31 activity accumulated in bouts of at least 10 minutes in duration or in bouts less than 10 minutes. One of these studies showed physical activity accumulated in bouts of less than 10 minutes was more strongly associated with lower triglycerides than physical activity accumulated in bouts of at least 10 38 minutes. Three cross-sectional studies examined the association between physical Glucose Control Measures. , 38 26 19 , 31 30 , 38 two with fasting insulin, and one with Hemoglobin A1c (HbA1c). activity and fasting glucose, For fasting glucose, one study showed that bouts of physical activity that were at least 3 minutes in 19 one study showed no difference in the duration were associated with lower fasting glucose, to-vigorous physical activity accumulated in bouts of association between fasting glucose and moderate- 31 less than 10 minute versus bouts of at least 10 minutes, and one study showed that physical activity accumulated in bouts of less than 10 minutes was more strongly associated with lower fasting glucose 38 when compared to physical activity accumulated in bouts of at least 10 minutes. For fasting insulin, one study showed no difference in the association when comparing moderate- to-vigorous physical 30 activity accumulated in less than 10 minutes and at least 10 minutes, and one study showed physical activity accumulated in bouts of less than 10 minutes was more strongly associated when compared to 38 physical activity accumulated in bouts of at least 10 minutes in duration. The one study that examined HbA1c showed that physical activity accumulated in bouts less than 10 minutes predicted lower HbA1c, whereas physical activity accumulated in bouts of at least 10 minutes in duration was not predictive of 26 lower HbA1c. Metabolic Syndrome . Two cross-sectional studies were reviewed that reported on the association 21 , 30 to-vigorous between physical activity and metabolic syndrome. One study showed that moderate- physical activity accumulated in bouts of either 1 to 9 minutes, 4 to 9 minutes, or 7 to 9 minutes in duration predicted lower odds of having metabolic syndrome independent of moderate- to-vigorous 21 An additional study reported that the physical activity accumulated in bouts of at least 10 minutes. odds of having metabolic syndrome did not differ when comparing physical activity accumulated in 30 bouts of less than 10 minutes versus at least 10 minutes. -14 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

133 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training C-reactive Protein . Two cross-sectional studies examined the association between physical activity and 31, 38 c-reactive protein. One study showed no difference in the association between c-reactive protein and physical activity accumulated in bouts of less than 10 minutes in duration and bouts of at least 10 31 One study showed that physical activity accumulated in bouts of less than 10 minutes was minutes. more strongly associated with lower c-reactive protein when compared to physical activity accumulated 38 in bouts of at least 10 minutes. One cross-sectional study examined the association Framingham Cardiovascular Disease Risk Score . 36 between physical activity and the Framingham Cardiovascular Disease Risk Score. This study showed that physical activity accumulated in bouts of 1 to 5 minutes, 6 to 10 minutes, 11 to 15 minutes, or 20 to 120 minutes in duration and during total waking time were negatively associated with Framingham Cardiovascular Disease Risk Score. Evidence on Specific Factors Demographic factors and weight status: The literature examined included studies that included . This participants representing a range of ages, sex, race/ethnicity, and likely socioeconomic status literature also included participants representing a range of weight status . However, the results presented in this literature did not specifically present results from analyses to compare whether the association between physical activity that varied in bout duration varied by these demographic ch aracteristics. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: for the Evidence Portfolio. edition/report/supplementary-material.aspx Public Health Impact 2 The 2008 Physical Activity Guidelines for Americans recommended that physical activity be accumulated in bouts of at least 10 minutes in duration to influence a variety of health-related outcomes. The evidence reviewed continues to support that physical activity accumulated in bouts of at least 10 minutes in duration can improve a variety of health-related outcomes. However, additional evidence, mostly from cross-sectional studies, suggests that physical activity accumulated in bouts that are less than 10 minutes is also associated with favorable health-related outcomes. Although published too late to include in our literature review, a recent study with device-based measures of physical activity and mortality as an outcome, demonstrates that bouts of less than even five minutes result in 40 These findings are of public health importance because it suggests that engaging in mortality benefits. -15 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

134 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training physical activity, regardless of length of the bout, may have health-enhancing effects. This is of particular importance for individuals who are unwilling or unable to engage in physical activity bouts that are at least 10 minutes in duration. Therefore, public health initiatives to enhance health should recommend including physical activity as an important lifestyle behavior regardless of the duration . Question 3. What is the relationship between high intensity interval training (HIIT) and reduction in cardiometabolic risk? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) Sources of evidence: Systematic reviews and/or meta-analyses Conclusion Statements Moderate evidence indicates that high intensity interval training can effectively improve insulin sensitivity, blood pressure, and body composition in adults. These high intensity interval training- induced improvements in cardiometabolic disease risk factors are comparable to those resulting from continuous, moderate-intensity aerobic exercise and are more likely to occur in adults at higher risk of PAGAC Grade: Moderate. cardiovascular disease and diabetes, compared to healthy adults. Insufficient evidence is available to determine whether a dose-response relationship exists between the quantity of high intensity interval training and several risk factors for cardiovascular disease and diabetes. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the effects of high intensity interval training on PAGAC cardiometabolic risk factors are influenced by age, sex, race/ethnicity, or socioeconomic status. Grade: Not assignable. Moderate evidence indicates that weight status influences the effectiveness of high intensity interval training to reduce cardiometabolic disease risk. Adults with overweight or obesity are more responsive than adults with normal weight to high intensity interval training ’s effects on improving insulin sensitivity, blood pressure, and body composition. PAGAC Grade: Moderate. Review of the Evidence The 2018 Advisory Committee based its conclusions on evidence published before May 2017, specifically 43 41- Participants were males and females from three existing systematic reviews and/or meta-analyses. -16 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

135 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training predominantly ages 18 years and older. The exposure was physical activity performed as high intensity interval training (HIIT) . . HIIT is a form of interval training For the purposes of this review, we used the following definition anaerobic exercise with less intense aerobic recovery consisting of alternating short periods of intense periods. There are no universally accepted lengths for either the anaerobic period, the recovery period, nor the ratio of the two; no universally accepted number of cycles for any HIIT session or the entire duration of the training bout; and no universally accepted relative intensity at which the intense anaerobic component should be performed. The outcomes of interest were all-cause and CVD mortality, CVD and type 2 diabetes incidences, cardiorespiratory fitness, and cardiometabolic disease risk factors. The Subc ommittee’s assessment and evaluation specifically focused on outcomes related to cardiometabolic disease risk factors (e.g., blood pressure, fasting blood lipids and lipoproteins, fasting blood glucose and insulin, and BMI), due to a lack of information regarding mortality and cardiometabolic morbidities. Evidence on the Overall Relationship Results from these systematic reviews and/or meta-analyses of clinical intervention studies consistently support that HIIT can effectively improve cardiorespiratory fitness (increase VO max) in adults with 2 41- 43 42, 43 varied body weight and health status. HIIT-induced improvements in insulin sensitivity, blood 43 41- 41, 43 pressure, an d body composition t or more consistently occur in adults who have overweigh obesity with or without high risk of CVD and diabetes, especially if these individuals train for 12 or more weeks. These HIIT-induced improvements in cardiometabolic disease risk are comparable in magnitude 42 Healthy adults who have to those achievable with continuous, moderate-intensity aerobic training. normal weight and lower risk of cardiometabolic disease do not typically show improvements in insulin sensitivity, blood pressure, and body composition with HIIT. Blood lipids and lipoproteins apparently are 41 not influenced by HIIT. 41 reported findings based on 65 individual studies involving 2,164 participants (including Batacan et al 936 individuals who performed HIIT). Participants were predominantly ages 18 years an d older. This meta-analysis included randomized controlled trials (RCTs) and non-randomized controlled trials and comparative studies in groups of individuals without (46 of 65 studies) or with (19 of 65 studies) a 41 ing “as defined high-intensity interval train Batacan et al diagnosed, current medical condition. F1 -17 2018 Physical Activity Guidelines Advisory Committee Scientific Report

136 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training activities with intermittent bouts of activity that were performed at maximal effort, great than or equal to 85% VO max, greater than or equal to 85% heart rate reserve or the relative intensity of at least 90% 2 he art rate max. ” The modes of exercise included treadmill running, cycling, and swimming. The 65 studies were categorized with respect to exercise training intervention duration and participant BMI 2 classification. Among groups of participants with normal weight (BMI 18.5 – 24.9 kg/m 12 ), short-term (< weeks) and long- max, but did not significantly or term ( ≥12 weeks) HIIT interventions increased VO 2 consistently influence clinical indexes of cardiometabolic disease risk (systolic and diastolic blood pressures; total cholesterol, HDL, LDL, and triglycerides; or fasting glucose and insulin). Among groups of 2 2 participants classified as having overweight (BMI 25-29.9 kg/m ≥30 kg/m ) or obesity (BMI ), short-term and long-term HIIT significantly and consistently increased VO max and decreased diastolic blood 2 pressure and waist circumference. Long-term HIIT also decreased resting heart rate, systolic blood pressure, and body fat percentage among groups with overweight or obesity. 42 Jelleyman et conducted a meta-analysis of 50 studies involving 2,033 participants (including 1,383 al individuals who performed HIIT) to assess the effect of HIIT interventions on indexes of blood glucose control and insulin resistance, compared with continuous training or control conditions. Both controlled (N=36, 72%) and uncontrolled (N =14, 28%) studies were included. HIIT was defined as “at least two bouts of vigorous or higher intensity exercise interspersed with periods of lower intensity exercise or 42 e rest” . complet Participants were ages 18 years and older and the HIIT intervention was 2 weeks or longer. Subgroup analyses were performed after stratifying participants based on health characteristics: healthy (well-trained, recreationally active, or sedentary); weight status (overweight or obese); metabolic syndrome (metabolic syndrome or type 2 diabetes); or with another chronic disease. VO max 2 P increased after HIIT by 0.30 liters per minute (95% CI: 0.25-0.35, <0.001), compared to baseline. The max was greater for HIIT than for non-exercising control conditions (weighted mean increase in VO 2 difference (WMD)=0.28 liters per minute, 95% CI: 0.12-0.44, P =0.001) and attenuated but still significant =0.001). HIIT compared with continuous training (WMD=0.16 liters per minute (95% CI: 0.07-0.25, P reduced body weight, compared to baseline, by 0.7 kg (95% CI: -1.19 to -0.25, P =0.002). Compared to non-exercise control, the HIIT-induced weight loss was 1.3 kg (95% CI: -1.90 to -0.68, P <0.00 1). HIIT- induced weight loss was not different than weight loss from continuous training. HIIT decreased fasting P <0.001). This response glucose, compared to baseline, by 0.13 mmol per liter (95% CI: -0.19 to -0.07, over time was not statistically different compared with non-exercise control and continuous training. Subgroup analysis showed that for the groups of individuals with metabolic syndrome or type 2 -18 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

137 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training diabetes, fasting glucose was reduced by HIIT, compared to non-exercise control, by 0.92 mmol per liter (95% CI: -1.22 to -0.63, P <0.001). HIIT decreased fasting insulin from baseline by 0.93 μU per liter (95% CI: -1.39 to -0.48, P <0.001), but this response was not different than the non-exercise control. HIIT decreased insulin resistance compared to baseline (change in Homeostasis Model Assessment of Insulin <0.001). Reduction in insulin resistance (results from P ; 95% CI: -0.47 to -0.18, Resistance score, -0.33 multiple insulin resistance models combined) was greater for HIIT versus non-exercise control (-0.49; 95% CI: -0.87 to -0.12) and HIIT versus continuous training (-0.35; 95% CI: -0.68 to -0.02). Within the metabolic syndrome or type 2 diabetes grouping, HIIT did not change HbA1c, compared to baseline, among all 13 studies reporting these data. Subgroup analyses showed that HIIT reduced HbA1c by 0.25% (95% CI: -0.27 to -0.23, P <0.001), compared to baseline. Among all studies, the HbA1c response over time (no change) was not statistically different between HIIT and control and continuous training groups. Subgroup analyses based on health (physical activity) status or other chronic diseases were either not significant or inconclusive due, in part, to limited available data. 43 conducted a quasi-systematic, qualitative review of 24 RCTs assessing the effects of HIIT Kessler et al interventions on changes in cardiometabolic disease risk factors. Fourteen of the 24 trials included a continuous moderate-intensity exercise control group, and the other 14 studies included a non-exercise control group. Participants had varied weight status (normal weight, overweight or obese) and health status (healthy (17 studies), CVD (5 studies), metabolic syndrome (1 study), type 2 diabetes (1 study) . Intervention durations ranged from two weeks to six mon ths. HIIT was categorized into two subtypes: aerobic interval training (19 studies) and sprint interval training (5 studies). For the purpose of the ommittee’s assessment, results only from aerobic interval training studies are described. This was Subc 43 done because of the low number of sprint interval training studies included in the Kessler et al review. Compared to baseline (i.e., changes over time), aerobic interval training increased VO max (14 of 14 2 studies), increased insulin sensitivity (4 of 4 studies), and decreased blood pressure in participants not ≥12 weeks). Other ingesting anti- hypertensive medication (5 of 5 studies with intervention periods indexes of cardiometabolic disease risk were not influenced by aerobic interval training, including fasting glucose, total cholesterol, HDL, LDL, and triglycerides. Results for body weight, BMI, body fat percent, and waist circumference were mixed, with improvements observed more consistently for aerobic . interval training interventions of 12 weeks or longer in participants with overweight or obesity Collectively, these aerobic interval training responses were comparable with continuous moderate- -19 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

138 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training intensity exercise, except VO max, which was greater for aerobic interval training versus continuous 2 moderate-intensity exercise. 41- 43 results Dose-Response: Among the three review articles the Committee systematically reviewed, were not presented from RCTs designed to assess dose-response relationships between duration of HIIT 41 Batacan et al and changes in cardiometabolic disease risk factors. Using meta-regression techniques, reported that VO max was predicted by longer HIIT intervention duration ( β coefficient 0.77; 95% CI: 2 0.35- g HIIT 1.18) and BMI (β coefficient 0.84; 95% CI: 0.29-1.38), but not by total time performin cient 0.0002; 95% CI: -0.0017-0.0021) among groups of participants with overweight (minutes) (β coeffi or obesity. Intervention duration, total time performing HIIT, and BMI did not predict the improvements observed in systolic blood pressure and diastolic blood pressure among groups with overweight or obesity. Other cardiometabolic risk factors were not assessed due to lack of heterogeneity of responses. 42 (also using meta-regression techniques) reported Regarding indexes of glucose control, Jelleyman et al that HIIT characteristics, interval intensity, and weekly high-intensity exercise did not predict the improvements (over time) in insulin resistance, fasting glucose, fasting insulin, or HbA1c. Evidence on Specific Factors Age, sex, race/ethnicity, socioeconomic status: Information on the race/ethnicity and socioeconomic status of participants was limited, inconsistently presented, and not statistically assessed. As a result, no conclusions about these relationships were possible. Weight status: Weight status significantly influenced the effect of HIIT on several risk factors of cardiometabolic disease, with groups of adults classified as having overweight or obesity, but not normal 42 , 43 41 weight, reducing blood pressure and body fat an d improving insulin sensitivity. Evidence on Participant Safety Participant safety is central to using HIIT as a tool to reduce the risk of cardiometabolic disease among adults, especially those who have overweight or obesity, with cardiometabolic disease risk factors, diagnosed CVD or type 2 diabetes, or another chronic disease. Although the Subcommittee did not address participant safety among adults performing HIIT, the issue is highly relevant with respect to 42 documented adverse events reported in the 50 studies using HIIT for health promotion. Jelleyman et al included in their meta-analysis. Among the 19 total adverse events reported from the 17 studies (34% of the total) that included this type of information, 18 adverse events were attributable to musculoskeletal -20 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

139 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training a injuries incurred with exercise, with 14 of 18 occurring with HIIT. None of the reported injuries was serious adverse event or necessitated the participant to discontinue the intervention or drop out of the study. Perhaps consistent with the very low incidence of adverse events, mean participant dropout rate was 10 ± 10 percent among the 36 (72%) of studies that documented attrition. The health and disease characteristics of the participants who experienced an adverse event were not presented or discussed. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx Public Health Impact The Subcommittee has identified moderate evidence to indicate that HIIT can effectively improve insulin sensitivity, blood pressure, and body composition in adults. These HIIT-induced improvements in cardiometabolic disease risk factors are comparable to those resulting from continuous, moderate- intensity aerobic exercise and are more likely to occur in adults with overweight and obesity. NEEDS FOR FUTURE RESEARCH Question 1. Step Count Per Day and Question 2. Bout D uration 1. Conduct additional longitudinal research, either in the form of prospective studies or randomized controlled trials, to examine the dose-response relationship between: Steps per day and health outcomes, and a) b) Whether physical activity accumulated in bouts of less than 10 minutes in duration enhances health outcomes. Rationale: This information is critical for setting target volumes of physical activity using steps per day as the metric and for firmly establishing that steps per day predicts the incidence of future disease outcomes. In this review, only one randomized controlled trial was identified and it did not include multiple arms to examine the effects of various doses of steps per day on outcomes. The majority of studies reviewed supporting the health benefits of physical activity accumulated in bouts of less than 10 minutes in duration used a cross-sectional design, with none of the randomized studies reporting on the effects of physical activity accumulated in bouts of less than 10 -21 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

140 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training minutes. Having this knowledge will inform potential cause and effect rather than simply associations. Include measurement methods in prospective and randomized controlled studies that will examine: 2. Whether the rate of stepping and the length (bouts) of continuous steps influence the a) relationship between steps per day and disease outcomes Whether physical activity performed in a variety of bout lengths has differential effects on b) health outcomes The studies reviewed used simple pedometers providing accumulated steps and could Rationale: neither address patterns nor intensity of steps per day. Additional physical activity assessment methods collecting these data should provide a better target for recommending physical activity volume. Based on the studies reviewed, randomized studies did not report on physical activity accumulated in bouts less than 10 minutes in duration, and only two prospective studies were identified that reported on physical activity accumulated in bouts less than 10 minutes. This may be a result of the methods used to assess physical activity in randomized and prospective studies, and suggests the need to include physical activity assessment methods that allow for these data to be available for analysis. Question 3. Hig h Intensity Interval Training 1. Conduct longer-term randomized controlled trials to assess the adherence to and the effects of high intensity interval training, compared to other types of physical activity programs, on physiological, morphological, and cardiometabolic health outcomes . They should address issues of dose-response and be of at least 6 months in duration . These randomized controlled trials should include diverse groups of adults who have overweight or obesity and/or who are at high risk of cardiovascular disease or type 2 diabetes . They should systematically assess adverse events, including musculoskeletal injuries, attributable to high intensity interval training, compared to other types of exercise training, among adults with a wide variety of health and disease characteristics. intervention periods are less than 12 weeks, which Rationale: Most high intensity interval training may be insufficient time to assess the magnitude and sustainability of clinically-important changes in some physiological, morphological, and cardiometabolic health outcomes. The willingness and -22 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

141 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training ability of individuals to adhere to high intensity interval training programs is currently unknown. Prescriptively designing these studies to include participants who have overweight or obesity and/or who are at high risk of cardiovascular disease or type 2 diabetes is important to inform health promotion practitioners and policy leaders on the utility of recommending high intensity interval training for health among a large proportion of the U.S. adult population . At present, evaluation of the safety of high intensity interval training among adults with varied health and disease characteristics is compromised by the limited data available, in part, due to the low proportion of studies reporting adverse events. REFERENCES Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee 1. Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. U.S. Department of Health and Human Services. 2. 2008 Physical Activity Guidelines for Americans . Washington, DC: U.S. Department of Health and Human Services; 2008. to-vigorous physical 3. LaMonte MJ, Lewis CE, Buchner DM, et al. Both light intensity and moderate- activity measured by accelerometry are favorably associated with cardiometabolic risk factors in older women: the Objective Physical Activity and Cardiovascular Health (OPACH) Study. . J Am Heart Assoc 2017;6(10). pii:e007064. d oi:10.1161/JAHA.117.007064. 4. Pate RR, Pratt M, Blair SN, et al. Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA . 1995;273(5):402-407. 5. Yates T, Henson J, Khunti K, et al. Effect of physical activity measurement type on the association between walking activity and glucose regulation in a high-risk population recruited from primary care. Int J Epidemiol . 2013;42(2):533-540. doi:10.1093/ije/dyt015. 6. Johnson ST, Eurich DT, Lytvyak E, et al. Walking and type 2 diabetes risk using CANRISK scores among older adults. Appl Physiol Nutr Metab . 2017;42(1):33-38. doi:10.1139/apnm-2016-0267. 7. Newton RL Jr, Han H, Johnson WD, et al. Steps/day and metabolic syndrome in African American Prev Med . 2013;57(6):855-859. doi:10.1016/j.ypmed.2013.09.018. adults: the Jackson Heart Study. 8. Colpani V, Oppermann K, Spritzer PM. Association between habitual physical activity and lower cardiovascular risk in premenopausal, perimenopausal, and postmenopausal women: a population- . 2013;20(5):525-531. doi:10.1097/GME.0b013e318271b388. Menopause based study. 9. Huffman KM, Sun JL, Thomas L, et al. Impact of baseline physical activity and diet behavior on . 2014;63(4):554- Metabolism metabolic syndrome in a pharmaceutical trial: results from NAVIGATOR. 561. doi:10.1016/j.metabol.2014.01.002. -23 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

142 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Ponsonby AL, Sun C, Ukoumunne OC, et al. Objectively measured physical activity and the 10. subsequent risk of incident dysglycemia: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Diabetes Care . 2011;34(7):1497-1502. doi:10.2337/dc10-2386. 11. Yates T, Haffner SM, Schulte PJ, et al. Association between change in daily ambulatory activity and cardiovascular events in people with impaired glucose tolerance (NAVIGATOR trial): a cohort analysis. . 2014;383(9922):1059-1066. doi:10.1016/S0140-6736(13)62061- 9. Lancet Yates T, Davies MJ, Haffner SM, et al. Physical activity as a determinant of fasting and 2-h post- 12. challenge glucose: a prospective cohort analysis of the NAVIGATOR trial. Diabet Med . 2015;32(8):1090- 1096. doi:10.1111/dme.12762. 13. Herzig KH, Ahola R, Leppäluoto J, Jokelainen J, Jämsä T, Keinänen-Kiukaanniemi S. Light physical activity determined by a motion sensor decreases insulin resistance, improves lipid homeostasis and reduces visceral fat in high-risk subjects: PreDiabEx study RCT. Int J Obes (Lond) . 2014;38(8):1089-1096. doi:10.1038/ijo.2013.224. U.S. Department of Health and Human Services. Physical Activity and Health: A Report of the 14. Surgeon General . Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion; 1996. 15. Alizadeh Z, Kordi R, Rostami M, Mansournia MA, Hosseinzadeh-Attar SMJ, Fallah J. Comparison between the effects of continuous and intermittent aerobic exercise on weight loss and body fat percentage in overweight and obese women: a randomized controlled trial. Int J Prev Med . 2013;4(8):881 – 888. 16. Asikainen TM, Miilunpalo S, Kukkonen-Harjula K, et al. Walking trials in postmenopausal women: effect of low doses of exercise and exercise fractionization on coronary risk factors. Scand J Med Sci Sports 292. – . 2003;13(5):284 17. Asikainen TM, Miilunpalo S, Oja P, et al. Walking trials in postmenopausal women: effect of one vs two daily bouts on aerobic fitness. Scand J Med Sci Sports . 2002;12(2):99 – 105. 18. Ayabe M, Kumahara H, Morimura K, Sakane N, Ishii K, Tanaka H. Accumulation of short bouts of non- exercise daily physical activity is associated with lower visceral fat in Japanese female adults. Int J Sports Med . 2013;34(1):62 – 67. doi:10.1055/s-0032-1314814. 19. Ayabe M, Kumahara H, Morimura K, Ishii K, Sakane N, Tanaka H. Very short bouts of non-exercise physical activity associated with metabolic syndrome under free-living conditions in Japanese female . 2012;112(10):3525 8. Eur J Appl Physiol – 3532. doi:10.1007/s00 421-012-2342- adults. Cameron N, Godino J, Nichols JF, Wing D, Hill L, Patrick K. Associations between physical activity and 20. BMI, body fatness, and visceral adiposity in overweight or obese Latino and non-Latino adults. Int J Obes (Lond) . 2017;41(6):873 – 877. doi:10.1038/ijo.2017.49. 21. Clarke J, Janssen I. Sporadic and bouted physical activity and the metabolic syndrome in adults. Med Sci Sports Exerc . 2014;46(1):76 – 83. doi:10.1249/MSS.0b013e31829f83a0. 22. Di Blasio A, Bucci I, Ripari P, et al. Lifestyle and high density lipoprotein cholesterol in 47. doi:10.3109/13697137.2012.758700. – . 2014;17(1):37 Climacteric postmenopause. -24 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

143 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Donnelly JE, Jacobsen DJ, Heelan KS, Seip R, Smith S. The effects of 18 months of intermittent vs 23. continuous exercise on aerobic capacity, body weight and composition, and metabolic fitness in previously sedentary, moderately obese females. Int J Obes Relat Metab D is . 2000;4(5):566 – 572. . Eguchi M, Ohta M, Yamato H. The effects of single long and accumulated short bouts of exercise on 24 rkers: a randomized controlled study. Ind Health . cardiovascular risks in male Japanese wo 2013;51(6):563 – 571. 25 . Fan JX, Brown BB, Hanson H, Kowaleski-Jones L, Smith KR, Zick CD. Moderate to vigorous physical 49. activity and weight outcomes: does every minute count? Am J Health Promot . 2013;28(1):41 – doi:10.4278/ajhp.120606-QUAL-286. . Gay JL, Buchner DM, Schmidt MD. Dose-response association of physical activity with HbA1c: 26 intensity and bout length. Prev Med . 2016;86:58 – 63. doi:10.1016/j.ypmed.2016.01.008. 27 . Glazer NL, Lyass A, Esliger DW, et al. Sustained and shorter bouts of physical activity are related to cardiovascular health. Med Sci Sports Exerc . 2013;45(1):109 – 115. doi:10.1249/MSS.0b013e31826beae5. 28 . Jakicic JM, Winters C, Lang W, Wing RR. Effects of intermittent exercise and use of home exercise . equipment on adherence, weight loss, and fitness in overweight women: a randomized trial. JAMA 1560. – 1999;282(16):1554 . Jakicic JM, Wing RR, Butler BA, Robertson RJ. Prescribing exercise in multiple short bouts versus one 29 continuous bout: effects on adherence, cardiorespiratory fitness, and weight loss in overweight women. Int J Obes Relat Metab Disord . 1995;19(12):893 – 901. 30 . Jefferis BJ, Parsons TJ, Sartini C, et al. Does duration of physical activity bouts matter for adiposity and metabolic syndrome? A cross-sectional study of older British men. Int J Behav Nutr Phys Act . 2016;13:36. doi:10.1186/s12966-016-0361- 2. 31. Loprinzi PD, Cardinal BJ. Association between biologic outcomes and objectively measured physical activity accumulated in >/=10-minute bouts and <10-minute bouts. Am J Health Promot . 151. doi:10.4278/ajhp.110916-QUAN-348. 2013;27(3):143 – 32. Murtagh EM, Boreham CA, Nevill A, Hare LG, Murphy MH. The effects of 60 minutes of brisk walking . 2005;41(1):92 – 97. Prev Med per week, accumulated in two different patterns, on cardiovascular risk. doi:10.1016/j.ypmed.2004.10.008. Quinn TJ, Klooster JR, Kenefick RW. Two short, daily activity bouts vs. 33. one long bout: are health and fitness improvements similar over twelve and twenty-four weeks? J Strength Cond Res . 2006;20(1):130 – 135. doi:10.1519/R-16394.1. 34 . Schmidt WD, Biwer CJ, Kalscheuer LK. Effects of long versus short bout exercise on fitness and – weight loss in overweight females. J Am Coll Nutr . 2001;20(5):494 501. 35 . Strath SJ, Holleman RG, Ronis DL, Swartz AM, Richardson CR. Objective physical activity Prev Chronic Dis accumulation in bouts and nonbouts and relation to markers of obesity in U.S. adults. . 2008;5(4):A131. -25 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

144 Part F. Chapter 1. Physical Activity Behaviors: Steps, Bouts, and High Intensity Training Vasankari V, Husu P, Vaha-Ypya H, et al. Association of objectively measured sedentary behaviour 36. and physical activity with cardiovascular disease risk. Eur J Prev Cardiol . 2017;24(12):1311 1318. – doi:10.1177/2047487317711048. 37. White DK, Gabriel KP, Kim Y, Lewis CE, Sternfeld B. Do short spurts of physical activity benefit – cardiovascular health? The CARDIA Study. 2358. Med Science Sports Exerc . 2015;47(11):2353 doi:10.1249/MSS.0000000000000662. 38. Wolff-Hughes DL, Fitzhugh EC, Bassett DR, Churilla JR. Total activity counts and bouted minutes of to-vigorous physical activity: relationships with cardiometabolic biomarkers using 2003 moderate- – 2006 – 700. doi:10.1123/jpah.2013-0463. NHANES. J Phys Act Health . 2015;12(5):694 39. Woolf-May K, Kearney EM, Owen A, Jones DW, Davison RC, Bird SR. The efficacy of accumulated short bouts versus single daily bouts of brisk walking in improving aerobic fitness and blood lipid – profiles. Health Educ Res . 1999;14(6):803 815. 40. Saint-Maurice PF, Troiano RP, Matthews CE, Kraus WE. Moderate- to-vigorous intensity physical J Am Heart Assoc . In press. activity and all-cause mortality: do bouts matter? 41 . Batacan RB Jr, Duncan MJ, Dalbo VJ, Tucker PS, Fenning AS. Effects of high-intensity interval training stematic review and meta-analysis of intervention studies. Br J Sports on cardiometabolic health: a sy . 2017;51(6):494-503. doi:10.1136/bjsports-2015-095841. Med 42 . Jelleyman C, Yates T, O'Donovan G, et al. The effects of high-intensity interval training on glucose regulation and insulin resistance: a meta-analysis. Obes Rev . 2015;16(11):942-961. doi:10.1111/obr.12317. Kessler HS, Sisson SB, Short KR. The potential for high-intensity interval training to reduce 43. . 2012;42(6):489-509. doi:10.2165/11630910-000000000- cardiometabolic disease risk. Sports Med 00000. -26 2018 Physical Activity Guidelines Advisory Committee Scientific Report F1

145 Part F. Chapter 2. S edentary Behavior . CHAPTER 2. SEDENTARY BEHAVIOR PART F Table of Contents F2 Introduction -1 ... F2 -2 Review of the Science ... F2 -2 ... Overview of Questions Addressed ... F2 -3 Data Sources and Process Used to Answer Questions ... Question 1: What is the relationship between sedentary behavior and all-cause mortality? -3 F2 Question 2: What is the relationship between sedentary behavior and cardiovascular disease mortality? F2 -11 ... ... F2 -15 dentary behavior and cancer mortality? Question 3: What is the relationship between se Question 4: What is the relationship between sedentary behavior and (1) type 2 diabetes, (2) weight -18 F2 status, (3) cardiovascular disease, and (4) cancer? ... to-vigorous physical activity on all-cause mortality vary by Question 5. Does the effect of moderate- amount of sedentary behavior? ... F2 -30 Overall Summary, Conclusions, and Public Health Impact ... F2 -33 Needs for Future Research ... F2 -33 References -35 ... F2 INTRODUCTION In general, sedentary behavior refers to any waking behavior characterized by an energy expenditure o f 1 1.5 METs or less while in a sitting, reclining, or lying posture. Most previous physical activity research has focused on the association between higher intensity (i.e., moderate- to-vigorous) physical activity and health outcomes. However, sedentary behavior has received an increasing amount of attention as a public health problem because: 1) it appears to have negative associations with health outcomes, and 2) ata collected by accelerometry in the U.S. ly prevalent behavior in the U.S. population. D it is a high National Health and Nutrition Examination Survey indicate that children and adults spend approximately F2 2018 Physical Activity Guidelines Advisory Committee Scientific Report -1

146 Part F. Chapter 2. S edentary Behavior 2 7.7 hours per day (55% of their monitored time) being sedentary. Thus, the potential population health impact of sedentary behavior is substantial. Given that much of the scientific evidence for an association between sedentary behavior and health has been published after 2008, the 2008 Physical Activity Guidelines Advisory Committee did not systematically assess the effects of sedentary behavior on health outcomes. Since then, a considerable amount of research has been conducted, and the 2018 Physical Activity Guidelines Advisory Committee decided to systematically review this literature to assess the effect of sedentary behavior on health outcomes. The Sedentary Behavior Subcommittee operationalized the definition of sedentary behavior to include self-reported sitting (leisure-time, occupational, total), television (TV) viewing or screen time, and data from objective, device-based assessments (accelerometry or inclinometry). Although these operational definitions do not capture all aspects of the definition of sedentary behavior (i.e., both posture and energy expenditure), they are widely used in the scientific literature as measures of time spent in sedentary behavior. The Subc ommittee examined the relationship between sedentary behavior and major causes of mortality and also assessed the relationship between sedentary behavior and weight status in addition to the incidence of common chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer. In addition to the relationship between the total duration of daily or weekly sedentary behavior and health outcomes, it is of interest to understand the associations between patterns of sedentary behavior, including bouts and breaks, and health outcomes. A bout of sedentary behavior can be operationalized as a period of uninterrupted sedentary time, whereas a break in sedentary behavior can 1 be operationalized as a non-sedentary bout in between two sedentary bouts. The potential health effects associated with sedentary bouts and breaks are also addressed in this chapter. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses five major questions: What is the relationship between sedentary behavior and all-cause mortality? 1. F2 2018 Physical Activity Guidelines Advisory Committee Scientific Report -2

147 Part F. Chapter 2. S edentary Behavior 2. What is the relationship between sedentary behavior and cardiovascular disease mortality? What is the relationship between sedentary behavior and cancer mortality? 3. 4. What is the relationship between sedentary behavior and (1) type 2 diabetes, (2) weight status, (3) cardiovascular disease, and (4) cancer? Does the effect of moderate- to-vigorous physical activity on all-cause mortality vary by amount 5. of sedentary behavior? Questions 1 through 4 each ha ve the following subquestions: a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Is the relationship independent of amounts of light, moderate, or vigorous physical activity? Is there any evidence that bouts or breaks d) in sedentary behavior are important factors? rocess Used to Answer Questions Data Sources and P A single literature search strategy was conducted to answer Questions 1, 2, and 3. Subsets of the resulting body of evidence were used to answer each question or subquestion . The databases searched included PubMed, Cochrane, and CINAHL. The systematic literature search to address Questions 1, 2, and 3 was conducted in three steps. Step 1 involved a search for existing systematic reviews and meta- analyses that could address the question. Step 2 involved reviewing the original research articles contained in the systematic reviews and meta-analyses to identify those that could provide evidence to address the questions, especially the subquestions related to dose-response and variation in the relationship by age, sex, race/ethnicity, socioeconomic status, or weight status. Original research articles contained in the systematic reviews and meta-analysis identified in Step 2 are not included as evidenc e in the evidence portfolio. Step 3 involved a de novo literature search of more recent original research studies published after the systematic reviews and meta-analyses. The systematic literature search to address Question 4 was conducted in two steps. The databases searched included PubMed, Cochrane, and CINAHL. Step 1 involved a search for existing systematic reviews and meta-analyses that could address the question. Step 2 involved a de novo literature search of more recent original research studies published after the systematic reviews and meta-analyses. The evidence used to address Question 5 was obtained from the evidence base compiled for Question 1. Question 1: What is the relationship between sedentary behavior and all-cause mortality? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) F2 2018 Physical Activity Guidelines Advisory Committee Scientific Report -3

148 Part F. Chapter 2. S edentary Behavior b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Is the relationship independent of amounts of light, moderate, or vigorous physical activity? d) Is there any evidence that bouts or breaks in sedentary behavior are important factors? Sources of evidence: Systematic reviews, meta-analyses, original research articles Conclusion Statement s Strong evidence demonstrates a significant relationship between greater time spent in sedentary behavior and higher all-cause mortality rates. PAGAC Grade: Strong. Strong evidence demonstrates the existence of a direct, curvilinear dose-response relationship between sedentary behavior and all-cause mortality, with an increasing slope at higher amounts of sedentary behavior. PAGAC Grade: Strong. Limited evidence suggests that the relationship between sedentary behavior and all-cause mortality does not vary by age, sex/ethnicity, or weight status PAGAC Grade: Limited. . Insufficient evidence is available to determine whether the relationship between sedentary behavior and all-cause mortality varies by socioeconomic status. PAGAC Grade: Not assignable. Strong evidence demonstrates that the relationship between sedentary behavior and all-cause mortality varies by amount of moderate- to-vigorous physical activity. PAGAC Grade: Strong. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and all-cause mortality. PAGAC Grade: Not assignable. Review of the Evidence Sources of evidence included: 1) systematic reviews and meta-analyses published from January 2000 to December 5, 2016, 2) the relevant original research articles cited by the systematic reviews and meta- analyses, and 3) recent original research articles published between January 2014 and January 30, 2017. The search for systematic reviews and meta-analyses returned a total of 201 articles and the titles were reviewed by two members of the Subcommittee. A total of 48 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the Subcommittee. Of these, 16 articles were deemed to be potentially relevant and the full papers were retrieved. A review of the full texts of these papers by two members of the Subcommittee identified F2 2018 Physical Activity Guidelines Advisory Committee Scientific Report -4

149 Part F. Chapter 2. S edentary Behavior nine systematic reviews and meta-analyses that addressed Question 1 (Supplementary Table S-F2-1). These 9 systematic reviews included information on 25 original research articles that included all-cause 3 mortality as an outcome. After excluding one study in breast cancer survivors, one study of 4 occupational sitting and physical activity that included a mix of sitting and physical activity exposures, 5 one study that only presented data on changes in sitting time, and two studies that presented only 6, 7 Sub baseline descriptions of cohorts, the committee was able to identify 20 original articles that addressed Question 1 (Supplementary Table S-F2-2 ). The de novo literature search of original research studies returned a total of 1,214 articles and the titles were reviewed by two members of the Subcommittee. A total of 62 articles were deemed potentially relevant based on the title search, and the abstracts of these papers were reviewed by two members of the Subcommittee. Of these, 38 articles were deemed to be potentially relevant and the full papers were retrieved. A review of the full texts of these papers by two members of the Subcommittee 8- 10 identified in identified 30 original studies that addressed Question 1. Note that three of the papers the search for original articles were duplicates of those identified from the systematic reviews and meta- analyses and they appear only in Supplementary Table S-F2-2. Supplementary Table S-F2-3 presents the 27 new original studies that address Question 1. Evidence on the Overall Relationship 19 11- A total of nine systematic reviews and meta-analyses that reviewed a total of 20 original studies have addressed the relationship between sedentary behavior and all-cause mortality, and they provide strong evidence demonstrating a significant relationship. The number of studies that addressed all-cause mortality encompassed by each of the reviews ranges from 3 to 16, with newer reviews reporting on a 18 greater number of studies as they appear in the literature. The meta-analysis of Biswas et al analyzed 14 prospective cohort studies and reported a hazard ratio of 1.22 (95% confidence interval (CI): 1.09- 1.41) for the relationship between sedentary behavior and all-cause mortality. The available studies represent several population cohorts that apply broadly to the U.S. population and the results are consistent in direction and the size of the effect. Based on the review of the more recent original research articles, 9 of 10 studies found a significant relationship between self-reported total or leisure sitting time and all-cause mortality, 3 out of 5 studies of TV viewing or screen time found a significant relationship between TV viewing or screen time and all- F2 2018 Physical Activity Guidelines Advisory Committee Scientific Report -5

150 Part F. Chapter 2. S edentary Behavior cause mortality, and 0 out of 2 studies found a significant relationship between occupational sitting time and all-cause mortality. Thirteen studies have reported on relationships between device-based objectively measured sedentary behavior (using accelerometry) and all-cause mortality. Of these, 11 studies relied on data from the National Health and Nutrition Examination Survey (NHANES). Although the analytical strategies differed, 10 of the 13 studies reported a significant relationship (1 in men only) between sedentary time and all- cause mortality (8 out of the 11 NHANES studies). Among the 3 NHANES studies that did not find a 20 significant relationship, one stratified their analysis by level of visual acuity, one compared risk for 21 below-median to above-median sedentary time, and the third compared risk across quartiles of 22 sedentary time. The 8 NHANES studies that reported a significant association between sedentary behavior and all-cause mortality used a variety of analysis strategies, including comparisons of quartiles 23 24 of sedentary behavior, comparing above-median to below-median sedentary time, continuous 28- 27 30 26 25, variable analysis, and isotemporal substitution analy sis. latent class analysis, Given the confines of the 24-hour period, interest is increasing in understanding inter-relationships among time spent in different aspects of daily living, such as sleep, sedentary behavior, and light-, moderate-, and vigorous-intensity physical activity, with outcomes such as all-cause mortality. To this end, several studies have used isotemporal substitution analyses to model the effects of replacing time spent in sedentary behavior with time spent in other behaviors such as standing, light-intensity activity, 28 -33 moderate- to-vigorous physical activity, or exercise. The results invariably show a reduction in mortality risk when sedentary behavior is replaced with higher intensity activities. Models in which an a equivalent duration of sedentary behavior is replaced with light-intensity physical activity predict reduction in mortality, and models in which sedentary behavior is replaced with moderate- or vigorous- intensity physical activity predict an even greater reduction in mortality. Because the models are “isotemporal , ” it cannot be determined whether the i ncrease in predicted benefit is due to the higher intensity of the physical activity per se or the higher volume of energy expended. Dose-response: Strong evidence also demonstrates the existence of a dose-response relationship between sedentary behavior and all-cause mortality. Two meta-analyses were used to provide evidence 15 17 for dose-response relationships between daily sitting or TV viewing, and all-cause mortality. Chau et 15 found that a spline model of best fit had hazard ratios of 1.00 (95% CI: 0.98-1.03), 1.02 (95% CI: 0.99- al 1.05) and 1.05 (95% CI: 1.02-1.08) for every 1-hour increase in daily sitting time in intervals between 0 to F2 -6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

151 Part F. Chapter 2. S edentary Behavior 3, more than 3 to 7, and more than 7 hours per day total sitting, respectively. Thus, the dose-response curve was curvilinear, and the slope of the relationship increased beyond 7 hours per day of sitting. 17 Similarly, Sun et al reported that TV viewing time was statistically significantly associated with all-cause mortality risk in a curvilinear, direct fashion that increases steadily and more rapidly as length of 17 =0.001). exposure increases ( P nonlinearity Of the 47 original studies identified through the systematic reviews and meta-analyses and the de novo search, 29 tested for the existence of a dose-response relationship, and 24 studies found a significant dose-response relationship. Figure F2-1 presents the dose-response curves from studies of self-reported sitting (Panel A) and TV viewing (Panel B) that included at least three amounts of sedentary behavior as 17 15, the exposure. The pattern of results generally mirrors those of the two previous meta-analyses, with increasing risk at higher amounts of sedentary behavior following a curvilinear relationship. Figure F2-1. Dose-Response Curves Showing Relationship Between Sedentary Behavior and All-Cause Mortality Note: The figure shows the reported hazard ratio for each category of sitting with the lowest category of sitting assigned as the referent at zero on the X-axis and the highest value assigned at 100. The original categories of -7 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

152 Part F. Chapter 2. S edentary Behavior sitting from the studies (tertiles, quartiles, quintiles, etc.) have been rescaled from 0 to 100 using an ordinal scale. For example, for a study with three categoires, the points were plotted at 0, 50 and 100. 35 34 10 2009 P etersen et al., 2014, Patel et al., 2010, Seguin et , Source: Adapted from data found in Katzmarzyk et al., 36 39 38 37 9 , 2015, Pavey et al. Matthews et al., 2012, 2016, van de Ploeg et al., 201 2, al., 2014, Warren Andersen et al., 42 41 8 43 40 Chau et al., 2015, Pulsford et al., 2015, Kim et al., 2013, and Martinez-Gomez et al., 2016. Inoue et al., 2008, Note: The figure shows the reported hazard ratio for each category of TV viewing with the lowest category of TV viewing assigned as the referent at zero on the X-axis and the highest value assigned at 100. The original categories of TV viewing from the studies (tertiles, quartiles, quintiles, etc.) have been rescaled from 0 to 100 using an ordinal scale. For example, for a study with three categoires, the points were plotted at 0, 50 and 100. 38 44 32 Source: Adapted from data found in Dunstan et al., 2010, Stamatakis et al., 2011, Matthews et al., 2012, 46 45 8 47 41 Basterra-Gortari et al., 2014, and Keadle Kim et al., 2013, Chau et al., 2015, Shuval et al., 2015, Ford, 2012, 48 et al., 2015. F2 -8 2018 Physical Activity Guidelines Advisory Committee Scientific Report

153 Part F. Chapter 2. S edentary Behavior Evidence on Specific Factors Demographic factors and weight status: Limited evidence suggests that the relationship between sedentary behavior and all-cause mortality does not vary by age, sex, race/ethnicity, or weight status. Available evidence is insufficient to determine whether the relationship between sedentary behavior and all-cause mortality varies by socioeconomic status. In general, studies reported no significant effect 35, 36 , 44 , 49 , 50 31, , 49 35 , 44 , 49 , 44 35, 36 or weight status, modification by age, and stratified analyses sex, gen erally , 41 , 38 37 , 51 28, 38, 39 , 41 , 49 , 49 28, 34 , 37 , 39 , 41 sex, race/ethnicity, and weight showed similar results across age, 38 , 41 28, 34 , 35, , 49 , 39 status, with varying levels of significance . In general, data are lacking on the variation in the observed associations by level of socioeconomic status. The available evidence suggests that the observed relationship between sedentary behavior and all-cause mortality applies broadly to the general adult population of the United States. Strong evidence demonstrates that the relationship between sedentary Amount of physical activity: behavior and all-cause mortality varies by the amount of moderate- to-vigorous physical activity. The effect of sedentary behavior on all-cause mortality is stronger among people who have low amounts of 18 moderate- to-vigorous physical activity. For example, in the meta-analysis of Biswas et al the risk of all- cause mortality was 1.16 (95% CI: 0.84-1.56) among those with high physical activity and 1.46 (95% CI: 19 conducted a harmonized 1.22-1.75) among those with low physical activity. Further, Ekelund et al meta-analysis using individual-level data from more than 1 million adults and reported that increasingly higher amounts of moderate- to-vigorous physical activity attenuated the relationship between sedentary behavior and all-cause mortality (Figure F2-2), and the relationship between self-reported sitting and mortality was not significant among those who reported participating in at least moderate- intensity physical activity for 60 to 75 minutes per day. Similar results were observed for TV viewing, although high amounts of physical activity did not completely attenuate the relationship between TV viewing and all-cause mortality. Evidence is insufficient to determine whether the association between sedentary behavior and all-cause mortality varies by level of light- or vigorous-intensity activity. F2 -9 2018 Physical Activity Guidelines Advisory Committee Scientific Report

154 Part F. Chapter 2. S edentary Behavior Figure F2-2. Relationship Between Sitting and All-Cause Mortality, Stratified by Amount of Moderate- to-Vigorous Physical Activity 19 Source: Adapted from data found in Ekelund et al., 2016. Insufficient evidence is available to determine whether bouts or breaks in sedentary Bouts and breaks: behavior are important factors in the relationship between sedentary behavior and all-cause mortality. Only one study was identified that included bouts of sedentary behavior in their definition of the 27 defined sedentary bouts as 30 or exposure. Using accelerometry data from NHANES, Evenson et al more minutes with at least 80 percent of the minutes falling below 100 counts per minute, allowing for less than 5 consecutive minutes above the threshold. Based on latent class analysis, the class with the highest percentage of the day in sedentary bouts had a higher risk of all-cause mortality compared to )=2.10; 95% CI: 1.11-3.97). However, further the class with fewer sedentary bouts (hazard ratio ( HR research is required to replicate these results. No studies were identified that examined the associations between breaks in sedentary behavior and all-cause mortality. Thus, a grade was not assignable for this question. -10 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

155 Part F. Chapter 2. S edentary Behavior For additional details on this body of evidence, visit: Supplementary Tables S-F2-1, S-F2-2, and S-F2- 3 for the and https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx Evidence Portfolio. Question 2: What is the relationship between sedentary behavior and cardiovascular disease mortality? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Is the relationship independent of amounts of light, moderate, or vigorous physical activity? Is there any evidence that bouts or breaks in sedentary behavior are important factors? d) Systematic reviews, meta-analyses, original research articles Sources of evidence: Conclusion Statements Strong evidence demonstrates a significant relationship between greater time spent in sedentary behavior and higher mortality rates from cardiovascular disease . PAGAC Grade: Strong. Strong evidence demonstrates the existence of a direct, positive dose-response relationship between sedentary behavior and mortality from cardiovascular disease. PAGAC Grade: Strong. Limited evidence suggests that the relationship between sedentary behavior and cardiovascular disease mortality does not vary by age, sex, race/ethnicity, or weight status. PAGAC Grade: Limited. Insufficient evidence is available to determine whether the relationship between sedentary behavior and mortality from cardiovascular disease varies by socioeconomic status. PAGAC Grade: Not assignable . Moderate evidence indicates that the relationship between sedentary behavior and mortality from cardiovascular disease varies by amount of moderate- to-vigorous physical activity. PAGAC Grade: Moderate. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and mortality from cardiovascular disease PAGAC Grade: Not assignable. . -11 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

156 Part F. Chapter 2. S edentary Behavior Review of the Evidence Sources of evidence included: 1) systematic reviews and meta-analyses published from January 2000 to December 5, 2016, 2) the relevant original research articles cited by the systematic reviews and meta- analyses, and 3) recent original research articles published between January 2014 and January 30, 2017. The search for systematic reviews and meta-analyses returned a total of 201 articles and the titles were reviewed by two members of the Subcommittee. A total of 48 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the Subcommittee. Of these, 16 articles were deemed to be potentially relevant and the full papers were Sub retrieved. A review of the full texts of these papers by two members of the committee identified five systematic reviews and meta-analyses that addressed Question 2 (Supplementary Table S-F2- 4). These 5 systematic reviews and meta-analyses included information on 12 original research articles that included cardiovascular disease mortality as an outcome. After excluding one study that presented only 7 11 original articles addressed Question 2 (Supplementary Table S-F2- a baseline description of a cohort, 5). The de novo literature search of original research studies returned a total of 1,214 articles and the titles were reviewed by two members of the Sub committee. A total of 62 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the Sub committee. Of these, 38 articles were deemed to be potentially relevant and the full papers were retrieved. A review of the full texts of these papers by two members of the Subcommittee identified seven original studies that addressed Question 2 (Supplementary Table S-F2-6). Evidence on the Overall Relationship A total of 5 systematic reviews and meta-analyses that reviewed 11 original studies have addressed the relationship between sedentary behavior and cardiovascular disease mortality, and they provide strong evidence demonstrating a significant relationship between sedentary behavior and cardiovascular 18 disease mortality. The meta-analysis of Biswas et al analyzed seven prospective cohort studies and reported a hazard ratio of 1.15 (95% CI: 1.11-1.20) for the relationship between sedentary behavior and 14 reported a relative risk of cardiovascular disease mortality. Further, a meta-analysis by Wi lmot et al 1.90 (95% CI: 1.36-2.66) for the relationship between sedentary behavior and cardiovascular disease mortality. Both meta-analyses reported a statistically significant summary risk estimate. However, the magnitude of the effect was quite different. The main reasons for the difference in the summary hazard -12 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

157 Part F. Chapter 2. S edentary Behavior ratios between these two meta-analyses relate to the selection of studies included in each review and differences in the exposure categories and types of sedentary behavior among the included studies. A total of 18 original studies were identified through the meta-analyses and systematic reviews (N=11) and the de novo search (N=7). Nine studies reported on the association with sitting or total sedentary time, eight reported on the association with TV or screen time, and three studies used device-based measures of sedentary time (accelerometry or arm band). A total of 13 of these 18 studies found a significant positive relationship between sedentary time and cardiovascular disease mortality. The available studies represent several population cohorts that apply broadly to the U.S. population and the results are consistent in direction and the size of the effect. Dose-response: Strong evidence also demonstrates the existence of a dose-response association between sedentary behavior and cardiovascular disease mortality. Seventeen original research studies tested for the existence of a dose-response association, and 10 reported a significant association. Except 52 for one study of TV viewing among Japanese adults, the studies that did not detect a significant dose- 22, 28 , 46 , 50 , 53 , 54 The results of the pooled analysis response association had small sample sizes (N< 10,000). 19 demonstrated that the associations among sedentary of 11 prospective cohort studies by Ekelund et al behavior, moderate- to-vigorous physical activity, and cardiovascular disease mortality were similar to those observed for all-cause mortality. Figure F2-3 presents the dose-response associations between to-vigorous sedentary time and cardiovascular disease mortality, stratified by amount of moderate- 19 physical activity. -13 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

158 Part F. Chapter 2. S edentary Behavior Figure F2-3. Relationship Between Sitting and Cardiovascular Disease Mortality, Stratified by Amount of Moderate- to-Vigorous Physical Activity 19 Source: Adapted from data found in Ekelund et al, 2016. Evidence on Specific Factors Demographic factors and weight status: Limited evidence suggests that the relationship between sedentary behavior and cardiovascular disease mortality does not vary by age, sex, race/ethnicity or 34 , 36 , 44 , 49 weight status. Among the available studies that tested for interaction effects, no significant 36 44 , 49 44 , 49 36, 36, , 49 , 44 34 , 36 sex, race/ethnicity, effect modification was observed for age, or weight status. In general, data are lacking on variation in the observed associations by level of socioeconomic status. The available evidence suggests that the observed relationship between sedentary behavior and mortality from cardiovascular disease applies broadly to the general adult population of the United States. Amount of physical activity: Moderate evidence suggests that the relationship between sedentary behavior and cardiovascular disease mortality varies by amount of moderate- to-vigorous physical activity. Several individual studies reported the interaction between sedentary behavior and physical 19 activity was not significant. However, the meta-analysis of Ekelund et al provided convincing evidence F2 -14 2018 Physical Activity Guidelines Advisory Committee Scientific Report

159 Part F. Chapter 2. S edentary Behavior that the association between sedentary time and cardiovascular disease mortality was influenced by moderate- to-vigorous physical activity. Some of the individual studies may have been underpowered to detect significant interaction effects, whereas the pooled analysis overcomes this limitation. Figure F2- 3 presents the relationship between sedentary behavior and mortality rates from cardiovascular disease, 19 to-vigorous physical activity. The strongest association between stratified by amount of moderate- sitting and cardiovascular disease mortality is observed among those who are physically inactive (moderate- to-vigorous physical activity ≤ 2.5 MET-hours per week), and the slope of the association diminishes across increasing categories of moderate- to-vigorous physical activity. Evidence is insufficient to determine whether the association between sedentary behavior and cardiovascular disease mortality varies by amount of light- or vigorous-intensity activity. Bouts and breaks: Insufficient evidence is available that bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and mortality from cardiovascular disease. No studies were identified that examined the relationship between breaks and/or bouts of sedentary behavior and mortality rates from cardiovascular disease. , S-F2-5, and S-F2-6 S-F2-4 es For additional details on this body of evidence, visit: Supplementary Tabl and for the https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx Evidence Portfolio. Question 3: What is the relationship between sedentary behavior and cancer mortality? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Is the relationship independent of amounts of light, moderate, or vigorous physical activity? Is there any evidence that bouts or breaks in sedentary behavior are important factors? d) Sources of evidence: Systematic reviews, meta-analyses, original research articles Conclusion Statements Limited evidence suggests a direct relationship between greater time spent in sedentary behavior and higher mortality rates from cancer. PAGAC Grade: Limited. Limited evidence suggests the existence of a direct, positive dose-response relationship between PAGAC Grade: Limited. sedentary behavior and mortality from cancer. -15 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

160 Part F. Chapter 2. S edentary Behavior Insufficient evidence is available to determine whether the relationship between sedentary behavior and cancer mortality varies by age, sex, race/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between sedentary behavior PAGAC Grade: and mortality from cancer varies by amount of moderate- to-vigorous physical activity. Not assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and mortality from cancer. PAGAC Grade: Not assignable. Review of the Evidence Sources of evidence included: 1) systematic reviews and meta-analyses published from January 2000 to December 5, 2016, 2) the relevant original research articles cited by the systematic reviews and meta- analyses, and 3) recent original research articles published between January 2014 and January 30, 2017. The search for systematic reviews and meta-analyses returned a total of 201 articles and the titles were Sub reviewed by two members of the committee. A total of 48 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the Sub committee. Of these, 16 articles were deemed to be potentially relevant and the full papers were committee identified five retrieved. A review of the full texts of these papers by two members of the Sub systematic reviews and meta-analyses that addressed Question 3 (Supplementary Table S-F2-7). These 5 systematic reviews included information on 10 original research articles that included cancer mortality 55 as an outcome. After excluding one study in colorectal cancer survivors and one study that presented a 7 baseline description of a cohort, Question 3 (Supplementary Table S- ed eight original articles address F2-8). The de novo literature search of original research studies returned a total of 1,214 articles and the titles Sub were reviewed by two members of the committee. A total of 62 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of committee. Of these, 38 articles were deemed to be potentially relevant and the full papers Sub the of the full texts of these papers by two members of the Subcommittee were retrieved. A review identified five original studies that addressed Question 3 (Supplementary Table S-F2-9). -16 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

161 Part F. Chapter 2. S edentary Behavior Evidence on the Overall Relationship The five systematic reviews/meta-analyses suggest that only a weak association exists between sedentary behavior and all-cancer mortality. For example, the meta-analysis of eight studies by Biswas 18 . A total of 13 original research reported a summary hazard ratio of 1.13 (95% CI: 1.05-1.21) et al studies were identified that addressed the association between sedentary behavior and cancer mortality. Five of the 13 studies reported a significant association, and the results were not always consistent (one in women only; one for TV viewing but not sitting; one in current smokers only). Cancer is a heterogeneous disease, and the major risk factors differ by cancer site. Further, associations between specific risk factors and cancer mortality are affected by cancer screening and treatment availability and efficacy. A limitation of most studies of sedentary behavior and cancer mortality is a failure to take these factors into account. Dose-response: Limited evidence suggests the existence of a dose-response association between sedentary behavior and cancer mortality. Thirteen original research studies tested for the existence of a dose-response association, and five reported a significant dose-response association in the total sample or in one or more subgroups. Evidence on Specific Factors Demographic factors and weight status: Insufficient evidence is available to determine whether the relationship between sedentary behavior and cancer mortality varies by age, sex, race/ethnicity, socioeconomic status, or weight status. Of the five studies that reported a significant association , 53 35 , 36 , 38 , 56 between sedentary behavior and cancer mortality, only one tested for effect modification, 36 and the results indicated no significant interactions wit h body mass index (BMI) and race/ethnicity. The study showed a significant interaction with age, with a significant association observed in women 70 to 79 years. However, this finding needs to be replicated ages 50 to 69 years but not in women ages in other studies before any definitive statements can be made about the effects of age on the observed associations. In general, data on variations in the observed associations by level of socioeconomic status are lacking . Amount of physical activity: Insufficient evidence is available to determine whether the relationship between sedentary behavior and cancer mortality is modified by physical activity. The pooled meta- 19 did not specifically test for an interaction between sedentary behavior and analysis by Ekelund et al moderate- to-vigorous physical activity on cancer mortality, and there did not appear to be a relationship -17 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

162 Part F. Chapter 2. S edentary Behavior between sedentary behavior (either sitting or TV time) and cancer mortality within quartiles of 36 moderate- to-vigorous physical activity. Further, the study by Seguin et al reported no significant interaction between sedentary time and physical activity ( P =0.51) . Evidence is insufficient to determine whether the association between sedentary behavior and mortality from cancer varies by amount of light or vigorous activity. Bouts and breaks: Available evidence is insufficient to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and mortality from cancer. No studies were identified that examined the relationship between breaks and/or bouts of sedentary behavior and mortality rates from cancer. For additional details on this body of evidence, visit: Supplementary Tables S-F2-7, S-F2-8, and S-F2- 9 https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx and for the Evidence Portfolios. For information on the relationship of physical activity and cancer, see Part F. Chapter 4: Cancer Prevention. Question 4: What is the relationship between sedentary behavior and (1) type 2 diabetes, (2) weight status, (3) cardiovascular disease, and (4) cancer? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Is the relationship independent of amounts of light, moderate, or vigorous physical activity? Is there any evidence that bouts or breaks in sedentary behavior are important factors? d) Sources of evidence: Systematic reviews, meta-analyses, original research articles Conclusion Statements Type 2 Diabetes Strong evidence demonstrates a significant relationship between greater time spent in sedentary behavior and higher risk of type 2 diabetes. PAGAC Grade: Strong. Limited evidence suggests the existence of a direct, graded dose-response relationship between PAGAC Grade: Limited. sedentary behavior and risk of type 2 diabetes. Insufficient evidence is available to determine whether the relationship between sedentary behavior PAGAC Grade: and type 2 diabetes varies by age, sex/ethnicity, socioeconomic status, or weight status. Not assignable. -18 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

163 Part F. Chapter 2. S edentary Behavior Insufficient evidence is available to determine whether the relationship between sedentary behavior PAGAC Grade: Not and type 2 diabetes varies by amount of moderate- to-vigorous physical activity. assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incidence of type 2 diabetes. PAGAC Grade: Not assignable. Weight Status Limited evidence suggests a positive relationship between greater time spent in sedentary behavior and higher levels of adiposity and indicators of weight status. PAGAC Grade: Limited. Limited evidence suggests the existence of a direct, graded dose-response relationship between greater sedentary behavior and higher levels of adiposity and indicators of weight status. PAGAC Grade: Limited. Insufficient evidence is available to determine whether the relationship between sedentary behavior and weight status varies by age, sex/ethnicity, socioeconomic status, or baseline weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between sedentary behavior PAGAC Grade: Not and weight status varies by amount of moderate- to-vigorous physical activity. assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and weight status. PAGAC Grade: Not assignable. Cardiovascular Disease Strong evidence demonstrates a significant relationship between greater time spent in sedentary PAGAC Grade: Strong. behavior and higher risk of incident cardiovascular disease. Strong evidence demonstrates the existence of a direct, graded dose-response relationship between sedentary behavior and risk of incident cardiovascular disease. PAGAC Grade: Strong. -19 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

164 Part F. Chapter 2. S edentary Behavior Insufficient evidence is available to determine whether the relationship between sedentary behavior and incident cardiovascular disease varies by age, sex/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between sedentary behavior to-vigorous physical activity. PAGAC and incident cardiovascular disease varies by amount of moderate- Gr ade: Not assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incidence of cardiovascular disease. PAGAC Grade: Not assignable. ncer Ca Moderate evidence indicates a significant relationship between greater time spent in sedentary PAGAC Grade: Moderate. behavior and higher risk of incident endometrial, colon, and lung cancers. Limited evidence suggests the existence of a direct dose-response relationship between sedentary behavior and incident endometrial, colon, and lung cancers. PAGAC Grade: Limited. Insufficient evidence is available to determine whether the relationship between sedentary behavior and incident cancer varies by age, sex/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between sedentary behavior and incident cancer varies by amount of moderate- to-vigorous physical activity. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incident cancer. PAGAC Grade: Not assignable. Review of the Evidence Sources of evidence included: 1) systematic reviews and meta-analyses published from January 2000 to February 21, 2017, and 2) recent original research articles published between January 2014 and April 25, 2017. -20 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

165 Part F. Chapter 2. S edentary Behavior The systematic literature search to address Question 4 was conducted in two steps. Step 1 involved a search for existing systematic reviews and meta-analyses that could address the question. The search strategy (from January 1, 2000 to February 21, 2017 returned a total of 201 articles and the titles were reviewed by two members of the Sub committee. A total of 48 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the committee. Of these, 22 articles were deemed to be potentially relevant and the full papers were Sub retrieved. A review of the full texts of these papers by two members of the Sub committee identified 11 systematic reviews and meta-analyses that addressed Question 4 (five for type 2 diabetes, two for weight status, five for cardiovascular disease, and eight for cancer) (Supplementary Table S-F2- 10 ). Step 2 involved a de novo literature search of original research studies published between January 1, 2014, and April 25, 2017. The search strategy returned a total of 1,877 articles and the titles were reviewed by two members of the Sub committee. A total of 200 articles were deemed potentially relevant based on the title search and the abstracts of these papers were reviewed by two members of the Sub committee. Of these, 44 articles were deemed to be potentially relevant and the full papers were retrieved. A review the full texts of these papers by two members of the Sub committee identified 34 original studies that addressed Question 4 (Supplementary Table S-F2- 11 ). Type 2 Diabetes Evidence on the Overall Relationship 14 11, , 13 , 18 12 Two systematic reviews addressed the issue of sedentary behavior and three meta-analyses and the incidence of type 2 diabetes (Supplementary Table S-F2- 10 ). All three meta-analyses reported significant pooled estimates of risk for incident type 2 diabetes associated with sedentary behavior. The pooled relative risk per 2 hours of TV viewing per day was 1.20 (95% CI: 1.14-1.27) among four original 11 papers analyzed by Grontved and Hu. The summary relative risk (from five cross-sectional and five 14 prospective studies) for type 2 diabetes reported by Wilmot et al was 2.12 (95% CI: 1.61-2.78) for highest versus lowest sedentary time. Finally, the summary hazard ratio for type 2 diabetes was 1.91 18 (95% CI: 1. Biswas et al. 64-2.22) from five studies analyzed by Eight original research articles were retrieved from the de novo literature search for incident type 2 57- , 61 64 , 59 57 Three diabetes (Supplementary Table S-F2-11). of the eight studies reported significant effects of higher sedentary behavior and greater risk of type 2 diabetes from fully adjusted models. An 58 , 64 , 62 reported significant effects of sedentary behavior on risk of type 2 additional three studies 2018 Physical Activity Guidelines Advisory Committee Scientific Report -21 F2

166 Part F. Chapter 2. S edentary Behavior diabetes in minimally adjusted models (e.g., age, sex) but the effects were attenuated to the null when additional covariates, including BMI, were added to the models. These results are supported by the 11 meta-analysis of Grontved and Hu who reported a that pooled relative risk per 2 hours of TV viewing per day on risk of type 2 diabetes was 1.20 (95% CI: 1.14-1.27), which was reduced to a relative risk of 1.13 (95% CI: 1.08-1.18) when the relative risk was calculated from models that included BMI or another obesity measure. These results suggest that BMI may be on the causal pathway between sedentary behavior and increased risk of type 2 diabetes. In other words, the effects of sedentary behavior on risk of type 2 diabetes may be operating, in part, through its association with BMI. Dose-response: Limited evidence suggests a graded, positive association between sedentary behavior 11 reported a significant, positive and incident type 2 diabetes. The meta-analysis of Grontved and Hu 57, 61 of four linear dose-response association between TV viewing and type 2 diabetes. Further, two 57 , 58 , 60, 61 original research studies that tested for linear dose-response associations reported a significant finding. Evidence on Specific Factors Available evidence is insufficient to determine whether the Demographic factors and weight status: relationship between sedentary behavior and incident type 2 diabetes varies by age, sex, race/ethnicity, nd socioeconomic status, or weight status. A single study stratified the analysis by race/ethnicity a reported a significant graded association only among Non-Hispanic Whites and not in Chinese 61 Two studies reported a significant interaction Americans, African Americans, or Hispanic Americans. 57, 62 between sedentary behavior and BMI on risk of diabetes, with significant effects of sedentary 64 behavior observed only among individuals with obesity. On the other hand, a single study reported no significant interaction between sedentary behavior and BMI on risk of diabetes ( P =0.65). Amount of physical activity: Insufficient evidence is available to determine whether the relationship to-vigorous between sedentary behavior and incident type 2 diabetes varies by amount of moderate- physical activity. Four of the original research studies considered the potential interactions between , 62 57 57, 58 , 64 Manini et al sedentary behavior and physical activity on incident type 2 diabetes. reported significant effects of daily sitting on incident type 2 diabetes among people with different amounts of 58 Smith and Hamer reported that physical activity (all P -values for trends <0.01). On the other hand, active participants who reported high TV viewing were not at elevated risk of type 2 diabetes, in comparison to inactive participants who reported high TV viewing, who were at significantly elevated -22 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

167 Part F. Chapter 2. S edentary Behavior 62 risk. Petersen et al reported a non-significant interaction between sitting time and moderate- to- vigorous physical activity ( P =0.68). However, the association between sitting time and incident type 2 64 diabetes was only significant in those who were inactive. Asvold et al reported a significant interaction between daily sitting time and leisure-time physical activity ( P =0.01), with a significant effect observed only in inactive participants. Thus, the evidence from these four studies is not consistent . Bouts and breaks: Insufficient evidence is available that bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incident type 2 diabetes. No studies were identified that addressed this topic. Weight Status Evidence on the Overall Relationship , 13 12 Two systematic reviews each reviewed 10 original research studies and concluded that evidence was insufficient or limited, respectively, that sedentary behavior was related to changes in body weight or other indicators of weight status, such as BMI, waist circumference, body fat, or overweight (BMI ≥25 2 2 nal research articles kg/m ) or obesity (BMI ≥30 kg/m ) (Supplementary Table S-F2-10). Fourteen origi 65- 78 (Supplementary Table S-F2-11) that were identified that were published between 2014 and 2017 ators of adiposity or weight status. explored associations between sedentary behavior and indic original studies, 11 reported a significant positive association between at least one sedentary Of the 14 67, -78 68 , 70 behavior and at least one indicator of adiposity or weight status, whereas three studies , 69 , 66 65 reported no significant results. However, the relationships observed among the studies that reported significant effects showed considerable heterogeneity. For example, among adults in the United Kingdom, the relationship between TV viewing and incident abdominal obesity (high waist 72 circumference) was significant, but the relationship with incident obesity (high BMI) was not. Among Swedish adults followed for 5 years, the association between computer gaming and incident overweight 73 Among Finnish adults, the association between screen time was significant in women, but not in men. and 6-year weight change was significant in men ages 30 to 39 years to 27 years but not in men ages 24 74 76 reported that occupational sitting tim e was associated with changes in waist or in women. Saidj et al circumference over 5 years, but not with changes in BMI. In the same study, the authors found no 76 Finally, among Chinese association between leisure-time sitting and either BMI or waist circumference. adults, the relationship between daily sedentary time and the incidence of obesity was significant in -23 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

168 Part F. Chapter 2. S edentary Behavior 78 men but not in women. However, the association with weight change per se was significant in both men and women. Several indicators of adiposity and weight status have been employed as outcomes in the available studies. Many studies included multiple analyses of subgroups (e.g., in men, in women, and total 71 70, 78 65, 70 , 71 , 74 , 78 , 74, for body sample). Significant results were reported in five out of seven analyses -77 67, , 73 , 75 67, 68 , 73 , 75, 76 68 67, 68 , 77 65, 67 -69, 71 , 75 ou t of 10 analyses f or BMI weight; four for out of nine analyses ; 3 71 75 71, 75 for fat mass; one out of two analyses for percent waist circumference; one out of one analysis 71 , 73 , 78 , 72 71 66 73, 78 out of 10 analyses for fat mass index; 2 for incident body fat; one out of one analysis 72 for incident central obesity (high waist overweight or obesity; and one out of one analysis circumference) . The results for weight status differed by the exposure variable used to measure sedentary behavior . However, some significant results were reported regardless of the exposure variable used. For example, 71 out of two significant results were reported for one or more of the indicators of weight status in one 71 69, in studies that used accelerometry to measu analyses re sedentary time; significant results were 76, 78 , 78 65, 66 , 76 reported for one or more of the indicators of weight status in three out of six analyses in studies that relied on self-reported measures of sitting time or total sedentary time; and significant 67- , 77 67, 68 , 70 , 72 -74 results were reported for one or more indicators of weight status for 8 out of 10 analyses , 72 77 -75, 70 in studies that used TV viewing or screen time as the exposure. The associations between measures of sedentary behavior and indicators of adiposity are complex. For example, four studies explored the existence of a reciprocal relationship between sedentary behavior 67, , 75, 76 71 d weight status an — i.e ., does weight status at baseline predict changes in sedentary behavior? 71, 67 75 , 76 67 Three of the four studies reported significant reciprocal effects and one did not. Helajarvi et al reported that consistently low TV viewing was associated with a smaller increase in BMI and waist circumference over approximately 10 years of follow-up in young Finnish adults, with no evidence of a 75 reciprocal relationship. On the other hand, Menai et al also reported a significant association between increased TV viewing over follow-up and increases in BMI and percent fat. However, a reciprocal relationship also was observed, with positive associations between baseline BMI, percent fat, and waist circumference and increases in TV viewing. Positive associations between accelerometer-determined increases in weight, fat mass, and fat mass index were observed among U.K. adults, nd sedentary time a and significant positive associations also were seen between the obesity indicators at baseline and -24 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

169 Part F. Chapter 2. S edentary Behavior 71 increases in sedentary time over follow- up. Similarly, association between baseline leisure-time sitting and changes in BMI or waist circumference was seen over 5 years of follow-up in Danish adults . However, higher BMI and waist circumference were both positively associated with greater increases in 76 P <0.0001). leisure-time sitting ( Dose-response: The issue of dose-response was addressed in 12 of the original research studies, mainly by testing for linear associations in regression models, or testing for linear trends across categorical 77 65- 72 , 74- exposures. A statistically significant linear dose-response associatio 12 n was observed in 9 of the , 70 67, 68 -72 77 , 74- studies for at least one subgroup for one of the weight-related outcomes. Evidence on Specific Factors Insufficient evidence is available to determine whether age, Demographic factors and weight status: sex, race/ethnicity, or baseline weight status are important factors in the relationship between sedentary behavior and weight status. Insufficient evidence is available to determine whether the association Amount of physical activity: to-vigorous physical between sedentary behavior and weight status varies by amount of moderate- 77 found no significant interaction between change in moderate- to-vigorous Shibata et al activity. physical activity and change in TV viewing on 12-year changes in waist circumference among Australian 66 adults. Although found no main effect of leisure- Bell et al time sitting on incident obesity in the study of U.K. adults, a significant interaction between sitting time and physical activity was seen at a 5-year =0.37) follow-up. At the 5-year follow- ( P =0.02) but not at a 10 -year ( P up, the combination of high physical activity and low sedentary time was associated with an odds ratio of 0.26 (95% CI: 0.11-0.64) for 66 incident obesity. Bouts and breaks: Insufficient evidence is available that bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and weight status. No studies were identified that addressed this topic. Cardiovascular Disease Evidence on the Overall Relationship 13 11, 14 , 18 , 79 One systematic review and four meta-analyses were identified that addressed the association ). All four between sedentary behavior and incident cardiovascular disease (Supplementary Table S-F2- 10 11 meta-analyses reported a statistically significant pooled estimate of risk. Grontved and Hu reported a -25 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

170 Part F. Chapter 2. S edentary Behavior 18 Biswas et al pooled relative risk of 1.15 (95% CI: 1.06-1.23) per 2 hours of TV viewing per day. Similarly, 79 reported summary hazard ratios of 1.14 (95% CI: 1.00-1.30) and 1.14 (95% CI: 1.09- and Pandey et al 1.19), respectively, for high versus low sedentary behavior and incident cardiovascular disease. Finally, 14 Wilmot et al reported a significant summary relative risk for cardiovascular events of 2.47 (95% CI: 1.44-4.24). Taken together, the results of these meta-analyses indicate that sedentary behavior is significantly associated with incident cardiovascular disease risk. 10, 10 -84 81 80 , 80, Three published between 2014 and 2017 fo und a of the six original research studies significant association between sedentary behavior and incident cardiovascular disease (Supplementary 10 11). Petersen et al Table S-F2- reported that daily sitting time was significantly associated with incident 80 myocardial infarction but not with incident coronary heart disease. Young et al reported a significant 81 Borodulin et al association between sedentary time and incident heart failure in U.S. men, and reported a significant association between daily sitting time and incident fatal and nonfatal . cardiovascular disease among Finnish adults Dose-response: Two meta-analyses addressed the issue of dose-response in the association between 11 11, 79 Grontved and Hu reported a significant sedentary behavior and incident cardiovascular disease. linear dose-response association between TV viewing and incident fatal and nonfatal cardiovascular 79 disease . In a similar vein, Pandey et al reported a significant, curvilinear dose-response association with increasing slope of risk at increasingly higher levels of sedentary time. Three of the recent research studies published between 2014 and 2017 reported significant dose-response associations between 10, , 81 80 sedentary behavior and incident cardiovascular disease. Evidence on Specific Factors Demographic factors and weight status: Insufficient evidence is available to determine whether the relationship between sedentary behavior and cardiovascular disease varies by age, sex, race/ethnicity, 80 socioeconomic status, or weight status, as few studies examined these interactions . Young et al reported that the association between sedentary time and incidence of heart failure was elevated in all ethnic groups, but was statistically significant only in Non-Hispanic White and Hispanic men . The 83 association also was significant in men with normal weight, overweight, and obesity. McDonnell et al reported no significant interactions between TV viewing and age, race or sex on risk of incident stroke. Available evidence is insufficient to determine whether the relationship Amount of physical activity: between sedentary behavior and cardiovascular disease varies by amount of moderate- to-vigorous -26 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

171 Part F. Chapter 2. S edentary Behavior physical activity. Two of the original research studies identified in the de novo literature search considered the potential interactions between sedentary behavior and physical activity on incident 10 . Petersen et al found no significant interaction between sitting time and leisure- cardiovascular disease time physical activity for myocardial infarction or coronary heart disease. On the other hand, Young et 80 al reported a small additive interaction effect between low physical activity and high sedentary time on incident heart failure (relative risk ( RR )=0.08; 95% CI: 0.03-0.14). Insufficient evidence is available that bouts or breaks in sedentary behavior are Bouts and breaks: important factors in the relationship between sedentary behavior and incident cardiovascular disease . No studies were identified that addressed this topic. Cancer Evidence on the Overall Relationship 89 12 , 13 , 85 , 86 87- 18, and four meta-analyses Four systematic reviews addressed the relationship between sedentary behavior and cancer incidence (Supplementary Table S-F2-10). Two meta-analyses addressed 18, 88 incidence of associations with total cancer incidence, two meta-analyses examined associations with 89 88 87, The several-site-specific cancers, and one meta-analysis addressed breast cancer incidence only. research studies included in the meta-analyses generally reported relative risks that were adjusted for several covariates, including physical activity. Six original research studies, published between 2014 and the relationship between sedentary behavior and incident cancer were 2017, that address ed 90- 95 n ies considered the relationship betwee (Supplementary Table S-F2-11). These stud identified 92 94 91 , 93 breast cancer, sedentary behavior and total cancer and site-specific cancers, ovarian cancer, 90 95 and lung cancer. prostate cancer, Total Cancer: Two meta-analyses examined the association between sedentary behavior and total 88 18, 88 cancer incidence. reported a summary relative risk of 1.20 (95% CI: 1.12-1.28) and Shen et al 18 Biswas et al reported a summary hazard ratio of 1.13 (95% CI: 1.05-1.21) for highest versus lowest levels of sedentary behavior and all-cancer incidence. Further, an original research study in a large cohort (American Cancer Prevention Study II Nutrition Cohort) reported a significant association 94 The results of between leisure-time sitting and total cancer incidence in women but not in men. studies that use total cancer incidence as the outcome should be interpreted with caution, given that cancer is a heterogeneous disease and specific cancers vary widely in their etiology and progression, as well as geographic distribution . 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2 -27

172 Part F. Chapter 2. S edentary Behavior Breast Cancer: Three meta-analyses examined the association between sedentary behavior and breast 87- 89 89 cancer incidence. Zhou et al reported non-significant associations between highest and lowest amounts of sitting time and breast cancer incidence (odds ratio ( OR )=1.05; 95% CI: 0.99-1.11) and highest versus lowest amounts of TV viewing and breast cancer (OR=1.07; 95% CI: 0.96-1.20), 87 respectively. Similarly, Schmid and Leitzmann also reported no relationship between highest versus lowest amounts of sedentary behavior and breast cancer incidence in their meta-analysis (RR=1.03; 95% 88 Shen et al CI: 0.95-1.12). On the other hand, reported a significant association between the highest versus the lowest amounts of sedentary behavior and breast cancer incidence (RR=1.17; 95% CI: 1.03- 88 Shen et al meta-analysis used three prospective cohort studies in their analysis, whereas 1.33). The 87 89 relied on 13 case-control and prospective studies, and Schmid and Leitzmann Zhou et al also relied on both case-control and prospective studies (9 studies for sitting and 6 studies for TV viewing). Of the two newer original research studies that were found, one reported a significant association with breast 91 93 cancer and the other did not. Endometrial Cancer: Two meta-analyses examined the association between sedentary behavior and 87, 88 endometrial cancer, and both reported a significant association. Comparing the highest versus 87 reported a summary relative risk of 1.36 (95% Schmid and Leitzmann lowest levels of sedentary time, 88 reported a summary relative risk of 1.28 (95% CI: 1.08-1.53) . CI: 1.15-1.60); whereas Shen et al 88 Colorectal Cancer: The meta-analysis by Shen et al reported a significant association comparing the highest versus lowest amounts of sedentary behavior and combined colorectal cancer (RR=1.30; 95% CI: 87 1.12-1.49); whereas Schmid and Leitzmann reported a significant association for the highest versus lowest amounts of sedentary behavior and colon cancer (relative risk = 1.28; 95% CI: 1.13-1.45) but not for rectal cancer (RR=1.03; 95% CI: 0.89-1.19) . Lung Cancer: Two meta-analyses examined the association between sedentary behavior and lung 87 , 88 cancer, and both reported a significant association. Comparing the highest versus lowest levels of 87 sedentary time, Schmid and Leitzmann ; reported a summary relative risk of 1.21 (95% CI: 1.03-1.43) 88 reported a summary relative risk of 1.27 (95% CI: 1.06-1.52). whereas Shen et al 87, 88 did not find significant Other Cancers: The two meta-analyses that examined site-specific cancers associations between sedentary behavior and risk of ovarian cancer, prostate cancer, stomach cancer, testicular cancer, renal cell carcinoma, or non-Hodgkin lymphoid neoplasms. In a more recent original research study using data from the American Cancer Prevention Study II Nutrition Cohort, the authors -28 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

173 Part F. Chapter 2. S edentary Behavior reported significant associations between leisure-time sitting and risk of multiple myeloma, invasive breast cancer, and ovarian cancer in women, but found no associations in men between sedentary 94 behavior and site-specific cancers. Dose-response: One meta-analysis examined dose-response associations between sedentary behavior er day of time spent being and cancer risk by modelling the association according to 2-hour increments p 87 Each 2-hour p er day of sitting time was related to significantly increased risk of colon sedentary. cancer (RR=1.08; 95% CI: 1.04-1.11), endometrial cancer (RR=1.10; 95% CI: 1.05-1.15), and a borderline statistically increased risk of lung cancer (RR=1.06; 95% CI: 1.00-1.11). Evidence on Specific Factors None of the identified meta-analyses stratified its analysis by Demographic factors and weight status: demographic factors or weight status. Only three original studies tested for interactions between 90, , 94 93 Therefore, the evid ence is insufficient to sedentary behavior and BMI, with varying results. determine whether the association between sedentary behavior and cancer risk varies by age, sex/ethnicity, socioeconomic status, or weight status. Amount of physical activity: None of the identified meta-analyses stratified its analysis by amount of physical activity. Three of the six original research studies tested for an interaction between sedentary 90 94 , 93, behavior and physical activity, and none was significant. Therefore, the evidence is insufficient to determine whether the association between sedentary behavior and cancer risk varies by amount of to-vigorous physical activity. moderate- Bouts and breaks: Insufficient evidence is available that bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incident cancer. No studies were identified that addressed this topic. For additional details on this body of evidence, visit: Supplementary Tables S-F2- 10 and S-F2- 11 , and https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx for the Evidence Portfolio. For information on the relationship of physical activity and cancer, see Part F. Chapter 4: Cancer Prevention. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2 -29

174 Part F. Chapter 2. S edentary Behavior Question 5. Does the effect of moderate- to-vigorous physical activity on all-cause mortality vary by amount of sedentary behavior? Meta-analyses, original research articles Sources of evidence: Conclusion Statemen t to-vigorous physical activity on all- Moderate evidence indicates that the beneficial effect of moderate- cause mortality varies by amount of sedentary behavior. Importantly, the relative reductions in risk are . PAGAC Grade: Moderate. larger for those who are the most sedentary Review of the Evidence The evidence used to address Question 5 was obtained from the evidence compiled for Question 1. The evidence base is described in greater detail in the section for Question 1. All systematic reviews/meta- analyses and original research articles were reviewed for potential inclusion in the evidence for Question 5. Cohort studies that included multiple amounts of moderate- to-vigorous physical activity as the exposure, in addition to at least two categories of sedentary time, were included in the evidence base. One meta-analysis of data from more than 1 million participants from 16 cohort studies was , 38 35 19 identified An additional three original research in addition to two original research articles. 36, 39 , 51 provided graphical representations of death rat studies es or hazard ratios across combined categories of sedentary behavior and moderate- to-vigorous physical activity. However, the purpose of these figures was to examine the shape of the association between sedentary behavior within different amounts of moderate- to-vigorous physical activity, and the point estimates were not provided in the to-vigorous figures. Finally, one study reported similar non-linear associations between moderate- physical activity in those who had more than 10.9 hours per day of sedentary behavior versus those who had 10.9 hours or less per day of sedentary behavior. However, estimates of relative risk were not 26 provided. The joint associations of moderate- to-vigorous physical activity with daily sitting and TV viewing from 19 Ekelund et al the meta-analysis of are plotted in Figure F2-4. In general, t he overall shapes of the dose- response relationships between moderate- to-vigorous physical activity and all-cause mortality are generally similar when stratified by level of sitting or TV viewing. However, the relative risks at every level of moderate-to-vigorous physical activity are consistently higher in the high sitting and high TV viewing groups. The reduction in risk of all-cause mortality is relatively greater for those who are the most sedentary. This is especially apparent at the lower amounts of moderate- to-vigorous physical 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2 -30

175 Part F. Chapter 2. S edentary Behavior activity. For example, among those who sit more than 8 hours per day, the risk for individuals in the second quartile (about 9.25 MET-hours per week) is 20 percent lower than the risk for individuals in the (≤ 2.5 M first quartile -hours per week). In contrast, among those who sit less than 4 hours per day, the ET risk for individuals in the second quartile is 12 percent lower than the risk for individuals in the first quartile. The level of risk associated with accumulating approximately 20 to 25 MET-hours per week of moderate- to-vigorous physical activity in the low sitting (<4 h/day) group is similar to the risk associated with accumulating 35 to 40 MET-hours per week in the high sitting (>8 h per day) group (Figure 4a). Similar results are observed across categories of TV viewing, except that the level of relative risk associated with high amount of moderate- to-vigorous physical activity in the high TV viewing ( ≥ 5 h/day) never achieves that of moderate or high amounts of moderate- to-vigorous physical activity in the low TV viewing (<1 h/day) group (Figure F2 ). These observations are supported by the results of two original research -4B 38, 94 studies in U.S. adults. It should be noted that both original research studies contributed data to the 19 Ekelund et al. Further research is required to determine why the associations pooled meta-analysis by differ somewhat for self-reported sitting versus self-reported TV viewing. -31 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

176 Part F. Chapter 2. S edentary Behavior ll-cause Mortality, and A to-Vigorous Physical Activity Figure F2-4 . Relationship Between Moderate- Stratified by Amounts of A) Sitting Time and B) TV Viewing 19 Source: Adapted from data found in Ekelund et al., 2016. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. -32 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

177 Part F. Chapter 2. S edentary Behavior OVERALL SUMMARY, CONCLUSIONS, AND PUBLIC HEALTH IMPACT Strong scientific evidence demonstrates that exposure to high amounts of sedentary behavior significantly increases the risk of all-cause mortality, cardiovascular disease incidence and mortality, and type 2 diabetes incidence. Moderate evidence indicates that high amounts of sedentary behavior are associated with the incidence of cancer, particularly for endometrial, colon and lung cancer. Further, limited evidence exists that sedentary behavior is associated with cancer mortality and weight status. Currently, sedentary behavior is highly prevalent in the U.S. population. Therefore, limiting excessive time spent sitting would reduce the population health impact associated with premature mortality and several major chronic diseases such as type 2 diabetes, cardiovascular disease, and cancer. For physically inactive adults, replacing sedentary behavior with light intensity physical activities is likely to produce some health benefits. Among all adults, replacing sedentary behavior with higher intensity (moderate- . to-vigorous) physical activities may produce even greater benefits Strong evidence demonstrates that the association between sedentary behavior and all-cause mortality to-vigorous physical activity, such that the hazardous effects of sedentary varies by amount of moderate- behavior are more pronounced in physically inactive people. Moderate evidence also indicates that the effects of moderate- to-vigorous physical activity vary by amount of sedentary behavior, such that those who are the most sedentary experience the greatest relative reductions in mortality risk associated with increases in physical activity. Further, individuals who are highly sedentary appear to require even higher amounts of physical activity to achieve the same level of absolute mortality risk as people who are less sedentary. Therefore, moderate- to- vigorous physical activity should be part of every adult’s lifestyle, especially for those who sit for large portions of the day. NEEDS FOR FUTURE RESEARCH 1. Conduct research using prospective cohorts on the interactive effects of physical activity and sedentary behavior on all-cause and cardiovascular disease mortality and incident cardiovascular disease, especially on the role of light-intensity physical activity on attenuating the relationship between sitting and mortality. Evidence on the role of physical activity in displacing the mortality risks associated with Rationale: sedentary behavior is limited. A better understanding of these interactive effects will allow for more -33 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

178 Part F. Chapter 2. S edentary Behavior specific recommendations regarding the amount and intensity of physical activity required to maximize health benefits among people with higher or lower levels of sedentary behavior. Given that associations between specific risk factors and cancer mortality are affected by cancer screening and treatment availability and efficacy, studies of the associations between sedentary behavior and all-cancer mortality are not a priority. 2. Conduct research using prospective cohorts on the role of bouts and breaks in sedentary behavior in relation to all-cause and cardiovascular disease mortality. Rationale: The preponderance of the existing evidence on prospective associations between sedentary behavior and health is based on the association between daily or weekly duration of sedentary behavior. More research is needed on the relationship between patterns of sedentary behavior and mortality and other health outcomes, especially the role of sedentary bouts and breaks. This information will contribute to the development of recommendations on how sedentary behavior patterns should be modified to maximize related health benefits . Given that associations between specific risk factors and cancer mortality are affected by cancer screening and treatment availability and efficacy, studies of the associations between sedentary behavior and all-cancer mortality are not a priority. Conduct research on how factors such as sex, age, race/ethnicity, socioeconomic status, and weight 3. status relate to the association between sedentary behavior and cardiovascular disease incidence and cardiovascular disease mortality. Compared to the evidence base for all-cause mortality, fewer studies have addressed Rationale: issues of effect modification by these factors on the relationship between sedentary behavior and cardiovascular disease incidence and mortality. This information will help determine how generalizable the potential benefits of reducing sedentary behavior are in preventing cardiovascular and whether different recommendations are required based one’s sex, disease age, race/ethnicity, . Given that associations between specific risk factors and cioeconomic status, or weight status so cancer mortality are affected by cancer screening and treatment availability and efficacy, studies of the associations between sedentary behavior and all-cancer mortality are not a priority. Conduct research using prospective cohorts to disentangle the independent effects of sedentary 4. behavior and adiposity on risk of type 2 diabetes. -34 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

179 Part F. Chapter 2. S edentary Behavior Rationale: Given that the association between sedentary behavior and type 2 diabetes is attenuated when body mass index is a covariate in the statistical models, this suggests that body mass index may be in the causal pathway between sedentary behavior and risk of type 2 diabetes. However, further research is required to understand the nature and direction of this relationship to better understand whether the relationship between sedentary behavior and type 2 diabetes is truly causal. 5. Conduct randomized controlled trials to test the health effects of interventions to replace time spent in sedentary behaviors with standing and light-, moderate-, and vigorous-intensity physical activity. The preponderance of the evidence on the health effects of sedentary behavior has come Rationale: from observational epidemiological studies. To develop public health guidelines and develop effective intervention strategies, more evidence is required on the positive and negative consequences associated with replacing sedentary behavior with greater intensity activities for short or long durations. REFERENCES 1. Tremblay MS, Aubert S, Barnes JD, et al. SBRN Terminology Consensus Project Participants. Int J Behav 8. 017;14(1):75. doi:10.1186/s12966-017-0525- Nutr Phys Act . 2 2. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors in the United Am J Epidemiol . 2008;167(7):875-881. doi:10.1093/aje/kwm390. States, 2003-2004. o CM, et al. The association between television watching time and all- 3. George SM, Smith AW, Alfan y. cause mortality after breast cancer. J Can cer Surviv . 2013;7(2):247-252. doi:10.1007/s11764- 013 -0265- 4. , Sorensen M, Skurtveit S. Occupational physical activity, overweight, and Graff-Iversen S, Selmer R mortality: a follow-up study of 47,405 Norwegian women and men. Res Q Exerc Sport . 2007;78(3):151- 161. 5. León-Muñoz LM, Martínez-Gómez D, Balboa-Castillo T, López-García E, Guallar-Castillón P, Rodríguez- Artalejo F. Continued sedentariness, change in sitting time, and mortality in older adults. Med Sci Sports . 2013;45(8):1501-1507. doi:10.1249/MSS.0b013e3182897e87. Exerc 6. Jørgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glümer C, Pisinger C. A randomized non- y for prevention of ischaemic heart disease: baseline results Inter99. pharmacological intervention stud . 2003;10(5):377-386. Eur J Cardiovasc Prev Rehabil -35 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

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182 Part F. Chapter 2. S edentary Behavior Wijndaele K, Sharp SJ, Wareham NJ, Brage S. Mortality risk reductions from substituting screen-time 33. Med Sci Sports Exerc . 2017;Jan 19. doi: 10.1249/MSS.0000000000001206. by discretionary activities. 34. Katzmarzyk PT, Church TS, Craig CL, Bouchard C. Sitting time and mortality from all causes, Med Sci Sports Exerc cardiovascular disease, and cancer. . 2009;41(5):998-1005. doi:10.1249/MSS.0b013e3181930355. 35. Patel AV, Bernstein L, Deka A, et al. Leisure time spent sitting in relation to total mortality in a prospective cohort of U.S. adults. Am J Epidemiol . 2010;172(4):419-429. doi:10.1093/aje/kwq155. 36. Seguin R, Buchner DM, Liu J, et al. Sedentary behavior and mortality in older women: the Women’s Health Initiative. . 2014;46(2):122-135. doi:10.1016/j.amepre.2013.10.021. Am J Prev Med 37. Warren Andersen S, Zheng, W, Sonderman, J, et al. Combined Impact of Health Behaviors on Mortality in Low-Income Americans. Am J Prev Med . 2016;51(3):344-355. 38. Matthews CE, George SM, Moore SC, et al. Amount of time spent in sedentary behaviors and cause- specific mortality in U.S. adults. Am J Clin Nutr . 2012;95(2):437-445. doi:10.3945/ajcn.111.019620. 39. van der Ploeg HP, Chey T, Korda RJ, Banks E, Bauman A. Sitting time and all-cause mortality risk in 222 497 Australian adults. Arch Intern Med . 2012;172(6):494-500. doi:10.1001/archinternmed.2011.2174. Inoue M, Iso H, Yamamoto S, et al. Daily total physical activity level and premature death in men and 40. women: results from a large-scale population-based cohort study in Japan (JPHC study). . Ann Epidemiol 2008;18(7):522-530. doi:10.1016/j.annepidem.2008.03.008. Kim Y, Wilkens LR, Park SY, Goodman MT, Monroe KR, Kolonel LN. Association between various 41. sedentary behaviours and all-cause, cardiovascular disease and cancer mortality: the Multiethnic Cohort Study. Int J Epidemiol . 2013;42(4):1040-1056. doi:10.1093/ije/dyt108. AR, Brunner EJ, Hillsdon M. Associations of sitting behaviours with Pulsford RM, Stamatakis E, Britton 42. all-cause mortality over a 16-year follow-up: The Whitehall II study. Int J Epidemiol . 2015;44(6):1909-16. doi:10.1093/ije/dyv191. 43. Martinez-Gomez D, Guallar-Castillon P, Rodriguez-Artalejo F. Sitting time and mortality in older adults with disability: A national cohort study. J Am Med Dir Assoc . 2016;17(10):960.e15-20. doi:10.1016/j.jamda.2016.07.016. 44. Dunstan DW, Barr EL, Healy GN, et al. Television viewing time and mortality: the Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Circulation . 2010;121(3):384-391. doi:10.1161/CIRCULATIONAHA.109.894824. 45 . Basterra-Gortari FJ, Bes- Rastrollo M, Gea A, Núñez‐Córdoba JM, Toledo E, Martínez -González MA. Television viewing, computer use, time driving and all-cause mortality: the SUN cohort. J Am Heart Assoc . 2014;3(3):e000864. doi:10.1161/JAHA.114.000864. 46. Ford ES. Combined television viewing and computer use and mortality from all-causes and diseases . 2012;12:70. of the circulatory system among adults in the United States. BMC Public Health doi:10.1186/1471-2458- -70. 12 -38 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

183 Part F. Chapter 2. S edentary Behavior 47 . Shuval K, Finley CE, Barlow CE, Nguyen BT, Njike VY, Gabriel KP. Independent and joint effects of sedentary time and cardiorespiratory fitness on all-cause mortality: The Cooper Center Longitudinal Study. BMJ Open . 2015;5(10):e008956. 48. Keadle SK, Arem H, Moore SC, Sampson JN, Matthews CE. Impact of changes in television viewing time and physical activity on longevity: A prospective cohort study. Int J Behav Nutr Phys Act . 2015;12:156. doi: 10.1186/s12966-015-0315- 0. 49. Wijndaele K, Brage S, Besson H, et al. Television viewing time independently predicts all-cause and . 2011;40(1):150-159. Int J Epidemiol cardiovascular mortality: the EPIC Norfolk study. doi:10.1093/ije/dyq105. 50 . Ensrud KE, Blackwell TL, Cauley JA, et al. Objective measures of activity level and mortality in older men. J Am Geriatr Soc . 2014;62(11):2079-2087. doi:10.1111/jgs.13101. 51. Matthews CE, Cohen SS, Fowke JH, et al. Physical activity, sedentary behavior, and cause-specific mortality in black and white adults in the Southern Community Cohort Study. Am J Epidemiol . 2014;180(4):394-405. doi:10.1093/aje/kwu142. 52 . Ikehara S, Iso H, Wada Y, et al. Television viewing time and mortality from stroke and coronary artery disease among Japanese men and women — the Japan Collaborative Cohort Study. Circ J . 14-1335. 95. doi:10.1253/circj.CJ- 2015;79(11):2389- 23 . Grace MS, Lynch BM, Dillon F, Barr EM, Owen N, Dunstan DW. Joint associations of smoking and 53 television viewing time on cancer and cardiovascular disease mortality. . 2017;140(7):1538- Int J Cancer 1544. doi:10.1002/ijc.30580. 54. Warren TY, Barry V, Hooker SP, Sui X, Church TS, Blair SN. Sedentary behaviors increase risk of cardiovascular disease mortality in men. Med Sci Sports Exerc . 2010;42(5):879-885. doi:10.1249/MSS.0b013e3181c3aa7e. 55 . Campbell PT, Patel AV, Newton CC, Jacobs EJ, Gapstur SM. Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. J Clin Oncol . 2013;31(7):876-885. doi:10.1200/JCO.2012.45.9735. 56. Lee J, Kuk JL, Ardern CI. The relationship between changes in sitting time and mortality in post- . 2016;38(2):270-278. doi:10.1093/pubmed/fdv055. menopausal U.S. women. J Public Health (Oxf) 57. Manini TM, Lamonte MJ, Seguin RA, et al. Modifying effect of obesity on the association between Obesity (Silver Spring) . 2014;22(4):1133 – 1141. sitting and incident diabetes in post-menopausal women. doi:10.1002/oby.20620. 58 . Smith L, Hamer M. Television viewing time and risk of incident diabetes mellitus: the English Diabet Med Longitudinal Study of Ageing. . 2014;31(12):1572 – 1576. doi:10.1111/dme.12544. 59 . Anjana RM, Sudha V, Nair DH, et al. Diabetes in Asian Indians-how much is preventable? Ten-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES-142). Diabetes Res Clin Pract . – 2015:109(2):253 261. doi:10.1016/j.diabres.2015.05.039. 60 . Barone Gibbs B, Pettee Gabriel K, Reis JP, Jakicic JM, Carnethon MR, Sternfeld B. Cross-sectional and longitudinal associations between objectively measured sedentary time and metabolic disease: the -39 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

184 Part F. Chapter 2. S edentary Behavior Diabetes Care – Coronary Artery Risk Development in Young Adults (CARDIA) study. . 2015;38(10):1835 1843. doi:10.2337/dc15-0226. 61. Joseph JJ, Echouffo-Tcheugui JB, Golden SH, et al. Physical activity, sedentary behaviors and the incidence of type 2 diabetes mellitus: the Multi-Ethnic Study of Atherosclerosis (MESA). BMJ Open . 2016;4(1):e000185. doi:10.1136/bmjdrc-2015-000185. Diabetes Res Care Petersen CB, Bauman A, Tolstrup JS. Total sitting time and the risk of incident diabetes in Danish 62. adults (the DANHES cohort) over 5 years: a prospective study. Br J Sports Med . 2016;50(22):1382 – 1387. doi:10.1136/bjsports-2015-095648. 63. Nguyen B, Bauman A, Ding D. Incident type 2 diabetes in a large Australian cohort study: does . J Phys Act Health physical activity or sitting time alter the risk associated with body mass index? – 19. doi:10.1123/jpah.2016-0184. 2017;14(1):13 64. Asvold BO, Midthjell K, Krokstad S, Rangul V, Bauman A. Prolonged sitting may increase diabetes risk . in physically inactive individuals: an 11 year follow- up of the HUNT Study, Norway. Diabetologia 2017;60(5):830 – 835. doi:10.1007/s00125- 016 -4193- z. 65. Altenburg TM, Lakerveld J, Bot SD, Nijpels G, Chinapaw MJ. The prospective relationship between sedentary time and cardiometabolic health in adults at increased cardiometabolic risk — the Hoorn . 2014;(11):90. doi:10.1186/s12966-014-0090- 3. Prevention Study. Int J Behav Nutr Phys Act 66. Bell JA, Hamer M, Batty GD, Singh-Manoux A, Sabia S, Kivimaki M. Combined effect of physical activity and leisure time sitting on long-term risk of incident obesity and metabolic risk factor clustering. Diabetologia – 2056. doi:10.1007/s00125-014-3323- 8. . 2014;57(10):2048 67. Helajarvi H, Rosenstrom T, Pahkala K, et al. Exploring causality between TV viewing and weight change in young and middle-aged adults. The Cardiovascular Risk in Young Finns study. PloS ONE . 2014;9(7):e101860. doi:10.1371/journal.pone.0101860. 68. Wiseman AJ, Lynch BM, Cameron AJ, Dunstan DW. Associations of change in television viewing time with biomarkers of postmenopausal breast cancer risk: the Australian Diabetes, Obesity and Lifestyle 19. doi:10.1007/s10552-014-0433- z. Study. Cancer Causes Control . 2014;25(10):1309 – 13 69. Wijndaele K, Orrow G, Ekelund U, et al. Increasing objectively measured sedentary time increases clustered cardiometabolic risk: a 6 year analysis of the ProActive study. Diabetologia . 2014;57(2):305 – 312. doi:10.1007/s00125-013-3102- y. 70 . Florencio MT, Bueno NB, Clemente A, et al. Weight gain and reduced energy expenditure in low- income Brazilian women living in slums: a 4-year follow-up study. Br J Nutr . 2015;114:462 – 471. doi:10.1017/S0007114515001816. 71 . Golubic R, Wijndaele K, Sharp SJ, et al. Physical activity, sedentary time and gain in overall and central body fat: 7-year follow-up of the ProActive trial cohort. Int J Obes (Lond) . 2015;39(1):142 – 148. doi:10.1038/ijo.2014.66. 72 . Smith L, Fisher A, Hamer M. Television viewing time and risk of incident obesity and central obesity: 8. . 2015;(2):12. doi:10.1186/s40608-015-0042- BMC Obes the English longitudinal study of ageing. -40 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

185 Part F. Chapter 2. S edentary Behavior Thomee S, Lissner L, Hagberg M, Grimby-Ekman A. Leisure time computer use and overweight 73. — a prospective study. BMC Public Health . 2015;(15):839. development in young adults doi:10.1186/s12889-015-2131- 5. Kaikkonen JE, Mikkila V, Juonala M, et al. Factors associated with six-year weight change in young 74. Scand J Clin Lab Invest . 2015;75(2):133 – 144. and middle-aged adults in the Young Finns Study. doi:10.3109/00365513.2014.992945. 75. Menai M, Charreire H, Kesse-Guyot E, et al. Determining the association between types of sedentary behaviours and cardiometabolic risk factors: A 6-year longitudinal study of French adults. Diabetes 121. doi:10.1016/j.diabet.2015.08.004. – Metab . 2016;42(2):112 Saidj M, Jorgensen T, Jacobsen RK, Linneberg A, Oppert JM, Aadahl M. Work and leisure time sitting 76. and inactivity: Effects on cardiorespiratory and metabolic health. Eur J Prev Cardiol . 2016;23(12):1321 – 2047487315619559. 1329. doi:10.1177/ 77. Shibata AI, Oka K, Sugiyama T, Salmon JO, Dunstan DW, Owen N. Physical activity, television viewing time, and 12-year changes in waist circumference. Med Sci Sports Exerc . 2016;48(4):633 – 640. doi:10.1249/MSS.0000000000000803. 78. Su C, Jia XF, Wang ZH, Wang HJ, Ouyang YF, Zhang B. Longitudinal association of leisure time physical activity and sedentary behaviors with body weight among Chinese adults from China Health and – 388. doi:10.1038/ejcn.2016.262. Nutrition Survey 2004-2011. Eur J Clin Nutr . 2017:71(3):383 79. Pandey A, Salahuddin U, Garg S, et al. Continuous dose-response association between sedentary time and risk for cardiovascular disease: a meta-analysis. JAMA Cardiol 583. . 2016;1(5):575 – doi:10.1001/jamacardio.2016.1567. Young DR, Reynolds K, Sidell M, et al. Effects of physical activity and sedentary time on the risk of 80. Circ Heart Fail . 2014;7(1):21 – 27. doi:10.1161/CIRCHEARTFAILURE.113.000529. heart failure. . Borodulin K, Karki A, Laatikainen T, Peltonen M, Luoto R. Daily sedentary time and risk of 81 cardiovascular disease: The National FI NRISK 2002 Study. J Phys Act Health . 2015;12(7):904 – 908. doi:10.1123/jpah.2013-0364. 82 . Chomistek AK, Chiuve SE, Eliassen AH, Mukamal KJ, Willett WC, Rimm EB. Healthy lifestyle in the primordial prevention of cardiovascular disease among young women. J Am Coll Cardiol . 2015;65(1):43 – 51. doi:10.1016/j.jacc.2014.10.024. McDonnell MN, Hillier SL, Judd SE, Yuan Y, Hooker SP, Howard VJ. Association between television 83. viewing time and risk of incident stroke in a general population: Results from the REGARDS study. Prev Med . 2016;87:1 – 5. doi:10.1016/j.ypmed.2016.02.013. 84. Moller SV, Hannerz H, Hansen AM, Burr H, Holtermann A. Multi-wave cohort study of sedentary work and risk of ischemic heart disease. Scand J Work Environ Health . 2016;42(1):43 – 51. doi:10.5271/sjweh.3540. 85. Lynch BM. Sedentary behavior and cancer: a systematic review of the literature and proposed – biological mechanisms. Cancer Epidemiol Biomarkers Prev . 2010;19:2691 2709. doi:10.1158/1055- -0815. 10 9965.EPI- -41 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

186 Part F. Chapter 2. S edentary Behavior Moore SC, Gierach GL, Schatzkin A, Matthews CE. Physical activity, sedentary behaviours, and the 86. prevention of endometrial cancer. Br J Cancer . 2010;103(7):933 – 938. doi:10.1038/sj.bjc.6605902. 87 . Schmid D, Leitzmann MF. Television viewing and time spent sedentary in relation to cancer risk: a 014;106(7):pii:dju098. doi:10.1093/jnci/dju098. Print 2014 Jul. meta-analysis. J Natl Cancer Inst . 2 88 . Shen D, Mao W, Liu T, et al. Sedentary behavior and incident cancer: a meta-analysis of prospective . 2014;9(8):e105709. doi:10.1371/journal.pone.0105709. studies. PLoS One . Zhou Y, Zhao H, Peng C. Associa 89 tion of sedentary behavior with the risk of breast cancer in women: servational studies. Ann Epidemiol . 2015;25(9):687 – 697. update meta-analysis of ob epidem.2015.05.007. doi:10.1016/j.ann Lynch BM, Friedenreich CM, Kopciuk KA, Hollenbeck AR, Moore SC, Matthews CE. Sedentary 90. behavior and prostate cancer risk in the NIH-AARP Diet and Health Study. Cancer Epidemiol Biomarkers Prev . 2014;23(5):882 – 889. doi:10.1158/1055-9965.EPI- 13-0808. 91 . Catsburg C, Kirsh VA, Soskolne CL, et al. Associations between anthropometric characteristics, cer risk in a Canadian cohort. Breast Cancer Res Treat – . 2014;145(2):545 physical activity, and breast can 552. doi:10.1007/s10549-014-2973- z. . Hildebrand JS, Gapstur SM, Gaudet MM, Campbell PT, Patel AV. Moderate- to-vigorous physical 92 activity and leisure-time sitting in relation to ovarian cancer risk in a large prospective U.S. cohort. . 2015;26(11):1691 – 1697. doi:10.1007/s10552- 015 -0656- 7. Cancer Causes Control . Nomura SJ, Dash C, Rosenberg L, Palmer J, Adams-Campbell LL. Sedentary time and breast cancer 93 . 2016;27(10):1239 Cancer Causes Control – incidence in African American women. 1252. doi:10.1007/s10552-016-0803- 9. 94. Patel AV, Hildebrand JS, Campbell PT, et al. Leisure-time spent sitting and site-specific cancer incidence in a large U.S. cohort. Cancer Epidemiol Biomarkers Prev . 2015;24(9):1350 – 1359. doi:10.1158/1055- 99 65.EPI- 15-0237. 95. Wang A, Qin F, Hedlin H, et al. Physical activity and sedentary behavior in relation to lung cancer Int J Cancer incidence and mortality in older women: the Women's Health Initiative. . – 2016;139(10):2178 2192. doi:10.1002/ijc.30281. -42 2018 Physical Activity Guidelines Advisory Committee Scientific Report F2

187 Physical Activity and Selected Health Outcomes • Part F. Chapter 3. Brain Health • Part F. Chapter 4. Cancer Prevention Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight • Gain • Part F. Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease

188 Part F. Chapter 3. Brain Health PART F. CHAPTER 3. BRAIN HEALTH Table of Contents ... F3 -1 Introduction ... Review of the Science -3 F3 Overview of Questions Addressed ... F3 -3 Data Sources and Process Used to Answer Questions ... F3 -4 Question 1: ... F3 -4 What is the relationship between physical activity and cognition? ationship between physical activity and quality of life? ... F3 -14 Question 2. What is the rel Question 3. What is the relationship between physical activity and (1) affect, (2) anxiety, and (3) -25 F3 ... depressed mood and depression? Question 4: What is the relationship between physical activity and sleep? ... F3 -37 Needs for Future Research ... F3 -46 -49 F3 References ... INTR ODUCTION Maintaining or improving brain health is a universal goal across the lifespan. In youth, we seek to enhance brain maturation and development, reach expected developmental milestones relative to thoughts and actions, and achieve academic goals, including school readiness and achievement. In late . Across the lifespan, we strive to ensure adulthood, we aim to avoid dementia and cognitive impairment high-quality brain health, as manifested by optimally functioning cognition, low levels of anxiety and feelings of depression, a positive assessment of perceptions of quality of life, and comfortable and effective sleep patterns . Despite these common goals, and the fact that recent research has provided much important information on these topics, the effects of physical activity on brain health remain poorly understood by the public. Additionally, physical activity is infrequently prescribed by health care . The professionals for prevention or treatment of medical conditions affecting the brain Physical Activity 1 focused on several mental health outcomes and this Guidelines Advisory Committee Report, 2008 literature has substantially grown over the past decade. Drawing from this expanded evidence base, the -1 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

189 Part F. Chapter 3. Brain Health 2018 Physical Activity Guidelines Advisory Committee Scientific Report addresses this important topic and examines the strength of the scientific evidence that would be the basis for public health guidelines. The term “Brain Health” can be broadly conceptualized as the optimal or maximal functioning of behavioral and biological measures of the brain and the subjective experiences arising from brain function (e.g., mood). This includes measurements of biological markers of the brain (e.g., structural brain morphology) or the subjective manifestations of brain function, including mood and anxiety, perceptions of quality of life, cognitive function (e.g., attention and memory), and sleep. Several decades of non-human animal research conclude that unequivocal evidence shows that physical activity positively affects behavioral and biological measures of brain health. This research has been supported by a rapidly expanding investigation of physical activity on brain health in humans . As such, for the first time, the scientific field is well-positioned for a comprehensive assessment of this broad and quickly maturing area of science with the aim of understanding and describing the public health implications regarding the relationship between physical activity and the benefits of maintaining brain health throughout the lifespan. 1 The 2008 Scientific Report concluded that physical activity “reduces the risk of depression and cognitive indicated that “there was some evidence that physical it ” In addition, decline in adults and older adults. activity would improve sleep” and described “limited evidence that physical activity would reduce 1 being and anxiety” distress/well- In the past 10 or more years, significant advancements have occurred . in both the sophistication of instruments and approaches to study brain health and the quality of research examining the influence of physical activity on brain health outcomes. This 2018 Scientific Report greatly expands on the statements made in 2008 by examining whether regular and long-term engagement in physical activity, as well as brief bouts of activity, are capable of improving cognitive function, perceptions of quality of life, affect, anxiety and depression, and sleep across the lifespan and in disorders and conditions with common deficits (e.g., dementia). This report 1 goes beyond the mental health definition used in the 2008 Scientific Report by further examining physical activity on other aspects of the brain, thus requiring a broader view that is more properly brain health Question 1 examines whether physical activity is an effective .” encompassed by the term “ method for improving cognitive function across the lifespan or reducing the risk for dementia. In it examines the effects of physical activity on cognitive function in conditions that are often addition, associated with cognitive deficits or problems (e.g., schizophrenia). Question 2 focus es on the influence -2 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

190 Part F. Chapter 3. Brain Health of physical activity on perceptions of quality of life. The Brain Health Subcommittee approached this - problem from a perspective of differentiating quality of life from well- being, with the term “well being” encompassing both cognitive-evaluative and affective components. The Subcommittee focused on the cognitive-evaluative components and assessed whether physical activity improves general quality of life and health-related domains of quality of life, which are defined as “a reflection of the way that 2 individuals perceive and react to their health status and to other, no nmedical aspects of their lives” . Question 3 focuses on the affective components of well-being, and examines the effect of physical activity on core affective responses (i.e., how pleasant and activated people feel during and after activity), state and trait anxiety, depressive symptoms, and clinical depression. Question 4 address es the research on the influence that physical activity has on sleep outcomes, including in individuals with sleep disorders. In each of these areas, the Subcommittee also examined whether evidence was available for e dose-response effects between the physical activity exposure and the outcome, and whether th relationship varied by age, race, sex, weight status, or sociodemographic characteristics. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses four major questions and related subquestions: 1. What is the relationship between physical activity and cognition? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) Does the relationship vary by sex, race/ethnicity, socioeconomic status, or weight status? b) Does the relationship exist across the lifespan? c) relationship vary for individuals with normal to impaired cognitive function (i.e., d) Does the dementia) e) What is the relationship between physical activity and biomarkers of brain health? What is the relationship between physical activity and quality of life? 2. Is there a dose-response relationship? If yes, what is the shape of the relationship? a) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) What is the relationship between physical activity and (1) affect, (2) anxiety, and (3) depressed 3. mood and depression? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? Does the relationship exist across a continuum of mood and affective disorders (e.g., c) depression)? d) What is the relationship between physical activity and brain structure and function? -3 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

191 Part F. Chapter 3. Brain Health 4. What is the relationship between physical activity and slee p? a) Is there a dose-response relationship for either acute bouts of physical activity, or regular physical activity? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) Does the relationship vary for individuals with normal to impaired sleep behaviors? If yes, for c) which sleep disorders? Data Sources and Process Used to Answer Questions The Brain Health Subcommittee determined that systematic reviews, meta-analyses, pooled analyses, and reports provided sufficient literature to answer all four research questions . The databases searched included PubMed, Cochrane, and CINAHL . What is the relationship between physical activity and cognition? Question 1: a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Does the relationship exist across the lifespan? d) Does the relationship vary for individuals with normal to impaired cognitive function (i.e., dementia) What is the relationship between physical activity and biomarkers of brain health? e) Systematic reviews and meta-analyses Sources of Evidence: Conclusion Statements During the course of the review, it was determined that an accurate description of the state of the science for addressing this question would require several additional subcategories. As such, separate grades were assigned for acute bouts of physical activity (subquestion a), different age groups (subquestion c), and medical conditions with cognitive impairment (subquestion d). Moderate evidence indicates a consistent association between greater amounts of physical activity and improvements in cognition, including performance on academic achievement tests; performance on neuropsychological tests, such as those involving processing speed, memory, and executive function; of dementia. Such evidence has been demonstrated across numerous populations and and risk individuals representing a gradient of normal to impaired cognitive health status. These effects are found across a variety of forms of physical activity, including aerobic activity (e.g., brisk walking), muscle-strengthening activity, yoga, and play activities (e.g., tag or other simple low organizational PAGAC Grade: Moderate. games). -4 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

192 Part F. Chapter 3. Brain Health dose response relationship exists between Insufficient evidence is available to determine whether a - physical activity and cognition because of conflicting findings across populations, cognitive outcomes, PAGAC Grade: Not a ssignable. and experimental approaches. Strong evidence demonstrates that acute bouts of moderate - - vigorous physical activity have a to transient benefit for cognition, including attention, memory, crystalized intelligence, processing speed, and executive control during the post recovery period following a bout of exercise. The findings indicate - that the effects are larger in preadolescen t children and older adults relative to other periods of the lifespan. PAGAC Grade: Strong. Insufficient evidence is available to determine the effects of moderate - to - vigorous physical activity on : Not cognition in children younger than PAGAC Grade age 5 years. a ssignable . Moderate evidence indicates an effect of both acute and long - term moderate - to - vigorous physical activity on brain, cognition, and academic outcomes (e.g., school performance, interventions psychometric profile of memory and executive function) in preadolescent children ages 5 to 13 years. Grade: Moderate . PAGAC - moderate to determine whether a relationship exists between is available - to Insufficient evidence physical activity and cognition in adolescents ages 14 to 18 years. PAGAC Grade : Not vigorous a ssignable. evidence Insufficient exists regarding the effect of long - term moderate - to - vigorous physical activity on N ot assignable. cognition in young or mid - life adults ages 18 to 50 years . PAGAC Grade: vigorous physical activity interventions Moderate evidence indicates an e - term moderate - to - ffect of long on cognitive and brain outcomes in adults ages 50 years and older. PAGAC Grade: Moderate. Limited evidence suggests that moderate - cognition to - vigorous physical activity has a stronger effect on in older compared to middle - aged and younger adults. Limited evidence also suggests a stronger effect of moderate - to - vigorous physical activity in older adult women compared to older adult men. PAGAC Grade: Limited. an effect of physical activity on cognition as a function of socioeconomic No evidence was observed for PAGAC status, race/ethnicity, or weight status. Grade: Not assignable 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 - 5

193 Part F. Chapter 3. Brain Health are with a reduced Strong evidence demonstrates that greater amounts of physical activity associated Grade: Strong. risk of developing cognitive impairment, including Alzheimer’s disease. PAGAC - to - Moderate evidence indicates that moderate vigorous physical activity interventions can improve cognition in individuals with dementia. Gr ade: Moderate PAGAC - to - vigorous physical activity can have beneficial effects on Moderate evidence indicates that moderate cognition in individuals with diseases or disorders that impair cognitive function, including attention deficit hyperactivity disorder , sch izophrenia, multiple sclerosis , Parkinson’s disease , and stroke. However, are lacking for several other major conditions that are clinically associated with impaired data . PAGAC Grade: Moderate . cognitive function (i.e., autism, cancer) Moderate evidence i ndicates that moderate - to - vigorous physical activity positively affects biomarkers of brain health and cognition. - induced changes to these biomarkers have been observed Physical activity across much of the lifespan, with considerably more evidence in child ren and older adults than in other age groups . PAGAC Grade: Moderate. vigorous - to - Limited evidence suggests that moderate on cognition has a stronger effect physical activity in older compared to middle Limited evidence also suggests a stronger effect aged and younger adults. - moderate - to - older adult physical activity in older adult women compared to of men. No vigorous evidence was observed for an effect of physical activity on cognition as a function of socioeconomic status , rac e/ethnicity, or body mass index. PAGAC Grade: Limited . a S trong evidence demonstrates that acute bouts of moderate - to - vigorous physical activity have cognition, including attention, transient benefit for , crystalized intelligence, processing speed, memory and executive control during the post - recovery period following a bout of exercise . The findings indicate that the effects are larger in preadolescent children and older adults relative to other periods of the lifespan. PAGAC Grade: Strong. Review of the E vidence , Cognitive and brain health are important to many facets of life including educational and academic attainment, job performance, quality of - life, and for disease s and disorders that directly or indirectly - , measurement of cognition includes a broad range of . For this questio n influence these outcomes that assess outcomes , including academic achievement, performance on neuropsychological tests , several processes attention, memory, processing speed, and executive function (an umbrella such as 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 - 6

194 Part F. Chapter 3. Brain Health term that represents a number of goal-directed processes that support thinking, reasoning, and problem solving), and dementia diagnoses. However, cognition as defined in this question — does not include — measurement of intelligence, motor function, personality, mood (addressed below in Question 3), and sensory and perceptual function. To address this question, the Subcommittee used 32 meta-analyses and systematic reviews of the literature that examined whether results from randomized controlled trials (RCTs) and prospective longitudinal studies are associated with cognitive outcomes. These reviews included results from 3-5 13, 14 9- 12 6-8 ), children (N=4 ), and adolescents (N=2 healthy young (N=3 ) and older adults (N=3 ) as well as populations with impaired cognition, such as children and adults with attention deficit hyperactivity 15- 17 18- 21 ), multiple disorder (ADHD) (N=3 ), adults with mild cognitive impairment or dementia (N=4 24 23 22 25 sclerosis (N=1 ), schizophrenia (N=1 ), and stroke (N=1 ). We also ), Parkinson’s disease (N=1 26- 29 included meta-analyses and reviews of the effects of acute exercise on cognitive outcomes (N=4 ), 30 ), and the effects of physical activity on the effects of sedentary behavior on cognitive outcomes (N=1 34 31- ). Included in these systematic reviews and meta-analyses were biomarkers of brain health (N=4 more than 350 empirical studies with more than 40,000 individuals. Evidence on the Overall Relationship The Subcommittee concluded that there is moderate evidence for an association between greater amounts of physical activity and improvements in cognition, including performance on academic achievement tests; performance on neuropsychological tests, such as those involving processing speed, memory, and executive function; and risk of dementia. Such evidence has been demonstrated across numerous populations and individuals representing a gradient of normal to impaired cognitive health status. These effects are found across a variety of forms of physical activity, including aerobic activity (e.g., brisk walking), muscle-strengthening activity, yoga, and play activities (e.g., tag or other low organizational games). The findings regarding the relationship between levels of physical activity and cognition show considerable consistency across a variety of experimental designs and cognitive outcomes used to assess this relationship. The effect sizes of physical activity on cognition ranged from 0.10 to 0.67 standard deviations (SD), depending on the population, cognitive outcome, experimental design, and physical activity exposure. To place this effect size in perspective, a diagnosis of vascular cognitive impairment, non-dementia (a prevalent sub-category of mild cognitive impairment), is t with cerebrovascular involvement, and impairment is evident in at considered when dementia is absen least one cognitive domain that is at least 1 and typically 1.5 SD outside of age- and education-adjusted 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -7

195 Part F. Chapter 3. Brain Health norms. These impairments occur most commonly in the domain(s) of executive function. Thus, these effect sizes for cognitive and brain health outcomes are generally considered small to moderate in magnitude, and consistently positive. Although the studies reviewed indicate that the effects of physical activity influence numerous cognitive domains, the positive effects have been demonstrated most consistently, and are most frequently studied, in the executive function domain. The improvements in executive function are temporary following acute bouts of physical activity, and become more sustained following participation in an ongoing physical activity routine. As is described below, the Subcommittee indicated a moderate, rather than strong, conclusion because the relationship between physical activity and cognition varied based on specific factors. Evidence on Specific Factors Lifespan: The effect of physical activity on cognition has been observed at different stages of the lifespan. However, the quantity of evidence is not uniform across the lifespan, and the preponderance of data come from research in preadolescent children, young adults, and older adults. 12 to unable to be determined in children younger Across childhood, effects ranged from n on -significant, than age 5 years because of a small number of studies with poor quality experimental designs and a high 9, 11 10 risk of bias, Cognitive domains with the largest effects to significant during school-age years. 9, 11 included executive function, attention, and academic achievement, but absolute measures of effect sizes were unable to be determined from these studies. In studies examining effects of engaging in phy sical activity on ADHD, the effect sizes ranged from 0.18 to 0.77 in favor of physical activity 17 15- ains most commonly affected in ADHD included improving cognitive performance. Cognitive dom 17 15, executive function (e.g., attention, inhibition, impulsivity). In adolescents, there were few rigorous experimental studies with control groups, few studies with well- described parameters and definitions of physical activity, and few studies with measures of cognitive function or academic achievement. Despite these limitations, the several reviews reported effect sizes in 14 while a systematic review indicated that 75 percent of favor of physical activity ranging up to 0.37, 13 studies in adolescents reported an association between physical activity and better cognitive function. However, as stated above, given that there were few rigorous experimental studies with randomized designs included in the reviews, the size and quality of the evidence is insufficient to provide a reliable grade. -8 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

196 Part F. Chapter 3. Brain Health 4, 5 for physical activity improving In young and mid-life adults, effect sizes ranged from 0.12 to 0.15 cognition. Effects were largest for the cognitive domains of executive function, attention, processing 5 4 speed, and short-term memory. In cognitively normal older adults, effect sizes ranged from non- 8 6 7 in favor of physical activity interventions positively influencing cognitive significant to 0.48 to .20 6 8 and outcomes. Effect sizes were greatest for measures of executive function, global cognition, 7 attention. Impaired cognitive function: Strong evidence demonstrates that greater amounts of physical activity are 20 associated with a reduced risk of cognitive decline and risk of dementia, including Alzheimer’s disease 18 For example, a meta-analysis of 15 prospective studies of 1 to 12 years in duration with more (AD). than 33,000 participants found that greater amounts of physical activity were associated with a 38 20 Another meta-analysis of 10 prospective studies with more percent reduced risk of cognitive decline. than 20,000 participants reported that greater amounts of physical activity were associated with a 40 18 percent reduced risk of developing AD. Moderate evidence indicates that physical activity 19, 21 e interventions can improve cognition in individuals with dementia, including AD. For example, on meta-analysis of 18 RCTs from 802 dementia patients reported an overall effect size of 0.42 and that this 19 These positive effects were effect was also significant for individuals with AD or non-AD dementias. found for interventions that were both high-frequency physical activity and low-frequency physical activity. However, given the heterogeneity in the assessment methods, insufficiently detailed description of the physical activity interventions, and moderate risks for bias, the strength of the evidence is rated as moderate. Moderate evidence also indicates that physical activity improves cognitive function in individuals with other diseases or disorders that impair cognitive function, including ADHD, schizophrenia, multiple sclerosis (MS), P arkinson’s disease , and stroke. Results regarding the efficacy of interventions to improve cognitive function in individuals with MS are 22 However conflicting. , interventions show the largest effects on executive function, learning, memory, and processing speed. (For more details on the effects of physical activity in individuals with MS, see Part F. Chapter 10. Individuals with Chronic Conditions .) Studies of P arkinson’s disease show significant 23 improvements in cognition following exercise interventions, with the largest effect sizes in domains of to-vigorous physical general cognitive function and executive function. In schizophrenia, moderate- activity interventions have shown improvements in measures of global cognition, working memory, and 24 In stroke populations, engaging in physical activity interventions attention, with effect sizes of 0.43. -9 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3

197 Part F. Chapter 3. Brain Health shows significant improvements in domains of global cognition, attention, memory, and visuospatial 25 abilities. Transient benefits have been observed resulting from acute bouts of physical activity in children with ADHD, such benefits have not been frequently measured in individuals with other conditions. but Despite consistency in effect sizes across conditions, the manner in which the studies were conducted and the quality of the cognitive outcomes and measures are variable. Thus, evidence on the effects of acute bouts of exercise on cognition in populations with cognitive deficits is insufficient. Effects also have been reported on biomarkers of brain health, including neurotrophic Biomarkers: , 34 33 31, 32 factors across the lifespan, but the and task-evoked brain activity, volume, and connectivity . For example, effects preponderance of data comes from work in children and adults over the age of 60 of physical activity on volumetric and brain activity patterns are more frequently reported, and studied, 31 in older adults and children than middle-aged adults. Similarly, effects of physical activity on measures of white matter might be less understood across the lifespan compared to functional and volumetric 34 data, but research on the effects of physical activity on white matter in mid-life is especially scarce. A number of approaches have been used to assess biomarkers of brain health and cognition, including grey matter morphology (i.e., volume, density, and thickness), white matter integrity, and cortical electrophysiology. Other approaches include assessing neural networks, including evoked responses from cognitively demanding tasks; circulating neurotrophic factors linked to cognitive function and neuroplasticity; cerebral blood flow; task-evoked functional activity; resting state functional connectivity; magnetic resonance spectroscopy; and positron emission tomography. Most of the work in this area has emerged in the last 5-10 years and has used functional or volumetric approaches to assess 31, 34 the health and integrity of the brain. The majority of studies in this rather small but growing area report small- to-moderate positive effect sizes ranging from 0.1 to 0.7 of physical activity on brain outcomes. : The included reviews rarely reported Demographic factors, weight status, and physical activity type 6 whether effects of physical activity on cognitive outcomes were modified by age, sex, race/ethnicity, 30 3 sedentary behavior o r physical socioeconomic status, presence of obesity, baseline fitness levels, activity intensity, frequency, or duration. However, one of the more consistent effects is that females 6 show larger effect sizes than males. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -10

198 Part F. Chapter 3. Brain Health The included reviews rarely report whether a dose-response relationship was observed Dose-response: 6 for the effects of physical activity on cognitive outcomes. However, one meta-analysis reported that among older adults, larger effects on cognition were observed in randomized controlled trials in which physical activity bouts lasted 46-60 minutes in duration (compared to bout durations lasting 15-30 minutes and 31-45 minutes) and the interventions occurred for at least 6 months compared to interventions lasting 1-3 and 4-6 months. In addition, physical activity has a general effect across the aspects of cognition that were studied (i.e., executive, controlled, spatial, and speed), but the effect was 6 selectively and disproportionately larger for tasks requiring greater amounts of executive control. : Studies demonstrate a small, transient improvement in cognition Acute bouts of physical activity following the cessation of a single, acute bout of physical activity, with effect sizes ranging from 0.014 to 29 26 -29 26- but significant 0.67. Reported effects were most consistent for domains of executive function, benefits were also realized for processing speed, attention, memory, and crystalized intelligence, the latter of which is a measure of general and verbal knowledge (e.g., what is the name of the first 27 , 29 26, or preadolescent children and Larger effects were also realized f president of the United States). 28 older adults relative to adolescents and young adults. Exercise intensity of an acute bout of activity had an effect on changes in cognition, with some findings suggesting an inverted-U shaped curve, as moderate-intensity exercise demonstrated a larger effect 29 27, and other studies indicating that very light-, light-, and than light- and vigorous-intensity exercise, moderate-intensity exercise benefited cognition, but hard-, very hard-, and maximal-intensity exercise 26 intensity demonstrated no benefit. The timing of the assessment of cognition relative to the cessation of the acute bout of exercise also demonstrated differences in the magnitude of the effect, with negative effects in cognition observed during the first 10 minutes following the exercise bout and the largest positive effect observed from 11 to 20 minutes and a smaller effect observed after 20 minutes 26 Physical activity bouts lasting 11 to 20 minutes following the acute physical activity bout. demonstrated the greatest benefits, with bouts lasting less than 11 minutes or more than 20 minutes 26 having smaller effects on cognition. Overall, this line of research warrants a moderate grade because studies reported significant variability in the quality of study design, including a lack of appropriate analytical approaches (e.g., intent- to-treat analyses), poor reporting of adherence and compliance, variability in how active participants were before assignment to the intervention, unknown reliability and validity of the cognitive assessments, 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -11

199 Part F. Chapter 3. Brain Health inadequate blinding, and variability in control group conditions. As such, the studies included in these meta-analyses and systematic reviews generally have a high risk of bias and low precision. However, despite these limitations, these studies appear to have high applicability, generalizability, and . The effects are also detectable using acute exercise paradigms, where preadolescent consistency children and older adults demonstrate large and consistent positive effects of moderate-intensity 29 26- physical activity, with some evidence to support 11 to 20 minutes in duration as being optimal for 26 cognitive outcomes. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report 1 concluded that strong evidence demonstrated that physical activity delays The 2008 Scientific Report . It also indicated that the incidence of dementia and the onset of cognitive decline associated with aging physical activity improves cognitive symptoms associated with dementia. Thus, the evidence described here considerably expands that described in 2008 by including significantly more observational studies and RCTs. This research finds that physical activity influences cognitive function across the lifespan, are including both cognitively normal and impaired populations (e.g., schizophrenia). The effects consistent across a variety of methods for assessing cognition (e.g., academic achievement and dementia diagnoses). The 2018 Scientific Report also demonstrates, for the first time, the positive effects of physical activity on biomarkers of brain health obtained from neuroimaging techniques (e.g., brain volume). Finally, the 2018 Scientific Report describes evidence on acute bouts of activity for improving cognitive function. Public Health Impact In 2017, the annual direct costs of Alzheimer’s disease to American society was estimated to be $259 . In 2010, it was estimated that in the last 5 years of life, the cost of dementia per person was billion 35 Given the $287,000 . Most of these costs are spent by the federal government under Medicare. exp ected increase in the number of Americans older than age 65 years, the costs associated with 35 Alzheimer’s disease or other dementias may increase to about $758 billion by the year 2050. Physical activity may be a highly effective approach for improving function and mitigating costs associated wit h 36 In an analysis by, about 13 percent (nearly 4.3 Alzheimer’s disease and other cognitive impairments. million) of Alzheimer’s disease cases worldwide and about 21 percent of Alzheimer’s disease cases in the United States are attributable to physical inactivity n . According to these results, a 25 percent reduction i 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -12

200 Part F. Chapter 3. Brain Health physical inactivity in the United States could potentially prevent 230,000 cases. The results from the of the argument that physical activity reduces the risk 2018 Scientific Report provide support for increasing physical activity in individuals with Alzheimer’s disease and other dementias and that Alzheimer’s disease could improve cognitive function. The public health impact of the results summarized in the 2018 Scientific Report goes beyond by demonstrating that physical activity influences cognitive function Alzheimer’s disease and dementia For example, academic achievement is a predictor of future job in children and healthy older adults. 37 39 38, Thus, these findings, which indicate that increasing opportunities and adult health outcomes. physical activity during childhood may positively influence cognition and academic achievement, may . have further downstream effects on many features of adult health and quality of life Healthy older adults, even in the absence of a dementia, often show evidence for cognitive losses and decline, especially on measures of processing speed, memory, and executive function . It is estimated that by the year 2050, the population of adults older than 65 years in the United States will reach 83.7 . An increase in the prevalence of cognitive million, which is nearly double the 2012 level of 43.1 million decline is expected given this increase in the number of adults over the age of 65. This report suggests that physical activity may be an effective approach for improving cognitive function in this population. is an effective approach for Finally, we conclude that moderate evidence es that physical activity indicat improving cognitive function in populations that often experience cognitive deficits including ADHD, Parkinson’s disease, multiple sclerosis, and schizophrenia. Evidence of such widespread benefit s for physical activity across the lifespan and in individuals with a range of cognitive deficits, suggest that physical activity could be used as both an important first-line approach for managing cognitive symptoms and for improving cognitive function in all individuals living in the United States . In summary, we provide compelling evidence that physical activity is related to a number of positive . This evidence comes from a variety of assessments that measure changes in brain cognitive outcomes . Further, a positive effect of physical structure and function, cognition, and applied academic outcomes activity on cognition is observed in children and adults, as well as in several special populations, suggesting that increasing physical activity may improve cognition in most, if not all, populations in the United States. Accordingly, such findings may serve to promote better cognitive function in healthy individuals, and serve to improve cognitive function in those suffering from certain cognitive and brain disorders. However, available scientific evidence is limited in certain populations (e.g., middle-aged 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -13

201 Part F. Chapter 3. Brain Health adults, those with autism spectrum disorder), and thus more research is needed to better understand the relation of physical activity to cognitive function in these individuals. Additionally, the modifying effects of sedentary behavior and other health outcomes (e.g., adiposity) on cognitive function are not . (For more details on the effects of sedentary behavior on other health well understood at this time outcomes, see .) However, as noted here, the evidence linking Part F. Chapter 2. Sedentary Behavior physical activity to positive cognitive outcomes is moderate, and a substantial portion of the population benefits from physical activity participation. . What is the relationship between physical activity and quality of life? Question 2 a) Does this relationship vary by population subgroup? Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Systematic reviews, meta-analyses, pooled analysis Data Sources: Conclusion Statements Strong evidence demonstrates that, for the general population, greater amounts of physical activity are associated with a positive perception of quality of life. PAGAC Grade: Strong. Strong evidence demonstrates that, for older adults (older than age 50 years; primarily 65 years and older), physical activity improves health-related quality of life when compared with minimal or no- Grade: Strong. treatment controls. PAGAC Strong evidence demonstrates that, for adults ages 18 to 65 years, physical activity improves health- PAGAC . Grade: Strong related quality of life when compared with minimal or no-treatment controls. Limited evidence suggests that among youth ages 5 to 18 years, lower levels of sedentary time are PAGAC associated with higher perceptions of global quality of life . Grade: Limited Moderate evidence indicates that physical activity improves quality of life in individuals with schizophrenia. Grade: Moderate. PAGAC Limited evidence suggests that physical activity improves quality of life for adults with major clinical PAGAC Grade: Limited. depression. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -14

202 Part F. Chapter 3. Brain Health Insufficient evidence is available because of a small number of controlled studies with mixed results to determine the relationship between physical activity and quality of life in individuals with dementia . Grade: Not assignable. Insufficient evidence is available to determine whether a dose-response relationship exists between physical activity and quality of life across populations. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the association between physical activity and PAGAC . quality of life varies as a function of race/ethnicity, socioeconomic status, or body mass index Grade: Not assignable. Review of the Evidence Introduction Quality of life (QoL) “is a reflection of the way that ind ividuals perceive and react to their health status 2 and to other, nonmedical aspects In its broadest form, QoL is sometimes referred to as their lives.” . of 40 satisfaction with life. QoL has a hierarchical structure, with domain-specific components under the 41 ; this umbrella of overall QoL (Figure 3- 1). One domain typically represents health-related QoL (HRQoL) domain is often split further into sub-domains/subscales of physical health-related QoL (e.g., evaluations of physical function) and mental health-related QoL (e.g., emotional health). Figure 3-1. Hierarchical Structure of Quality of Life 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -15

203 Part F. Chapter 3. Brain Health Maintaining or improving QoL is a universal goal. Being physically active has been suggested as one way to enhance perceptions of, and feelings of, QoL. This question focuses on the scientific literature that describes QoL as experienced by the general population across the lifespan. It also includes an assessment of the effects of physical activity on QoL in individuals with mental health issues. QoL among individuals who have a chronic physical condition, such as diabetes or osteoarthritis, is considered in Part F. Chapter 10. Individuals with Chronic Conditions. The literature reviewed here focused on QoL and HRQoL, specifically. Searches were not conducted on “well - being” or its derivatives, such as subjective well -being, positive well-being, or psychological well- 40 being. Those well-being concepts typically blend cognitive/evaluative and affective components and this question is limited to the cognitive/evaluative aspects widely known as quality of life. Literature Reviewed To answer this question, the Subc ommittee reviewed 18 systematic reviews across the following 59 -58 53 52 42- 51 individuals adults, youth, with dementia), populations: older adults (general), older adults ( 60, 61 52 individuals with depression, with schizophrenia, and 14 meta-analyses across the following 73 62- 64 65- 70 71, 72 general), populations: adults, and older adults (with dementia), a, older adults ( schizophreni 76 74, 75 older adults. ne pooled analysis on depression We also included o Po General pulation - Older Adults 42 46 The number of studies per review ranged from 6 However, many reviews included outcomes to 53. other than QoL, such as body composition and muscle strength. Thus, the number of studies reviewed 46 43 to 42, with many reviews that included both physical activity and QoL was smaller, ranging from 1 65 42 45 50 44 49 =4 =2 ), (N=4 ), (N ), (N=5 ), (N=3 ), (N=6 including fewer than 10 studies: (N ). The definition of “older adult” varied by study and primarily included individuals ages 65 years and older, but all studies included individuals of at least age 50 years and older. The systematic reviews 42 covered the following timeframes: inception (of the database) to January 2016, 2000-November 46 44 43 45 2012, 2006 - December 2000 to April 2015, inception to February 2010, 1966 to December 2006, 49 47 48 50 51 2008, 1993 - December, 2007. 1998 to July 2011, 2013, inception to December 2013, 1955 – 65 The meta-analyses covered an extensive timeframe: 2001 to June 2010, inception to September 70 69 66 67 2010, 1973 to August 2007, to May 1950 to November 2010, eption inception to July 2012, i nc 68 2013. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -16

204 Part F. Chapter 3. Brain Health QoL was most often conceptualized as HRQoL, and assessed using the 36-item Short Form Health Survey 42- 45 , (SF- 36) , a widely-used self-report measure of perceived physical and mental health and functioning. 42 49 , 65 -70, 76 Other QoL WHOQoL- measures that were used across studies included: MacNew global score, 43 46, 68 EuroQoL Group 5 - Dimension Self-Report Questionnaire, Bref, Mental health-related quality of 50 47 Satisfaction with Life Scale and Life life, World Health Organization (WHO) QoL for Elderly Scale, 66 68 and QoL operationalized as depression, vitality, and A, PGCMS and DQoL, Satisfaction Index- 48 perceived health. General Population - Adults 55 53, 62 The number of studies reviewed ranged from 14 The number of studies reviewed that to 56. included both physical activity and QoL was 179. The definition of adult varied from study to study. However, studies typically reported a mean age older , 63 , 64 , 58 53- 55 , 57 tic reviews covered the following than 18 years and younger than 65 years. The systema 53 54 55 1980 to August inception to November 2009, 1985 to December 2014, timeframes: 1806 to 2006, 58 63 57 56 inception to May 2015, 2001 to January 2016, and inception to February 2013. 2010, The meta- 62 64 and inception to 2011. analyses covered: inception to September 2007, 54, 57 , 58 , 62, 64 QoL was most often conceptualized as HRQoL, and assessed with the SF- 36 . Other QoL , 62 54, 58 62 measures included Satisfaction with Life Scale, and WHOQo L. General Population - Youth One systematic review was included, and covered inception to October 2013. A total of 91 studies were included, but only 14 addressed a QoL outcome. The mean age of those 14 studies ranged from 59 approximately 10 years of age to approximately 17 years of age. Individuals with Schizophrenia Systematic reviews that included a search for both physical activity and QoL ranged from 10 studies 60 an update to this review that included 13 studies s, including 332 participants in a qualitative analysi 61 s with 29 studies including 1,109 individuals with involving 549 participants, and a meta-analysi 61 60, 73 schizophrenia. Although the earlier reviews, included num erous outcomes, the most recent systematic review and meta-analyses included 770 participants in controlled or non-controlled studies in 73 which QoL was systematically measured. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -17

205 Part F. Chapter 3. Brain Health 60 61 The reviews covered the following timeframe: inception to July 2011, July 2011 to October 2014, and 73 inception to 2015. QoL was most often conceptualized as HRQoL, and assessed with the SF-36 or SF -12, the WHOQoL-Bref, 73 and the EuroQoL Group 5- Dimension Self-Report Questionnaire. Individuals with Depression 74 52 to June 2013, inception to May 2013, The reviews covered the following timeframes: inception and 75 inception to January 2013. Two of these reviews included 7 studies, and another that examined the . effects of yoga included 12 RCTs The number of studies reviewed that included both physical activity and QoL (N=10 studies) is much 75 that smaller than the total number of studies in the systematic reviews, ranging from one study 52 and a included only the Mental Component of the SF-36, four studies in older adults with depression, meta-analysis including four studies comparing physical activity to non-active controls, one study comparing physical activity to antidepressant medication, and one with comparison to cognitive therapy 74 for depression. 52 , 74, 75 36. QoL was conceptualized as HRQoL, and assessed in most cases with the SF- Individuals with Dementia 52, 71 72 The number of studies ranged from 2 studies to 13 studies. The reviews covered the following 52 71 72 to February 2009. inception to June 2013, timeframes: inception to February 2016, and inception Notably, these reviews included numerous other outcomes. QoL was most often conceptualized as 71, 72 such as HRQoL, and assessed with the SF-36 or disease-specific scales for patients with dementia, 52 the Alzheimer's Disease Related Quality of Life (ADQRL). The total number of studies with both physical activity interventions and QoL was 14. These included approximately 920 individuals for qualitative analyses, within which 6 studies with 385 individuals underwent quantitative meta-analyses. 72 The latter provided little evidence for physical activity to improve QoL in individuals with dementia. Physical Activity Exposures 46, 44- Types of physical activity varied across studies and included multicomponent exercise interventions, 52 43 48 , 49, 50 , 54 , 55 , 62 , 65- 67 , 71 , 72 , 73 42, , 72 , 54 , 56 , 62 , 72 , 73 43, 52, 56 , 62 , 70 aerobic training, resistance training, pilates, 47 , 71 , 73, 75 58 69 51 , 52 , 64 63 56 active video games, Zumba dance, gardening, walking, and yoga. qigong and tai chi, Some studies focused on physical activity volume, typically during leisure time, and did not differentiate 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -18

206 Part F. Chapter 3. Brain Health 53 , 57 type of activity. Of the studies reviewed, only one presented specific information on the frequency, 70 intensity, time, and type (FITT) principles for exercise prescription, however, the FITT principles were not reported in relation to QoL outcomes. Evidence on the Overall Relationship General Population - Older Adults Overall, results showed that physical activity consistently resulted in improvements in QoL in older adults. One meta-analysis reported that collectively, exercise programs (1,317 participants) improved the QoL (overall and health-related combined) of older adult participants (Z=2.23, =0.03), and the P 68 pooled standardized mean difference (SMD) was 0.86 (95% confidence interval ( CI): 0.11-1.62). In another meta-analysis, statistically significant improvements were found for the physical function subscale of the physical function component summary score of the SF-36 as a result of physical activity 67 In that review, no differences were found for the other g=0.41, 95% CI: 0.19-0.64, P <0.001). ’ (Hedges health-related quality of life (HRQoL) subscales, though the subscales of vitality (energy/fatigue), social functioning, role limitations due to emotional problems, and mental health (emotional well-being) were 67 Some reviews showed a wide range in QoL score improvement, from 17.1 in the positive direction. percent to 178 percent, and SF-36 subscales that improved were physical function, role limitations due 42 to physical health or emotional problems, pain, general health, and vitality (energy/fatigue). A systematic review of 10 studies on Pilates in the elderly included 4 studies showing improvement in domains of HRQoL including World Health Organ ization’s Quality of Life domains of sensorial abilities, activities, social participation, intimacy, while a meta-analysis pooling effects of HRQoL, depression, and activities of daily living showed a large composite positive effect size (Hedges ’ g=0.93; 95% CI: 0.631- 50 70 1.25, <0.001). w found improved HRQoL in six sub-scales of the The Raymond et al P systematic revie SF- 36, including physical functioning, role limitations due to physical health, vitality (energy/fatigue), ole limitations due to emotional problems, and mental health (emotional well-being) social functioning, r 49 ( P range <0.001-0.04); and a study in the Stevens et al systematic review showed significant improvements in vitality (energy/fatigue; odds ratio ( OR )=4.43; 95% CI: 0.31-8.54) and general health (OR =5.46; 95% CI: 1.69-9.24) scores in intervention groups vs. controls. A review of yoga studies SF-36, the estimated standardized reported that for the composite physical health subdomain of the mean difference (0.65; 95% CI: 0.02-1.28) favored the yoga intervention. On the composite mental health subdomain scale of the SF-36, the estimated standardized mean difference again favored yoga 69 – (SMD = 0.66; 95% CI: 0.10 1.22). 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -19

207 Part F. Chapter 3. Brain Health Physical activity as part of other activities that involve mental and physical components, such as qigong 51 L in both healthy and chronically ill individuals. and tai chi, hold great potential for improving Qo However, effect sizes were not included, it was not reported which of the subdomains of Qo L were improved, and results and conclusions were not separated by healthy and chronically ill participants. Moreover, given the mind-body nature of these modes of physical activity, it is not clear whether changes in QoL would be the result of changes in physical activity or other components of the activity (e.g., breathing, meditation). 76 In a pooled analysis, participants who were active for more than 150 minutes per week of physical activity but then dropped to fewer than 150 minutes per week from baseline to 6 months showed a 11.8 physical function scores. In contrast, those who were active for fewer than P <0.001) in SF- 36 point drop ( 150 minutes per week of physical activity but then increased to more than 150 minutes per week from 76 baseline to 6 months showed an increase of 5.1 points in SF-36 physical function scores. These results indicate the importance of maintaining physical activity for maintaining HRQoL in late adulthood. QoL domains are more equivocal. Studies examining non- The effects of physical activity on non- HR HRQoL domains show consistent and positive associations between physical activity and the domains of functional capacity, general QoL, and autonomy. These domains have been related to QoL in the elderly . However, few studies were methodologically rigorous. Effect sizes were generally small or moderate and 43 varied widely between studies and across QoL domains. Among frail older adults, one review found no significant differences in QoL among studies that used 65 water exercises, flexibility exercises, tai chi, and resistance exercises and others had too few studies to 46- 48 dies of QoL were not intended to capture objective measures of These stu make a conclusion. physical function (e.g., balance, gait speed), as the measures of QoL were developed to assess perceptions of functioning. Thus, in the context of frail older adults, beneficial effects of physical activity on measures of physical function may not be immediately apparent on perceptions of functioning that are captured by common instruments assessing QoL. In summary, the evidence points to a positive effect of physical activity on both overall and health- related QoL in older adults. Physical health-related QoL has been investigated more consistently than mental health-related QoL. The limited available literature suggests that the physical activity effects on physical and mental health composite scores appear to be similar in both direction and magnitude. There were insufficient studies and sample sizes to adequately analyze effects of different exercise 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -20

208 Part F. Chapter 3. Brain Health training modalities on QoL, few studies with extended follow-up, and few studies that differentiated the effects as a function of functional ability or frailty status . General Population - Adults 53- , 62- 64 58 ded that a positive association existed between physical Of nine studies, seven (78%) conclu , 56- 58 , 63 , 64 53 , 54 Of six that studied phy activity and overall QoL. sical function, all (100%) concluded that a 55, 57 , 58 , 62 53- All positive association existed between physical activity and the physical subdomain of QoL. nine studies examined psychological QoL, and eight out of the nine (89%) concluded that a positive , 54, 56 -58 , 62 -64 53 association existed between physical activity and QoL. Of the nine studies, the exposure variable was primarily aerobic physical activity, mostly leisure-time 56 , 62 , 57 , 54 53 58 63 physical activity in four, gardening in one, Zumba dancing in one, walking in one, qigong 64 and a mixture of aerobic, and related alternative or complementary types of physical activity in one, 55 strength training, and alternative or complementary types in one. The one meta-analysis reporting average effect sizes yielded a positive but not statistically significant N= 7; SMD=0.11; 95% CI: -0.03 to 0.24) and statistically trend for physical activity on overall QoL ( N= 6; SMD=0.22; 95% CI: 0.07-0.37) and significant positive effect sizes for physical health QoL ( 62 6; SMD=0.21; 95% CI: 0.06-0.36). psychological well-being ( N= Another review included 15 studies, of which 4 RCTs, 3 cohort studies, and 5 cross-sectional studies 53 Three provided sufficient information about the physical activity exposure and measurement of QoL. of the four RCTs reported significant improvements in reported QoL for the exposure group compared with the control group. All three of the cohort studies reported significantly higher QoL among those who were more physically active. All five of the cross-sectional studies reported a positive association between more physical activity and higher assessed QoL. 57 included 58 individual studies, 18 of which assessed QoL with the SF-36. Three of the 18 Pucci et al were cohort studies and 15 were cross-sectional. Of the three cohort studies, all reported positive associations for mental health and two of the three for physical health and vitality. Of the 15 cross- sectional studies, 13 reported positive associations between physical activity and the physical health domain and 9 reported positive associations for the mental health domain, with positive associations for subdomains related to vitality (9 studies) and pain (8 studies). 2018 Physical Activity Guidelines Advisory Committee Scientific Report -21 F3

209 Part F. Chapter 3. Brain Health The other six reviews reported similarly positive associations between greater amounts of physical , 63 , 58 , 64 56 54- activity and higher assessments of QoL. General Population - Youth There was no evidence available on the relationship between physical activity and QoL among youth. The evidence pertaining to the relationship between sedentary behavior and QoL among youth comes 59 from one systematic review. Of the 91 studies included in the review, 12 cross-sectional studies and 3 longitudinal studies provided information about the relationship between sedentary behavior and QoL among youth ages approximately 9 to 17 years. Nine of the 12 cross-sectional studies and 2 of the 3 longitudinal studies reported a negative association between sedentary behavior time and QoL. Individuals with Dementia Overall, little evidence supports a relationship between physical activity and QoL for individuals with dementia. A qualitative analysis of 14 studies reveals only 5 out of 13 studies reporting a positive , 72 71 52, relationship between physical activity interventions and improvements in QoL in this population. Meta-analyses showed no significant differences in five out of six studies for QoL outcomes for 72 The average effect was individuals in physical activity intervention groups compared with controls. 0.21 to 0.87) although this effect was inflated by a single small and non-significant (SMD=0.33; 95% CI: - outlier. Without that outlier, the effect was near zero (SMD=0.06; 95% CI: -0.10 to 0.22). These reviews examined a diversity of physical activity modalities, including aerobic training, strength training, 72 combined aerobic and resistance training, flexibility, balance, yoga, and tai chi. L, including physical Two studies of dementia patients found positive effects on selected domains of Qo 71 role functioning, while a more recent review with six studies had conflicting results for the association 52 between physical activity and Qo L in dementia. In summary, the evidence for a relationship between physical activity and QoL is conflicting, in part due to the small number of studies that systematically evaluated QoL, and inconsistency in outcome of QoL. In addition, the number of studies and sample sizes were insufficient to adequately measures analyze effects of different exercise training modalities on QoL, and no studies differentiated their effects based upon the categorical type of dementia (AD, A Disease and related dementias) or lzheimer’s the stage(s) of dementia in the participants. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -22

210 Part F. Chapter 3. Brain Health Individuals with Schizophrenia Moderate evidence supports the positive effects of physical activity on QoL for individuals with schizophrenia. These results come from consistent findings from systematic reviews from inception to 60, 61 The positive effects of physical 2014 for inpatients and outpatients across the adult age span. activity are shown in a meta-analysi s that examined 11 controlled and uncontrolled intervention studies, g=0.55, P <0.01), as well as for domains with moderate standardized effect sizes for overall QoL (Hedges ’ 73 g=0.50), social (Hedges ’ of physical (Hedges ’ g=0.62 g=0.67), and environmental QoL (Hedges ). Mental ’ ’ ’ g=0.58) and yoga QoL did not change in this population (Hedges g=0.38). Both aerobic exercise (Hedges ’ interventions (Hedges g=0.58) were found to be effective, consistent with reports from other systematic reviews. In addition to these effects of physical activity on QoL, the meta-analyses show that physical activity is associated with improvements on several other important outcomes that are related g=0.32, ’ <0.001); positive symptoms (Hedges P g=0.39, ’ including total symptom severity (Hedges to QoL, ’ P g=0.27, ’ <0.001) and general symptoms (Hedges P <0.01), negative symptoms (Hedges P g=0.49, g=0.32, P <0.01). Collectively, these consistently small to ’ <0.05); and global functioning (Hedges moderate effects indicate that individuals with schizophrenia and schizophrenia spectrum disorders may show improvements in QoL with physical activity. Individuals with Depression Limited evidence from 11 controlled studies suggests that physical activity improves selected domains of QoL for adults with major clinical depression, while the evidence for bipolar disorder is insufficient and , 75 , 74 52 understudied. Meta-analyses of four RCTs in adults with clinical depression comparing physical activity to either placebo or no physical activity found no statistically significant differences for the mental (SMD=-0.24; 95% CI: -0.76 to 0.29), psychological (SMD=0.28; 95% CI: -0.29 to 0.86), and social domains (SMD=0.19; 74 However, two studies reported a moderate effect size for improved 95% CI: -0.35 to 0.74). environment domain (SMD=0.62; 95% CI: 0.06-1.18), and four out of four studies reported a moderate effect size for improved physical domain (SMD=0.45; 95% CI: 0.06-0.83) in favor of the group assigned to structured physical activity. By contrast, controlled studies comparing physical activity to other therapeutic modalities for the treatment of depression, including cognitive therapy, as well as antidepressant medication, showed no between-group differences in the QoL mental or physical 74 A review of four RCTs in older adults with depression found that physical activity improved domains. 2018 Physical Activity Guidelines Advisory Committee Scientific Report -23 F3

211 Part F. Chapter 3. Brain Health 52 comparing yoga to a relaxation control group showed improvement of RCT One QoL in most reports. 75 50 percent or greater on the mental QoL domain. Collectively, these studies provide limited evidence for a moderate effect size of physical activity on physical and mental domains, but not overall QoL outcomes for adults with depression, when compared to placebo or inactive controls. In older adults with clinical depression, limited evidence from a small 52 number of controlled studies suggests that physical activity is associated with improved QoL outcomes. Thus, advancing age may serve as a response modifier for the effects of physical activity on QoL, consistent with our report that physical activity has a strong positive effect on HRQoL in the non- depressed older population. Evidence on Specific Factors Dose-response: Meta-analyses did not report on the effect of different doses of physical activity on QoL outcomes. Meta-analyses of older adults rarely Demographic factors, weight status, and physical activity type: reported whether effects of physical activity on QoL outcomes were modified by age, sex, socioeconomic status, race/ethnicity, presence of obesity, or baseline fitness levels, exercise intensity, frequency, or duration. One study that examined these associations found no significant differences when HRQoL outcomes were stratified according to country in which the study was conducted, sex, type 67 of physical activity program, and whether the physical activity sessions were supervised. In adults, systematic reviews and the meta-analysis rarely examined whether the effect of physical activity on QoL outcomes were modified by age, sex, baseline fitness levels, socioeconomic status, presence of obesity, or exercise intensity, frequency, or duration. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report 1 The 2008 Scientific Report included a section on well-being, which was broadly defined as the absence of distress. The conclusions from prospective cohort studies that “evidence from that report were indicates a small- The results that are physically active.” to-moderate association that favors people that we describe here as a part of the 2018 Scientific Report significantly expand on these results by focusing on QoL instead of a more limited definition of well-being. In addition, the 2018 Scientific Report extends 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -24

212 Part F. Chapter 3. Brain Health the 2008 findings by examining the effects of physical activity on physical and mental domains of HRQoL from RCTs that were conducted across the lifespan and in populations that often show significant losses . in QoL (e.g., schizophrenia) Public Health Impact Improved perceptions of quality of life can be expected to decrease the use of health-care delivery services and help to limit the rising costs of medical care in the United States. Reductions and low levels 77 of quality of life have been linked with mortality risk in older adults and are associated with greater use 78 of health-care services. Perceptions of quality of life can also serve as a barometer of healthy aging. For individuals with schizophrenia and schizophreniform disorders, improved perceptions of quality of life, along with related outcomes of improved positive and negative symptoms, general symptoms, and global functioning, indicate that greater physical activity can be a useful adjunct for management of such conditions. Given the large proportion of the population with chronic conditions and the growing number of older Americans, an improved sense of quality of life from regular physical activity can be ected to influence feelings of suffering and resultant demands on the health care system. exp Improved perceptions of quality of life also can be expected to reduce feelings of stress among individuals without chronic conditions. Americans report increasing levels of stress in their lives due to 79 This stress interferes with many aspects of health that can work, money, and the future of the nation. be mitigated by a higher sense of quality of life induced by regular physical activity. Thus, even in the absence of manifest disease, the benefits of physical activity are important for enabling Americans to live productive and rewarding lives. Question 3. What is the relationship between physical activity and (1) affect, (2) anxiety, and (3) depressed mood and depression? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Does the relationship exist across a continuum of mood and affective disorders (i.e., depression)? en physical activity and brain structure and function? d) What is the relationship betwe s, meta-analyses, review of reviews Systematic review Sources of Evidence: Conclusion Statements Strong evidence demonstrates from studies of acute bouts of exercise that negative affect increases as e experimentally imposed exercise intensity increases, and that negative affect is greatest when th 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -25

213 Part F. Chapter 3. Brain Health ventilatory threshold. Such evidence has been demonstrated in acute intensity exceeds the lactate or adolescents and in adults up throug h middle - age. PAGAC Grade: Strong. bouts of exercise in Strong evidence demonstrates that acute bouts of exercise can reduce state anxiety and that regular participation as well as longer durations of moderate - to - vigorous physical activity can reduce trait . anxiety in adults an d older adults. PAGAC Grade: Strong Insufficient evidence is available to determine the relationship between physical activity and anxiety PAGAC Grade: Not a ssignable . among youth. Insufficient evidence is available to determine whether a relationship exists between physical activity and anxiety among individuals with dementia or intellectual disability. PAGAC Grade: N ot assignable. experiencing depression. Strong evidence demonstrates that physical activity reduces the risk of PAGAC Grade: Strong. Strong evidence demonstrates that physical activity interventions reduce depressive symptoms in PAGAG Grade: individuals with and without major depression across the lifespan. . Strong whether a relationship between physical activity and ufficient evidence is available to determine Ins among exists individuals depression with dementia, stroke, or intellectual disability. PAGAC Grade: N ot assignable. response of effect of physical activity on depression. In adults, limited evidence suggests a do se - PAGAC . Limited Grade: nsufficient evidence is available to determine the dose - response of physical activity on In youth, i depression PAGAC Grade: Not assignable. . Strong evidence demonstrates that experimentally imposed high - intensity physical activity reduces pleasure while exercising. PAGAC Grade: Strong. response of exercise on anxiety. PAGAC Grade: N - ot Insufficient evidence is available on the dose . assignable 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 - 26

214 Part F. Chapter 3. Brain Health depressive symptoms can be reduced by even limited volumes and Moderate evidence indicates that intensities of physical activity and that greater frequencies and volumes of activity have a larger effect on reducing depressive symptoms. PAGAC Grade: Moderate. Insufficient evidence is avail able to determine whether sex, race/ethnicity, socioeconomic status, or PAGAC Grade: N weight status modify the associations between exercise and affect. . ot assignable Moderate evidence indicates that exercise reduces state anxiety more for females, adult s older than age 25 years, and sedentary individuals than for other population subgroups. PAGAG Grade: Moderate . Insufficient evidence is available to determine whether age, sex, race/ethnicity, socioeconomic status, or PAGAC Grade: weight status modify the associatio ns between exercise and trait anxiety. N ot assignable. Limited evidence is available that females show greater reduction in depressive symptoms with physical activity than do males. PAGAG Grade: Moderate. Strong evidence demonstrates that phy sical activity reduces anxiety symptoms in individuals with anxiety disorders and reduces depressive symptoms in individuals with major depression. PAGAC Grade: Strong . Insufficient evidence is available to determine whether physical activity influences ma rkers of brain PAGAC structure and function in the context of affect, anxiety, or depressed mood and depression. . ssignable a Not Grade: Review of the Evidence m ood, and reduc ing Elevating one’s goals and are essential for anxiety and depression are ubiquitous In this question , measurement of affect, anxiety, and maintaining a healthy and productive life. depression includes subjective experiences of feeling states based on pleasure and arousal, feelings of apprehension and worry, dep ressive symptoms, as well as clinical diagnoses of anxiety or depression analyses and systematic reviews of disorders. To address this question, the Subcommittee used 5 3 meta - the literature that examined whether results from al studies are and prospective longitudin RCTs s and ), anxiety (N= affect (N= 3; 1 meta - analys i associated with 2 systematic review s 1 3 ; 5 meta - analyses; systematic 4 1 8 systematic reviews ), or depressed mood or clinical depression (N= 41 ; 2 7 meta - analyses; . These reviews included r ) reviews esults from healthy young and older adults, children, and adolescents 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 - 27

215 Part F. Chapter 3. Brain Health as well as populations such as adults with dementia, schizophrenia, and stroke. We also included meta- tcomes. analyses and reviews of the effects of acute exercise on affect and state anxiety ou Affect Evidence on the Overall Relationship For this question, the term “affect” is defined as the transient and subjective experience of feeling states 80 Results based on independent dimensions of valence (pleasure/displeasure) and activation (arousal). from 10 experimental studies of affective responses during exercise (N=241 participants) were examined 81 Samples included in this review ranged from adolescents through in one high-quality meta-analysis. middle adulthood. Most samples had poor to average fitness levels (VO range = 23.3-48.7). Exercise 2peak bouts involved using a treadmill or cycle ergometer for 15 to 40 minutes, although most tests were 82 20-minute bouts. All studies used the single-item Feeling Scale. The lactate threshold limited to 15- to and ventilatory threshold are physiological markers that typically serve as reference points for intensity when marking these changes. Effects were estimated as the difference in affective valence (as defined at a given intensity when that intensity was by the scales used in the study, such as the Feeling Scale) imposed compared to when it was self-selected. When the imposed and self-selected exercise bouts were performed at equal intensities, no difference in affective valence was seen. When the imposed exercise intensity was varied experimentally, a clear dose-response pattern emerged. At exercise intensities below the lactate/ventilatory threshold, a small effect occurred (d = -0.36; 95% CI: -0.67 to - 0.04), and imposed exercise intensity was slightly less pleasant than self-selected exercise. At the lactate/ventilatory threshold, a medium-sized effect occurred (d = -0.57; 95% CI: -0.99 to -0.15), and imposed exercise intensity was moderately less pleasant than self-selected exercise. Above the lactate/ventilatory threshold, a large effect occurred (d = -1.36; 95% CI: -1.86 to -0.87), and imposed exercise intensity was much less pleasant than self-selected exercise. Findings regarding the effects of interval versus continuous exercise were mixed across nine experimental studies in which the type and intensity of exercise along with the timing of rest periods 83 Four studies documented a were carefully controlled and manipulated by the investigative teams. more unpleasant affective response during interval versus continuous exercise; four studies documented no difference in affective responses during interval and continuous exercise. Only one study reported more pleasure during interval versus continuous exercise. Six studies found no differences in post-exercise affect between interval and continuous exercise. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -28

216 Part F. Chapter 3. Brain Health Non-experimental evidence from ecological momentary assessments provides insight into relations 84 between physical activity and subsequent affective responses over a 3-hour interval. In 8 out of 11 studies, physical activity was associated with more pleasant and activated subsequent affective states following the activity bout. Results were mixed with regard to physical activity and unpleasant feelings. Two studies found no association between physical activity and subsequent unpleasant feelings and two studies found that physical activity was associated with reduced unpleasant feelings. A fifth study found that physical activity did not lead to acute reductions in unpleasant feelings but that people who were typically more active reported fewer unpleasant feelings in general. Dose-response: Strong evidence shows an effect of physical activity on immediate affective responses and that this effect is moderated by the imposed dose of activity. Evidence on Specific Factors Little is known about the persistence of the effects of Demographic factors and other moderators: physical activity on affective states across time or how they might be moderated by individual variability in demographic or other biological or environmental factors. Biomarkers: Insufficient evidence was available from the reviewed literature to determine whether physical activity modifies biomarkers of brain structure and function in the context of affect. There were no studies reviewed that examined brain measures or other biomarkers. Anxiety as a noticeable, psychophysiological emotional state, which is Here, the Subcommittee defines anxiety most often characterized by feelings of apprehension, fear or expectations of fear, worry, nervousness, and physical sensations arising from activation of the autonomic nervous system (e.g., increased muscle tension, elevated heart rate, sweating). This normal human emotion becomes pathological (i.e., clinical anxiety or an anxiety disorder) when it results in changes in thoughts and actions, occurs even in the 85 Anxiety absence of an eliciting event, and when the response is disproportionate and unmanageab le. and anxiety disorders are the most prevalent of mental disorders. With increasing levels of stress in the modern world, symptoms of anxiety are often elevated in those without clinical manifestations of anxiety. To date, hundreds of studies have examined the effects of exercise on anxiety reduction, both following single bouts of exercise (state anxiety: how anxious an individual feels at the moment) and as a result of regular exercise training (trait anxiety: how anxious an individual feels most of the time). The 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -29

217 Part F. Chapter 3. Brain Health majority of this work has examined the effects of exercise in individuals without elevated symptoms of anxiety and/or not diagnosed with any clinical anxiety disorders. Evidence on the Overall Relationship To examine the effects of acute exercise bouts on measures of state anxiety, the Subcommittee ) reviewed evidence from a meta-analysis of 36 RCTs (involving 1,233 individuals [726 females] 86 examining the effects of acute exercise on state anxiety published since 1990. Samples varied from an rs. Of these samples, 17 were ea of 25.3 y adolescence through middle-aged adults, with average age reportedly active, 6 were sedentary, 2 had a mixture of active and inactive participants, and 11 did not report baseline activity levels. Exercise bouts included continuous exercise on a treadmill or cycle ergometer or resistance exercise, lasting 20 to 30 minutes (1 study used 45 minutes and another used 20 ) used either the 10- or 50 minutes). The vast majority of the studies (75% -item State Anxiety 87 Inventory to assess anxiety before and after the exercise (or control) bouts. Study designs were either within-subject (64%) or between-subject (36%) randomizing, counterbalancing, or both the exercise – %). 64 treatment with a control (most often a quiet rest control The results from this analysis found that physical activity led to a small, but significant reduction in state anxiety symptoms following acute exercise compared with control (Hedges g=0.16). Several moderator ’ variables indicated that anxiety reduction was greater if: participants were female (Point Estimate=0.23), aged older than 25 y ea rs (Point Estimate=0.42), or sedentary (Point Estimate=0.39); the exercise intensity was high (compared to light or moderate; Point Estimate=0.36 vs 0.08, 0.03); the exercise modality involved a treadmill (Point Estimate=0.24); the control condition was quiet rest (Point Estimate=0.23); randomization and counterbalancing were used (Point Estimate=0.25); and overall study quality was high (PEDro score >6; Point Estimate=0.19). To examine the effects of long durations (i.e., weeks or months of regular activity) of physical activity on measures of trait anxiety, the Subcommittee extracted evidence from studies reviewed in meta- 88- 94 93 90 91- analyses, systematic reviews, and a quantitative review of 18 meta-analyses ; 4 of these meta- ly RCTs and analyses were conducted using 1 of these used clinically and non-clinically anxious on 95 to 65 adults. Samples ranged from children to older adults, with the majority ranging from age 18 88, , 93 89 , 92 yea rs. Four of the reviews focused on participants with either elevated anxiety symptoms or a clinical anxiety disorder. Exercise training involved aerobic and resistance exercise, with average duration of sessions and exercise intensity not well specified. Intervention lengths ranged from 2 weeks 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -30

218 Part F. Chapter 3. Brain Health to 6 months, with a range of 1 to 7 training sessions per week. Outcome measures varied considerably, from assessments of anxiety symptoms to clinical assessments of anxiety; all were used to assess anxiety before and after the exercise (or control) interventions. Control comparisons involved standard care a waitlist group that is tested several (most often pharmacotherapy or cognitive behavioral therapy), times before beginning the intervention, a placebo group, o r an other exercise intervention. 94 Physical activity had a significant effect on the reduction of trait anxiety. One review reported a 90 for non-RCT studies; d=0.45 from RCTs) and another review 31 moderate effect (Cohen d (d)=0. reported a small- to-moderate effect for resistance exercise training (d=0. 42 ). Reviews comparing the 88, 89 , 94 , 93 effects of exercise to other treatments consistently reported that exercise interventions were at 94 least as effective as standard care treatment for anxiety and sometimes even better. To use one 88 of exercise compared to various control groups (including active treatments) example, a meta-analysis as, and not inferior to, on trait anxiety in patient populations showed that exercise was as efficacious established treatments. Although most of the evidence is based on patient samples, evidence also 92 91, Finally, a meta-analysis of supports the anxiolytic effects of exercise in healthy older adult samples. 90 revealed that ng resistance exercise training it significantly reduced trait anxiety 16 studies examini symptoms (d=0. 42), more so in healthy individuals (d=0.50) compared to participants with a physical (d=0.15) or mental illness (d=0. 37 ). In addition, there is not strong evidence for a dose-response effect based on effect sizes that resistance exercise training is comparable to the positive ars and it appe effects of aerobic exercise training for reducing trait anxiety. In youth two of the five studies reported information about the relationship between physical activity , and anxiety. The review of reviews reported that vigorous exercise interventions compared with no 96 -0.48; 95% CI: -0.97 to 0.01). D= intervention was not associated with a reduction in anxiety (SM There was insufficient evidence from reviews to determine if physical activity reduces state or trait anxiety in individuals with dementia or intellectual disabilities. For individuals with post-traumatic stress disorder (PTSD), limited evidence suggests that physical activity is an effective treatment for anxiety symptoms. The Subcommittee examined evidence from 98 97, one of which was four reviews, two of which were systematic reviews, a systematic review and 99 and one of which examined PTSD and physical activity studies more descriptively, thus meta-analysis, 100 This literature suffers from a lack of not allowing any conclusions regarding magnitude of effect. experimental studies, with only two RCTs examining exercise and seven RCTs examining yoga. Overall, 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -31

219 Part F. Chapter 3. Brain Health the evidence indicates that exercise may have beneficial effects on PTSD symptoms and that regular physical activity may reduce risk of developing PTSD. The evidence also suggests that yoga may be useful (d=0. ) in alleviating PTSD symptoms, but the studies show little consistency regarding the type of yoga 48 and the length of treatment. Dose-response : Limited evidence suggests a dose-response effect of physical activity on either state or trait anxiety symptoms. Evidence on Specific Factors : Moderate evidence indicates that state anxiety reduction is moderated by sex Demographic factors and age such that females and those older than age 25 years show greater reductions in state anxiety 86 after participating in physical activity. Insufficient evidence was available from the examined literature on whether other demographic factors (race/ethnicity, socioeconomic status) moderate the effect of physical activity on anxiety symptoms (e.g., race). Biomarkers: Insufficient evidence was available from the reviewed literature to determine whether physical activity modifies biomarkers of brain structure and function in the context of anxiety or anxiety 94 disorders. Despite hypotheses from rodent and animal research, were no studies reviewed that examined brain measures or other biomarkers in humans in relation to physical activity and anxiety. Depression For this question, depression is defined as an unpleasant, low activation feeling state characterized by sadness, or feelings of hopelessness or guilt. In the extreme, these feelings can manifest as the clinical disorder of major depression. In this section, we have separated the results for depression based on studies focusing on physical activity as a prevention for depression from those studies focusing on its effects as a treatment. We included 14 systematic reviews and 27 meta-analyses of this literature. Evidence on the Overall Relationship Adults In the context of preventing depressive symptoms and major depression across the lifespan in both children and adults, the reviews and meta-analyses showed that greater amounts of physical activity are strongly associated with a reduced risk of developing depression. For one systematic review, 83 percent (25 of 30) of prospective observational studies found that greater amounts of physical activity were 101 . Even low amounts of activity associated with a reduced risk of experiencing depression at follow- up 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -32

220 Part F. Chapter 3. Brain Health (less than 150 minutes per week) were associated with significantly reduced risk of depression, although more activity was associated with larger effects. Engaging in more than 30 minutes per day of activity reduced the odds of experiencing depression by 48 percent. Similarly, another meta-analysis found that increased sedentary behavior across 11 prospective studies was associated with an increased risk of 102 depression (relative risk [RR]=1.14; 95% CI: 1.06 to 1.21). Limitations of this literature are that most studies used self-reported assessments of physical activity and multiple metrics of depression and depressive symptoms. Otherwise, these studies were generally of high methodologic quality. In the context of treatment, many studies have examined whether engaging in physical activity (through physical activity interventions) is an effective approach for reducing depressive symptoms or features of major depression. Most of these studies last approximately 12 weeks in duration. All of the meta- to-large effect sizes for the analyses and systematic reviews examined showed consistent and moderate- 68, 74 , 103-110 n- effect of physical activity on depressive symptoms across the adult lifespan, including in no 108 111-1 13 reported a moderate-sized effect of physical demented elderly. For example, Josef sson et al ’ activity interventions on depressive symptoms (Hedges g = -0.77). Several reports found that the average effect sizes for physical activity treatment ranged from -0.53 to -1.39 across studies. Effect sizes ten d to be larger for individuals with major depression (-1.03) and of more moderate size for individuals without clinical depression but with depressive symptoms (-0.59). When physical activity is compared to either cognitive behavioral therapy or anti-depressant pharmaceutical treatments, the groups show no significant differences, indicating that physical activity is as effective for treating depression as these 114 other common approaches for treatment. The effects cannot be explained solely by placebo effects. 75, 115 , 116 tai chi and Limited evidence also suggests beneficial effects on depressive symptoms from yoga, 117-120 121 ng, or dance. qigo Unfortunately, this literature is plagued by low methodological rigor and analysis, which limit the conclusions that can be drawn. Insufficient evidence is available to determine whether physical activity is an effective treatment for , 124 100 99, 122 123 depression and depressive symptoms for caregivers, people with dementia, PTSD, schizophrenia, intellectual disabilities, or other individuals with other neurologic/psychiatric , 126 71, 125 conditions. Youth , 128 127 54, For the effects of physical activity in youth, the evidence base comprised two meta-analyses, 129 , 130 96 The meta-analyses included a total of 15 and one review of reviews. two systematic reviews, 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -33

221 Part F. Chapter 3. Brain Health , 128 54 , 127 ; all studies were experimental in design. unique studies, with 2 studies included in both reviews 129, 96 130 Each of the systematic reviews included six longitudinal studies. The review of reviews included four systematic reviews that had appropriate exposures and outcomes for this question; the sum of RCTs included in each of the 4 reviews totaled 93. In all of the reviews, parameters of physical activity were obtained from a variety of self-report instruments. Similarly, symptoms of depression were 131 assessed with a wide variety of tools, standard and non-standard. All five studies reported statistically significant reductions in depressive symptoms in the more physically 128 54, active groups. One meta-analysis reported a Hedges ’ g= -0.26 (95% CI: -0.43 to -0.08) ; another a 127 standardized mean difference of -0.61 (95% CI: -1.06 The review of reviews reported a to -0.16). statistically significant reduction in the standardized mean difference among the more physically active 96 The review of reviews groups compared with inactive controls (SMD = -0.62; 95% CI: -0.81 to -0.42). also reported that physical activity interventions were comparable with psychologic and pharmaceutical therapies in terms of the reduction in depressive symptoms. One systematic review reported statistically significant reductions in depressive symptoms among the physically active groups in five of the six 129 pertinent studies, and a nearly significant reduction ( P < 0.10) in the sixth. The other systematic review reported significant ly higher levels of depressive symptoms among the more sedentary groups in 130 all five of the pertinent studies. One meta-analysis of adolescents that summarized results from eight RCTs reported that physical activity reduced depressive symptoms (SMD= -0.48), although this effect did 132 In studies limited to not reach significance when only the higher quality studies were examined. samples with clinical depression, physical activity had a significant effect on reducing depressive symptoms (SMD= -0.43). Dose-response : In adults, modest evidence suggests a dose-response effect of physical activity on depression. Even brief amounts (20 minutes per day) of activity is sufficient to show a reduction in depressive symptoms, but longer durations of activity have a larger effect. In youth, although the physical activity exposure was aerobic in nature and presumably approximated current guidelines in volume and intensity, none of the reviews provided outcome information at more than two levels of exposure, which prevented an assessment of dose-response. Evidence on Specific Factors Several reports indicate that the effects might be moderated Demographic factors and weight status: 74 by the sex of the individual, with studies including more females showing larger effect sizes. Despite 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -34

222 Part F. Chapter 3. Brain Health 94 this effect modification, there are other reports showing similar effects across males and females. In any case, potential sex differences (or lack thereof) should be interpreted with caution because of the higher prevalence of depression and depressive symptoms in females. In contrast, little to no information was provided about the influence, if any, of age, race/ethnicity, socioeconomic status, or weight status on the relationship between physical activity and measures of depressive symptoms or major depression. In youth, little to no information was provided about the influence, if any, of age (within the ages 5 to 18 132 sex, race/ethnicity, socioeconomic status, or weight status on the relationship between years), physical activity and the outcomes of interest. Biomarkers: In both adults and youth, insufficient evidence was available from the meta-analyses and reviews to determin e whether physical activity modifies biomarkers of brain structure and function in 133 Research using animal models of depression have the context of depression or depressive symptoms. described several mechanisms by which physical activity is likely leading to reductions in depressive 133 but research in humans have not verified these mechanisms with a sufficient number of symptoms, high-quality studies. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report 1 -based, prospective cohort studies provide The 2008 Scientific Report concluded that “population substantial evidence that regular physical activity protects against the onset of depression symptoms and major depressive disorder.” In addition, it concluded that RCTs showed that physical activity “ reduces depression symptoms in people diagnosed as depressed, healthy adults, and medical patients 1 without psychiatric disorders.” In the context of anxiety, the 2008 Scientific Report concluded that “a small number of nationally representative and population-based cross-sectional and prospective cohort studies supports that regular physical activity protects against the onset of anxiety disorders and anxiety 1 The 2008 Scientific Report also concluded that “participation in physical activity programs symptoms.” The findings from the 2018 Scientific Report are consistent with those reduces anxiety symptoms.” reported in 2008 but significantly extend them to include more information from prospective observational studies in the context of depression and from RCTs that now definitely demonstrate that physical activity is an effective treatment for reducing anxiety and depressive symptoms. In addition, the 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -35

223 Part F. Chapter 3. Brain Health 2018 Scientific Report includes an assessment of acute bouts of physical activity on measures of affect and state anxiety. Finally, the 2018 Scientific Report also provides an examination of physical activity on reducing depression and state and trait anxiety across multiple age groups and populations (e.g., youth). Public Health Impact 134 In the United States, fewer than half of children and adults engage in regular physical activity. Affective responses during, but not following, exercise predict adherence at 6- and 12-month follow- 135 A Adherence and health benefits can be optimized by regulating the intensity of exercise. ups. tradeoff should be expected between exercise intensity (and expected health benefits) and adherence. When vigorous-intensity exercise training is imposed, affective responses are likely to undermine adherence and additional interventions should be considered for improving affective responses and supporting adherence (see ). . Promoting Regular Physical Activity Part F. Chapter 11 . According to the Major depression is one of the most common mental disorders in the United States 136 estimated 16.1 million adults ages years or 18 National Survey on Drug Use and Health in 2015, an older, or approximately 6.7 percent of all US adults, had experienced at least one major depressive episode in the past year. These estimates were highest in adult females (8.5%) compared to males (4.7%) and in those between the ages of to 25 years (10.3%) . Children and adolescents also 18 experience episodes of major depression with an estimate of 3 million, or 12.5 percent, of adolescents ages 12 to 17 years in the United States experiencing at least one episode in the past year. Similar to adults, female adolescents had higher prevalence (19.5%) compared to males (5.8%) . These high prevalence rates have staggering costs associated with them . For example, in 2010, it was reported that annual costs related to major depression were $210.5 billion in the United States. Furthermore, major 44 to 15 depression was the leading cause of disability for individuals ages years, with almost 400 million 137 disability days per year. -month prevalence of any 12 Anxiety disorders are similarly prevalent and debilitating . For example, the anxiety disorder is 18.1 percent in the United States with females being 60 percent more likely than males to experience an anxiety disorder . Although healthcare costs associated with anxiety disorders not been studied as frequently as in depression, a 1990 study found that annual costs associated ve ha with anxiety disorders exceeded $46 billion. Despite these startling statistics, long-term adherence to many pharmaceutical treatments remains poor, and a better understanding of the impact of non-pharmaceutical interventions, such as physical 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -36

224 Part F. Chapter 3. Brain Health in this chapter clearly indicate that physical activity is an activity, is needed. The results report ed of depression that would clearly have downstream effective and robust approach for reducing the risk consequences for quality of life, health care costs, and job productivity. Furthermore, these results also demonstrate that physical activity is an effective approach for improving both anxiety and depressive symptoms (symptoms that often co-occur), with effect sizes that are similar to that of the most effective pharmaceutical approaches. In sum, physical activity holds great promise as a means for preventing and treating common mood disorders that are a significant source of disability, lower quality of life, and increased health care burden. Question 4: What is the relationship between physical activity and sleep? Is there a dose-response relationship for either acute bouts of physical activity, or regular physical a) activity? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Does the relationship exist for individuals with impaired sleep behaviors or disorders? If yes, for which sleep disorders? Sources of evidence : Systematic reviews, meta-analyses Conclusion Statements Strong evidence demonstrates that both acute bouts of physical activity and regular physical activity improve sleep outcomes in adults . PAGAC Grade: Strong. Moderate evidence indicates that longer duration acute bouts of physical activity and regular physical activity improve sleep outcomes. These positive effects are independent of exercise intensity. PAGAC Grade: Moderate. Moderate evidence indicates that the effects of physical activity on sleep outcomes in adults are preserved across age and sex, with the exception of sleep onset latency, which declines with age. PAGAC Grade: Moderate. Insufficient evidence is available to examine relationships between physical activity and sleep in children , and adolescents and whether the relationships vary according to race/ethnicity, socioeconomic status or weight status. PAGAC Grade: Not assignable. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -37

225 Part F. Chapter 3. Brain Health to-vigorous physical activity improves Moderate evidence indicates that greater amounts of moderate- sleep in adults who report sleep problems, primarily symptoms of insomnia, and for obstructive sleep apnea. PAGAC Grade: Moderate. Review of the Evidence Introduction Sleep is a reversible behavioral state of perceptual disengagement characterized by unresponsiveness to 138 139 It i s an important determinant of health and well-being across the lifespan. It is the environment. an essential biological function important for neural development, learning, memory, emotional 140 Sleep consists of four formally recognized stages regulation, and cardiovascular and metabolic health. and has several features that comprise the totality of sleep (Table F3-1). These stages and features are used by researchers to study sleep and, in a less formal manner, are used by everyone to recognize the 138 , 141 -143 Insomnia and obstructive sleep apnea, two common disorders of quality and value of sleep. , 145 , 144 85, 137 sleep, are also defined in Table F3-1. Table F3-1. Components of Sleep and Common Sleep Disorders Sleep Outcomes and Behaviors Definitions Length of time between going to bed and falling asleep. Sleep (onset) latency Total time of actual sleep, which is the sum of all time spent in each of the Total sleep time (TST) components (see Stages of sleep, below). Wake-time after sleep onset Amount of time spent awake after sleep onset and before the final (WASO) awakening, usually in the morning. The percentage of time of actual sleep out of all the time sleeping and Sleep efficiency 143 trying to sleep. 100*(TST/(Sleep latency + TST + WASO) Sleep normally progresses through a series of four stages in repeated Stages of sl eep cycles of about 90 minutes. The two earliest phases of sleep (except in infants), stages N1 and N2, -Rapid Eye Movement Non characterized by progressively deepening sleep as determined by brain (NREM) Light Sleep wave activity and arousal thresholds. Stage N3, deep sleep, is characterized by slow brain wave activity. Slow NREM Slow Wave Sleep wave sleep is associated with memory consolidation. Slow wave (deep) (Deep Sleep) sleep is maximal in children and declines with age. Rapid Eye Movement REM sleep is characterized by episodes of rapid eye movements, brain wave activation, lack of tone in skeletal muscles, and dreaming. Sleep (REM) 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -38

226 Part F. Chapter 3. Brain Health Sleep Outcomes and Behaviors Definitions Subjective perception of whole sleep experience. The most common scale used in this report and in the field of sleep medicine is the Pittsburgh Sleep Sleep Quality and its measurement Quality Index that scores subjective sleep quality, latency, duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, 146 and daytime dysfunction. Subjective perception of daytime sleepiness. The most common scale used Daytime Sleepiness and its in this report and in the field of sleep medicine is the Epworth Sleepiness measurement Scale, in which subjects estimate how likely they are to doze off during 8 147 daytime conditions ranging from TV watching to driving. Prevalent Sleep Disorders Diagnostic Criterion, Symptom Profile, Prevalence Insomnia disorder; Chronic Difficulty falling asleep, staying asleep, or early awakening associated with Insomnia Disorder distress or impairment (e.g., fatigue, poor concentration) ≥3 times per , 145 144 , 148 . week for ≥3 months Difficulty falling asleep, staying asleep, or early awakening associated with Insomnia symptoms distress or impairment (e.g., fatigue, poor concentration) less often or less 144 prolonged than for insomnia disorder. 15 or more apnea or hypopnea events ≥ 10 seconds in duration per hour based on monitoring, or 5 events per hour plus one or more signs or symptoms: 1) sleepiness, non-restorative sleep, fatigue, insomnia, 2) Obstructive Sleep Apnea (OSA) awakening with breath holding, gasping, choking, 3) bed partner notes snoring or breathing interruptions, 4) diagnosis of hypertension, mood disorder, cognitive dysfunction, coronary heart disease, heart failure, atrial , 150 141 , 149 fibrillation, type 2 diabetes mellitus (all linked to OSA). Literature Reviewed 142 159-163 55, , 151-158 and six systematic reviews. The evidence base comprised nine meta-analyses Ten of the 55, 1, 162 , 151 , 153 , 154 , 156 , 157 , 159 , 16 142 reviews included only experimental studies, two of the reviews included 158, 163 , 155 , 160 152 and three included only cross-sectional studies. only longitudinal studies, The 15 reviews included a total of 166 unique studies, 5 of which were cited in three different reviews, and 9 of which were cited in two reviews. Sleep - General Population 55, , 163 , 161 142, 160 , 156 , 155 152 focused on sleep stages and Four meta-analyses and four systematic reviews 152 , 160 features in the general population. Two of the reviews included only adolescents, and one of 160 included only female adolescents. those On e meta-analysis included 11 cross-sectional studies each 152 with questionnaire-reported physical activity, presumably of moderate- to-vigorous intensity. The 160 systematic review included two studies in which sedentary behavior was the exposure. The remaining , 156 , 161 , 163 142 , 155 55, six reviews, all of which focused on adults, included information from 122 unique 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -39

227 Part F. Chapter 3. Brain Health , 156 142 , 156 155 142, studies. Of the 3 meta-analyses, 2 included only experimental studies ; the third included 155 12 cross-sectional studies and 1 experimental study. Two of the three systematic reviews included 163 55, 161 The studies within these ; the third included only longitudinal studies. only experimental studies six reviews that focused primarily on adults included exposures that were mostly aerobic activities but were highly diverse, including activities such as walking, bowling, and yoga. One review included studies on the effects of a single acute bout of moderate- to-vigorous physical activity as well as assessing 142 to-vigorous intensity physical activity. habitual moderate- Obstructive Sleep Apnea 151, 153 , 154 Three meta-analyses focused on obstructive sleep apnea. All of the 18 studies included in the three reviews were experimental trials; the physical activity interventions were mostly supervised exercise programs in which the subjects accumulated around 150 minutes per week of mostly moderate-intensity physical activity. Insomnia , 162 , 163 159 156-158 focused on adults with insomnia. One systematic reviews Three meta-analyses and three 158 included 4 longitudinal and 12 cross-sectional studies; sedentary behavior was the is meta-analys 157 included 6 experimental studies; the exposure was exposure of interest. The other meta-analysis either moderate-intensity physical activity or high-intensity strength training. The two systematic 159, 162 n experimental studies of adults, one of which included only women. The included seve reviews 157-159 , 162 included exposure was mostly moderate-intensity aerobic activity. Collectively, the four reviews 25 unique studies, 9 experimental, 4 longitudinal, and 16 cohort. Evidence on the Overall Relationship , 163 142 , 155 , 156 55, 161 The three meta-analyses and the three systematic reviews all reported beneficial effects of greater amounts of physical activity on one or more aspect of sleep. The strongest evidence comes from analyses of 66 controlled intervention studies involving 2,863 community dwelling adults 142 ranging from age 18 to 88 years, including a majority without sleep problems (89%). The findings to-moderate size benefits of both regular physical activity and acute bouts of consistently show small- physical activity on multiple sleep outcomes, including total sleep time (both habitual and acute), sleep efficiency (both habitual and acute), sleep onset latency (both habitual and acute), sleep quality (habitual, insufficient information regarding acute), and rapid eye movement sleep (acute, insufficient information regarding habitual) (Table F3-2). to-vigorous physical activity also Acute bouts of moderate- 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -40

228 Part F. Chapter 3. Brain Health shorten the time awake after falling asleep and reduce the time in Stage 1 sleep. Acute bouts further 142 improve deep sleep; this effect is stronger among individuals who are habitually active. Table F3- of Habitual Moderate- to-Vigorous Physical Activity 2. Effect on Sleep Outcomes in Adults Compared to Controls and Acute Bouts of Moderate- to-Vigorous Physical Activity Compared to Controls Regular Physical Activity Acute Bouts of Physical Activity Sleep Outcome Cohen d effect size, 95% CI, and P Cohen d effect size, 95% CI, and P value value d=0.35 (95% CI: 0.00-0.70) d=0.17 (95% CI: -0.02-0.32) Sleep Onset Latency =0.03 <0.05 P P d=0.22 (95% CI: 0.10-0.34) d=0.25 (95% CI: 0.07- 0.43) Total Sleep Time <0.001 P =0.005 P d=0.38 (95% CI: 0.21-0.55) Wake-time after sleep Insufficient data onset P <0.001 d=0.25(95% CI: 0.12-0.39) d=0.30 (95% CI: 0.06-0.55) Sleep Efficiency <0.001 P =0.02 P d=0.35 (95% CI: 0.18-0.52) Shorter Time in Stage Insufficient data 1 Sleep <0.001 P The effects of an acute bout are greater d=0.19 (95% CI: 0.02-0.35) Longer time in Slow among individuals with higher baseline Wave Sleep =0.03 P physical activity -0.27 (95% CI: -0.45 to -0.08) d= Rapid Eye Movement Insufficient data Sleep P =0.005 d=0.74 (95% CI: 0.48-1.00) Insufficient data Sleep Quality Note: Effect size using Cohen d defines the strength of the relationship, with d=0.01 very small, d=0.20 small, d=0.50 medium, and d=0.80 a large magnitude effect 142 Source: Adapted from data found in Kredlow et al., 2015. to-vigorous physical activity is performed appears The time of day at which an acute bout of moderate- unrelated to most aspects of sleep. A comparison of the effect of acute bouts of moderate- to-vigorous physical activity performed more than 8 hours before bedtime, 3 to 8 hours before bedtime, and less than 3 hours before bedtime, showed no detectable difference on sleep onset latency, total sleep time, 142 y Physical activit sleep efficiency, slow wave sleep, stage 2 sleep, or rapid eye movement sleep latency. bouts performed less than 3 hours before bedtime were associated with significantly reduced wake time after sleep onset, and reduced stage 1 sleep, indicating less time spent in light sleep and fewer 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -41

229 Part F. Chapter 3. Brain Health awakenings. In contrast, physical activity bouts performed 3 to 8 hours before bedtime were associated 142 with reduced REM sleep. Moderate evidence indicates a dose-response relationship between the length in Dose-response: minutes but not the intensity or modality of moderate- to-vigorous physical activity and sleep outcomes. In adults, this evidence is supported by analyses from 59 controlled studies (N=2,863 participants) in which the length in minutes of acute physical activity bouts was found to moderate the beneficial effects on sleep onset latency (less), total sleep time (more), slow wave sleep (more), and rapid eye movement 142 In terms of regular physical activity, limited but concordant evidence suggests that more sleep (less). to-vigorous physical activity in each individual session is also associated with minutes of moderate- greater beneficial effects on reducing sleep onset latency. Taken together, these findings provide – to consistent evidence for a relationship between greater length in minutes of moderate- vigorous physical activity bouts associated with benefits to multiple objective and physiological sleep outcomes. In contrast to the length of each physical activity session, the number of weeks of the exercise intervention had a small but statistically significant effect on total sleep time, but no effect on sleep 142 quality, latency, or efficiency. slow wave on Regular physical activity levels influence the response to an acute bout of physical activity sleep. Among individuals with high baseline physical activity, acute bouts of physical activity are associated with significantly greater time in slow wave sleep, whereas those with low baseline physical activity levels have non-significant differences. However, the amount of regular or baseline physical activity does not alter the effect of an acute bout on sleep onset latency, sleep efficiency, and total sleep 142 time. Thus, most of the beneficial effects of acute bouts of physical activity on sleep are similar for individuals with both low and high baseline physical activity levels. to-vigorous physical activity on sleep outcomes is not known to vary for The effect of moderate- different types of physical activity. Although few of the included studies provided sufficient details of the intervention to inform the analyses, no differences were noted for the effects of light-, moderate-, or 142 Similarly, no differences were noted in a comparison of aerobic vigorous-intensity physical activity. with anaerobic physical activity. Mind-body exercises, such as tai chi or yoga, provided benefits equivalent to standard aerobic exercise. The effect on deep sleep was significantly better for biking than running, but their effects did not differ on other parameters of sleep. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -42

230 Part F. Chapter 3. Brain Health Evidence on Specific Factors Age: In adults, moderate evidence indicates that relationships between physical activity and sleep , 142, 155- 158 outcomes are consistent in their effects across young, middle-aged, and older men and women. 162 , 163 Consistent evidence indicates a reduced beneficial effect of greater physical activity amount on sleep latency with aging, consisting of a 0.15 standard deviation decrease in the beneficial effects of 142 In contrast, age does not moderate the regular physical activity for every decile increase in mean age. relationship between greater amounts of regular physical activity and its beneficial effects on total sleep time, sleep efficiency, and sleep quality. In contrast to systematic reviews in adults that include many controlled intervention studies, in children and adolescents, studies examining the relationship between physical activity and sleep are mostly 152 , 155 , 159 cross-sectional, with a few cohort studies. A meta-analysis of 15 studies of 12,604 individuals ages to 24 years, reported a beneficial effect of physical activity on sleep with an overall standard 14 155 mean difference CI: 0.41-1.13). Another meta-analysis of 11 cross-sectional studies of 0.77 (95% reported a relationship between greater physical activity and earlier bedtime, but not sleep onset 152 Similarly, analyses of epidemiological studies including adolescent females latency or total sleep time. 160 ed a relationship between increased screen-based sedentary time and greater sleep problems. report Other demographic factors and weight status: Limited evidence suggests that greater physical activity volume provides a slightly greater benefit for men than women on a few sleep outcomes (stage 1 sleep and wake time after sleep onset), but the strong relationship between greater physical activity and the majority of reported and device-measured sleep outcomes is not significantly different for men and 142 women. Data were insufficient to determine whether the relationship between physical activity varied by race/ethnicity, socioeconomic factors, or body weight. Obstructive sleep apnea: Moderate evidence indicates that physical activity is associated with significant improvements (reduction) in apnea hypopnea index (AHI), reduced daytime sleepiness, and improved sleep efficiency for individuals with obstructive sleep apnea. The AHI, the most widely used metric for grading the severity of obstructive sleep apnea, is the mean number of apneic plus hypopneic events per hour. Ts of supervised aerobic, muscle-strengthening, or combined aerobic and RC A meta-analysis of five a significant reduction in AHI index of -6.27 (95% CI: ed resistive training including 129 participants show to-moderate effect size improvement in sleep efficiency, as well as reduced to -3.99), and a small- -8.54 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -43

231 Part F. Chapter 3. Brain Health 154 daytime sleepiness, compared to controls. Another meta-analysis of 180 participants in 6 RCTs and 2 pre-post studies (the pre-post studies contributed 10 percent of the total number of participants ) reported a decrease in AHI (unstandardized mean difference (USMD) =-0.536 (95% CI: -0.865 to -0.206) 151 Finally, a network and reduced Epworth sleepiness scale (USMD=-1.246; 95% CI : -2.397 to -0.0953). meta-analysis compared the effectiveness of supervised aerobic exercise training with continuous 153 positive airway pressure (CPAP), mandibular advancement devices (MAD), and weight loss on AHI. , 165 164 CPAP, MAD, and weight loss are accepted treatments with demonstrated effectiveness. The analysis included a total of RCTs with 4,325 participants. The reduction in AHI for the supervised 80 exercise programs (-17.23; 95% CI: -25.82 to -8.54) was not inferior to CPAP (-25.27; 95% CI: -28.52 to - 22.03), MAD (-15.20; 95% CI: -19.50 to -10.91), or weight loss (-12.27; 95% CI: -18.79 to -5.75). Similar results were found for daytime sleepiness index. However, the supervised exercise programs included a total of only 72 participants. Collectively, these findings provide moderate strength evidence for a consistent relationship between greater physical activity and clinically significant improvements in sleep outcomes for adults with obstructive sleep apnea . of physical activity on sleep Moderate evidence indicates a similar beneficial relationship Insomnia: parameters in insomnia. A meta-analysis of 12 cross-sectional and 4 cohort studies with sample sizes ranging from 300 to 7,880 adults per study reported that sedentary behavior was associated with an increased risk of insomnia (poole OR =1.18; 95% CI; 1.01-1.36) and sleep disturbance (pooled OR =1.38; 158 95% CI: 1.28-1.49). A meta-analysis of 6 RCTs including 305 middle-aged and older adults indicates that physical activity interventions including aerobic or resistance training are associated with small- to- moderate effect sizes improving sleep quality (SMD=0.47; 95% CI: 0.08-0.86), sleep onset latency 157 (SMD=0.58; 95% CI: 0.08-1.08), and reduced sleep medication use (SMD=0.44; 95% CI: 0.14-0.74). Other systematic reviews of clinical trials in adults with chronic insomnia and sleep complaints report similar relationships between greater physical activity and sleep onset latency, sleep quality, and total 159 , 162 wake time after sleep onset. None of the reviews reported on sleep problems among children or adolescents. In addition, beyond obstructive sleep apnea and general sleep problems including insomnia, evidence from systematic reviews is insufficient to analyze relationships between physical activity and sleep for other sleep disorders. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -44

232 Part F. Chapter 3. Brain Health Comparing 2018 Findings with the 2008 Scientific Report 1 -based studies concluded that “A small number of observational, population The 2008 Scientific Report provides initial evidence supporting a positive association of regular participation in physical activity 1 with lower odds of disrupted or insufficient sleep, including sleep apnea.” The 2008 Scientific Report also concluded that “a small number of RCTs supports the conclusion that regular participation in ponent of good sleep hygiene.” physical activity has favorable effects on sleep quality and is a useful com The 2018 Scientific Report considerably extends these findings by including a significantly larger body of evidence, the results of which indicate that strong evidence now shows positive effects of both regular and acute physical activity on many different sleep outcomes. The 2018 Scientific Report also extends the 2008 findings to include both the effects of physical activity on sleep apnea as well as insomnia and other sleep complaints. Public Health Impact 139 , 166 Sleep is integral to health and well-being across the lifespan. The most common clinically recognized problems with sleep are insomnia and obstructive sleep apnea. Using strict diagnostic 144 An estimated 26 criteria, around 10 percent of adults suffer from clinically diagnosed insomnia. 167, 168 to 70 years suffer from obstructive sleep apnea, 30 percent of adults ages and the prevalence appears to be rising, in part because a major risk factor for obstructive sleep apnea is obesity. Beyond these specific disorders, one-quarter of the population reports getting insufficient sleep at least 15 out 170 139, 169 of every 30 days and one-third report getting less than the recommended amount of sleep. 142 Twenty-five percent to 48 percent of the population report a sleep problem of some kind. of accidents, The health effects of sleep problems are significant. They are associated with increased risk 150 obesity, cardiovascular risk factors, heart disease, stroke, and all-cause mortality. The National Highway Traffic Safety Administration estimates that 2.5 percent of all fatal vehicle crashes and 2 percent of nonfatal crashes involve drowsy driving; others have placed the estimate as high as 15 140 The United States sustains economic losses up to $411 billion per year and percent to 33 percent. 171 loses an equivalent of 1.23 million working days per year due to insufficient sleep. Obstructive sleep apnea, in particular, has strong associations with hypertension, heart failure, obesity, type 2 diabetes, myocardial infarction, stroke, up to 5-fold higher incidence of traffic and industrial accidents, and 50 , 173 , 172 150 percent higher mortality. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -45

233 Part F. Chapter 3. Brain Health The strong evidence in this question demonstrating the beneficial effects on sleep of both acute bouts and habitual participation in moderate- to-vigorous physical activity demonstrates that substantial medical and economic costs would be favorably influenced by a more physically active society. Less easily measurable but as important are the reported benefits associated with feeling well rested and more energetic. Finally, the strong evidence that habitual moderate- to-vigorous physical activity reduces the risk of excessive weight gain (see Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain ), an important risk factor for obstructive sleep apnea, indicates that physical activity could have a favorable impact on the incidence, as well as the treatment of, obstructive sleep apnea. NEEDS FOR FUTURE RESEARCH Conduct randomized controlled trials of moderate- 1. to-vigorous physical activity across the lifespan, including in youth, to better understand its effects on cognitive development, quality of life and health-related quality of life, state and trait anxiety, and sleep outcomes. Rationale: Despite considerable research focused on the importance of physical activity on brain health in adults and older adults, the paucity of knowledge during other periods of the lifespan , should be addressed to better understand physical activity effects on cognition, quality of life affect, anxiety and depression, and sleep outcomes, and how they may change, across the entire lifespan . Physical activity may beneficially affect measures of brain health in common childhood disorders such as attention deficit hyperactivity disorder and autism spectrum disorder, but the impact on these conditions, or the long-term impact of physical activity during childhood on adult outcomes are largely unknown. 2. Conduct randomized controlled trials that manipulate the physical activity dose in a systematic fashion to improve the understanding of the dose-response relationship and durability of physical activity effects on brain health. Conduct these studies in healthy children and adults, and also in populations with conditions and impairments of brain health (e.g., dementia, sleep disorders, mood disorders). Rationale: To date, little evidence exists to draw strong conclusions about the optimal intensity, , duration, and frequency of physical activity to enhance brain health (i.e., cognition, quality of life anxiety, depression, sleep). This work is critically needed to better inform the public and practitioners about the amount of activity needed to observe changes in brain health outcomes in healthy individuals and in individuals with cognitive, sleep, or mood disorders. Although the current 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -46

234 Part F. Chapter 3. Brain Health literature base does not allow for a firm understanding of a dose-response relationship between either acute or chronic physical activity on brain health, recommended doses of physical activity (e.g., moderate-to vigorous-intensity) have demonstrated positive effects on brain health across the lifespan. to-vigorous physical activity in Conduct randomized controlled trials of both light and moderate- 3. individuals with cognitive (e.g., dementia), mood (e.g., anxiety, depression), sleep (e.g., insomnia), and other mental health disorders (e.g., schizophrenia) to better understand its effects on brain health in these conditions, including aspects of quality of life and health-related quality of life . Further, conduct randomized controlled trials and observational studies in individuals at different stages or severity of impairment, including studies in individuals at risk of disease (e.g., genetic risk) as well as individual with comorbid conditions (e.g., anxiety and depression) to examine whether physical activity delays or prevents disease onset and progression, or interacts with common treatments used by individuals with disorders and diseases . Knowledge of this area varies across impairments, with some diseases and disorders Rationale: having significantly more research than others (e.g., depression). Yet, even in the context of some of these more common conditions, there is a paucity of research on some outcomes that are highly relevant for optimal functioning, such as the impact of physical activity on sleep, cognitive, and quality of life in individuals with depression. In addition, little is known about the effects of physical activity on conditions that often co-occur, like anxiety and depression. Other conditions that are also associated with impaired brain health (e.g., autism spectrum disorder, cancer, traumatic brain injury) have received little focus to date. Research in this area would contribute to a better understanding of etiologic subcategories of cognitive, sleep, mood, and other mental health conditions such as Alzheimer’s disease and related dementias, and Lewy Body, Vascular, and Mixed Dementias, which are increasingly recognized and diagnosed within the domains of impaired mental and neurological health in aging. 4. Conduct randomized controlled trials of physical activity that examine brain imaging and other biomarker metrics across the lifespan and in conditions characterized by cognitive, mood, and sleep impairments. These studies could yield a better understanding of circulating biomarkers (e.g., Rationale: gene) and ApoE4 neurotrophins) associated with brain health, and the relative roles of genetic (e.g., 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -47

235 Part F. Chapter 3. Brain Health environmental risk factors (e.g., stroke risk factors, traumatic brain injury) as covariates influencing the response to physical activity. To date, although candidate biomarkers and environmental risk factors have been identified, little systematic study in humans has emerged in the literature especially in relation to markers associated with affect, anxiety, depression, and sleep. Conduct studies to monitor sedentary time and conduct randomized controlled trials that 5. systematically reduce sedentary behaviors to improve the understanding of the impact of varying contexts, patterns, and durations of sedentary behavior on brain health outcomes (e.g., depression symptoms) throughout the lifespan and in populations with brain health disorders and diseases. The understanding of the effects of sedentary behavior on brain health is in its infancy. Rationale: Given that recent evidence indicates that sedentary behavior is distinct from physical inactivity, a greater understanding of the effect of sedentary behavior on brain health may inform and target interventions aimed at improving brain health across a variety of populations, including school-aged , as these populations spend considerable time during children, middle-aged adults, and older adults their day engaged in sitting and other sedentary behaviors. In addition, portable health technologies that continuously measure physical activity, estimate its intensity, and characterize sleep behavior, may offer inroads to better understand such relationships, and perhaps test novel interventions using connected health approaches. Conduct appropriate analyses to examine effect modification by demographic factors. Such 6. analytical approaches require studies that include large samples and substantial variation in sample characteristics (i.e., race/ethnicity, socioeconomic status). Rationale: Although some understanding of the effects of physical activity during the developing years and in aging has emerged, evidence for other demographic factors has not been demonstrated in a systematic fashion, affording little opportunity to form strong conclusions about any potential effect of these factors. Findings that incorporate other demographic factors stand to generalize the physical activity-brain health literature, improving understanding of this relationship more broadly across the U.S. population, deepening understanding of health disparities, and informing interventions aimed at improving brain health. 7. Conduct randomized controlled trials and prospective observational studies that will improve understanding of the latency and persistence of the improvements in brain health following both up acute and regular physical activity. These studies should have larger sample sizes, longer follow- 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -48

236 Part F. Chapter 3. Brain Health periods, and a broader range of instruments and outcomes relevant for brain health (e.g., mental subdomain of health-related quality of life, affect). To date, the temporal dynamics of the effects of physical activity on brain health are Rationale: poorly understood . Yet, it is known that individuals start and stop exercise regimens on a regular basis and such variability in the consistency of physical activity may differentially influence the impact of physical activity on brain health outcomes . It is possible that the persistence of the effects might also depend on the dose of activity (frequency, intensity, time, type), the age of the individual, the presence of a disorder or disease, or other factors. Enrolling samples of sufficient size to support mediator analyses (i.e., exploration of putative mechanisms through which the interventions operate) will provide useful information for adapting the interventions to optimize uptake among different subgroups as well as to identify key elements that are essential to improving brain health. 8. Conduct randomized controlled trials and prospective observational research on the impact of muscle-strengthening exercises (often referred to in the literature as resistance training) and other forms of physical activity (e.g., yoga, tai chi), and other modes of activity on brain health outcomes. Rationale: Most research in this area has been conducted using aerobic exercise approaches (e.g., brisk walking). Given the effects of muscle-strengthening exercises and the increased popularity of many other forms of physical activity (e.g., yoga, tai chi) and the evolving evidence of their influence on multiple health outcomes, it will be important to understand how these different modalities differentially influence cognition, quality of life, affective, anxiety, depression, and sleep outcomes. REFERENCES Physical Activity Guidelines Advisory Committee 1. Physical Activity Guidelines Advisory Committee. Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. of-life measurements. JAMA . 2. Gill TM, Feinstein AR. A critical appraisal of the quality of quality- 1994;272(8):619-626. 3. Etnier JL, Nowell PM, Landers DM, Sibley BA. A meta-regression to examine the relationship between aerobic fitness and cognitive performance. . 2006;52(1):119-130. Brain Res Rev 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -49

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245 Part F. Chapter 3. Brain Health 118 . Sarris J, Moylan S, Camfield DA, et al. Complementary medicine, exercise, meditation, diet, and lifestyle mo dification for anxiety disorders: a review of current evidence. Evid Based Complement Alternat Med . 2012. 2012:809653. doi:10.1155/2012/809653. 119 . Yin J, Dishman RK. The effect of Tai Chi and Qigong practice on depression and anxiety symptoms: a systematic review and meta-regression analysis of randomized controlled trials. Database of Abstracts of Reviews of Effects . 2014;(2):135-146. 120 . Wang F, Lee Ek, Wu T, et al. The effects of Tai Chi on depression, anxiety, and psychological well- 1(4):605-617. Int J Behav Med being: a systematic review and meta-analysis. . 2014;2 Cochrane Da tabase . Meekums B, Karkou V, Nelson EA. Dance movement therapy for depression. 121 Syst Rev . 2015;(2):CD009895. doi:10.1002/14651858.CD009895.pub2. 122 . Loi SM, Dow B, Ames D, et al. Physical activity in caregivers: What are the psychological benefits? Arch Gerontol Geriatr . 2014;59(2):204-210. doi:10.1016/j.archger.2014.04.001. 123 . Abraha I, Rimland JM, Trotta FM, et al. Systematic review of systematic reviews of non- pharmacological interventions to treat behavioural disturbances in older patients with dementia. The BMJ Open SENATOR-OnTop series. . 2017;7(3):e012759. doi:10.1136/bmjopen-2016-012759. . Barreto Pde S, Demougeot L, Pillard F, Lapeyre-Mestre M, Rolland Y. Exercise training for managing 124 behavioral and psychological symptoms in people with dementia: A systematic review and meta- Ageing Res Rev analysis. 4(Pt B):274-285. doi:10.1016/j.arr.2015.09.001. . 2015;2 . Adamson BC, Ensari I, Motl RW. Effect of exercise on depressive symptoms in adults with 125 neurologic disord ers: a systematic review and meta-analysis. Arch Phys Med Rehabil . 2015;96 (7):1329- 1338. doi:10.1016/j.apmr.2015.01.005. 126 . Eng JJ, Reime B. Exercise for depressive symptoms in stroke patients: a systematic review and meta-analysis. Cli n Rehabil . 2014;28(8):731-739. doi:10.1177/0269215514523631. 127 . Radovic S, Gordon MS, Melvin GA. Should we recommend exercise to adolescents with depressive . 2017;53(3):214-220. doi:10.1111/jpc.13426. J Paediatr Child Health symptoms? A meta-analysis. 128 . Brown H, Pearson N, Braithwaite R, Brown W, Biddle S. Physical activity interventions and Sports Med . depression in children and adolescents: a systematic review and meta-analysis. 2013;43:195-206. doi:10.1007/s40279- 012 -0015- 8. . Hoare E, Skouteris H, Fuller-Tyszkiewicz M, Millar L, Allender S. Associations between obesogenic 129 risk factors and depression among adolescents: a systematic review. Obes Rev . 2014;15(1):40-51. doi:10.1111/obr.12069. 130 . Hoare E, Milton K, Foster C, Allender S. The associations between sedentary behaviour and mental health among adolescents: a systematic review. Int J Behav Nutr Phys Act . 2016;13(1):108. https://doi.org/10.1186/s12966-016-0432-4 . doi: . Korczak DJ, Madigan S, Colasanto M. Children's physical activity and depression: a meta-analysis. 131 . 20 Pediatrics 17;139(4):1-14. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -58

246 Part F. Chapter 3. Brain Health 132 . Carter T, Morres ID, Meade O, Callaghan P. The effect of exercise on depressive symptoms in stematic review and meta-analysis. adolescents: a sy . 2016;55(7):580- J Am Acad Child Adolesc Psychiatry 590. doi:10.1016/j.jaac.2016.04.016. 133 . Schuch FB, Deslandes AC, Stubbs B, Gosmann NP, Silva CT, Fleck MP. Neurobiological effects of exercise on major depressive disorder: a systematic review. Neurosci Biobehav Rev . 2016a;61:1-11. doi:10.1016/j.neubiorev.2015.11.012. 134 . Troiano RP, Berrigan D, Dodd KW, Masse LC, Tilert T, McDowell M. Physical activity in the United States measured by accelerometer. Med Sci Sports and Exerc . 2008;40(1):181-188. doi:10.1249/mss.0b013e31815a51b3. . Rhodes RE, Kates A. Can the affective response to exercise predict future motives and physical 135 activity behavior? A systematic review of published evidence. Ann Behav Med . 2015;49(5):715-731. -5. doi:10.1007/s12160-015- 9704 . Center for Behavioral Health Statistics and Quality. Key substance use and mental health indicators 136 in the United States: Results from the 2015 National Survey on Drug Use and Health. HHS Publication No. SMA 16-4984, NSDUH Series H-51. Rockville, MD: Substance Abuse and Mental Health Services; 2016. https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH- FFR1-2015.pdf. Accessed January 4, 2018. . Greenberg PE, Fournier AA, Sisitsky T, Pike CT, Kessler RC. The economic burden of adults with 137 major depressive J Clin Psychiatry . 2015;76(2):155-162. disorders in the United States (2005 and 2010). doi:10.4088/JCP.14m09298. 138 . Carsakadon MA, Dement WC. Monitoring and staging human sleep. In Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine, 5th edSt. Louis: Elsevier Saunders; 2017. 139 . Office of Disease Prevention and Health Promotion. Sleep health. Washington, DC: Office of Disease Prevention and Health Promotion; 2017. https://www.healthypeople.gov/2020/topics- objectives/topic/sleep-health . . Mukherjee S, Patel SR, Kales SN, et al. An official American Thoracic Society statement: the 140 importance of h Am J Respir Crit Care Med . ealthy sleep. Recommendations and future priorities. 2015;191(12):1450-1458. doi:10.1164/rccm.201504-0767ST. 141 . Berry RB, Brooks R, Gamaldo CE, et al. The AASM Manual for the Scoring of Sleep and Associated Events: rules, terminology and technical specifications, version 2.4. Darien, IL: American Academy of Sleep Medicine; 2017. 142 . Kredlow MA, Capozzoli MC, Hearon BA, Calkins AW, Otto MW. The effects of physical activity on sleep: a meta-analytic review. J Behav Med . 2015;38(3):427-449. doi:10.1007/s10865-015-9617- 6. . . Reed DL, Sacco WP. Measuring sleep efficiency: what should the denominator be? J Clin Sleep Med 143 16;12(2):263-266. doi:10.5664/jcsm.5498. 20 144 . Lichstein KL, Petrov ME, Taylor DJ, McCrae CS. Insomnia: epidemiology and risk factors. In Kryger ement WC. Principles and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders; MH, Roth T, D 2017. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -59

247 Part F. Chapter 3. Brain Health 145. American Academy of Sleep Medicine. International classification of sleep disorders, 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. 146 . Mollayeva T, Thurairajah P, Burton K, Mollayeva S, Shapiro CM, Colantonio A. The Pittsburgh sleep as a screening tool for sleep dysfunction in clinical and non-clinical samples: a systematic quality index review and meta-analysis. Sleep Med Rev . Feb 2016. doi:10.1016/j.smrv.2015.01.009. Sleep . Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. . 147 – 545. 1991;14(6):540 148 . American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5), 5th ed. Washington, DC: American Psychiatric Association; 2013. 149 . Berry RB. Sleep breathing disorders. In Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders; 2017. 150 . Greenberg DL. Obstructive sleep apnea. In Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders; 2017. 151 . Aiello KD, Caughey WG, Nelluri B, Sharma A, Mookadam F, Mookadam M. Effect of exercise training Respir Med . 2016;116:85-92. on sleep apnea: a systematic review and meta-analysis. doi:10.1016/j.rmed.2016.05.015. 152 . Bartel KA, Gradisar M, Williamson P. Protective and risk factors for adolescent sleep: a meta- Sleep Med Rev analytic review. . 2015;21:72-85. doi:10.1016/j.smrv.2014.08.002. 153 . Iftikhar IH, Bittencourt L, Youngstedt SD, et al. Comparative efficacy of CPAP, MADs, exercise- training, and dietary weight loss for sleep apnea: a network meta-analysis. Sleep Med . 2017;30:7-14. doi:10.1016/j.sleep.2016.06.001. 154 . Iftikhar IH, Kline CE, Youngstedt SD. Effects of exercise training on sleep apnea: a meta-analysis. Lung . 2014;192(1):175-184. doi:10.1007/s00408-013-9511- 3. 155 . Lang C, Kalak N, Brand S, Holsboer-Trachsler E, Pühse U, Gerber M. The relationship between physical activity and sleep from mid adolescence to early adulthood. A systematic review of . 2016;28:32-45. methodological approaches and meta-analysis. Sleep Med Rev doi:10.1016/j.smrv.2015.07.004. . Rubio-Arias JÁ, Marín-Cascales E, Ramos-Campo DJ, Hernandez AV, Pérez-López FR. Effect of 156 exercise on sleep quality and insomnia in middle-aged women: a systematic review and meta-analysis of randomized controlled trials. Maturitas . 2017;100:49-56. doi:10.1016/j.maturitas.2017.04.003. 157 . Yang PY, Ho KH, Chen HC, Chien MY. Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review. J Physiother . 2012;58(3):157-163. doi:10.1016/S1836-9553(12)70106- 6. 158 . Yang Y, Shin JC, Li D, An R. Sedentary behavior and sleep problems: a systematic review and meta- Int J Behav Med . 2017;24(4):481-492. analysis. 159 . 2011;pii:2302. BMJ Clin Evid . Alessi C, Vitiello MV. Insomnia (primary) in older people. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -60

248 Part F. Chapter 3. Brain Health 160. Costigan SA, Barnett L, Plotnikoff RC, Lubans DR. The health indicators associated with screen- based sedentary behavior among adolescent girls: a systematic review. J Adolesc Health . 2013;52(4):382-392. doi:10.1016/j.jadohealth.2012.07.018. . Dolezal BA, Neufeld EV, Boland DM, Martin JL, Cooper CB. Interrelationship between sleep and 161 Adv Prev Med matic review. . 2017;2017:1364387. doi:10.1155/2017/1364387. exercise: a syste 162 . Passos GS, Poyares DL, Santana MG, Tufik S, Mello MT. Is exercise an alternative treatment for . 2012;67(6):653-660. chronic insomnia. Clinics (Sao Paulo) . Smagula SF, Stone KL, Fabio A, Cauley JA. Risk factors for sleep disturbances in older adults: 163 evidence from prospective studies. Sleep Med Rev . 2016;25:21-30. doi:10.1016/j.smrv.2015.01.003. 164 . Freedman N. Positive airway pressure treatment for obstructive sleep apnea. In Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders; 2017. . Patil S, Winocur E, Buenaver L, Smith MT. Medical and device treatment for obstructive sleep 165 apnea. In Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine, 5th ed. St. Louis: Elsevier Saunders; 2017. . Institute of Medicine, Committee on Sleep Medicine and Research. Sleep disorders and sleep 166 deprivation: an unmet public health problem. Washington, DC: National Academies Press; 2006. 167 . Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol . 2013;177(9):1006-1014. 168 . American Academy of Sleep Medicine. Rising prevalence of sleep apnea in U.S. threatens public health. Washington, DC: American Academy of Sleep Medicine; 2014. https://aasm.org/rising- prevalence- of-sleep-apnea- in-u-s-threatens-public-health/ . . Centers for Disease Control and Prevention, Epidemiology Program Office. Perceived insufficient 169 mong adults: United States, 2008. . 2009;58(42):1175-1179. MMWR rest or sleep a 170 . Centers for Disease Control and Prevention (CDC). Sleep and sleep disorders. CDC website. . Accessed January 29, 2018. https://www.cdc.gov/sleep/index.html . Hafner M, Stepanek M, Taylor J, Troxel WM, Van Stolk C. Why sleep matters mic costs the econo — 171 of insufficient sleep: a cross-country comparative analysis. Cambridge, UK: Rand Corp; 2016. 172 . . Kato M, Adachi T, Koshino Y, et al. Obstructive sleep apnea and cardiovascular disease. Circ J 2009;73(8):1363-1370. 173 . Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med . 2010;182(2):269-277. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F3 -61

249 Part F. Chapter 4. Cancer Prevention PART F. CHAPTER 4. CANCER PREVENTION Table of Contents ... -2 Introduction F4 Review of the Science ... F4 -3 F4 Overview of Questions Addressed ... -3 ... F4 -4 Data Sources and Process Used to Answer Questions Question 1: What is the relationship between physical activity and specific cancer incidence? ... F4 -5 -5 ... F4 ... Bladder Cancer ... F4 -7 Breast Cancer ... -15 Colon Cancer F4 ... ... F4 -18 Endometrial Cancer Esophageal Cancer ... F4 -22 ... ... F4 -25 Gastric Cancer ... Renal Cancer -27 F4 Lung Cancer -30 F4 ... Hematologic Cancers ... F4 -33 -37 F4 Head and Neck Cancers ... Ov arian Cancer ... F4 -39 Pancreatic Cancer ... F4 -42 Prostate Cancer ... F4 -44 Brain Canc F4 -47 er ... Thyroid Cancer ... F4 -49 Rectal Cancer ... F4 -51 Other Cancers ... F4 -54 F4 -54 ... Question 2: What is the relationship between sedentary behavior and cancer incidence? F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -1

250 Part F. Chapter 4. Cancer Prevention Overall Summary and Conclusions ... F4 -56 -59 F4 ... Needs for Future Research References ... F4 -60 ON INTRODUCTI In 2017, 1,688,780 new cancer cases and 600,920 cancer deaths are projected to occur in the United 1 States. On average, 38 percent of American women and 42 percent of American men will be diagnosed 2 Although several genetic causes of cancer have been with an invasive cancer over their lifetimes. 3 In addition to lack of physical identified, most cases of cancer are due to the environment or lifestyle. activity, other known lifestyle and preventable causes of cancer include tobacco use, alcohol intake, diet, obesity, and behaviors that increase exposure to oncogenic viruses. Therefore, there is great need and possibilities for cancer prevention through lifestyle change. There are more than 100 types of cancer based on body site or cell of origin. Furthermore, most cancers include subtypes defined by anatomy, histology, or genomics. Cancer types and subtypes often differ in etiology or natural course. Therefore, studying the association of physical activity with cancer risk is tantamount to determining the effect of physical activity on scores of endpoints. In this report, subtypes of cancer sites are listed where etiologies, including physical activity exposure, are known to vary by subtype. Decades of epidemiologic research have identified a physically active lifestyle as protective against the occurrence of some common cancers. The 2008 Physical Activity Guidelines Advisory Committee concluded that a moderate, inverse relationship existed between increased levels of physical activity 4 and reduced risks of colon and breast cancers. The 2008 Committee also found some evidence of reductions in risk of lung, endometrial, and ovarian cancers with increased physical activity, but no 4 change in risk of prostate or rectal cancers. Information was deemed too sparse to make conclusions 4 Physical Activity Guidelines Advisory Committee Report, 2008 provided probable for other cancers. The risk reduction levels, based on reviews of individual reports; no meta-analyses were performed, and none were found from the literature at that time. Since that report was released, the epidemiologic literature has grown enough to allow the use of meta-analytic and pooled analysis techniques to provide robust estimates of the effect of physical activity on occurrence of both common and rarer cancers. F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -2

251 Part F. Chapter 4. Cancer Prevention Interest in understanding the health effects associated with sedentary behavior (sitting) is also increasing. The 2008 Advisory Committee did not review the evidence on the association between sedentary behavior and cancer incidence. However, since 2008, an emerging literature has accumulated with respect to the association between sedentary time and cancer incidence and the Cancer Prevention Subcommittee included a question on this issue. (For additional information on the health effects associated with sedentary behavior, see .) Part F. Chapter 2. Sedentary Behavior The 2008 Scientific Report also cited some mechanisms that may explain the associations between 4 physical activity and cancer risk, but did not perform a systematic review. Given the extremely large 5-8 literature in this area, including human experimental, observational, animal models, and other laboratory work, the Cancer Prevention Subcommittee was not able to perform a systematic review of ommittee recognizes Subc the literature on mechanisms linking physical activity to cancer. However, the that this topic is a critical area of research that needs further attention and helps provide more understanding of how physical activity is related to cancer. Finally, while many of the reviewed cancers occur in children as well as adults (e.g., leukemia, lymphoma), the etiology of these cancers often differs significantly in children versus adults. In addition, the usual long latency period for physical activity to protect against cancer development in adults will likely not be relevant to cancers occurring in children. For this reason, the literature revi ew on physical activity and cancer risk has been limited to adults. Therefore, the Subcommittee limited its search to cancers in adults. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses two major questions and related subquestions: 1. What is the relationship between physical activity and specific cancer incidence? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Does the relationship vary by specific cancer subtypes? present in individuals at high risk, such as those with familial predisposition to Is the relationship d) cancer? F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -3

252 Part F. Chapter 4. Cancer Prevention 2. What is the relationship between sedentary behavior and cancer incidence? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Is the relationship independent of levels of light, moderate, or vigorous physical activity? that bouts or breaks in sedentary behavior are important factors? d) Is there any evidence Data Sources and Process Used to Answer Questions d Systematic literature searches were conducted to answer Questions 1 and 2. The databases searche included PubMed, Cochrane, and CINAHL. The literature search to address Question 1 was limited to systematic reviews, meta-analyses, and pooled analyses. The literature search strategy to address Question 2 was expanded to also include original research articles, and was conducted in two steps. Step 1 involved a search for existing systematic reviews and meta-analyses that could address the question. Step 2 involved a de novo literature search of more recent original research studies published after the systematic reviews and meta-analyses. Question 2 is the same as the cancer component of Part F. Chapter 2. Sedentary Behavior .) Question 4 in the sedentary behavior chapter (for details, see In the studies included in the meta-analyses, systematic reviews, and pooled analyses, physical activity was measured by self-report, with different types of physical activity questionnaires. In many studies, participants were presented with a list of typical activities (e.g., walking, running, biking), and asked to indicate the frequency and duration of each activity. Other studies used more general questions about time spent in moderate- or vigorous-intensity activities. Most collected information on recreational activities, several also included occupational activities, and only a few included household activities. Some estimated total physical activity, adding up all of these activities; most limited estimation o f amount of activity to leisure time activity. Most of the meta-analyses estimated MET-hours per week of erate and vigorous physical activities where data were available, but the cut- points for “highest” mod versus “lowest” activity levels varied across studies . Although most studies assigned a MET value of 6 for vigorous activities, some assigned a value of 8. 9 Most of the meta-analyses, as well as the large pooled study, were restricted to prospective cohort studies in order to minimize error from reporting that might occur because of recall of past physical activity levels that is required in case-control studies. However, for some more rare cancers, meta- Subc analyses or pooled analyses did include case-control studies. For this reason, the ommittee did not F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -4

253 Part F. Chapter 4. Cancer Prevention exclude results from systematic reviews, meta-analyses, or pooled analyses in making conclusions about the associations between physical activity and risk for specific cancers. Question 1: What is the relationship between physical activity and specific cancer incidence? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Does the relationship vary by specific cancer subtypes? t in individuals at high risk, such as those with familial predisposition to d) Is the relationship presen cancer? Sources of evidence: Meta-analyses, systematic reviews, pooled analyses Cancers for Which Physical Activity Shows Strong Evidence of a Protective Effect Bladder Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of physical activity are associated with reduced risk PAGAC Grade: Strong. of developing bladder cancer. Moderate evidence indicates a dose-response relationship between increasing physical activity levels and decreasing risk of bladder cancer. PAGAC Grade: Moderate. Limited evidence suggests that the effects of physical activity on bladder cancer risk are lower for men PAGAC Grade: than for women. Insufficient evidence is available to determine whether the . Limited effects of physical activity on risk of bladder cancer differ by specific age, race/ethnicity, socioeconomic groups, or weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the effects of physical activity are similar for all types of bladder cancer. PAGAC Grade: Not assignable Insufficient evidence is available to determine whether the effects of physical activity on bladder cancer PAGAC Grade: Not assignable. risk differ in individuals at elevated risk of bladder cancer. Review of the Evidence Based on data from 2010 to 2014, the incidence rate of bladder cancer was 19.8 per 100,000 men and 10 women per year. The number of deaths was 4.4 per 100,000 men and women per year. Several factors F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -5

254 Part F. Chapter 4. Cancer Prevention increase risk of bladder cancer, including smoking, exposure to certain occupational toxins, and arsenic 11 in drinking water. Bladder cancer is more common in individuals older than age 55 years than in younger individuals, in men than in women, and in individuals with a personal or family history of cancer of the urinary tract. Sub To examine the association between physical activity and risk of bladder cancer, the committee 12 reviewed one published meta-analysis. The meta-analysis contained data from 11 cohort a nd 4 case- control studies. The Subcommittee also reviewed one pooled analysis of 12 large prospective cohort 9 studies and meta-analysis data from the World Cancer Research Fund, which included data from 12 13 cohort studies. Evidence on the Overall Relationship A considerable body of epidemiologic data exists on the association between physical activity and risk of developing bladder cancer. The meta-analysis reported that risk of bladder cancer was significantly lower for individuals engaging in the highest versus lowest categories of recreational or occupational 12 RR )=0.85; 95% confidence interval ( CI): 0.74-0.98). physical activity level (relative risk ( Most studies adjusted for multiple potential confounding factors, including age, body mass index (BMI), and other bladder cancer risk factors. Similar to these findings, the pooled analysis of 12 cohort studies found a th th versus percentile level for leisure time physical statistically significant relationship between the 90 10 9 activity and decreased risk of bladder cancer (RR=0.87; 95% CI: 0.82-0.92). In contrast, the World Cancer Research F und meta-analysis summary result for highest versus lowest physical activity, which did not include studies focused on occupational physical activity, showed a non-statistically significant 13 effect (RR=0.94, 95% CI: 0.83-1.06). Dose-response: The meta- an alysis examined the dose-response relationship by quartiles of physical activity in each study. Compared with the least active quartile, those in quartiles 2, 3, and 4 had RR (95% 12 CIs) of 0.90 (0.83-0.97), 0.86 (0.77-0.96), and 0.83 (0.72-0.95), respective The pooled analysis of 12 ly. cohort studies found a significant linear relationship between increasing leisure time physical activity 9 <0.0001; P P percentile and decreasing risk of bladder cancer ( =0.59). non-linear overall Evidence on Specific Factors The meta-analysis found some differences in physical activity effect on bladder cancer risk between Sex: 12 Although the pooled men (RR=0.92, 95% CI: 0.82-1.05) and women (RR=0.83; 95% CI: 0.73-0.94). F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -6

255 Part F. Chapter 4. Cancer Prevention analysis found that the effect size of physical activity on risk of bladder cancer was similar in men and 9 P =0.81). women, the association was statistically significant only in women ( heterogeneity None of the analyses provided data within specific age groups. Age: Race/ethnicity: All but one study in the meta-analysis were conducted in the United States and Europe; the one study in Asia (men only) showed a non-statistically significant association of physical activity 12 with bladder cancer risk (RR=0.94; 95% CI: 0.77-1.15). None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and bladder cancer incidence. Hence, no conclusions can be made on this factor. th th The pooled analysis examined associations between the 90 percentile versus 10 Weight status: percentile of physical activity level by BMI. Risk of bladder cancer associated with physical activity level 9 2 2 = 0.80). P versus BMI >25 kg/m did not differ for those with BMI <25.0 kg/m ( on interacti Cancer subtype: Neither the meta-analysis nor the pooled analysis provided data by subtype of bladder cancer. Individuals at high risk : No information was provided in the meta-analysis or in the pooled analysis about the effects of physical activity in individuals at elevated risk of bladder cancer. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Breast Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of physical activity are associated with a lower risk of breast cancer. PAGAC Grade: Strong. Strong evidence demonstrates that a dose-response relationship exists between greater amounts of physical activity and lower breast cancer risk. PAGAC Grade: Strong. Moderate evidence indicates that greater amounts of physical activity are associated with a greater risk . reduction in all women regardless of body mass index Insufficient evidence is PAGAC Grade: Moderate. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4 -7

256 Part F. Chapter 4. Cancer Prevention available to determine whether the amount of physical activity and risk of breast cancer incidence varies at the relationship between physical by age. PAGAC Grade: Not assignable . Limited evidence suggests th Insufficient evidence PAGAC Grade: Limited. activity and breast cancer does not vary by race/ethnicity. is available to determine whether the relationship between physical activity and breast cancer varies by socioeconomic status. PAGAC Grade: Not assignable . Limited, but inconsistent, evidence suggests that the relationship between physical activity and breast cancer varies by specific histologic types of breast cancers. Limited PAGAC Grade: . Limited evidence suggests that the relationship between physical activity and breast cancer is apparent in women at increased breast cancer risk, as an enhanced effect of physical activity was associated with PAGAC Grade: premenopausal breast cancer in women with a positive family history of breast cancer. Limited. Review of the Evidence Based on data from 2010 to 2014, the incidence rate of female breast cancer was 124.9 per 100,000 14 women per year. The number of deaths was 21.2 per 100,000 women per year. Most commonly, breast cancer occurs in ducts of the breast (ductal carcinoma); lobular carcinoma and inflammatory breast cancer are less common. Breast cancers are typically categorized by estrogen receptor (ER) and progesterone receptor (PR) status (positive (+)/negative (-)), as well as by presence of human epidermal growth factor type 2 receptor (HER2/neu positive (+)/negative (-)). Breast tumors can be further characterized by grade, which is the degree of cellular abnormality seen microscopically. Stage of breast cancer is determined by both pathological and clinical diagnosis. In situ (or Stage 0) breast cancer is that which has not invaded based the lining of the duct or lobule. By definition, Stages 1-4 is invasive breast cancer that has spread to local or distant tissues The major risk factors for breast cancer, besides increasing age and physical inactivity, are: inherited changes in genetic factors, a first degree family history of breast cancer, increased mammographic density, atypical hyperplasia, radiation therapy, alcohol intake, early age at menarche and late age at menopause, first full-term pregnancy after age 30 years and nulliparity, long term use of menopausal 15 hormone therapy, overweight or obesity after menopause, and White race. 16- 19 9, 20 The Subcommittee used information from four meta-analyses and two pooled analyses. The 16 Wu et al included 31 prospective cohort studies published to November 2012. The meta-analysis by F4 2018 Physical Activity Guidelines Advisory Committee Scientific Report -8

257 Part F. Chapter 4. Cancer Prevention 17 meta-analysis by Neilson et al included 80 reports from 67 different studies published to June 2015. 18 included 38 prospective cohort studies published between 1987 and The meta-analysis by Pizot et al 19 by Liu et al included 126 cohort studies that examined a variety of cancers. Of 2014. The meta-analysis these, nine studies were included in the breast cancer analysis and five of them were used in the dose- 20 Gong et al response analysis. The pooled analysis by included four studies combined in the African 9 American Breast Cancer Consortium. The pooled analysis by included nine cohort studies Moore et al with 35,178 breast cancer cases. All types of physical activity were included in the meta-analyses by Wu 16 18 and Pizot et al Neilson ; recreational physical activity only was included in the meta-analyses by et al 17 20 9 19 et al Liu et al and the pooled analysis by Moore et al. The pooled analysis by Gong et al and included vigorous physical activity but did not specify what type of activity was specifically recorded and 17 was likewise restricted to used as the exposure assessment. The meta-analysis by Neilson et al moderate- to-vigorous recreational physical activity. The dose-response relationship was tested in all of 9, 16- 20 near statistically significant these meta-analyses and pooled analyses, and evidence for a li association between greater amounts of physical activity and lower breast cancer risk was observed in 19 16- four of these meta-analyses. Evidence on the Overall Relationship 16 estimated that the highest versus the lowest categories of all types of The meta-analysis by Wu et al physical activity in the 38 cohort studies they included was associated with a decreased risk of breast 16 also presented the results stratified by menopausal cancer (RR=0.88; 95% CI: 0.85-0.90). Wu et al status. For premenopausal women, the random effects model estimates were 0.77 (95% CI: 0.69-0.86) 16 and for postmenopausal women the effect estimates were 0.88 (95% CI: 0.87-0.92). These authors also presented the results for the association between breast cancer incidence and physical activity by type of activity. For occupational activity, the relative risk was 0.84 (95% CI: 0.73-0.96); for non-occupational activity, it was 0.87 (95% CI: 0.82-0.91); for recreational activity, it was 0.87 (95% CI: 0.83-0.91); for 16 household activity, it was 0.89 (95% CI: 0.83-0.95), and for walking, it was 0.87 (95% CI: 0.79-0.96). 17 reported all results for the association between physical activity and breast cancer risk Neilson et al stratified by menopausal status. Data from 36 case-control and 13 cohort studies were combined to to-vigorous estimate the relative risk of premenopausal breast cancer associated with modera te- recreational activity; for postmenopausal women, data from 38 case-control and 26 cohort studies were 2018 Physical Activity Guidelines Advisory Committee Scientific Report -9 F4

258 Part F. Chapter 4. Cancer Prevention combined. For premenopausal women, the estimated odds ratio (OR) was 0.80 (95% CI: 0.74-0.87) and for postmenopausal women, the odds ratio was 0.79 (95% CI: 0.74-0.84). 18 Pizot et al presented the results for all types of physical activity combined. These authors found a statistically significant reduction for breast cancer incidence when comparing the highest versus the lowest amounts of all types of physical activity combined (OR: 0.88; 95% CI: 0.85-0.91). When examining the associations by type of activity, they reported risk reductions for non-occupational physical activity (OR=0.88; 95% CI: 0.85-0.92 from 30 studies) and occupational physical activity (OR=0.87; 95% CI: 0.83- 18 0.90) based on 11 studies). Pizot et al also reported the results for the association between all types of physical activity combined and breast cancer risk by menopausal status. Premenopausal and postmenopausal women had very similar risk reductions for highest versus lowest levels of physical 18 activity (RR=0.87; 95% CI: 0.78-0.96 and RR=0.88; 95% CI: 0.85-0.91, respectively). Pizot et al also provided risk estimates for studies that used comparable methods for assessing physical activity. Risk reductions were greater in studies that measured physical activity in hours per week (RR=0.81; 95% CI: 0.76-0.87) than in MET-hours per week (RR=0.87; 95% CI: 0.83-0.91) or in other units (RR=0.89; 95% CI: 18 0.85-0.92). 19 reported decreased risk of overall breast cancer incidence when they compared participants Liu et al with the highest to the lowest amounts of leisure time physical activity (RR=0.88; 95% CI: 0.84-0.91). In their pooled analysis from the African American Breast Cancer Epidemiology and Risk Consortium, 20 Gong et al reported that any vigorous activity versus none was associated with a reduction in odds of breast cancer incidence of 0.88 (95% CI: 0.81-0.96). th th 9 percentile to those in the 10 Moore et al percentile of physical compared participants in the 90 activity in their pooled analysis and found a statistically significant association with breast cancer )=0.90; 95% CI: 0.87-0.93). incidence (hazard ratio ( HR Dose-response: Evidence for a linear statistically significant association between greater amounts of 16- 19 Using data physical activity and lower breast cancer risk was observed in four of the meta-analyses. 16 observed a statistically significant linear relationship between higher from three studies, Wu et al amounts of non-occupational physical activity and lower breast cancer risk. The risk of breast cancer was 2 percent lower (RR=0.98; 95% CI: 0.97-0.99) for every 25 MET-hours per week increment in non- occupational activity (roughly equivalent to 10 hours per week of light household activity). Using data on -10 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

259 Part F. Chapter 4. Cancer Prevention 16 recreational activity from seven studies, Wu et al estimated that the risk of breast cancer was 3 percent lower (RR=0.97; 95% CI: 0.95-0.98) for every 10 MET-hours per week increment in recreational 16 also found a Wu et al activity (roughly equivalent to 4 hours per week of walking at 2 miles per hour). linear relationship between breast cancer risk and moderate plus vigorous recreational activity usin g data from eight studies. The risk of breast cancer was 5 percent lower (RR=0.95; 95% CI: 0.93-0.97) for 16 every 2 hours per week increment in moderate plus vigorous activity. When examining vigorous 16 found that the risk of breast cancer Wu et al recreational activity only with data from eight studies, was 5 percent lower (RR=0.95; 95% CI: 0.92-0.97) for every 2 hours per week spent in this level of recreational activity. 17 to-vigorous recreational activity plotted dose-response curves across levels of moderate- Neilson et al by menopausal status and found a statistically significant, curvilinear dose-response relationship for both menopausal groups. The authors speculated that this curvilinear dose-response association to-vigorous recreational activity went beyond suggested a point of diminishing returns when moderate- 20 to 30 MET-hours per week. However, the 95% confidence intervals were wide at the upper levels of activity, which precluded any definitive conclusions about the nature of this dose-response relationship 17 also plotted dose-response curves with respect to activity at very high levels of activity. Neilson et al duration (hours per week) using data from 13 studies and they found a clear inverse linear association with postmenopausal breast cancer risk. For premenopausal breast cancer risk, using data from 10 studies they observed a J-shaped, statistically significant non-linear trend with an inflection point around 3 hours per week. These studies were distinct from those in the MET-hours per week analysis. The authors investigated the possible reasons for this J-shaped association and suggested that measurement error, covariate adjustment, and heterogeneity across these studies might partially explain these 17 is the only meta-analysis to examine the dose-response unexpected findings. The study by Neilson et al relationships separately for premenopausal and postmenopausal breast cancer. 18 Pizot et al performed dose-response analyses with 11 studies that reported physical activity in MET- hours per week and with 11 studies that reported duration of physical activity in hours per week and noted statistically significant dose-response relationships between amounts of physical activity and breast cancer risk without evidence for a threshold. 19 also found a statistically significant decreasing risk for breast cancer across categories of Liu et al leisure time physical activity estimated in MET-hours per wee k. -11 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

260 Part F. Chapter 4. Cancer Prevention 20 Gong et al tested for a linear trend across categories of hours per week of vigorous physical activity and found evidence for a statistically significant trend, although the dose-response association was not very evident with the highest category of physical activity (7 hours per week), which was associated with a risk of 0.86 (95% CI: 0.68-1.10) compared with the lowest category (<2 hours per week), which had a risk of 0.90 (95% CI: 0.81-1.01). 9 Finally, Moore et al also found a linear dose-response relationship between increasing levels of leisure time physical activity and decreased breast cancer risk ( <0.0001). P Evidence on Specific Factors 20 reported results by age (<50 years v ersus ≥ 50 years) and Age: Only the pooled analysis by Gong et al found comparable risk reductions for both age groups of 15 and 12 percent that were borderline statistically significant. Several of these meta-analyses and pooled analyses did examine the effects of physical activity on breast cancer risk by menopausal status, which could be a proxy for age. Overall, there appears to be a somewhat greater breast cancer risk reduction associated with higher amounts of phy sical activity among postmenopausal women than premenopausal women. 20 which included only American women of African , The pooled analysis by Gong et al Race/ethnicity: ancestry, reported a statistically significant 12 percent decreased risk associated with vigorous physical 17 presented the results for studies by racial groups and found statistically Neilson et al activity. significant reductions in premenopausal breast cancer risk for White, White-Hispanic, and Asian women. For postmenopausal women, statistically significant reductions in breast cancer risk also were evident for White-Hispanic and Asian women. No statistically significant risk reductions were found for Hispanic 9 17 or Black women in either menopausal category. pooled analysis found similar Moore et al The associations between highest versus lowest physical activity level and breast cancer risk in black and white women ( heterogeneity = 0.24) (Figure F4-1) P . No other studies presented their results by race/ethnic groups. -12 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

261 Part F. Chapter 4. Cancer Prevention th Figure F4-1. Summary Multivariable Hazard Ratios and 95% Confidence Intervals (CI) for a Higher (90 th percentile) versus Lower (10 percentile) Level of Leisure-Time Physical Activity, by Cancer Type, Stratified by Race/Ethnicity 9 , Association of leisure-time physical activity with risk of 26 Source: Reproduced with permission from [Moore et al – 825 types of cancer in 1.44 million adults. 2016. 176(6):816 ]. Copyright©(2016) American Medical Association. All rights reserved. None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and breast cancer incidence. Hence, no conclusions can be made on this factor. Weight status: A statistically significant effect modification of the association between breast cancer 17 Neilson et al, incidence and physical activity by BMI was found in the meta-analysis by with greater risk 2 reductions found in both premenopausal and postmenopausal women with a BMI <25 kg/m (RR=0.85; 2 95% CI: 0.73-0.99 and RR=0.84; 95% CI: 0.77- kg/m I ≥ 25 0.92, respectively) than in women with a BM 18 Pizot et al reported risk % CI: 0.98-1.00 and RR=0.88; 95% CI: 0.82-0.95, respectively). (RR=0.99; 95 reductions in breast cancer incidence for both women with low and high BMI (RR=0.84; 95% CI: 0.78- 9 0.90 and RR=0.87; 95% CI: 0.81-0.93). In contrast, in the Moore et al pooled analysis no effect modification by BMI was observed for the association between leisure time physical activity and breast cancer incidence. Cancer subtype: The association between physical activity and different breast cancer subtypes was 16, 17 , 19 , considered in four of these meta-analyses and pooled analyses but the findings were inconsistent. 20 16 Wu et al found stronger risk reductions for invasive breast cancers than in situ tumor stage cancers (RR=0.81; 95% CI: 0.73-0.91 versus RR=0.86; 95% CI: 0.74-0.99). These results also were found in the 19 in which greater risk reductions for invasive cancers compared with in situ meta-analysis by Liu et al, 16 also reported that women with estrogen receptor Wu et al breast cancers were found. -13 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

262 Part F. Chapter 4. Cancer Prevention negative/progesterone receptor negative breast cancer tumors had a greater reduction in risk compared with estrogen receptor positive/progesterone receptor positive breast cancer cases (RR=0.77; 95% CI: 20 reported a statistically significant inverse Gong et al 0.65-0.90 and RR=0.93; 95% CI: 0.87-0.98). association with vigorous physical activity for estrogen receptor positive breast cancer (OR=0.88; 95% CI: 0.80-0.98) but not for estrogen receptor negative breast cancer (OR=0.93; 95% CI: 0.82-1.06). Pizot et 18 observed stronger risk reductions for women with estrogen receptor negative breast cancer al (OR=0.80; 95% CI: 0.83-0.90) than for estrogen receptor positive breast cancers (OR=0.89; 95% CI: 0.83- 17 found statistically significant associations between 0.95) associated with physical activity. Neilson et al moderate- to-vigorous recreational activity and ductal and lobular tumor histology in postmenopausal women but observed no inverse associations for mucinous or tubular breast cancers. They also stratified their study results by hormone receptor status and found inverse and statistically significant associations for estrogen receptor positive/progesterone receptor positive premenopausal and postmenopausal breast cancers. In addition, they found that tumors with several combinations of hormone receptor and HER2/neu status were also protected with high levels of physical activity including: 1) estrogen receptor positive, 2) progesterone receptor positive, 3) estrogen receptor positive/progesterone receptor 4) HER2 positive, or 5) HER2 negative/estrogen receptor positive/progesterone receptor negative, positive postmenopausal breast cancer. In addition, physical activity protected against: 1) estrogen , HER2 negative, or p53 premenopausal breast receptor negative/progesterone receptor negative 17 cancers. No clear pattern of greater risk reductions by tumor grade was seen. Other factors : No effect modification by geographic location (i.e., America, Europe, Asia) was observed 16 Wu et al. No other analyses examined effect modification of the association in the meta-analysis by between physical activity and breast cancer incidence by geographic location. The pooled analysis by 20 of African Americans suggested that having no family history of breast cancer conferred Gong et al Neilson et greater risk reduction associated with physical activity than having a positive family history. 17 al found limited evidence that a positive family history of breast cancer was associated with a greater risk reduction than no family history in premenopausal women (RR=0.28; 95% CI: 0.14-0.58 versus RR=0.72; 95%CI: 0.58-0.88). For postmenopausal women, the effect of physical activity on reducing breast cancer risk in women with and without a family history of breast cancer was nearly equal (RR=0.85; 95% CI: 0.70-1.02 versus RR=0.83; 95% CI: 0.75-0.92). The stratified analyses in the meta- 17 for premenopausal women with a family history of breast cancer were based analysis by Neilson et al on only three studies and must be interpreted with caution. -14 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

263 Part F. Chapter 4. Cancer Prevention 17 20 Neilson et al, In the analyses by physical activity conferred a greater benefit for breast Gong et al and 17 Neilson et al cancer risk reduction among parous women as compared to nulliparous women. In the meta-analysis, premenopausal parous women had a 36 percent risk reduction (OR=0.64; 95% CI: 0.46- 0.90) associated with higher amounts of moderate- to-vigorous recreational activity. 18 The meta-analysis by Pizot et al, showed a statistically significant effect modification between hormone replacement therapy use and breast cancer risk. A beneficial effect of physical activity was observed only in those women who never used hormone replacement therapy while ever users had no 17 risk reductions associated with physical activity. Neilson et al found that not using hormone replacement therapy and ever use were both associated with statistically significant reduced breast cancer risks but that the effects were stronger in non-users than ever users. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: for the Evidence Portfolio. edition/report/supplementary-material.aspx Colon Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of recreational, occupational, or total physical Strong. PAGAC Grade: activity are associated with a lower risk of developing colon cancer. Strong evidence demonstrates a dose-response relationship between increasing physical activity levels PAGAC Grade: Strong. and decreasing risk of colon cancer. Strong evidence demonstrates that the effects of physical activity on colon cancer risk are evident in PAGAC Grade: . Strong both men and women. Insufficient evidence is available to determine whether the effects of physical activity on risk of colon cancer differ by specific age, race/ethnic, or Moderate evidence indicates PAGAC Grade: Not assignable . socioeconomic groups in the United States. that weight status does not affect the associations between physical activity and colon cancer risk. PAGAC Grade: Moderate. Strong evidence demonstrates that greater amounts of physical activity are associated with a lower risk Strong. of developing both proximal and distal colon cancer. PAGAC Grade: Insufficient evidence is available to determine whether the effects of physical activity on colon cancer risk differ in individuals at elevated risk of colon cancer. Not assignable. PAGAC Grade: -15 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

264 Part F. Chapter 4. Cancer Prevention Review of the Evidence Colon cancer is the third most commonly diagnosed cancer in the United States in both men and 21 Based on data from 2010-2014, the incidence rate of colon cancer in the United States was women. . Risk factors for colon cancer include: increased age, African- 28.2 per 100,000 men and women per year American race or Jewish ethnicity, family history of colorectal cancer, personal history of adenomatous colorectal polyps, history of certain inflammatory bowel conditions, a known family history of a hereditary colorectal cancer syndrome, diabetes mellitus, smoking, obesity, alcohol intake, and eating 22 red and processed meats. To examine the association between physical activity and risk of colon cancer, 8 systematic reviews were , 23- 28 -29 23 19, 19 reviewed alyses, as well as one pooled analysis of 12 large included meta-an of which 7 9 The Subcommittee also reviewed meta-analysis data from the World prospective cohort studies. 30 , 31 Because the association of physical activity with colon and rectal cancer Cancer Research Fund. differs by site (see the section on rectal cancer, below), the Subcommittee did not include studies where colorectal cancer was the outcome of interest because the relationship between physical activity and colon cancer likely would be obscured. The reviews contained data from between 8 and 21 epidemiologic studies. Evidence on the Overall Relationship A large body of epidemiologic data exists on the association between physical activity and risk of developing colon cancer. The most recent meta-analysis reported that risk of colon cancer is significantly reduced for individuals engaging in the highest versus lowest categories of physical activity level 19 Other meta-analyses found similar effect sizes showing inverse (RR=0.81, 95% CI: 0.83-0.93). associations between highest versus lowest levels of physical activity and risk of developing colon , 30 23- 27 , 31 cancer. Most studies adjusted for multiple potential confounding factors, including age, BMI, and colon cancer risk factors, although adjustment for colon cancer screening (which could be related to physical activity level) was not typically done. To address this issue, one meta-analysis examined the associations between physical activity and colon cancer risk before 1993 (before testing fecal occult by blood was widely used), between 1993 and 1999, and after 1999 when colon cancer screening ( 28 endoscopy) became widely available. The risk estimates for physical activity and colon cancer risk did not differ between the time periods. Studies published before 1993 (RR=0.74; 95% CI: 0.67-0.82); those -16 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

265 Part F. Chapter 4. Cancer Prevention published between 1993 and 1999 (RR=0.78, 95% CI: 0.70-0.86); and those published after 1999 (RR=0.78; 95% CI: 0.73-0.83) demonstrated similar risk reductions for this association. Dose-response: A dose-response relationship is apparent, with risk decreasing at higher levels of physical activity. A dose-response meta-analysis of three cohort studies found that per 30 minutes per 31 In day of recreational physical activity, the relative risk of colon cancer was 0.88 (95% CI: 0.80-0.96). contrast, dose-response estimates per 5 MET-hours per week of total physical activity were significant 31 on ly for distal colon cancer, with a relative risk of 0.92 (5 studies, 95% CI: 0.89-0.96). One meta- analysis estimated dose-response by percentile of physical activity, and found a linear reduction in risk th th across the 20 percentiles and estimated risk reductions between these two percentiles of 0.13 to 95 23 in men and 0.14 in women. This same meta-analysis plotted risk for colon cancer by leisure time physical activity in those studies with MET- ho urs per week or MET-minutes per week data, and found dose-response risk reductions in both men and women. The pooled analysis of 12 cohort studies found a significant relationship between increasing leisure time physical activity percentile and decreased risk of 9 =0.4). P colon cancer ( P <0.0001; overall non-linear Evidence on Specific Factors Sex: Meta-analyses found that physical activity reduced colon cancer risk in both men and women, and 23 there were no statistically significant differences in this effect by sex overall, or for proximal or distal 24, 26 colon cancer. Age: None of the analyses or the systematic review provided data within specific age groups. Race/ethnicity: Studies in the United States and Europe were primarily in Caucasians. One systematic review of Japanese studies reported on data from two cohort and six case-control studies, and found that the association of increased physical activity with reduced risk for colon cancer was stronger in men 29 than women, and stronger in proximal than distal cancer. The pooled analysis of 12 cohort studies th th percentile versus examined the association between the 90 10 percentile of physical activity level in 9 = P The hazard ratio was similar in the two groups ( Black and White individuals (Figure F4-1). heterogeneity 0.96). None of the analyses or the systematic review presented data on the effect of Socioeconomic status: socioeconomic status on the association between physical activity and colon cancer incidence. Hence, no conclusions can be made on this factor. -17 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

266 Part F. Chapter 4. Cancer Prevention th th percentile versus Weight status: 10 The pooled analysis examined associations between the 90 2 percentile of physical activity level by BMI. Risk of colon cancer for those with BMI <25.0 kg/m did not 2 9 differ from that of individuals with BMI ( P -value for effect modification=0.81). kg/m >25 Two meta-analyses were conducted on studies that included data by anatomic Cancer subtype: 24, 26 most to least active individuals, the relative risks for proximal colon cancer were subsite. Comparing 24 26 almost identical in the two reports: 0.73 (95% CI: 0.66-0.81) and 0.76 (95% CI: 0.70-0.83). Similarly, the relative risks for distal colon cancer were almost identical in the two reports: 0.74 (95% CI: 0.68- 26 24 0.80) A dose-response meta-analysis of three cohort studies found that and 0.77 (95% CI: 0.71-0.83). per 30 minutes per day of recreational physical activity, the relative risks of proximal and distal colon 31 cancer were 0.89 (95% CI: 0.82-0.96), and 0.87 (95% CI: 0.77-0.98), respectively. Individuals at high risk : No information was provided in the systematic review or analyses about effects of physical activity in individuals at elevated risk of colon cancer. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Endometrial Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of physical activity are associated with a lower risk PAGAC Grade: Strong. of endometrial cancer. Moderate evidence indicates that a dose-response relationship exists between greater amounts of physical activity and lower endometrial cancer risk. PAGAC Grade: Moderate. Moderate evidence indicates that greater amounts of physical activity are associated with a greater risk 2 reduction in women with a body mass index of greater than 25 kg/m compared to women with a body 2 mass index of less than 25 kg/m . PAGAC Grade: Moderate. Insufficient evidence is available to determine whether the association between physical activity and risk of endometrial cancer varies by PAGAC Grade: Not assignable. age, race/ethnicity, or socioeconomic status. Insufficient evidence is available to determine whether specific histologic types of endometrial cancers modify the relationships between amounts of physical activity and risk of endometrial cancer. PAGAC Grade: Not assignable. -18 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

267 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether the effects of physical activity on endometrial cancer risk differ in individuals at elevated risk of endometrial cancer. PAGAC Grade: Not assignable. Review of the Evidence Based on data from 2010 to 2014, the incidence rate of endometrial cancer was 25.7 per 100,000 32 The number of deaths was 4.6 per 100,000 women per year. Several factors increase women per year. risk of endometrial cancer, including obesity and having metabolic syndrome, hyperinsulinemia, nulliparity, early age at menarche, late age at menopause, polycystic ovarian syndrome, first degree 32 relative with endometrial cancer, and Lynch syndrome. 9 19, 33 -35 The Subcommittee used information from four meta-analyses led analysis. and one poo The meta- 33 analysis by Keum et al included 20 studies (10 cohort and 10 case-control studies) published to 34 September 2013. The meta-analysis by Moore et al included nine prospective studies published to 35 included 33 studies (15 prospective cohort studies, Schmid et al December 2009. The meta-analysis by 3 retrospective cohort studies, 1 case-cohort study and 14 case-control studies). The meta-analysis by 19 Liu et al included 126 cohort studies. Of these, nine studies were a binary endometrial cancer analysis 9 included 9 cohort studies and five of them were used in the dose-response analysis. The pooled analysis with 5,346 endometrial cancer cases. Recreational physical activity was included in two of the meta- 34 9 19, 33 included recreational and occupational activity in led analysis. Moore et al analyses and the poo 35 included recreational, occupational, and household activity and walking their review and Schmid et al 19, 33 , 35 in their review. The dose-response relationship was examined in three of the meta-analyses and 9 in the pooled analysis. Evidence on the Overall Relationship 33 Keum et al found that the highest versus lowest categories of leisure time The meta-analysis by physical activity in the 20 studies they included were associated with a decreased risk of endometrial 34 cancer (RR=0.82; 95% CI: 0.75-0.90). The meta-analysis by Moore et al reported that the highest vers us lowest amounts of recreational physical activity were associated with a statistically significant reduction in endometrial cancer incidence (RR=0.73; 95% CI: 0.58-0.93). These authors also presented the results for highest versus lowest amounts of occupational physical activity and found similar risk reductions 35 Schmid et al presented the results for all types of physical activity (OR=0.79; 95% CI: 0.71-0.88). combined as well as by type of activity. These authors found a statistically significant reduction for endometrial cancer incidence when comparing the highest versus the lowest amounts of all types of -19 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

268 Part F. Chapter 4. Cancer Prevention physical activity combined (OR=0.80; 95% CI: 0.75-0.85). When examining the associations by type o f activity, they reported risk reductions for recreational (OR=0.84; 95% CI: 0.78-0.91), occupational (OR=0.81; 95% CI: 0.75-0.87), and household (OR=0.70; 95% CI: 0.47-1.02) activities as well as for 35 walking (OR=0.82; 95% CI: 0.69-0.97). Schmid et al also presented their results by the intensity of physical activity and reported that endometrial cancer risk was decreased with all intensity levels of physical activity (light, moderate- to-vigorous, and vigorous) and these risk reductions were all statistically significant. The greatest reduction in endometrial cancer incidence was associated with light- intensity physical activity for which a relative risk of 0.65 was observed (95% CI: 0.49-0.86). Moderate- to-vigorous and vigorous-intensity physical activity had similar associations, with endometrial cancer risk 35 19 reported a null of RR=0.83 (95% CI: 0.71-0.96) and 0.80 (95% CI: 0.72-0.90), respectively. Liu et al association for overall endometrial cancer incidence when they compared participants with the highest 9 Moore et al to the lowest amounts of leisure time physical activity (RR=0.94; 95% CI: 0.77-1.15). th th compared participants in the 90 percentile of physical activity and found percentile to those in the 10 a statistically significant decreased risk of endometrial cancer (HR=0.79; 95% CI: 0.68-0.92). 33 observed a non-linear statistically significant relationship between greater Keum et al Dose-response: . They estimated that per 3 amounts of leisure time physical activity and lower endometrial cancer risk MET-hours per week, the relative risk was 0.98 (95% CI : 0.95-1.00) and per 1 hour per week, the RR was 35 : 0.93-0.98). Schmid et al 0.95 (95% CI restricted their assessment of dose-response to studies that reported their results in MET-hours per week and to account for variability in the range of MET-hou r levels in the individual studies, they performed analyses summarizing studies that provided the risk estimates for 3-8, 9-20 and greater than 20 MET-hours as compared to less than 3 MET-hours of physical : 0.64-0.98), and activity per week. They obtained relative risks of 0.94 (95% CI : 0.74-1.20), 0.79 (95% CI : 0.71-1.06) for 3-8, 9-20 and greater than 20 MET-hours as compared to less than 3 MET- 0.87 (95% CI hours of physical activity per week. In addition, within the range of 0 to approximately 40 MET-hou rs per week of recreational physical activity, they observed a non-linear inverse dose-response relationship for recreational physical activity with endometrial cancer risk ( P <0.05), which indicated a 5 percent -linearity non reduced risk of endometrial cancer for those engaging in 12 MET-hours per week of recreational activity 19 compared to those not engaging in regular physical activity (RR=0.95 (95% CI : 0.91-0.99). Liu et al estimated the hazard ratios across categories of leisure time physical activity from 0 to 40 MET-hours per week in increments of between 10 and 20 MET-hours per week. They found no evidence for a linear 9 -trend=0.46). However, did observe a statistically significant linear Moore et al P dose-response trend ( -20 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

269 Part F. Chapter 4. Cancer Prevention dose-response trend ( <0.0001) between greater amounts of physical activity and lower endometrial P cancer risk. Evidence on Specific Facto rs the analyses presented their results stratified by different age groups, hence, no Age: None of conclusions can be made regarding the role of age on the association between physical activity and endometrial cancer. Race/ethnicity: No conclusions can be made regarding the role of race/ethnicity in the association between physical activity and endometrial cancers because none of the analyses considered these factors. Socioeconomic status: None of the analyses presented data on the effect of socioeconomic status on the association be tween physical activity and endometrial cancer incidence. Hence, no conclusions can be made on this factor. A statistically significant effect modification of the association between endometrial Weight status: 35 cancer incidence and physical activity by BMI was found in the meta-analysis by Schmid et al, with a 2 I ≥ 25 kg/m greater risk reduction found in women with a BM (OR=0.69 (95% CI : 0.52-0.9 1) than in 2 9 pooled analysis, effect (OR=0.97; 95% CI: Moore et al women with a BMI <25 kg/m . In the 0.84-1.13) modification by BMI was observed for the association between leisure time physical activity and endometrial cancer incidence. This pooled analysis showed no effect of physical activity on endometrial 2 cancer incidence for women with a BMI <25 kg/m but stronger risk reductions were observed for those 9 2 pooled analysis). t al (Note: no risk estimates were provided in the Moore e I ≥ 25 with a BM kg/m None of the analyses considered the association with physical activity for different Cancer subtype: endometrial cancer subtypes. No effect modification by geographic location (i.e., America, Europe, Asia) was observed Other factors: 35 33 Keum et al Schmid et al. or in the meta-analyses by Likewise, no effect modification was observed by 33, 35 use or hormone therapy, oral contraceptives, menopausal status, or parity. There was some indication that smokers who were more physically active as compared to the least active smokers had a : 0.71-0.87) than non-smokers who greater reduction in endometrial cancer incidence (RR=0.79 (95% CI 33 were the most active compared to the least active (RR=0.87 (95% CI : 0.73-1.03). -21 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

270 Part F. Chapter 4. Cancer Prevention For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx Esophageal Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of recreational, occupational, or total physical activity are associated with a lower risk of developing adenocarcinoma of the esophagus. PAGAC Grade: Strong . Limited evidence suggests that greater amounts of physical activity are not associated with a lower risk of developing squamous cell carcinoma of the esophagus. PAGAC Grade: Limited. Limited evidence suggests a dose-response relationship between physical activity and risk of PAGAC Grade: Limited. adenocarcinoma of the esophagus. Available evidence is insufficient to determine whether the effects of physical activity on esophageal cancer risk differ by age, sex, race/ethnicity, weight status, socioeconomic status, or in individuals at elevated risk of esophageal cancer. Not assignable. PAGAC Grade: Review of the Evidence Based on data from 2010-2014, the incidence rate of esophageal cancer in the United States was 4.2 per 36 100,000 men and women per year, and deaths from this cancer were 4.1 per 100,000. Esophageal cancer is classified into two main types: adenocarcinoma, which occurs in the lower part of the esophagus, and squamous cell carcinoma, which develops in the upper part. Risk factors for esophageal 37 adenocarcinoma include obesity, Barrett’s esophagus, smoking, and ga stro-esophageal reflux disease. Risk factors for squamous cell carcinoma of the esophagus include smoking, alcohol use, and exposure 38 to some forms of human pap illo ma virus. The Subcommittee reviewed evidence of associations between physical activity and esophageal cancer 41 39- 9 risk. Three meta-analyses were reviewed, and one po Because the oled analysis of six cohort studies. biology and etiology of the two types of esophageal cancers differ considerably, the Subcommittee focused on results that were separate for these types rather than for all esophageal cancer combined. Two dozen epidemiologic studies on the association between physical activity and risk of developing esophageal cancer have been published. Some meta-analyses limited the evidence to studies with -22 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

271 Part F. Chapter 4. Cancer Prevention 40 incidence outcomes only, while others included studies with either incidence or mortality as the 39 disease indicator. Evidence on the Overall Relationship 39 24 individual In the most comprehensive meta-analysis of physical activity and esophageal cancer risk, studies were available for the meta-analysis, of which 9 were cohort and 15 were case-control studies. This meta-analysis found that risk of esophageal adenocarcinoma was statistically significantly reduced for individuals engaging in highest versus lowest levels of activity (RR=0.79; 95% CI: 0.66-0.94). Conversely, physical activity was not related to risk of squamous cell carcinoma of the esophagus (RR=0.94; 95% CI: 0.41-2.16). Other meta-analyses found similar effect sizes showing inverse associations between highest versus lowest levels of physical activity and risk of developing , 41 40 When all types of adenocarcinoma of the esophagus, but not squamous cell esophageal cancer. esophageal cancer were combined, adjustment for smoking, adiposity, and alcohol intake did not substantially alter effect sizes. Similar trends were seen in the pooled analysis (adenocarcinoma 9 HR=0.58, 95% CI: 0.37-0.89; squamous cell esophageal cancer HR=0.80, 95% CI: 0.61-1.06). Dose-response: One meta-analysis performed dose-response analyses for all esophageal cancers 41 combined from five studies. The meta-analysis reported that the middle and highest tertiles or quartiles of physical activity were associated with reductions of 12 percent (RR=0.88 95% CI: 0.7-1.1) 41 However, given that these analyses were and 24 percent (RR -0.76; 95% CI: 0.60-0.97), respectively. only for combined adenocarcinoma and squamous cell carcinoma, the dose-response relationship cannot be accurately defined. The pooled analysis estimated dose-response using within-study percentile; with increasing percentile of physical activity, incidence of esophageal adenocarcinoma was 9 Because the percentiles were not defined <0.0001). statistically significantly and linearly decreased ( P for dose, the dose-response relationship cannot be accurately determined. Evidence on Specific Factors : None of the analyses reported effects of physical activity by specific age groups. Age Sex : Analysis by sex was performed for all esophageal cancers combined in all reviewed meta-analyses; risk reduction was higher for women than men, but data were not presented for adenocarcinoma of the 41 39- However, given that these analyses were only for adenocarcinoma and squamous cell esophagus. carcinoma combined, the relationship within sex cannot be accurately defined. In the pooled analysis, -23 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

272 Part F. Chapter 4. Cancer Prevention similar effects of physical activity on reduced risk for adenocarcinoma of the esophagus were seen for both men and women ( P =0.75). Given the discrepancies between the meta-analysis and the effect modification pooled analysis, the Subcommittee could not determine whether physical activity reduces risk for esophageal cancer in both sexes. Race/ethnicity : Studies included primarily Caucasian and Asian populations, with little difference observed between the two populations for combined adenocarcinoma and squamous cell carcinoma of the esophagus. No analyses were available for adenocarcinoma by race/ethnicity. Socioeconomic status: None of the analyses presented data on the effect of socioeconomic status on the association between physical activity and esophageal cancer incidence. Hence, no conclusions can be made on this factor. 9 examined the effect of highest versus lowest level of physical Weight status : The pooled analysis 2 2 versus . The >25 kg/m activity on esophageal adenocarcinoma in individuals with BMI <25 kg/m analysis found similar effect sizes in the two groups, although the statistically significant effect was limited to those in the overweight/obese group ( P =0.60). BMI did not change the effect of effect modification =0.60). Because no physical activity on squamous cell carcinoma of the esophagus ( P effect modification information was available from a meta-analysis, the Subcommittee could not conclude that weight status was unrelated to physical activity effect. : No information was provided in the analyses about effects of physical activity in Individuals at high risk individuals at elevated risk of esophageal cancer. Cancer subtype : In the most comprehensive meta-analysis of physical activity and esophageal cancer 39 24 individual studies were available for the meta-analysis, of which risk, 9 were cohort and 15 were case-control studies. This meta-analysis found that risk of esophageal adenocarcinoma was statistically significantly reduced for individuals engaging in highest versus lowest levels of activity (RR=0.79; 95% CI: 0.66-0.94). Conversely, physical activity was not related to risk for squamous cell carcinoma of the esophagus (RR=0.94; 95% CI 0.41-2.16). For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. -24 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

273 Part F. Chapter 4. Cancer Prevention Gastric Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of physical activity are associated with a lower risk of developing gastric cancer . PAGAC Grade: Strong. Moderate evidence indicates that as levels of physical activity increase, risk of gastric cancer decreases. PAGAC Grade: Moderate. Insufficient evidence is available on whether the effects of physical activity on gastric cancer risk vary by sex, age, race/ethnicity, socioeconomic groups, or weight status . PAGAC Grade: Not assignable. Moderate evidence indicates that as levels of physical activity increase, the risk of both subtypes of — Moderate. PAGAC Grade: decreases. gastric cancer — cardia and non-cardia adenocarcino ma Insufficient evidence is available to determine whether the effects of physical activity on gastric cancer risk differ in individuals at elevated risk of gastric cancer. PAGAC Grade: Not assignable. Review of the Evidence In the United States, the incidence rate of gastric cancer is 7.3 per 100,000 men and women per year, 42 based on data from 2010 to 2014. The major risk factor for this cancer is infection with Helicobacter pylori. Other risk factors include smoking, genetics, some industrial chemicals, and regular intake of highly salted foods. Gastric cancer is classified into two main subtypes: cardia adenocarcinoma and noncardia adenocarcinoma. Biologically, cardia gastric cancer is similar to the adjacent esophageal adenocarcinoma. Evidence on the Overall Relationship The Subcommittee reviewed five meta- an alyses on the associations between physical activity and 39, 40 45 , 43- 9 Because the biology and gastric cancer and one pooled analysis of seven cohort studies. etiology of the two subtypes of gastric cancers may differ, results that were separate for these subtypes, as well as all gastric cancer combined, were reviewed. Considerable evidence indicates that physical activity is associated with a reduced risk of gastric cancer. 44 40, Some meta-analyses limited studies to those with incidence outcomes only, while one included -25 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

274 Part F. Chapter 4. Cancer Prevention 39 studies with either incidence or mortality as the outcome. This latter found no difference in effect size when studies with fatal cases as endpoints were removed. 44 22 In the most comprehensive meta-analysis of physical activity and incident gastric cancer risk, individual studies were available for the meta-analysis, of which 10 were cohort and 12 were case- control studies. This meta-analysis found that risk of gastric cancer was statistically significantly reduced for individuals engaging in highest versus lowest levels of activity (RR=0.81; 95% CI: 0.73-0.89). Similar 9, 39, 40 , 43 , 45 Adjustment for results were found in the other meta-analyses and the pooled analysis. smoking, adiposity, and alcohol intake did not substantially alter effect sizes. 45 Dose-response : One meta-analysis estimated dose-response analyses for all gastric cancers combined. Compared with the least active individuals, those in the middle activity tertile had an adjusted odds ratio of 0.91 (95% CI: 0.82-1.02), and those in the highest tertile had an adjusted odds ratio of 0.78 (95% CI: 45 The pooled analysis estimated dose-response using within- = 0.08). 0.68-0.90) ( P difference between groups 9 With increasing percentile of physical activity, incidence of gastric cardia cancer was study percentile. = 0.02, statistically significantly, but non-linearly, decreased ( P P = 0.0037) . With increasing overall non-linear percentile of physical activity, incidence of gastric noncardia cancer was statistically significantly P = 0.58). P = 0.015, decreased ( overall non-linear Evidence on Specific Factors ne of the analyses reported the effects of physical activity on gastric cancer by age group. Age: No Sex: Analysis by sex was performed for all gastric cancers combined. Risk reduction was statistically 44 significant in men (RR=0.87; 95% CI: 0.77-0.99), but not women (RR=0.77; 95% CI: 0.53-1.12). Race/ethnicity: Studies included primarily Caucasian and Asian populations, with little difference 44 -analysis, 3 of 10 cohort studies and 6 of 12 case-control studies were of between the two. In one m eta Asian populations. The relative risk of high versus low physical activity on all gastric cancer combined was 0.82 (95% CI: 0.74-0.90). None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and gastric cancer incidence. Hence, no conclusions can be made on this factor. -26 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

275 Part F. Chapter 4. Cancer Prevention th percentile of level of physical Weight status: The pooled analysis examined the effect of 90th versus 10 2 9 2 activity on gastric cancer in individuals with BMI <25 kg/m versus >25 kg/m . The study found that high physical activity level was associated with decreased gastric cardia cancer in individuals with BMI >25 2 2 kg/m for effect modification: 0.02). In contrast, physical activity P , but not in those with BMI <25 kg/m ( was not statistically significantly associated with risk for gastric noncardia cancer in either BMI category. Cancer subtype: The analyses estimated overall associations by cancer subtype (gastric cardia versus noncardia). In the largest meta-analysis, high physical activity levels were associated with noncardia 44 In contrast, (RR=0.62; 95% CI: 0.52-0.75), but not gastric cardia cancer (RR=0.80; 95% CI: 0.64-1.01). th 10 percentile of level of physical pooled analysis found a significant association between 90th versus activity and risk of gastric cardia cancer (HR=0.80; 95% CI: 0.64-0.95), but no significant association with 9 gastric noncardia cancer. Individuals at high risk: No information was provided in the analyses about effects of physical activity in individuals at elevated risk of gastric cancer. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Renal Cancer Conclusion Statements Strong evidence demonstrates that greater amounts of physical activity are associated with reduced risk Strong. of developing renal cancer. PAGAC Grade: Limited evidence suggests that a dose-response relationship exists between increasing physical activity Limited. levels and decreasing risk of renal cancer. PAGAC Grade: Limited evidence suggests that the effects of physical activity on renal cancer risk are similar for men Limited . and women. PAGAC Grade: Limited evidence suggests that the effects of physical activity on . Insufficient evidence is available renal cancer risk do not vary by weight status. PAGAC Grade: Limited to determine whether the effects of physical activity on risk of renal cancer differ by specific age, PAGAC Grade: Not assignable. race/ethnic, or socioeconomic groups. Insufficient evidence is available to determine whether the effects of physical activity are similar for all PAGAC Grade: Not assignable. subtypes of renal cancer. -27 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

276 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether the effects of physical activity on renal cancer risk differ in individuals at elevated risk of renal cancer. PAGAC Grade: Not assignable. Review of the Evidence Based on data from 2010 to 2014, the incidence rate of renal cancer was 15.6 per 100,000 men and 46 Several factors women per year. The number of deaths was 3.9 per 100,000 men and women per year. increase risk of renal cancer, including smoking, obesity, exposure to certain occupational toxins, 47 hypertension, and history of some rare medical conditions. Renal cancer is more common in men than in women and in individuals with a personal or family history of cancer of the urinary tract. To examine the association between physical activity and risk of renal cancer, the Subcommittee 48 reviewed one published meta-analysis. The meta-analysis contained data from 11 cohort and 8 case- control studies. The Subcommittee also reviewed 1 pooled analysis of 11 large prospective cohort 9 studies and meta-analysis data from the World Cancer Research Fund, which included data from 12 49 cohort studies. Evidence on the Overall Relationship A considerable body of epidemiologic data exists on the association between physical activity and risk of developing renal cancer. The meta-analysis (19 cohort studies, of which 2 used renal cancer mortality as the endpoint) reported that risk of renal cancer was significantly lower for individuals engaging in the 48 highest versus lowest categories of physical activity level (RR=0.88; 95% CI: 0.79-0.97). Most studies adjusted for multiple potential confounding factors, including age, BMI, and renal cancer risk factors. When the analysis was limited to the 17 cohort studies that did not use renal cancer mortality as the endpoint, risk estimates were similar (RR=0.88; 95% CI: 0.80-0.98). Similar to these findings, the pooled th th 10 versus analysis of 11 cohort studies found a statistically significant relationship between the 90 percentile level for leisure time physical activity and decreased risk of renal cancer (RR=0.77; 95% CI: 9 0.70-0.85). und meta-analysis found similar results for highest versus The World Cancer Research F lowest: 1) total physical activity (RR=0.89; 95% CI: 0.72-1.10); 2) occupational physical activity (RR=0.96; 49 95% CI: 0.76-1.23); and 3) recreational physical activity (RR=0.84; 95% CI: 0.70-1.01). The meta-analysis did not examine the dose-response relationship of physical activity Dose-response: with renal cancer risk. The pooled analysis of 11 cohort studies found a significant linear relationship -28 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

277 Part F. Chapter 4. Cancer Prevention between increasing leisure time physical activity percentile and decreasing risk of renal cancer 9 =0.624). ( P P <0.0001; overall non-linear Evidence on Specific Factors The meta-analysis found some differences in the effects of physical activity on renal cancer risk Sex: 48 between men (RR=0.91; 95% CI: 0.81-1.03) and women (RR=0.85; 95% CI: 0.57-1.29). In that meta- analysis, studies that presented data for men and women combined had a combined relative risk of 0.85 (95% CI: 0.73-0.98). The pooled analysis found that the effect size of physical activity on risk for renal 9 cancer was similar, and statistically significant, in both men and women. None of the analyses provided data within specific age groups. Age: All but three studies in the meta-analysis were conducted in the United States and Race/ethnicity: Europe; a meta-analysis of the three studies in Asia showed no association of physical activity with renal 48 cancer risk (RR=1.00; 95% CI: 0.83-1.20). None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and renal cancer incidence. Hence, no conclusions can be made on this factor. th th The pooled analysis examined associations between the 90 percentile versus 10 Weight status: percentile of physical activity level by BMI. Risk of renal cancer associated with physical activity level did 9 2 >25 ( not differ for those with BMI <25.0 kg/m = 0.39). versus BMI P interaction Cancer subtype: Neither the meta-analyses nor the pooled analysis provided data by subtype of renal cancer. Individuals at high risk: No information was provided in the meta-analyses or pooled analysis about effects of physical activity in individuals at elevated risk of renal cancer. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: for the Evidence Portfolio. edition/report/supplementary-material.aspx -29 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

278 Part F. Chapter 4. Cancer Prevention Cancers for Which Physical Activity Shows Moderate Evidence of a Protective Effect Lung Cancer Conclusion Statements Moderate evidence indicates that greater amounts of physical activity are associated with a lower risk of lung cancer. PAGAC Grade: Moderate. Limited evidence suggests that a dose-response relationship exists between greater amounts of physical activity and lower lung cancer risk. PAGAC Grade: Limited. Limited evidence suggests that the relationship between amount of physical activity and risk of lung PAGAC Grade: Limited. cancer does not vary by age. Limited evidence suggests that greater amounts of physical activity are associated with a greater risk reduction in females than in males. PAGAC Grade: Limited evidence suggests that greater amounts of physical activity are associated with a Limited. 2 than in those with higher greater risk reduction in those with a body mass index of less than 25 kg/m Insufficient evidence is available to determine whether this PAGAC Grade: Limited. body mass index. relationship varies by race/ethnicity or socioeconomic status because these factors have yet to be examined in the studies conducted to date. PAGAC Grade: Not assignable. Limited evidence suggests that specific histologic types of lung cancers do not modify the relationships PAGAC Grade: Limited. between amounts of physical activity and risk of lung cancer incidence. Moderate evidence indicates that greater amounts of physical activity are associated with a greater risk reduction in current and former smokers than in never smokers. PAGAC Grade: Moderate. Review of the Evidence Between 2010 and 2014, the incidence rate of lung and bronchus cancer was 55.8 per 100,000 men and 50 women per year. The number of deaths was 44.7 per 100,000 men and women per year. Lung cancer is the number one cause of cancer mortality in the U.S. The main risk factor for lung cancer is both active and passive tobacco use. Other risk factors include occupational exposures (including arsenic, radon, chloromethyl ethers, chromium, nickel, polycyclic aromatic hydrocarbons), outdoor air pollution (i.e., . particulate matter) and dietary intake (i.e., low fruit and vegetable intake) 9 -55 51 19, The Subcommittee used information from six meta-analyses and one pooled analysis. The meta- 51 Sun et al analysis by included 14 prospective cohort studies published to May 2012 with 1,644,305 -30 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

279 Part F. Chapter 4. Cancer Prevention 52 participants. The meta-analysis by Buffart et al included seven prospective cohort studies published to 53 November 2011 . The meta-analysis by Schmid et al included 25 studies (18 prospective cohort, 6 case- control, and 1 nested case-control) published to September 2015 that included 3,147,747 participants 55 and 29,123 cases. The Brenner et al meta-analysis included 28 studies (6 case-control and 22 cohort) 54 meta-analysis included 18 studies (12 cohort and 6 case- Zhong et al published to May 2015. The 19 Liu et al control) published to January 2014 that included 2,648,470 participants and 26,453 cases. The meta-analysis included 126 cohort studies, which included 15 studies in a lung cancer analysis and a 9 pooled analysis that included 12 cohort studies with 19,133 cases . All types of physical activity were 51, 54 included in two of th e meta-analyses and leisure time/recreational physical activity was included in 19, 52 , 53, 55 9 included only leisure time/recreational the four remaining meta-analyses. The pooled analysis 52 physical activity in their report. The dose-response relationship was tested in one of the reviews only 52 Buffart et al review were restricted and no evidence for an association was found. The analyses in the to smokers only. Evidence on the Overall Relationship 51 The first meta-analysis published by Sun et al found risk reductions for both medium and high levels of physical activity compared to low levels with relative risks of 0.87 (95% CI : 0.83-0.90) and 0.77 (95% CI : 52 by Buffart et al, which was restricted to smokers only, 0.73-0.81), respectively. The meta-analysis reported reductions for moderate, moderate- to-vigorous, and vigorous physical activity amounts compared to low a mounts that were all statistically significant decreases (moderate: RR=0.79; 95% CI : : 0.81-0.93; vigorous physical activity: 0.70-0.90; moderate-to-vigorous physical activity: RR=0.87; 95% CI 55 reported a 25 percent reduction in lung cancer risk when RR=0.74; 95% CI : 0.67-0.82) . Brenner et al comparing the highest versus lowest amounts of physical activity in all studies combined (RR=0.75; 95% 53 CI: 0.68-0.84). Schmid et al similarly reported a 21 percent reduction in lung cancer risk when comparing the highest versus lowest amounts of physical activity (RR=0.79; 95% CI : 0.72-0.87) . Zhong et 54 : 0.84-0.90) and al reported reductions for both moderate amounts of physical activity (0.87; 95% CI 19 high amounts of physical activity (RR=0.75; 95% CI : 0.68-0.84) . Liu et al reported an analysis for overall lung cancer that compared the highest to the lowest amounts of leisure time physical activity that was a th 9 th null association (RR=0.99; 95% CI : 0.97-1.01). Moore et al percentile to the 10 compared the 90 percentile of physical activity and found a statistically significant risk reduction of about 26 percent 0.71-0.77). (HR=0.74; 95% CI: -31 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

280 Part F. Chapter 4. Cancer Prevention Dose-response: The dose-response relationship was not examined in any of the studies with the 9 Moore et al exception of the pooled analysis that provided dose-response curves for the association between physical activity and lung cancer incidence. There was a statistically significant linear trend (P <0.0001) between greater amounts of physical activity and lower lung cancer risk. trend Evidence on Specific Factors 55 Age: Brenner et al examined sub-group effects by age and found no statistically significant differences by age subgroups. 52 Buffart et al examined the association by sex (this study examined smokers only) and found a Sex: stronger protective effect of higher levels of physical activity among women than among men (RR=0.68; 95% CI : 0.57-0.82 and RR=0.85; 95% CI : 0.77-0.93, respectively). Race/ethnicity: No conclusions can be made regarding the role of race or ethnicity in the association between physical activity and lung cancers . None of the meta-analyses reported on these population 9 subgroups, preventing any systematic conclusions related to these factors. The Moore et al pooled analysis, however, found similar associations between highest versus lowest physical activity level and 9 ). =0.90) (Figure F4-1 lung cancer risk in Black and White individuals ( P heterogeneity Socioeconomic status: None of the analyses presented data on the effect of socioeconomic status on the association between physical activity and lung cancer incidence. Hence, no conclusions can be made on this factor. 9 Weight status: A statistically significant effect modification by BMI was found in the Moore et al pooled 2 2 analysis, with stronger reductions for participants with BMI <25 kg/m than for those ≥ 25 kg/m . 53 Schmid et al examined the effects by different histologic type and no statistically Cancer subtype: significant differences by cancer subtype were found. 9 Moore et al, with strong Other factors : Clear effect modification by smoking status was found by reductions for the association between physical activity and lung cancer observed for current and 54 found similar magnitude Zhong et al former smokers but not for never smokers ( P <0.001). effect modification risk reductions for former, current, and never smokers. These risk reductions ranged between 24 to 26 53 percent and were statistically significant. Schmid et al also reported effect modification by smoking status, with substantial risk reductions for the association between physical activity and lung cancer for 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4 -32

281 Part F. Chapter 4. Cancer Prevention former smokers (RR=0.68; 95% CI: 0.51-0.90), current smokers (RR=0.80; 95% CI: 0.70-0.90) but not for 55 Brenner et al never smokers (RR=1.05; 95% CI: 0.78-1.40). Likewise, reported no association between physical activity and lung cancer for never smokers (RR=0.96; 95% CI: 0.79-1.18) whereas former smokers had a risk reduction between higher amounts of physical activity and lung cancer (RR=0.77; 95% CI: 0.69-0.85) as did current smokers (RR=0.77; 95% 0.72-0.83). For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx for Which Physical Activity Shows Limited Evidence for a Protective Effect Cancers Hematologic Cancers Conclusion Statements Limited evidence suggests a null relationship between physical activity and leukemia incidence. Limited evidence suggests that physical activity has a protective effect on lymphoma and myeloma such that PAGAC Grade: Limited. greater amounts of physical activity reduce the risk of lymphoma and myeloma. Insufficient evidence is available to determine whether a dose-response relationship exists between greater amounts of physical activity and reduced risk of hematologic cancers. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether sex modifies the relationship between physical activity and Hodgkin lymphoma, with a risk reduction observed with physical activity for females only. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether body mass index, smoking, or alcohol affect the relationship between physical activity and risk of developing other hematologic cancers, or whether this relationship varies by sex, age, race/ethnicity, or socioeconomic status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity varies . PAGAC Grade: Not assignable by specific types of hematologic cancers. Insufficient evidence is available to determine whether the effects of physical activity on hematologic cancers differ in individuals at elevated risk of hematologic cancers. . PAGAC Grade: Not assignable -33 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

282 Part F. Chapter 4. Cancer Prevention Review of the Evidence Hematologic cancers, which include cancers that originate in the blood cells, have three main types: 1) leukemia (cancer of the blood and bone marrow, including chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, and other subtypes); 2) lymphoma (cancer of the lymphatic system with Hodgkin lymphoma and non-Hodgkin lymphoma as the two main types); and 3) myeloma (cancer of the plasma cells) . Between 2010 and 2014, the incidence rate of leukemia was 13.7 per 100,000 men and women per year. The number of deaths was 6.8 per 56 100,000 men and women per year. For non-Hodgkin lymphoma, the incidence rate for this same time period was 19.5 per 100,000 men and women per year. The number of deaths was 5.9 per 100,000 men 57 For Hodgkin lymphoma, the incidence rate was 2.6 per 100,000 men and women and women per year . 58 per year. The number of deaths was 0.3 per 100,000 men and women per year. For myeloma, the incidence rate was 6.6 per 100,000 men and women per year. The number of deaths was 3.3 per 59 100,000 men and women per year. The main known risk factors for leukemia are: radiation, chemical exposures (e.g., benzene), chemotherapy, Down syndrome, and having a family history of leukemia. The main risk factors for lymphoma are: age older than 50 years, male sex, Caucasian race, having an autoimmune disease, HIV/AIDS, high fat and meat diet, and pesticide exposure. For myeloma, the main risk factors are: African American race, age older than 50 years, male sex, obesity, and exposure to radiation and the petroleum industry . 9, 62 , 61 19, 60 The analyses. The Subcommittee used information from three meta-analyses and two pooled 60 meta-analysis by Jochem et al included 23 studies (15 cohort and 8 case-control studies) conducted up 61 Vermaete et al included 12 studies (7 to 2013 with 19,334 hematologic cancers. The meta-analysis by case-control and 5 cohort studies) also published by 2013 with 9,511 lymphomas . The third meta- 19 included 126 cohort studies conducted to the end of 2014 that included 8 studies analysis, by Liu et al, used in the lymphoid neoplasm analysis (number of cases not specified). The pooled analysis by 62 Aschebrook-Kilfoy et al was based on the InterLymph Non-Hodgkin Lymphoma Subtypes Project, which included 14 case-control studies published by the end of 2011, included 324 cases of Mycosis fungoides 9 and Sézary syndrome (rare cutaneous T-cell lymphomas). The pooled analysis included 12 Moore et al U.S. and European cohort studies of which 10 cohorts reported on myeloid leukemia with 1,692 cases, 9 cohorts on myeloma with 2,161 cases, 11 cohorts for non-Hodgkin lymphoma with 6,953 cases, and 10 -34 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

283 Part F. Chapter 4. Cancer Prevention cohorts for lymphocytic leukemia with 2,160 cases . All types of physical activity were included in two of 60, 61 19 and leisure-type physical activity was included in the third meta-analysis. The the meta-analyses 9 62 first pooled analysis included all types of physical activity combined, and the second pooled analysis included only recreational and leisure time physical activity in their report. Evidence on the Overall Relationship None of the analyses that were identified combined all types of hematologic cancers to provide an overall estimate of the association with physical activity. Rather, separate estimates were provided in each review given the different etiologies of these cancers. A null association between physical activity and leukemia was reported in two analyses (RR=0.97 ; 95% 60 9 CI: 0.84-1.13 ; HR=0.98; 95% CI: 0.87-1.11 ), with the latter study reporting on lymphocytic leukemia. For non-Hodgkin lymphoma, a non-statistically significant risk reduction of about 8 to 9 percent was found in 3 of the reviews that considered this hematologic cancer when comparing the highest versus 60 61 ; HR=0.91; ; 0.92; 95% CI: 0.81-1.04 the lowest levels of physical activity (RR=0.91; 95% CI: 0.82-1.00 9 ). 95% CI: 0.83-1.00 For Hodgkin lymphoma, a non-statistically significant risk reduction of about 16 to 18 percent was 60 reported in 2 reviews that included this hematologic cancer (RR=0.86; 95% CI: 0.58-1.26 ; OR=0.82; 95% 61 CI: 0.47-1.42 ). Two studies reported on all types of lymphoma combined in association with physical activity and reported a 10 percent reduction in all types of lymphoma with greater amounts of physical activity 60 61 (pooled RR=0.90; 95% CI: 0.81-0.99 and pooled OR=0.90; 95% CI: 0.79-1.02 ). Another meta-analysis reported on lymphoid neoplasms combined and reported a null association between greater amounts of 19 physical activity and lymphoid neoplasms (RR=0.97; 95% CI: 0.86-1.10). Two studies reported separate results for multiple myeloma/myeloma, with risk reductions ranging 60 9 ) when comparing the from 14 to 17 percent (RR=0.86; 95% CI: 0.68-1.09 ; HR=0.83; 95% CI: 0.72-0.95 highest to lowest levels of physical activity in these studies. Other rare types of hematologic cancers also were reported separately in the meta-analysis by Jochem 60 et al and no associations between physical activity and risk of follicular lymphoma and large B-cell lymphoma (RR=0.98; 95% CI: 0.85-1.11) and chronic lymphocytic lymphoma/small lymphocytic -35 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

284 Part F. Chapter 4. Cancer Prevention lymphoma (RR=0.99; 95% CI: 0.75-1.29) were observed. Finally, the InterLymph NHL subtypes project reported on the associations between moderate and vigorous physical activity and mycosis fungoides and Sezary syndrome as well. For moderate physical activity, the fully adjusted odds ratio was 0.46 (95% 62 CI: 0.22-0.97) and for vigorous physical activity, the odds ratio was 0.58 (95% CI: 0.32-1.08). 9 Dose-response: observed a statistically significant trend between increasing percentiles of Moore et al =0.0035), myeloma ( physical activity and decreasing risk of myeloid leukemia ( P P =0.007) and trend trend =0.007). Two other analyses that also examined the dose-response trends non-Hodgkin lymphoma ( P trend did not find any evidence of an association between increasing physical activity levels and all 62 60 hematologic cancers combined or for mycosis fungoides and Sezary syndrome. Evidence on Specific Factors Age: No ne of the analyses reported on the effects of physical activity for different age groups for any specific hematologic cancers. 60 and no statistically significant effect Only one meta-analysis examined effect modification by sex Sex: modification was observed. Different risk estimates were found, however, for Hodgkin lymphoma for which a statistically significant risk reduction was observed for women but not for men (RR=0.56; 95% CI: 0.37-0.86 and RR=1.04; 95% CI: 0.58-1.87), respectively. No conclusions can be made regarding the role of race or ethnicity in the association Race/ethnicity: . None of these analyses reported on these between physical activity and hematologic cancers population subgroups, preventing any systematic conclusions related to these factors. None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and hematologic cancer incidence. Hence, no conclusions can be made on this factor. 9 pooled analysis or adiposity Moore et al Weight status: No effect modification by BMI was found in the 60 meta-analysis. in the Jochem et al Cancer subtype: As described above, hematologic cancers are comprised of several different cancer sites and the results are described above. No studies to date have provided results on specific subtypes within each of these hematologic cancers. -36 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

285 Part F. Chapter 4. Cancer Prevention Other factors : No effect modification by alcohol or smoking status was found for any of the hematologic 9 60 Moore et al reported an effect modification by smoking cancers in the meta-analysis by Jochem et al. status for myeloma but none for the other hematologic cancers. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Head and Neck Cancers Conclusion Statements Limited evidence suggests that greater amounts of physical activity are associated with a lower risk of PAGAC Grade: Limited. head and neck cancer incidence. n Insufficient evidence is available to determine whether a dose-response relationship exists betwee physical activity and head and neck cancer incidence. PAGAC Grade: Not assignable. Limited evidence suggests that the relationship between physical activity and head and neck cancer . PAGAC Grade: Limited. Insufficient evidence is incidence does not vary by age, sex, BMI, or smoking available to determine whether this relationship varies by race/ethnicity or socioeconomic status PAGAC Grade: Not because these factors have yet to be examined in the studies conducted to date. assignable. Limited evidence suggests that this relationship varies by specific types of head and neck cancers. PAGAC Grade: Limited. Insufficient evidence is available to determine whether the effects of physical activity on head and neck PAGAC Grade: Not assignable. cancers differ in individuals at elevated risk of head and neck cancers. Review of the Evidence 63 In 2014, an estimated 346,902 people were living with head and neck cancers in the United States . These cancers include cancers that originate in the oral cavity, pharynx, larynx, paranasal sinuses and nasal cavity, and salivary glands . The main known risk factors for head and neck cancers are tobacco and 64 alcohol use and infection with human papillomavirus. 9, 65 The pooled analysis by Nicolotti et The Subcommittee used information from two pooled analyses. 65 combined 4 case-control studies from the International Head and Neck Consortium (INHANCE) that al -37 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

286 Part F. Chapter 4. Cancer Prevention 9 included 2,289 cases and 5,580 controls, and the Moore et al pooled analysis included 12 U.S. and . Both European cohort studies; of these, 11 cohorts reported on head and neck cancers with 3,985 cases of these pooled analyses included only recreational and leisure time physical activity in their reports. Evidence on the Overall Relationship The INHANCE pooled analysis observed a risk reduction for all head and neck cancers combined for both moderate recreational physical activity (OR=0.78; 95% CI: 0.66-0.91) and high recreational physical 9 Moore et al activity (OR=0.72; 95% CI: 0.46-1.16). The pooled analysis by report ed a risk reduction for th th percentile of study participants’ physical to 10 all head and neck cancers when comparing the 90 activity levels (HR=0.85; 95% CI: 0.78-0.93). No dose-response analyses were conducted in either of these pooled analyses. Dose-response: Evidence on Specific Factors 65 examined results stratified by age and reported a decreased risk for The INHANCE pooled analysis Age: study participants ages 45 years or older (OR=0.66; 95% CI: 0.48-0.91) but not for participants younger than age 45 years (OR=0.76; 95% CI: 0.17-3.52). No stratification on age was reported i n the Moore et 9 al pooled analysis. No effect modification by sex was observed in the INHANCE consortium analysis. For all head and Sex: neck cancers combined, the risk reductions for both females (OR=0.64; 95% CI: 0.27-1.54) and males (OR=0.75; 95% CI: 0.38-1.46) were similar in magnitude and non-statistically significant. No 9 consideration of effect modification by sex was made in the pooled analysis by Moore et al. Rac e/ ethnicity: No conclusions can be made regarding whether or not the inverse relationship between physical activity and head and neck cancer varies by race or ethnicity. The studies did not report on these population subgroups, preventing any systematic conclusions related to these factors. Socioeconomic status: Neither pooled analysis presented data on the effect of socioeconomic status on the association between physical activity and head and neck cancer incidence. Hence, no conclusions can be made on this factor. 9 pooled analysis. Moore et al Weight status: No effect modification by BMI was found in the -38 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

287 Part F. Chapter 4. Cancer Prevention 65 considered specific subtypes of head and neck cancer Cancer subtype: Only the INHANCE consortium and reported risk reductions for oral cavity and pharyngeal cancers but not for laryngeal cancers. For oral cavity cancers, moderate amounts of physical activity (OR=0.74; 95% CI: 0.56-0.97) and high amounts of physical activity (OR=0.53; 95% CI: 0.32-0.88) were both associated with around a 25 percent and nearly 50 percent risk reductions, respectively, compared to the least active study participants. For pharyngeal cancers, both moderate and high amounts of physical activity were also associated with risk reductions of about 30 percent to 40 percent (OR=0.67; 95% CI: 0.53-0.85) and OR=0.58; 95% CI: 0.38-0.89) . The associations for laryngeal cancer and physical activity were inconsistent with other head and neck cancers. For moderate amounts of physical activity, a non- statistically significant reduction was observed, and for high amounts of physical activity, an increased risk was reported (OR=0.81; 95% CI: 0.60-1.11) and OR=1.73; 95% CI: 1.04-2.88), respectively. The 9 pooled analysis did not report on specific types of head and neck cancers separately. Moore et al : No effect modification by smoking status was found in either pooled analysis and no Other factors evidence exists regarding the relationship among individuals at high risk of head and neck cancers. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Ovarian Cancer Conclusion Statements Limited evidence suggests a weak relationship between greater levels of physical activity and lower risk of ovarian cancer. PAGAC Grade: Limited. Limited evidence suggests that no dose-response relationship exists between greater amounts of physical activity and lower ovarian cancer risk. PAGAC Grade: Limited. Insufficient evidence is available to determine whether the relationship between physical activity and ovarian cancer is modified by age, race/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity and ovarian cancer is modified by specific histologic types of ovarian cancers. PAGAC Grade: Not assignable -39 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

288 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether the effects of physical activity on ovarian cancer PAGAC Grade: Not assignable risk differ in individuals at elevated risk of ovarian cancer. Review of the Evidence Based on data from 2010 to 2014, the incidence rate of ovarian cancer was 11.7 per 100,000 women per 66 year. The number of deaths was 7.4 per 100,000 women per year. The risk factors for ovarian cancer include obesity; nulliparity; first degree family history of ovarian, breast or colorectal cancer; family cancer syndromes (e.g., hereditary breast and ovarian cancer syndrome, hereditary nonpolyposis colon cancer); personal history of breast cancer; and estrogen-only therapy after menopause. Ovarian cancer risk is decreased with oral contraceptive use of at least 3 to 6 months and some forms of injectable 67 hormonal contraceptive. 9, 69 19, 68 The and two pooled anal yses. The Subcommittee used information from two meta-analyses 68 meta-analysis by Zhong et al included 19 studies (9 prospective cohort and 10 case-control studies) 19 included 126 cohort studies, published between 1984 and June 2014. The meta-analysis by Liu et al which included 9 studies in an ovarian cancer analysis. The pooled analysis from the Ovarian Cancer 69 Association Consortium (OCAC) by included 9 case-control studies published to Cannioto et al 9 included 9 cohort studies September 2016 with 8,309 cases and 12,612 controls. The pooled analysis 19 with 2,880 ovarian cancer cases. Recreational physical activity was included in one meta-analysis and 9, 69 in both the pooled analyses, and non-occupational physical activity was included in the meta-analysis 68 19, 68 Zhong et al. The dose-response relationship was tested in two of the meta-analyses by and in the 9 pooled analysis. Evidence on the Overall Relationship 69 found chronic physical inactivity compared to some Cannioto et al The pooled-analysis published by physical activity was associated with an increased risk of ovarian cancer (OR=1.34; 95% CI: 1.14-1.57). 68 Zhong et al The meta-analysis by reported that any non-occupational physical activity versus none was associated with a borderline statistically significant reduction in ovarian cancer incidence (RR=0.92; 95% CI: 0.84-1.00). These authors also presented the results for moderate and high amounts of non- occupational physical activity compared to low amounts and found similar risk reductions (OR=0.91; 19 95% CI: 0.85-0.99 and OR=0.89; 95% CI: 0.79-1.01, respectively). Liu et al reported a null association for overall ovarian cancer when they compared participants with the highest to the lowest amounts of 9 th Moore et al compared participants in the 90 leisure time physical activity (RR=0.96; 95% CI: 0.74-1.26). -40 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

289 Part F. Chapter 4. Cancer Prevention th percentile to those in the 10 percentile of physical activity and found no association with ovarian cancer incidence (HR=1.01; 95% CI: 0.91-1.13). 68 observed a non-statistically significant relationship between increasing Dose-response: Zhong et al amounts of non-occupational physical activity and decreasing ovarian cancer risk. In addition, Zhong et 68 reported that a 2 MET-hours per week or 2 hours per week increment in non-occupational activity al conferred a relative risk of ovarian cancer risk of 0.98 (95% CI: 0.96-1.01) and 0.97 (95% CI: 0.94-1.01), 19 estimated the hazard ratios across categories of leisure time physical activity, respectively. Liu et al from 0 to 80 MET-hours per week in increments of between 10 and 20 MET-hours per week. They found 9 also found no evidence for a no evidence for a linear dose-response trend ( P =0.28). Moore et al trend =0.77). linear dose-response trend ( P trend Evidence on Specific Factors None of the analyses presented their results stratified by different age groups. As a result, no Age: conclusions about the role of age on the association between physical activity and ovarian cancer can be made. No effect modification by race on the association between recreational physical activity Race/ethnicity: 69 ancer incidence was observed in the pooled analysis by Cannioto et al. s No other analyse and ovarian c considered the effect of race/ethnicity on this association. None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and ovarian cancer incidence. Hence, no conclusions can be made on this factor. 69 Weight status: Cannioto et al, with a A statistically significant effect modification by BMI was found by 2 greater increased risk associated with physical inactivity in women with a BMI < 25 kg/m (OR=1.33; 95% 2 9 >25 kg/m CI: 1.19-1.49) than in women with a BMI (OR=1.21; 95% CI: 1.09-1.34). In the Moore et al pooled analysis, no effect modification by BMI was observed for the association between leisure time physical activity and ovarian cancer incidence. 54 Zhong et al examined the effects by different ovarian cancer subtype (borderline and Cancer subtype: invasive tumors) and no statistically significant differences by cancer subtype were found. No other analyses considered the association with physical activity for different ovarian cancer subtypes. -41 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

290 Part F. Chapter 4. Cancer Prevention No effect modification by menopausal status was observed in the pooled analysis by Other factors: 69 Cannioto et al. No other analyses considered menopausal status or any other factors as potential effect modifiers of the association between physical activity and ovarian cancer incidence. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Pancreatic Cancer Conclusion Statements Limited evidence suggests that greater amounts of physical activity are associated with a lower risk of developing pancreatic cancer. PAGAC Grade: Limited. Limited evidence suggests that a dose-response association does not exist between physical activity and Limited. PAGAC Grade: pancreatic cancer. Limited evidence suggests that the effects of physical activity on pancreatic cancer risk do not vary by Limited sex. PAGAC Grade: . Insufficient evidence is available to determine whether the effects of physical activity on pancreatic cancer risk vary by age, race/ethnicity, socioeconomic groups, or weight PAGAC Grade: Not assignable. status. Insufficient evidence is available to determine whether the effects of physical activity on pancreatic PAGAC Grade: Not assignab le. cancer risk differ by cancer subtypes. Insufficient evidence is available to determine whether the effects of physical activity on pancreatic cancer risk differ in individuals at elevated risk for pancreatic cancer. PAGAC Grade: Not assignable. Review of the Evidence Pancreatic cancer is the third leading cause of cancer mortality in the United States, and its incidence is 71, 70 possibly due to increasing prevalence of obesity and diabetes, two risk factors for the disease. rising, 72 Based on data from 2010 to 2014, the incidence rate of pancreatic cancer in the United States was 12.5 per 100,000 men and women per year and the number of deaths was 10.9 per 100,000 men and 73 women per year. -42 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

291 Part F. Chapter 4. Cancer Prevention Evidence on the Overall Relationship The Subc ommittee reviewed five systematic reviews on the association between physical activity and 74- 77 19, 75 -77 19, r, included met a-analyses. The Subcommittee also risk of pancreatic cancer, of which fou 9 reviewed one pooled analysis of 10 cohort studies. In the most recent of the 4 meta-analyses of 75 physical activity and pancreatic cancer risk, 26 individual studies were available for the meta-analysis, of which three quarters represented cohort studies. Some studies included in the meta-analyses and systematic review used mortality as a proxy for incidence. Because the five-year survival rate for pancreatic cancer is only seven percent, mortality provides a reasonable estimate for incidence. The 75 Farris et al meta-analysis suggests that risk of pancreatic cancer is statistically significantly reduced for individuals engaging in highest versus lowest levels of activity (RR=0.89; 95% CI: 0.82-0.96), but the 75 effect was stronger in case-control studies. Similar results were seen in the systematic review and 77 , 76, 74 19, other meta-analyses. The pooled analysis found no association between high levels of physical 9 activity and risk of pancreatic cancer (HR=0.93; 95% CI: 0.83-1.08). 19, 75 , 76 he Dose-response: However, t Dose-response relationships were assessed in three meta-analyses. analyses found no statistically significant associations between increased dose of physical activity and 19, 76 risk of pancreatic cancer, including assessments of duration, frequency, and energy expenditure. Similarly, the pooled analysis did not find evidence of a dose-response relationship between physical = 0.36). activity level and risk of pancreatic cancer ( P = 0.08, P overall non-linear Evidence on Specific Factors 75 Age: One meta-analysis examined the association of physical activity with pancreatic cancer by age, and found that only in studies with median age younger than 50 years was physical activity associated with reduced risk (RR=0.61; 95% CI: 0.50-0.75). In comparison, the estimates for studies with median ages 50 to 60 years and older than 60 years were RR=0.93 (95% CI: 0.87-1.01) and RR=1.00 (95% CI: 0.89-1.12), respectively. Meta-analyses found similar effects of physical activity on pancreatic cancer risk in males and Sex: females, although neither subgroup analysis was statistically significant. In contrast, those studies that 75 combined sexes showed significant effects (RR=0.79; 95% CI: 0.68-0.91). 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4 -43

292 Part F. Chapter 4. Cancer Prevention Race/ethnicity: Studies included primarily Caucasian individuals. One meta-analysis reported results by geographic area of included studies (United States, Canada, Europe, Asia), and found that effect size was 75 similar across areas but was of marginal statistical significance within areas. Socioeconomic status: None of the analyses or the systematic review presented data on the effect of socioeconomic status on the association between physical activity and pancreatic cancer incidence. Hence, no conclusions can be made on this factor. Weight status: One meta-analysis reported that adjustment for adiposity somewhat attenuated the 76 In the pooled association between physical activity and pancreatic cancer risk in cohort studies. analysis, BMI status did not change the lack of association between physical activity and risk of 9 pancreatic cancer development. Cancer subtype: None of the analyses or the systematic review reported on effects of physical activity on subtypes of pancreatic cancer (adenocarcinoma vs. neuroendocrine tumors). However, 95 percent of pancreatic cancers are adenocarcinomas. Individuals at high risk: No information was provided in the systematic review or analyses about effects of physical activity in individuals at elevated risk of pancreatic cancer. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- terial.aspx for the Evidence Portfolio. edition/report/supplementary- ma Prostate Cancer Conclusion Statements Limited evidence suggests a weak relationship between greater levels of physical activity and lower prostate cancer risk. PAGAC Grade: Limited. Insufficient evidence is available to determine whether a dose-response relationship exists between PAGAC Grade: Not assignable. higher levels of physical activity and lower prostate cancer risk. Insufficient evidence is available to determine whether the association between physical activity and we ight status, socioeconomic status, or smoking status prostate cancer varies by age, race/ethnicity, . PAGAC Grade: Not assignable. -44 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

293 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether the relationship between physical activity and prostate cancer varies by tumor sub-type, as risk reductions were observed with increased levels of PAGAC Grade: Not physical activity in both men with aggressive versus non-aggressive prostate cancer. assignable. Review of the Evidence Between 2010 and 2014, the incidence rate of prostate cancer was 119.8 per 100,000 men per year. The 78 number of deaths was 20.1 per 100,000 men per year. The main risk factors for prostate cancer are: older age, family history of prostate cancer, elevated endogenous androgen exposure, high dietary fat 79 and dairy products intake, and possibly some occupational exposures. 9 19, 80 The Subcommittee used information from two meta-analyses and one p ooled analysis. The first 80 meta-analysis by Liu et al included 43 studies (19 prospective cohort studies and 24 case-control 19 included 126 studies) published to May 2011 with 88,294 cases. The second meta-analysis by Liu et al 9 pooled analysis cohort studies; of these, 18 were included in a prostate cancer analysis. The Moore et al 7 were included in the prostate cancer analysis with 46,890 cases included 12 cohort studies; of these, . 80 by Liu et al and leisure time All types of physical activity were included in the first meta-analysis 19 physical activity was included in second meta-analysis by Moore et Liu et al and the pooled analysis by 9 al. Evidence on the Overall Relationship 80 pu found risk reductions for all types of physical activity. For Liu et al The first meta-analysis blished by total physical activity, when comparing the highest versus lowest amounts of physical activity, a 10 percent risk reduction was observed that was statistically significant (RR=0.90; 95% CI: 0.84-0.95). Occupational physical activity showed larger reductions than did total physical activity, with a relative risk of 0.81 (95% CI: 0.73-0.91), while recreational physical activity showed smaller risk reductions, with 19 Liu et al a relative risk of 0.95 (95% CI: 0.80-1.00), respectively. In the meta-analysis, when the association between the highest to the lowest amounts of leisure time physical activity was assessed as 9 a binary analysis, the relative risk was 0.93 (95% CI: 0.85-1.01) for overall prostate cancers. Moore et al th th percentile to the 10 percentile of physical activity and found a moderate risk compared the 90 increase of about 5 percent for higher amounts of physical activity (HR=1.05; 95% CI: 1.03-1.08). -45 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

294 Part F. Chapter 4. Cancer Prevention Dose-response: Evidence for a dose-response relationship between increasing percentiles of physical 9 activity and slightly increased prostate cancer risk was found in the pooled analysis Moore et al <0.0048). No other meta-analyses examined the dose-response relationship between physical ( P trend activity and prostate cancer risk. Evidence on Specific Factors 80 Age: Liu et al examined sub-group effects by age and found stronger risk reductions for men ages 20 to 65 years versus men older than age 65 years. 80 examined the associations between physical activity and population source. Race/ethnicity: Liu et al For total physical activity, they found stronger risk reductions for European and American populations than for Canadian and Asia-Pacific study populations. In addition, they examined race as an effect modifier and found larger risk reductions for Blacks (RR=0.74; 95% CI: 0.57-0.95) than for Whites 9 Moore et al pooled analysis found similar lack of associations (RR=0.86; 95% CI: 0.77-0.97). The P between highest versus lowest physical activity level and prostate cancer risk in Black and White men ( 9 No studies examined effect modification by socioeconomic status. =0.35) (Figure F4-1). heterogeneity None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and prostate cancer incidence. Hence, no conclusions can be made on this factor. Weight status: No evidence for effect modification by BMI was found in either the meta-analysis by Liu 80 9 2 or the Moore et al compared to those with pooled analysis for participants with BMI <25 kg/m et al 2 BMI 25 kg/m ≥ . 80 Cancer stage and subtype: Liu et al examined the associations between physical activity and prostate cancer risk by cancer stage. They found no effect modification for localized versus advanced prostate 19 examined the effects of physical activity within subgroups of prostate cancer Liu et al cancer stage. defined by tumor aggressiveness. For non-aggressive prostate cancer, the relative risk was 0.98 (95% CI: 0.79-1.21) and for aggressive prostate cancer, the relative risk was 0.89 (95% CI: 0.71-1.12). 80 9 Liu et al Other factors : No effect modification by smoking status was found by Moore et al. considered the associations between physical activity and prostate cancer stage by history of prostate specific antigen (PSA) testing and found that men with a previous history of a test had no benefit from -46 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

295 Part F. Chapter 4. Cancer Prevention physical activity (RR=1.05; 95% CI: 0.92-1.20) while those with no previous PSA test did have a non- statistically significant reduction in risk of prostate cancer (RR=0.83; 95% CI: 0.63-1.11). For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Brain Cancer Conclusion Statements Insufficient evidence is available to determine whether a relationship between physical activity and Limited evidence suggests that overall brain cancer incidence exists. PACAC Grade: Not assignable. physical activity decreases the risk of certain types of brain cancer. Specifically, a reduced risk is observed for glioma and meningioma. PAGAC Grade: Limited. Insufficient evidence is available to determine whether a dose-response relationship exists between physical activity and brain cancer incidence. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity and brain cancer incidence varies by age, sex, race/ethnicity or socioeconomic status because these factors Insufficient PAGAC Grade: Not assignable. have yet to be examined in the studies conducted to date. evidence is available to determine whether the relationship between physical activity and brain cancer incidence varies by body mass index . PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity and brain cancer incidence differs in individuals at high risk of brain cancer. PAGAC Grade: Not assignable. Review of the Evidence In 2014, an estimated 162,341 people were living with brain and other nervous system cancers in the 81 United States. Brain cancer has many different types and the causes of brain cancer remain unknown. 9 82 and one pooled analysis. The Subcommittee used information from one meta-analysis The meta- analysis included four studies of meningioma (three cohort and one case-control study) and five studies 82 9 of glioma (three cohort and two case-control studies). The pooled analysis by Moore et al included 12 U.S. and European cohort studies; of these, 10 cohorts were included in the brain cancer analysis, with 82 meta-analysis included 2,982 meningioma cases from 9 studies and Niedermaier et al . The 2,110 cases 3,057 glioma cases from 7 studies. The type of physical activity assessed in the studies included in the -47 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

296 Part F. Chapter 4. Cancer Prevention 9 82 was restricted to leisure time Moore et al was not specified and the pooled analysis by meta-analysis physical activity. Evidence on the Overall Relationship Some evidence of an inverse relationship between physical activity and certain types of brain cancer was found. For meningioma, a reduced risk was reported when comparing study participants with the 82 highest versus the lowest levels of physical activity (RR=0.73; 95% CI: 0.61-0.88). Similarly, a reduced 82 risk of glioma was reported with higher levels of physical activity (RR=0.86; 95% CI: 0.76-0.97). This risk 9 reduction for brain cancer (no brain cancer sub-type specified) was not observed in the pooled analysis. th th percentile of study participants’ physical activity levels, In that study, when comparing the 90 to 10 the hazard ratio was 1.06 (95% CI: 0.93-1.20). No dose-response analysis was conducted in the meta-analysis because of the Dose-response: 82 heterogeneous physical activity assessments done in the studies that were assessed. The pooled 9 found no evidence for a dose-response relationship between increasing percentiles of physical analysis activity and brain cancer risk. Evidence on Specific Factors Age: The two analyses adjusted for age but did not stratify their results by age group, therefore providing no evidence for effect modification by age. 82 No effect modification by sex was observed in the meta-analysis by Sex: and no Niedermaier et al 9 consideration of sex was made in the pooled analysis by Moore et al. Race/ethnicity: No conclusions can be made regarding whether or not the inverse relationship between physical activity and brain cancer varies by race or ethnicity. The studies did not report on these population subgroups, preventing any systematic conclusions related to these factors. None of the analyses presented data on the effect of socioeconomic status on Socioeconomic status: the association between physical activity and brain cancer incidence. Hence, no conclusions can be made on this factor. 9, 82 No effect modification by BMI was found in either of the two analyses. Weight status: -48 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

297 Part F. Chapter 4. Cancer Prevention 82 considered specific subtypes of brain Niedermaier et al Only the meta-analysis by Cancer subtype: cancer and found risk reductions for both meningioma and glioma. 9 Other factors : No effect modification by smoking status was found in the pooled analysis. No studies considered the effect of physical activity among individuals at high risk of brain cancer. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: for the Evidence Portfolio. edition/report/supplementary-material.aspx Cancers for Which Physical Activity Shows Evidence for No Effect Thyroid Cancer Conclusion Statements Moderate evidence indicates that greater amounts of physical activity are not associated with risk of PAGAC Grade: developing thyroid cancer. Moderate. Insufficient evidence is available to determine whether physical activity levels and risk of thyroid cancer have a dose-response relationship. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the effects of physical activity on thyroid cancer PAGAC Grade: Not assignable. differ by specific sex, age, race/ethnicity, or socioeconomic groups. Insufficient evidence is available to determine whether weight status affects the association between physical activity and thyroid cancer risk. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the association of physical activity with thyroid cancer risk differs by subtype of thyroid cancer. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the association of physical activity with thyroid PAGAC Grade: Not assignable. cancer risk differs in individuals at elevated risk of thyroid cancer. Review of the Evidence 83 Based on data from The incidence and mortality of thyroid cancer are increasing in the United States. 2010 to 2014, the incidence rate of thyroid cancer was 14.2 per 100,000 men and women per year. The number of deaths was 0.5 per 100,000 men and women per year. Although the increase in incidence is in part due to increased screening, the increased mortality suggests that part of the increase in -49 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

298 Part F. Chapter 4. Cancer Prevention incidence is real. Risk factors for thyroid cancer include being female, radiation exposure, some 85 84, hereditary conditions, low iodine intake, and obesity. The Subcommittee reviewed evidence of associations between physical activity and thyroid cancer risk. 86 87 One meta-analysis was reviewed, as well as one pooled analysis of 5 cohorts, and one pooled analysis 9 of 11 cohort studies. Evidence on the Overall Relationship A small number of epidemiologic studies have examined the association between physical activity and risk of developing thyroid cancer. In the meta-analysis of physical activity and thyroid cancer risk, data 86 from eight cohort and three case-control studies were included. The meta- analysis suggests that risk for thyroid cancer is not associated with high versus low levels of activity (RR=1.06; 95% CI: 0.79-1.42). When the meta-analysis was limited to cohort studies, physical activity was associated with increased 86 risk of thyroid cancer (RR=1.28; 95% CI: 1.01-1.63). The five-cohort pooled analysis found no significant 87 association between physical activity and thyroid cancer risk (RR=1.18; 95% CI: 1.00-1.39). The pooled analysis of 11 cohorts similarly found no statistically significant association between high levels of 9 physical activity and thyroid cancer risk (RR=0.92; 95% CI: 0.81-1.06). 9 Dose-response: The larger pooled analysis showed no statistically significant associations between increased dose of physical activity and risk of thyroid cancer . Evidence on Specific Factors 87 Age: Risk estimates by age were presented only in the pooled analysis of five cohorts. They observed - =0.03), whereby the statistically significant differences according to age at diagnosis ( P interaction association was strongest for thyroid cancers diagnosed before age 50 years (80 cases, HR=2.58; 95% CI: P 1.41-4.74, =0.002) compared to thyroid cancers diagnosed at ages 50 to 59 years (127 cases, trend HR=1.09; 95% CI: 0.72-1.66, P =0.68) or at ages 60 years or older (611 cases, HR=1.11; 95% CI: 0.92- trend 87 87 Given that this subgroup association was evident only in a subset of all of the P =0.28). 1.34, trend 9, 86 studies that have addressed thyroid cancer and physical activity, the Subcommittee could not determine that high levels of physical activity increases risk of thyroid cancer in young individuals. The relative risk estimates for women in the individual studies stratified by sex (approximately half) Sex: reflect the overall risk estimate. The pooled analysis found similar risk estimates between men and women (both showing no statistically significant associations). In the smaller pooled analysis, association -50 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

299 Part F. Chapter 4. Cancer Prevention was non-statistically significantly stronger in men (HR=1.40; 95% CI: 1.06-1.86) compared to women 87 (HR=1.07; 95% CI: 0.87-1.32; P =0.21). interaction Race/ethnicity: The studies included in these analyses were primarily from Caucasian individuals. 86 that showed data for Asians had similar relative risks to those from the Studies in the meta-an alysis U.S. and European studies. Socioeconomic status: None of the analyses presented data on the effect of socioeconomic status on the association between physical activity and thyroid cancer incidence. Hence, no conclusions can be made on this factor. Weight status: The pooled analysis of five cohorts found the association for high versus low physical 2 : activity was statistically significantly stronger among participants with BMI ≥ 25 kg/m (HR=1.34; 95% CI 87 2 (HR=0.92; 95% CI: 0.69-1.22; P The =0.03). 1.09-1.64) compared to those with BMI <25 kg/m interaction 2 versus >25 pooled analysis of 11 cohorts, in contrast, found no difference in effect by BMI <25 kg/m 2 9 (P kg = 0.37). /m effect modification Cancer subtype: Neither the meta-analysis nor the larger pooled analysis reported on the effects of physical activity by subtypes of thyroid cancer (papillary, follicular, medullary, anaplastic). In the pooled analysis of five cohorts, the association was non-statistically significantly stronger for follicular thyroid cancer (HR=1.55; 95% CI: 1.03-2.35) compared to papillary thyroid cancer (HR=1.18; 95% CI: 0.97-1.44; 87 P = 0.24). interaction Individuals at high risk: No information was provided in the meta-analysis or pooled analyses about effects of physical activity in individuals at elevated risk of thyroid cancer. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Rectal Cancer Conclusion Statements Limited evidence suggests that greater amounts of physical activity are not associated with risk of PAGAC Grade: developing rectal cancer. Limited. -51 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

300 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether a dose-response relationship between increasing physical activity levels and decreasing risk of rectal cancer exists. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the effects of physical activity on rectal cancer risk differ by sex, age, race/ethnicity, weight status, or socioeconomic groups in the United States. Not assignable. PAGAC Grade: Insufficient evidence is available to determine whether the effects of physical activity on rectal cancer risk differ by subtype of rectal cancer. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the effects of physical activity on rectal cancer risk differ in individuals at elevated risk for rectal cancer. Not assignable. PAGAC Grade: Review of the Evidence Based on data from 2010-2014, the incidence rate of rectal cancer in the United States was 11.8 per 21 Risk factors for rectal cancer include: increased age, obesity, 100,000 men and women per year. personal history of adenomatous colorectal polyps, family history of colorectal cancer, certain genetic 30 89 , 88, polymorphisms , inflammatory bowel disease, alcohol use, and cigarette smoking. To examine the association between physical activity and risk of rectal cancer, the Subcommittee 23 19, 19, , 26, 23 29 , 26 of which three reviewed four systematic reviews included meta-analyses. The 9 Subcommittee also reviewed one pooled analysis of 12 large prospective cohort studies and meta- 30 , 31 The reviews contained data from between 5 analysis data from the World Cancer Research F . und and 14 epidemiologic studies. Evidence on the Overall Relationship A considerable body of epidemiologic data exists on the association between physical activity and risk of developing rectal cancer. The most recent published meta-analysis (nine cohort studies) reported that risk of rectal cancer did not differ for individuals engaging in the highest versus lowest categories of 19 physical activity level (RR=1.07; 95% CI: 0.93-1.24). Other meta-analyses similarly found no associations between highest versus lowest levels of physical activity and risk of developing rectal 23, , 30 , 31 26 cancer. Most studies adjusted for multiple potential confounding factors, including age, BMI, and rectal cancer risk factors, although adjustment for colorectal cancer screening (which could be related to physical activity level) was not typically done. In contrast to these findings, the pooled analysis -52 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

301 Part F. Chapter 4. Cancer Prevention th th of 12 cohort studies found a statistically significant relationship between the 90 versus percentile 10 9 level for leisure time physical activity and decreased risk of rectal cancer (RR=0.87; 95% CI: 0.80-0.95). It is not clear why the results of the pooled analysis differ from those of the meta-analyses. The pooled analysis included only a subset of studies contained in the meta-analyses. In addition, the pooled analysis compared the top versus bottom decile of physical activity, while the meta-analyses used whatever the source studies reported as high or low activity levels, typically top and bottom quartiles. Dose-response: Given the lack of overall associations between physical activity and risk of rectal cancer, none of the meta-analyses examined dose-response relationships. The pooled analysis of 12 cohort studies found a significant U-shaped relationship between increasing leisure time physical activity 9 P percentile and risk of rectal cancer ( P =0.0002; =0.0008). non-linear overall Evidence on Specific Factors Sex: The pooled analysis found that the effect of physical activity on risk of rectal cancer was statistically 9 P =0.09). significant in men, but not women ( heterogeneity Age: None of the analyses or the systematic review provided data within specific age groups. Studies in the United States and Europe were primarily in Caucasians. A systematic Race/ethnicity: review of Japanese studies reported on data from two cohort and six case-control studies, and found no 29 association of higher physical activity with risk of rectal cancer. Socioeconomic status: None of the analyses or the systematic review presented data on the effect of socioeconomic status on the association between physical activity and rectal cancer incidence. Hence, no conclusions can be made on this factor. th th The pooled analysis examined associations between the 90 percentile versus 10 Weight status: 2 percentile of physical activity level by BMI. Risk of rectal cancer for those with BMI <25.0 kg/m did not 9 2 >25 kg/m differ from that of individuals with BMI ( P =0.50). effect modification None of the analyses or the systematic review considered the association with physical Cancer subtype: activity for different rectal cancer subtypes. Individuals at high risk : No information was provided in the systematic review or analyses about effects of physical activity in individuals at elevated risk of rectal cancer. -53 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

302 Part F. Chapter 4. Cancer Prevention https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: edition/report/supplementary-material.aspx for the Evidence Portfolio. Other Cancers No systematic reviews or meta-analyses included sufficient information to make conclusions about the associations between physical activity and occurrence of other cancers, including liver, gallbladder, small 9 intestine, soft tissue, or melanoma. However, the pooled analysis by Moore et al, provided some data on these cancers that are useful to note. Statistically significantly reduced risks were observed for the th th CI: 0.55-0.98) 90 versus 10 . percentile of physical activity level for liver cancer (HR=0.73; 95% CI: 1.16- Statistically significantly increased risks were seen for malignant melanoma (HR=1.27; 95% 1.40). No statistically significant associations were observed for cancers of the small intestine (HR=0.78; 95% CI: 0.60-1.00), soft tissue (HR=0.94; 95% CI: 0.67-1.31), and gallbladder (HR=0.72; 95% CI: 0.51- 1.01). Question 2: What is the relationship between sedentary behavior and cancer incidence? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? Is the relationship independent of levels of light, moderate, or vigorous physical activity? c) t bouts or breaks in sedentary behavior are important factors? Is there any evidence tha d) Sources of evidence: Meta-analyses, systematic reviews, original research articles Conclusion Statements Moderate evidence indicates a significant relationship between greater time spent in sedentary behavior and higher risk of incident cancer, particularly for endometrial, colon, and lung cancer. PAGAC Grade: Moderate. Limited evidence suggests the existence of a direct dose-response relationship between sedentary PAGAC Grade: Limited. behavior and incident endometrial, colon, and lung cancers. Insufficient evidence is available to determine whether the relationship between sedentary behavior and incident cancer varies by age, sex, race/ethnicity, socioeconomic status, or weight status . PAGAC Grade: Not assignable. -54 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

303 Part F. Chapter 4. Cancer Prevention Insufficient evidence is available to determine whether the relationship between sedentary behavior PAGAC Grade: Not and incident cancer varies by amount of moderate- to-vigorous physical activity. assignable. Insufficient evidence is available to determine whether bouts or breaks in sedentary behavior are important factors in the relationship between sedentary behavior and incident cancer. PAGAC Grade: Not assignable. Review of the Evidence Sources of evidence included systematic reviews and meta-analyses published from January 2000 to February 21, 2017, and recent original research articles published between January 2014 and April 25, 2017. The sources of evidence were identified through the same search that was used to provide . Further details about the search evidence for Question 4 in Part F. Chapter 2. Sedentary Behavior strategy are provided in that chapter. For details on the review of the evidence to address Question 2, the reader is referred to Part F. Chapter 2: Sedentary Behavio r. Briefly, two meta-analyses examined the association between sedentary 91 90, behavior and total cancer incidence, and reported summary relative risk estimates of 1.20 (95% CI: 91 90 1.12-1.28) and 1.13 (95% CI: 1.05-1.21) for highest versus lowest levels of sedentary behavior. Two meta-analyses examined the association between sedentary behavior and endometrial cancer, and both reported a significant association when comparing the highest versus lowest levels of sedentary 92 time: a relative risk of 1.36 (95% CI: 1.15-1.60) was reported by Schmid and Leitzmann, and a relative 90 90 risk of 1.28 (95% CI: 1.08-1.53) was reported by Shen et al. reported a The meta-analysis by Shen et al = statistically significant association between sedentary behavior and combined colorectal cancer (RR 92 .30; 95% CI: 1.12-1.49); whereas Schmid and Leitzmann reported a statistically significant association for colon cancer (RR=1.28; 95% CI: 1.13-1.45) but not for rectal cancer (RR =1.03; 95% CI: 0.89-1.19). These two meta-analyses also examined the association between sedentary behavior and lung cancer, and both reported a statistically significant association when comparing the highest versus lowest levels 92 Schmid and Leitzmann, of sedentary time: a relative risk of 1.21 (95% CI: 1.03-1.43) was reported by 90 It is important to note that and a relative risk of 1.27 (95% CI: 1.06-1.52) was reported by Shen et al. many studies reported significant associations between sedentary behavior and incident cancer risk -55 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

304 Part F. Chapter 4. Cancer Prevention ysical activity as a vigorous ph - to - using statistical models that included an estimate of moderate covariate. ONCLUSIONS C OVERALL SUMMARY AND analyses, and pooled analyses comprising hundreds of - In reviewing 45 systematic reviews, meta with several million study participants, the Subcommittee determined that strong epidemiologic studies els to reduced risks of bladder, breast, colon, evidence linked highest versus lowest physical activity lev endometrial, esophageal adenocarcinoma, renal, and gastric cancers, with risk reductions ranging from approximately 10 percent to 20 percent. The Subcommittee found evidence of a 25 percent reduction in cancer risk with highest versus lowest levels of physical activity, but could not rule out confounding lung by tobacco use and therefore considered the association to be a lower grade of strength. The ssociation between increased physical Subcommittee determined that limited evidence suggested an a activity and decreased risks of hematologic, head and neck, ovary, pancreas, and prostate cancers. No grade could be assigned for brain cancer. The Subcommittee found limited evidence of no effect of on risk of thyroid or rectal cancer. Finally, due to lack of evidence, the Subcommittee physical activity did not review several other cancer sites. - A dose response relationship between physical activity and specific cancer risk was evident, but given the inconsistent metho ds of measuring and categorizing physical activity levels in the various studies, analyses, and pooled analyses, it was not possible to determine exact levels of physical activity meta - that provide given levels of effect. Investigation by cancer subtype s howed that increased physical activity is associated with reduced risk of breast cancer regardless of hormone receptor status, and of colon cancer originating both proximally ed with reduced and distally. Conversely, although high levels of physical activity were associat adenocarcinoma of the esophagus, no statistically significant effect was observed for squamous cell cancer of the esophagus. Little information was available for other subtypes of cancer. Effects of physical activity on specific cancer risk were clearly seen for both women and men for colon and renal cancers, while for other cancers such as bladder, esophagus, gastric, lung, and pancreas, differences by sex could not be ruled out. Little information was available on differences in physical a ctivity effect on cancer risk by age or socioeconomic status. Few estimates were available for specific 56 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4 -

305 Part F. Chapter 4. Cancer Prevention race/ethnic groups other than Whites. For several cancers, individuals of Asian race appeared to have similar protection from physical activity as do non-Asian individuals. The pooled analysis suggested that, , similar to Whites, physical activity reduces risks of lung, colon, and breast cancers in African Americans but is not related to prostate cancer risk in African Americans. For some particular U.S. populations (Latino, Native American, Pacific Islander), data are so sparse that systematic reviews, meta-analyses, and pooled analyses have not presented data on these race/ethnic populations. Weight status affected the association between physical activity and risk of several cancers, including breast, endometrium, lung, ovary, and thyroid, and possibly for esophageal adenocarcinoma and gastric cardia cancers. and The Subcommittee’s review of the literature on sedentary behavior and risk of endometrial, colon, lung cancers found that highest versus lowest levels of sedentary time increased risks of these cancers by a statistically significant range of 20 percent to 35 percent, with an evidence grade of strong. Conclusions could not be drawn for associations between sedentary time and other specific cancers. In summary, the Subcommittee’s review of the extensive epidemiologic literature resulted in convincing evidence linking increased physical activity to lower risk of several commonly occurring cancers in adults, as well as possible lower risk of several other cancers in adults. These effects appear to apply broadly across sex, most cancer subtypes, and, for most cancers, regardless of weight status. Most of the existing data on physical activity and cancer risk come from studies of Whites. The existing data on other racial and ethnic groups, including African Americans and Asians, suggest that physical activity confers similar benefits. Although data on diverse racial and ethnic groups are insufficient, there are no data to say that physical activity will not help individuals of all races and ethnicities. Table F4-1. Summary of Associations of Physical Activity and Sedentary Behavior with Specific Cancers, with Subcommittee-assigned Evidence Grade Evidence Grade* Cancer Physical activity protects: Bladder, breast, colon, endometrium, esophagus Strong (adenocarcinoma), renal, gastric Lung Moderate Hematologic, head & neck, ovary, pancreas, prostate Limited Not assignable Brain No effect of physical activity: -57 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

306 Part F. Chapter 4. Cancer Prevention Cancer Evidence Grade* Limited Thyroid Rectal Limited Sedentary behavior increases risk: Endometrium, colon, lung Moderate Note: *Evidence grade refers to strength of evidence in the literature regarding associations between physical activity and cancer risk. For effect sizes and directions of these associations, see reviews of evidence with specific cancers. Comparing 2018 Findings with the 2008 Scientific Report 4 The concluded that evidence supported a Physical Activity Guidelines Advisory Committee Report, 2008 moderate, inverse relation between physical activity and the development of colon and breast cancer. In that report, few studies detailed the associations by subgroups (age, sex, weight status, cancer site) or by particular types of physical activity. It further concluded that there was no association between physical activity and the development of prostate or rectal cancer. 4 did not comment on the associations between physical activity and risk of The 2008 Scien tific Report bladder, gastric, endometrial, renal, hematological, head and neck, pancreatic, ovarian, brain, or thyroid cancers because few studies in these cancers were available at that time. Further, given that the evidence of associations between sedentary behavior and cancer incidence has largely been published since 2008, the prior report did not include information on this exposure. 4 reviewed some mechanisms that may explain the associations between The 2008 Scientific Report physical activity and cancer risk, but the review was not systematic. Public Health Impact In 2017, an estimated 1,688,780 Americans will be diagnosed with a new cancer and 600,920 individuals 1 From our review, regular aerobic physical activity likely confers substantial beneficial will die of cancer. effects on reducing risks for occurrence of several cancers, notably some of the most commonly occurring cancers (e.g., breast, colon, and lung cancers), as well as several obesity-related cancers (e.g., postmenopausal breast, colon, esophageal adenocarcinoma, and renal). Given the significant impact of cancer on quality of life, financial stability, and mortality, the reduction in risk of common cancers from high levels of physical activity could have a large public health impact. Substantial reductions in the incidence of cancer, mortality from cancer, and cancer-related costs would be expected if currently -58 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

307 Part F. Chapter 4. Cancer Prevention inactive individuals became more physically active. Therefore, the Subcommittee believes that all individuals should be encouraged to engage in recommended levels of physical activity in order to reduce risk for developing cancer. NEEDS FOR FUTURE RESEARCH 1. Conduct epidemiologic studies of effects of physical activity on risk of cancer for specific cancer sites that have not been adequately studied, preferably large prospective cohort studies. Rationale: Very little evidence exists on the relationship between physical activity and the risk of cancer at several sites, particularly the rare cancers. Therefore additional pooled datasets and meta- analyses may be needed. Additional studies would provide the data necessary for the useful insights that would be possible through analyses of pooled datasets and meta-analyses. 2. Conduct epidemiologic studies of effects of physical activity on risk of cancer in specific race, ethnic, and socioeconomic groups. Rationale: Few studies have had sufficiently large numbers of participants from specific racial, ethnic, or socioeconomic subgroups to assess the effects of physical activity on risk of developing of cancer cancer. This additional research is particularly important, as many groups are at high risk (i.e., African Americans are at increased risk for colon, prostate, and breast cancers), are typically diagnosed with more advanced disease (i.e. individuals from low socioeconomic groups or others without access to medical care), and are often insufficiently active. Conduct studies to test effect modification by age on the associations between physical activity and 3. cancer risk. Some evidence suggests that risk for some cancers such as colon and breast is increasing Rationale: in younger age groups, who are also less active today than in previous generations. It would be important to know whether physical activity can be protective in this younger age group. Conduct epidemiologic studies, preferably prospective cohort studies, to determine effects of 4. specific types of physical activity on cancer risk. -59 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

308 Part F. Chapter 4. Cancer Prevention Rationale: Few data are available on the associations of specific activities on cancer risk. It would be useful to know whether moderate-intensity activities such as walking are sufficient to provide protection. Also, insufficient data exist on associations of other activities such as muscle- strengthening activity on cancer risk. 5. Conduct epidemiologic studies, preferably prospective cohort studies, to more precisely determine dose-response effect of physical activity on cancer risk. All data in available studies have been from self-reported recall of usual activities. Rationale: Collecting data with device-based measures of activity will be important, as will determining precise measures of dose of activity. Conduct randomized controlled clinical trials testing exercise effects on cancer incidence. 6. : All available data are from observational studies, which could suffer from confounding Rationale effects of other variables. Randomized trials in high risk individuals could be more cost-effective, as trials with smaller sample sizes or shorter follow-up durations might be feasible. REFERENCES 17;67(1):7-30. CA Cancer J Clin . 20 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. doi:10.3322/caac.21387. 2. American Cancer Society. Lifetime risk of developing or dying from cancer. https://www.cancer.org/cancer/cancer-basics/lifetime-probability- of-developing- or-dying-from- cancer.html. Updated March 23, 2016. Accessed January 3, 2018. Lancet . 2014;383(9916):549-557. 3. Vineis P, Wild CP. Global cancer patterns: causes and prevention. doi:10.101 6/S0140-6736(13)62224- 2. elines Advisory Committee Physical Activity Guid 4. Physical Activity Guidelines Advisory Committee. Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. Nat Rev Cancer . 2008;8(3):205-211. 5. McTiernan A. Mechanisms linking physical activity with cancer. doi:10.1038/nrc2325. 6. Koelwyn GJ, Quail DF, Zhang X, White RM, Jones LW. Exercise-dependent regulation of the tumour Nat Rev Cancer microenvironment. . 2017;17(10):620-632. doi:10.1038/nrc.2017.78. -60 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

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312 Part F. Chapter 4. Cancer Prevention 47. American Cancer Society. Risk factors for kidney cancer. https://www.cancer.org/cancer/kidney- cancer/causes-risks-prevention/risk-factors.html. Accessed January 3, 2018. 48. Behrens G, Leitzmann MF. The association between physical activity and renal cancer: systematic review and meta-analysis. Br J Cancer . 2013;108(4):798-811. doi:10.1038/bjc.2013.37. Continuous 49. World Cancer Research Fund International, American Institute for Cancer Research. ; 2015. Update Project Report: Diet, Nutrition, Physical Activity and Kidney Cancer http://www.wcrf.org/kidney-cancer-2015 . Accessed January 16, 2018. 50. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: . Accessed January 3, 2018. lung and bronchus cancer. https://seer.cancer.gov/statfacts/html/lungb.html 51. Sun JY, Shi L, Gao XD, Xu SF. Physical activity and risk of lung cancer: a meta-analysis of prospective cohort studies. Asian Pac J Cancer Prev . 2012;13(7):3143-3147. 52. Buffart LM, Singh AS, van Loon EC, Vermeulen HI, Brug J, Chinapaw MJ. Physical activity and the risk . 2014;17(1):67-71. of developing lung cancer among smokers: a meta-analysis. J Sci Med Sport doi:10.1016/j.jsams.2013.02.015. 53. Schmid D, Ricci C, Behrens G, Leitzmann MF. Does smoking influence the physical activity and lung Eur J Epidemiol . 2016;31(12):1173-1190. cancer relation? A systematic review and meta-analysis. doi:10.1007/s10654-016-0186- y. 54. Zhong S, Ma T, Chen L, et al. Physical activity and risk of lung cancer: a meta-analysis. Clin J Sport Med . 2016;26(3):173-181. doi:10.1097/JSM.0000000000000219. 55. Brenner DR, Yannitsos DH, Farris MS, Johansson M, Friedenreich CM. Leisure-time physical activity and lung cancer risk: a systematic review and meta-analysis. Lung Cancer . 2016;9 5:17-27. doi:10.1016/j.lungcan.2016.01.021. 56. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: leukemia. https://seer . https://seer.cancer.gov/statfacts/html/leuks.html . Accessed January 3, 2018. 57. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: non-Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html . Accessed January 3, 2018. 58. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: https://seer.cancer.gov/statfacts/html/hodg.html . Accessed January 3, 2018. Hodgkin lymphoma. 59. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: myeloma. https://seer.cancer.gov/statfacts/html/mulmy.html . Accessed January 3, 2018. 60. Jochem C, Leitzmann MF, Keimling M, Schmid D, Behrens G. Physical activity in relation to risk of hematologic cancers: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev . 2014;23(5):833-846. doi:10.1158/1055-9965.EPI- 13-0699. 61. Verma ete NV, Wolter P, Verhoef GE, et al. Physical activity and risk of lymphoma: a meta-analysis. . 2013;22(7):1173-1184. doi:10.1158/1055-9965.EPI- Cancer Epidemiol Biomarkers Prev 0182. 13- -64 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

313 Part F. Chapter 4. Cancer Prevention 62 . Aschebrook-Kilfoy B, Cocco P, La Vecchia C, et al. Medical history, lifestyle, family history, and factors for mycosis fungoides and Sézary syndrome: the InterLymph Non-Hodgkin occupational risk Lymphoma Subtypes Project. J Natl Cancer Inst Monogr . 2014;2014(48):98-105. doi:10.1093/jncimonographs/lgu008. 63 . National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: oral cavity and pharynx cancer. https://seer.cancer.gov/statfacts/html/oralcav.html . Accessed January 3, 2018. . National Cancer Institute. Head and neck cancers. w.cancer.gov/types/head-and- https://ww 64 neck/head-neck-fact-sheet . Accessed January 3, 2018. 65 . Nicolotti N, Chuang SC, Cadoni G, et al. Recreational physical activity and risk of head and neck cancer: a pooled analysis within the international head and neck cancer epidemiology (INHANCE) Consortium. Eur J Epidemiol 3. . 2011;26(8):619-628. doi:10.1007/s10654-011-9612- 66 . National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: ovarian cancer. https://seer.cancer.gov/statfacts/html/ovary.html . Accessed January 3, 2018. . American Cancer Society. What are the risk factors for ovarian cancer? 67 w.cancer.org/cancer/ovarian-cancer/causes-risks-prevention/risk-factors.html . Accessed https://ww January 3, 2018. 68 . Zhong S, Chen L, Lv M, Ma T, Zhang X, Zhao J. Nonoccupational physical activity and risk of ovarian cancer: a meta- Tumour Biol . 2014;35(11):11065-11073. doi:10.1007/s13277-014-2385- z. analysis. 69 . Cannioto R, LaMonte MJ, Risch HA, et al. Chronic recreational physical inactivity and epithelial Cancer Epidemiol ovarian cancer risk: evidence from the Ovarian Cancer Association Consortium. Biomarkers Prev . 2016;25(7):1114-1124. doi:10.1158/1055-9965.EPI- 15 -1330. 70 . American Cancer Society. Cancer Facts & Figures 2017. Atlanta, GA: American Cancer Society; 2017. 71 . Genkinger JM, Spiegelman D, Anderson KE, et al. A pooled analysis of 14 cohort studies of . 2011;129(7):1708-1717. anthropometric factors and pancreatic cancer risk. Int J Cancer doi:10.1002/ijc.25794. 72 . Elena JW, Steplowski E, Yu K, et al. Diabetes and risk of pancreatic cancer: a pooled analysis from the Cancer Causes Control . 2013;24(1):13-25. doi:10.1007/s10552- pancreatic cancer cohort consortium. 012-0078- 8. 73 . National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: pancreatic cancer. . Accessed January 3, 2018. https://seer.cancer.gov/statfacts/html/pancreas.html 74 . Bao Y, Michaud DS. Physical activity and pancreatic cancer risk: a systematic review. Cancer Epidemiol Bioma rkers Prev . 2008;17(10):2671-2682. doi:10.1158/1055-9965.EPI- 08-0488. . Farris MS, M osli MH, McFadden AA, Friedenreich CM, Brenner DR. The association between leisure 75 Cancer time physical activity and pancreatic cancer risk in adults: a systematic review and meta-analysis. Epidemiol Biomarkers Prev 15-0301. . 2015;24(10):1462-1473. doi:10.1158/1055-9965.EPI- -65 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

314 Part F. Chapter 4. Cancer Prevention 76 . Behrens G, Jochem C, Schmid D, Keimling M, Ricci C, Leitzmann MF. Physical activity and risk of systematic review and meta-analysis. . 2015;30(4):279-298. Eur J Epidemiol pancreatic cancer: a doi:10.1007/s10654-015-0014- 9. 77. O’Rorke MA, Cantwell MM, Cardwell CR, Mulholland HG, Murray LJ. Can physical activity modulate 6(12):2957-2968. pancreatic cancer risk? A systematic review and meta-analysis. Int J Cancer . 2010;12 doi:10.1002/ijc.24997. National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: 78. prostate cancer. . Accessed January 3, 2018. https://seer.cancer.gov/statfacts/html/prost.html 79 . National Cancer Institute. Prostate Cancer Prevention (PDQ®) – Health Professio nal Version. https://www.cancer.gov/types/prostate/hp/prostate-prevention-pdq#section/_17 . Updated March 17, 2017. Accessed January 3, 2018. 80. Liu Y, Hu F, Li D, et al. Does physical activity reduce the risk of prostate cancer? A systematic review and meta-analysis. Eur Urol . 2011;60(5):1029-1044. doi:10.1016/j.eururo.2011.07.007. 81 . National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: brain and other nerv . Accessed ous system cancer. https://seer.cancer.gov/statfacts/html/brain.html January 3, 2018. . Niedermaier T, Behrens G, Schmid D, Schlecht I, Fischer B, Leitzmann MF. Body mass index, physical 82 activity, and risk o Neurology . 2015;85(15):1342-1350. f adult meningioma and glioma: a meta-analysis. doi:10.1212/WNL.0000000000002020. 83 . National Cancer Institute; Surveillance, Epidemiology, and End Results Program. Cancer stat facts: . Accessed January 3, 2018. thyroid cancer. https://seer.cancer.gov/statfacts/html/thyro.html 84 . American Cancer Society. Thyroid cancer risk factors. https://ww w.cancer.org/cancer/thyroid- cancer/causes-risks-prevention/ri sk-factors.html . Accessed January 3, 2018. 85 . Schmid D, Ricci C, Behrens G, Leitzmann MF. Adiposity and risk of thyroid cancer: a systematic Obes Rev . 2015;16(12):1042-1054. doi:10.1111/obr.12321. review and m eta-analysis. . Schmid D, Behrens G, Jochem C, Keimling M, Leitzmann M. Physical activity, diabetes, and risk of 86 thyroid cancer: a systematic review and meta-analysis. Eur J Epidemiol . 2013;28(12):945-958. doi:10.100 7/s10654-013-9865- 0. 87. Kitahara CM, Platz EA, Beane Freeman LE, et al. Physical activity, diabetes, and thyroid cancer risk: a . 2012;23(3):463-471. Cancer Causes Control pooled analysis of five prospective studies. doi:10.1007/s10552-012-9896- y. 88 . Cheng J, Chen Y, Wang X, et al. Meta-analysis of prospective cohort studies of cigarette smoking and n and rectal cancers. . 2015;24(1):6-15. doi: Eur J Cancer Prev the incidence of colo 10.1097/CEJ.0000000000000011. Kuipers EJ, Grady WM, Lieberman D, et al. Nat Rev Dis Primers 89. . 2015;1:15065. doi:10.1038/nrdp.2015.65. -66 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

315 Part F. Chapter 4. Cancer Prevention 90 . Shen D, Mao W, Liu T, et al. Sedentary behavior and incident cancer: a meta-analysis of prospective 14;9(8):e105709. doi:10.1371/journal.pone.0105709. . 20 studies. PLoS One h PI, Faulkner GE, et al. Sedentary time and its association with risk for disease incidence, . Biswas A, O 91 spitalization in adults: a systematic review and meta-analysis. . Ann Intern Med mortality, and ho 2015;162(2):123-132. doi:10.7326/M14-1651. 92 . Schmid D, Leitzmann MF. Television viewing and time spent sedentary in relation to cancer risk: a J Natl Cancer Inst . 2014;106(7). doi:10.1093/jnci/dju098. Print 2014 Jul. meta-analysis. -67 2018 Physical Activity Guidelines Advisory Committee Scientific Report F4

316 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 5. CARDIOMETABOLIC HEALTH PART F. CHAPTER AND PREVENTION OF WEIGHT GAIN Table of Contents ... Introduction -1 F5 Review of the Science ... F5 -3 Overview of Questions Addressed ... F5 -3 Data Sources and Process Used to Answer Questions F5 -4 ... -4 F5 ... Question 1. What is the relationship between physical activity and prevention of weight gain? Question 2. In people with normal blood pressure or prehypertension, what is the relationship between physical activity and blood pressure? ... F5 -12 Question 3: In adults without diabetes, what is the relationship between physical activity and type 2 -21 F5 ... diabetes? ... F5 -27 Needs for Future Research ... Refe rences F5 -30 INTRODU CTION ommittee identified cardiometabolic health and weight management as key areas to include in this The C report, with a focus on preventing the onset of specific outcomes . The Committee considered the broad areas of cardiometabolic health and weight management when determining the specific areas to be examined in this 2018 Physical Activity Guidelines Advisory Committee Scientific Report , and also how this report could expand the conclusions provided in the Physical Activity Guidelines consider ed 1 Advisory Committee Report, 2008 . Within this context, the Cardiometabolic Health and Prevention o f committee prioritized three areas for this chapter that included the association ub Weight Gain S between physical activity and prevention of weight gain, incidence of hypertension, and incidence of type 2 diabetes mellitus . The rationale for inclusion of these areas within this report follows. Excessive body weight has been shown to be associated with numerous negative health outcomes that include, but are not limited to cardiovascular disease (CVD), diabetes, some forms of cancer, and F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -1

317 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 2, 3 Recent estimates indicate that prevalence of overweight (body mass index musculoskeletal disorders. 2 (BMI) 25 to ) in the United States for adult men is approximately 40 percent and for women is <30 kg/m 4 2 with estimates of obesity (BMI >30 kg/m 30 percent, ) for men being approximately 35 percent and for 5 women being 40 percent. Thus, an ongoing need for effective treatments for both overweight and obesity is recognized . From a public health perspective, however, the strategies that prevent or minimize weight gain, which may result in a lower prevalence of overweight and obesity, are important . This chapter focuses on physical activity to lower the health consequences of excessive body weight and its potential influence on body weight, with a particular focus on minimizing weight gain, maintaining body weight, and preventi ng overweight and obesity in adults . The potential influence of physical activity on body weight in youth is addressed in Part F. Chapter 7. Youth and during pregnancy is addressed in Part F. Chapter 8 . Women Who are Pregnant or Postpartum , and the potential influence of sedentary behavior on body weight is addressed in Part F. Chapter 2. Sedentary Behavior . CVD is the leading cause of death in the United States and the world, accounting for approximately 1 in 6, 7 Hypertension is 31 %) worldwide. 3 deaths (807,775, or 30.8%) in the United States and 17.3 million ( the most common, costly, and preventable CVD risk factor Seventh Report of the Joint . According to the 8 National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) blood pressure classification scheme, hypertension affects 86 million (34%) adults in the United States 6, 7 and 1.4 billion (31% ) adults globally. Hypertension also is the most common primary diagnosis in the United States, and the leading cause for medication prescriptions among adults older than age 50 9 Another 36 percent of adults in the United States have prehypertension, and one in five adults years. 6, 10 By 2030, it is estimated that with prehypertension is estimated to develop hypertension in 4 years. 41 percent of adults in the United States will have hypertension, and almost an equal amount will have prehypertension . From 2010 to 2030, the total direct costs attributed to hypertension are projected to triple ($130.7 to $389.9 billion), while the indirect costs due to lost productivity will double ($25.4 to 6 7, $42.8 billion). Curbing this growing and expensive public health crisis is a national and global priority. 11 This chapter focuses on physical activity and its potential influence to prevention hypertension . The influence of physical activity on resting blood pressure in adults with hypertension is addressed in Part F. . 10. Individuals with Chronic Conditions Chapter Diabetes mellitus, more commonly referred to as diabetes, is a chronic disease characterized by a deficiency and/or defect in the action of insulin. Type 2 diabetes is characterized by a relative resistance to insulin usually accompanied by resistance to the effect of insulin and comprises 90 to 95 percent of all F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -2

318 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain . The risk of developing type 2 diabetes is reduced by regular participation in moderate- cases of diabetes 23 million people (9.4% of the U.S. population) are known to to-vigorous physical activity. An estimated 12 The prevalence rises from about 3 percent among people ages have type 2 diabetes. 18 to 44 years to 12 45 to 64 years, and 21 percent of people ages 65 years and older. Common 13 percent of people ages complications of diabetes affect the eyes, kidneys, nerves, and blood vessels, leading to, among other problems, loss of vision, kidney failure, and lower limb amputations. Risk factors for these conditions are common among people with diabetes: 88 percent have overweight or obesity, 41 percent report no moderate- to-vigorous physical activity, 74 percent have high blood pressure, 16 percent have a hemoglobin A1c ( HbA1 c) value greater than 9 percent . In 2012, the total estimated cost of diabetes in 13 the United States was $176 billion in direct medical costs and $69 billion in reduced productivity. People with type 2 diabetes have medical expenditures about 2.3 times higher than they would if they did not have the disease . This chapter focuses on type 2 diabetes prevention because the risk of developing the condition is reduced by regular participation in moderate- to-vigorous physical activity. . The . Women Who are Pregnant or Postpartum Chapter 8 Gestational diabetes is addressed in Part F. Part F. relationship between sedentary behavior and the incidence of type 2 diabetes is described in Chapter 2. Sedentary Behavior . Among individuals who already have type 2 diabetes, the effect of habitual moderate- to-vigorous physical activity on the development of other chronic diseases, quality of Part F. Chapter 10. life, physical function, and the prevention of disease progression is described in Individuals with Chronic Conditions. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses 3 major questions and related subquestions: What is the relationship between physical activity and prevention of weight gain? 1. a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) c) Does the relationship vary based on levels of light, moderate, or vigorous physical activity? lood pressure or prehypertension, what is the relationship between physical In people with normal b 2. activity and blood pressure? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, weight status, or b) resting blood pressure level? F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -3

319 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain c) Does the relationship vary based on frequency, duration, intensity, type (mode), or how physical activity is measured ? 3. In adults without diabetes, what is the relationship between physical activity and type 2 diabetes? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Does the relationship vary based on : frequency, duration, intensity, type (mode), and how physical activity is measured? Data Sources and Process Used to Answer Questions the Subcommittee determined that existing reviews For Question 1 (prevention of weight gain) (systematic reviews, meta-analyses, pooled analyses, and reports) identified from an initial search did not answer the research question. A complete de novo search of original research was conducted. The Subcommittee determined that systematic reviews, meta-analyses, pooled analyses, and reports provided sufficient literature to answer research Questions 2 and 3. In an effort to reduce duplication of efforts, the searches for existing reviews and title triage for Question 2 (blood pressure) and Question 3 (incidence of type 2 diabetes) were done concurrently with the Chronic Conditions Subcommittee’s Question 3 (individuals with hypertension) and Question 4 (individuals with type 2 diabetes). The search strategies for each of these questions were developed to address the needs of both Subcommittees. Title triage addressed the inclusion criteria of both Subcommittees. Abstract and full-text triage were done separately for each Subcommittee . For complete details on the systematic literature review process, see Part E. Systematic Review Literature Search Methodology. Question 1. What is the relationship between physical activity and prevention of weight gain? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? c) Does the relationship vary based on levels of light, moderate, or vigorous physical activity? Sources of evidence: Original research articles Conclusion Statements Strong evidence demonstrates a relationship between greater amounts of physical activity and attenuated weight gain in adults, with some evidence to support that this relationship is most pronounced when physical activity exposure is above 150 minutes per week PAGAC Grade: Strong. . F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -4

320 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Limited evidence suggests a dose-response relationship between physical activity and the risk of weight gain in adults, with greater amounts of physical activity associated with lower risk of weight gain. PAGAC Grade: Limit ed . Limited evidence suggests that the relationship between greater amounts of physical activity and attenuated weight gain in adults varies by age, with the effect diminishing with increasing age. The evidence from studies of older adults, however, is inconsistent PAGAC Grade: Limited. . Moderate evidence indicates that the relationship between greater amounts of physical activity and attenuated weight gain in adults does not appear to vary by sex. PAGAC Grade: Moderate. Insufficient evidence is available to determine whether the relationship between greater amounts of physical activity and attenuated weight gain in adults varies by race/ethnicity PAGAC Grade: Not . assignable. Insufficient evidence is available to determine whether the relationship between greater amounts of PAGAC Grade: Not physical activity and attenuated weight gain in adults varies by socioeconomic status. assignable. Insufficient evidence is available to determine whether the relationship between greater amounts of PAGAC Grade: Not physical activity and attenuated weight gain in adults varies by initial weight status. assignable. Strong evidence demonstrates that the significant relationship between greater time spent in physical to-vigorous physical activity. activity and attenuated weight gain in adults is observed with moderate- PAGAC Grade: Strong . Insufficient evidence is available to determine an association between light-intensity activity and PAGAC Grade: Not assignable. attenuated weight gain in adults. Review of the Evidence 46 14- committee reviewed evidence from 33 original research studies. ub To answer this question, the S Most of the studies showing an association between greater physical activity and attenuated weight -24 , 27- 14- 18 , 20, 22 46 31 , 34- 36 , 38- with follow-up periods ranging gain (N=26) were prospective cohort studies, after a block randomized controlled trial up from 1 to 22 years and one study involving 6-year follow- (RCT) . For the seven studies not showing an effect, six were cohort studies with the follow-up period F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -5

321 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 19 25 , 32 , 33 , 37 , 21, Three of these studies had follow-up periods of 2 or fewer ranging from 1 to 20 years. 21 , 24 , 33 26 years, and one was a secondary analysis of data from a randomized study. Of studies showing an inverse association with weight gain, 7 studies assessed physical activity at one , 31 , 22, 27 , 28 17 , 35 , 41 whereas 19 studies assessed time point to examine the association with weight gain, 14- , 30 , 16, 18 , 20 , 23 , 24 , 29 physical activity at two or more time points to assess this association with weight gain. 34 , 36, 38 -40 , 42 -46 For the seven studies that examined the association with weight gain but did not show an , 33 32 21, effect, three studies measured physical activity at one time point and four studies measured , 37 , 26 19, 25 physical activity at multiple time points. The studies reviewed provided substantial information to allow for evaluation of an overall association between physical activity and either weight gain, increase in BMI, or development of obesity. Although data were available to examine whether these associations were influenced by sex and age, very limited information was provided within the studies reviewed to examine the influence of race/ethnicity, socioeconomic status, initial weight status, or dietary intake and eating behaviors, on the relationship between physical activity and weight gain. Moreover, although substantial information was provided for to-vigorous physical activity, few studies provided data for light-intensity physical activity moderate- . Evidence on the Overall Relationship Twenty-six of 33 studies demonstrate a significant relationship between greater amounts of physical , 27- 14- 18 , 20 , 22 -24 31 46 , 34- 36 , 38- ies that activity and attenuated weight gain in adults. Eleven of the 26 stud is demonstrated a relationship reported data for the vo lume of physical activity where the effect , 40 , 43 , 45 , 41 17, 20 , 27 , 29, 30 , 34 , 36 observed. e evidence for a specific volume threshold of physical activity that Th is associated with prevention of weight gain in adults is inconsistent . Studies find that at least 1 h ou r per wee k of moderate intensity reduces the risk of developing obesity in both normal weight women (incidence rate ratio (IRR)=0.81; 95% confidence interval (CI) : 0.71-0.93) and overweight women 39 r per ou (IRR=0.88; 95% CI: 0.81-0.95) ; however, a similar result may be observed with less than 1 h 45 wee k if the activity is of vigorous intensity, rather than moderate intensity. Williams and Wood have k (~2.8 miles per week (~28 minutes per week at a reported that running equivalent to 4.4 km per w ee 10-minute per mile pace) in men and 6.2 km per week (~3.8 miles per week (~38 minutes per week at a 10-minute per mile pace) in women may be sufficient to prevent weight gain associated with aging. Some evidence also supports the need to achieve at least 150 minutes per week of moderate intensity 30 29, , 43 Studies also support physical activity to minimize weight gain or to prevent increases in BMI. F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -6

322 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain s of physical activity to prevent or minimize weight gain, with some studies reporting this greater amount 36 effect with greater than 150 minutes per week at a moderate intensity, 500 or more MET-minutes per 20, 41 , 34 27 17, >167 minutes per week at a 3-MET intensity), week ( or more than 300 minutes per week. Dose-Response : Some of the reviewed studies provided data on the dose-response relationship of 17, 27 , 36 , 41 20 maintenance of a healthy weight, and development of physical activity and weight gain, 39 obesity. 41 Sims et al P <0.08) for minimized weight gain in women engaging in more than 8.3 – reported a trend ( 20 MET-h rs per week (>167-400 minutes per week at a 3-MET intensity) or more than 20 MET-h ou rs ou per week (>400 minutes per week at a 3-MET intensity) of physical activity, compared with those engaged in less than 1 .7 MET-hours per week (<33 minutes per week at a 3-MET intensity) . A physical activity volume of 1.7-8.3 MET-hours per week was not protective against weight gain, however. Two studies provide evidence of a dose-response to prevent weight gain of approximately 2 kg . Moholdt 36 et al identified four groups based on physical activity ( “ Inactive ” : no leisure-time physical activity; Below Recommended “ : active <150 minutes per week in moderate intensity or <60 minutes per week ” “ in vigorous intensity leisure-time physical activity; ” : active at 150 minutes per week in Recommended “ moderate intensity or 60 minutes per week in vigorous intensity leisure-time physical activity; Above ” : active >150 minutes per w ee k in moderate intensity or >60 minutes per w ee k minutes Recommended ee k in vigorous intensity leisure-time physical activity). For men, compared with those in the per w >2.3 kg was 0.97 (95% CI: 0.87-1.08) for those in the “Inactive” category, the risk of gaining “Recommended” category and 0 .79 (95% CI: 0.69-0.91) for those in the “Above Recommended” category. A similar pattern was observed in women, with the risk of 0.97 (95% CI: 0.88-1.07) for those in the “Recommended” category and 0 .69 (95% CI: 0.59-0.82) for those in the “Above Recommended” 27 category 300 or more . Gebel et al reported a 10 percent reduction in the odds of ≥ 2kg weight gain with to-vigorous physical activity compared with less than 150 minutes per minutes per week of moderate- week of moderate- to-vigorous physical activity; however, 150-249 minutes per w ee k was not predictive of weight change. 17 reported that the odds of gaining Blanck et al 10 or more pounds ( >4.5 kg) was significantly lower with 18 or more MET-h ou rs per week (0.88 ; 95% CI: 0.77-0.99) in women with normal weight compared with . Compared to the reference, the the reference of more than 0 but less than 4 MET-h ou rs per week (1.0) odds of gaining this magnitude of weight did not differ with 0 MET-h rs per week (1.01; 95% CI: 0.82- ou F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -7

323 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 1.01), 4 to less than 10 MET-h ou rs per week (0.93; 95% CI: 0.80-1.08), and 10 to less than 18 MET-h ou rs per week (0.99; 95% CI: 0.87-1.14) . 20 Brown et al report on a dose-response relationship for physical activity and the odds of maintaining a 2 ). Compared with less than 0.7 MET-h rs per week, the healthy weight (i.e., BMI of >18.5 to <25 kg/m ou odds ratio (OR) for maintaining a normal BMI was 1.18 (95% CI: 1.00-1.40) for 0.7 to less than 8.3 MET- hou rs per week, 1.23 (95% CI: 1.03-1.47) for 8.3 to less than 16.7 MET-h ou rs per week, and 1.44 (95% CI: 20 1.20-1.72) for 16.7 or more MET-h ou rs per week (Figure F5- 1). Figure F5-1. Odds of Maintaining a Healthy Weight by Level of Physical Activity 20 Source: Adapted from data found in Brown et al., 2016. 39 reported on the dose-response relationship for vigorous intensity physical activity and Rosenberg et al the likelihood of developing obesity. In women with normal weight and overweight, when compared to less than 1 h ou r per w ee k, the incidence of developing obesity was significantly reduced in a graded manner, with vigorous intensity activity of 1 to 2 h rs ou rs per w ee k (0.87 ; 95% CI: 0.81-0.93), 3 to 4 h ou pe k (0.82; 95% CI: rs ou r wee ; 95% CI: 0.71-0.87), and 7 or more h 0.75 -0.88), 5 to 6 h ou rs per w eek (0.79 39 7; 95% CI: 0.69-0.85) (Figure F5- 2). per w ee k (0.7 F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -8

324 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Figure F5-2. Incidence Rate Ratio of Developing Obesity at Various Levels of Vigorous Physical Activity 39 Source: Adapted from data found in Rosenberg et al., 2013. Evidence on Specific Factors Age: In general, the 26 studies in which a significant inverse association between physical activity and weight gain was observed encompassed a broad age range that included young, middle-aged, and older studies analyzed the data specifically by age, with the evidence suggesting attenuation of this adults. Six , 44 34- 36 , 41 , 46 g age in both men and women. This pattern of results was association with increasin 35 inconsistent in the studies that included both men and women, however . MacInnis et al reported a significant inverse association between physical activity and magnitude of weight gain across a mean follow-up of approximately 12 years in adults ages to 49 years, with this association not observed in 40 46 adults ages to 59 years or 60 to 69 years . Williams reported that running attenuated weight gain in 50 men younger than 55 years of age and in women younger than 50 years of age. 36 These results are not consistent with the finding of Moholdt et al, who reported that physical activity was significantly associated with reduced odds of gaining 2.3 or more kg in both men and women. Additional analyses, however, showed a significant interaction with age with a lower odds of a 2.3 or more kg weight gain in physically active adult men ages 40 years or older but not in those younger . In contrast, the inverse association between physical activity and odds of a 2.3 or more kg weight gain was observed across the age spectrum (younger than age 40 years, age 40 t o 59 years, and age 60 years and 44 older) in women. Moreover, Williams and Thompson reported that the weight gain associated with the . years of age and 45 years or older 45 cessation of running was consistent between men less than F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report -9

325 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain However, among women, weight gain was greater in women ages 45 years or older compared with their younger counterparts. Two studies examined the association between physical activity and weight gain only in women . Lee et 34 weight examined data from the Women’s Health Initiative study and reported a trend for greater al gain with lower levels of activity in women younger than age 64 years, but not in women ages 65 years 41 . Similar findings were reported by Sims et al and older in a study of post-menopausal women ages 50 to 79 years, which showed attenuated weight gain with great er amounts of physical activity in women 60 to 59 years, but not in those of ages 50 to 69 years or 70 to 79 years. ages The 26 studies in which a significant inverse association between physical activity and weight gain Sex: , 39 15, 14, 16 , 17 , 20, 22 , 28, 31 , 34 , 41 or both men and wom was observed included either women (N=10) en (N=16). 18 , 23, 24 , 27 , 29 , 40 , 43- 46 Of the 16 studies that included both men and women, 6 did not analyze the data , 43 24 , 29 , 40 18, , 27 separately by sex. Of the 10 studies that presented findings separately by sex, 8 reported that the association between physical activity and weight gain was consistent for both men and , 42 15, 30 , 35 , 36 , 38 23, , 44 -46 women. Race/ethnicity: In general, the 26 studies in which a significant inverse association between physical activity and weight gain was observed encompassed diverse races and ethnicities. When specified, for studies conducted based on adults residing in the United States, a broad range of races and ethnicities 41 , 31, , 30 18, 24 to be represented in the study samples ed appear or the sample included only black/African 39 Americans. Some of the studies were conducted in countries outside of the United States, including 23 15 20, 28 36 38 27 , 35 , 43 42 France, Norway, Australia, South Africa, Great Britain, Spain, and the Sweden, 22 14, tudies included race or ethnicity as a covariate in the analyses, none of Philippines. Although some s them presented data separately by race or ethnicity to allow for comparisons . Socioeconomic status: Of those studies showing an inverse association between physical activity and weight gain, some studies provided a measure of socioeconomic status as a descriptive variable or as a covariate in analyses . Only one study isolated the effect of socioeconomic status on the association between physical activity and weight gain, and it was reported that socioeconomic status attenuated 18 this association even though it remained statistically significant. The 26 studies in which a significant inverse association between physical activity and Weight status: weight gain was observed included adults of normal, overweight, and obese weight status. However, 19 -10 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

326 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain of these studies did not report on whether the association between physical activity and weight gain varied by initial weight status. Of the remaining seven studies, two reported that the association did not 39 , 41 three reported the association to be more favorable in adults who had differ by weight status, 17, 31, 34 normal weight versus overweight or obesity, and two studies reported results showing a more 15 , 36 favorable pattern in adults with overweight compared to those with normal weight. Light, moderate, or vigorous physical activity : In the 26 studies in which a significant inverse association between physical activity and weight gain was observed, investigators examined a variety of domains of physical activity . Th ese included leisure-time/recreational activity, occupational activity, household activity, walking, and total steps of physical activity . Moreover, various intensities of physical activity (light, moderate, vigorous, moderate- to-vigorous) were assessed across these studies. Total leisure-time physical activity was consistently inversely associated with weight change across the , 29 28 18, 24 15, , , 34 38 17, 23 42 , 35, , 41, on moderate intensity, vigorous intensity, g Studies reportin studies reviewed. , 36 -31 27 20, , 40 35 , 39, 44 -46 and moderate- physical activity sh owed consistent patterns of to-vigorous intensity inverse associations with weight gain . Light-intensity physical activity, however, was either not 29 24 or was associated with weight gain. associated with weight change 35 28, Walking was not consistently associated with change in weight or BMI or with the incidence of 39 43 Smith et al developing obesity. In contrast, however, reported that achieving 10,000 steps or more ,000 steps per day. 10 per day attenuated weight gain compared with not achieving . Occupational activity was inversely Studies also examined occupational and household activity 35 , 22, 14 g observed with moderate- and vigorous associated with weight gain, with this association bein 35 14, 14 intensity occupational activity, Household activity but not with ligh t-intensity occupational activity. 35 22, does not appear to minimize weight gain. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report 1 concluded physical activity was The Physical Activity Guidelines Advisory Committee Report, 2008 1 1 associated with modest weight loss, and reductions in prevention of weight gain following weight loss, 1 This evidence review expands these previous findings by providing total and regional adiposity. evidence from prospective studies for an inverse association between physical activity and both weight 2018 Physical Activity Guidelines Advisory Committee Scientific Report -11 F5

327 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain gain and incidence of obesity, and a positive association between physical activity and maintenance of a 2 BMI within a range of >18.5 to <25 kg/m . Evidence also exists to support that attenuation of weight gain is most pronounced when physical activity exposure is more than 150 minutes per week. Public Health Impact Weight gain that results in overweight or obesity is associated with increased risk for numerous chronic conditions . This is a significant health concern in the United States due to the high prevalence of both . Thus, while it is important to focus on effective treatments for overweight and overweight and obesity obesity, there is also a need to implement effective public health strategies to prevent weight gain and the onset of both overweight and obesity . The scientific evidence supports that physical activity can be an effective lifestyle behavior to prevent or minimize weight gain in adults . Therefore, public health initiatives to prevent weight gain, overweight, and obesity should include physical activity as an important lifestyle behavior . Question 2. In people with normal blood pressure or prehypertension, what is the relationship between physical activity and blood pressure? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, weight status, or b) resting blood pressure level? c) Does the relationship vary based on frequency, duration, intensity, type (mode), or how physical activity is m easured? : Systematic reviews, meta-analyses Source of evidence Conclusion Statements Strong evidence demonstrates that physical activity reduces blood pressure among adults with . prehypertension and normal blood pressure PAGAC Grade: Strong. Strong evidence demonstrates an inverse dose-response relationship between physical activity and PAGAC Grade: Strong. incident hypertension among adults with normal blood pressure. Insufficient evidence is available to determine whether a dose-response relationship exists between physical activity and incident hypertension among adults with prehypertension. PAGAC Grade: Not assignable. -12 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

328 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Insufficient evidence is available to determine whether the relationship between physical activity and blood pressure varies by age, sex, race/ethnicity, socioeconomic status, or weight status among adults with normal blood pressure and prehypertension . PAGAC Grade: Not assignable. Strong evidence demonstrates the magnitude of the blood pressure response to physical activity varies by resting blood pressure level, with greater benefits occurring among adults with prehypertension than PAGAC Grade: Strong. . normal blood pressure Insufficient evidence is available to determine whether the relationship between blood pressure and physical activity varies by the frequency, intensity, time, and duration of physical activity, or how physical activity is measured among adults with normal blood pressure and prehypertension PAGAC . Grade: Not assignable. Moderate evidence indicates the relationship between resting blood pressure level and the magnitude of benefit does not vary by type (mode, i.e., aerobic, dynamic resistance, combined) of physical activity PAGAC Grade: Moderate. among adults with normal blood pressure and prehypertension. Review of the Evidence 56 47- To answer this question, the S ub committee reviewed 10 meta-analyses (Supplemental Table 5- 1). The coverage dates ranged from earliest coverage to 2016, the total number of included studies ranged from 9 to 93, and the total included study sample size consisted of 485,747 adults ranging from 233 to 55, 56 330,222 participants and . Two meta-analyses examined longitudinal prospective cohort studies, 56 47- 54 47- -analyses The 10 meta eight meta-analyses examined randomized controlled trials. included 47, adults with hypertension and normal blood pressure, while five included adults with prehypertension. 51 , 50, , 53 48 Because the literature reviewed for this question was based upon the JNC 7 blood pressure 8 for data classification scheme, the Subcommittee used the JNC 7 blood pressure classification scheme extraction purposes. The JNC 7 defines these blood pressure classifications as follows : Hypertension is defined as having a resting systolic blood pressure of 140 mmHg or greater and/or a resting diastolic blood pressure 90 mmHg or greater, or taking antihypertensive medication, regardless of the resting . Prehypertension is defined as a systolic blood pressure from 120 to 139 mmHg and blood pressure level . Normal blood pressure is defined as having a systolic /or diastolic blood pressure from 80 to 89 mmHg . However, it should blood pressure less than 120 mmHg and diastolic blood pressure less than 80 mmHg be noted that during the preparation of the 2018 Scientific Report, the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines released the 2017 -13 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

329 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 57 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults . The new guidelines define hypertension as a resting systolic blood pressure of 130 mmHg or greater and/or a resting diastolic blood pressure 80 mmHg or greater, or taking antihypertensive medication, . Furthermore, the term prehypertension was eliminated regardless of the resting blood pressure level and elevated blood pressure was added indicating a resting systolic blood pressure between 120 to 129 mmHg and a diastolic blood pressure < 80 mmHg . However, the new guidelines did not alter the conclusion statements made in this report. Evidence on the Overall Relationship Strong evidence demonstrates that physical activity reduces blood pressure among adults with prehypertension and normal blood pressure . Eight meta-analyses of RCTs examined the blood pressure , 53 51 47 , 48 , 50, response to physical activity among initially sedentary adults with prehypertension and/or 47 54 , 51- -49 analyses involving adults with prehypertension, five normal blood pressure. Of the five meta- reported a statistically significant reduction in systolic blood pressure and four reported a statistically the seven meta- significant reduction in diastolic blood pressure (see Supplementa ry Table S-F5-2). Of analyses involving adults with normal blood pressure, three reported a statistically significant reduction and one reported a statistically significant rise in systolic blood pressure, and six reported a statistically significant reduction in diastolic blood pressure (see Supplementa ry Table S-F5-2). Blood pressure reductions of the magnitude observed in these meta-analyses of about 2 to 5 mmHg for systolic blood pressure and 1 to 4 mmHg for diastolic blood pressure may be sufficient to reduce the risk of coronary heart disease by 4 to 5 percent and stroke by 6 to 8 percent among adults with prehypertension and , 59 8, 58 normal blood pressure. Furthermore, they may be of sufficient magnitude to lower the resting blood pressure of some samples with prehypertension into normotensive ranges. When studies disclosed the information, the frequency of physical activity ranged from 1 to 7 days per week, with 3 days per week most common; the intensity ranged from low to vigorous, with low to moderate most common; the time ranged from 8 to 63 minutes per session, with 30 to 60 minutes per session most common; and the study duration ranged from 4 to 52 weeks, with 16 to 20 weeks most common. ommittee also regarded the association between physical activity and the risk of developing The S ubc hypertension (referred to as incident hypertension) as an indicator of the blood pressure response to 55 examined this association among 136,846 adults with normal blood physical activity . Huai et al pressure at baseline . After an average of 10 years (2 to 45 years) of follow up, 15,607 adults developed hypertension (11.4% of the sample) . In this meta-analysis, high amounts (i.e., volume and/or intensity) 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5 -14

330 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain of leisure-time physical activity were associated with a 19 percent decreased risk of incident hypertension compared to the referent group engaging in low amounts of leisure-time physical activity . Moderate amounts of leisure-time physical activity were (relative risk (RR)=0.81 ; 95% CI : 0.76-0.85) associated with an 11 percent decreased risk of hypertension compared to the referent group engaging 55 in low amounts of leisure-time physical activity ( RR=0.89 ; 95% CI: 0.85-0.94) . However, H uai et al found no significant associations with occupational and commuting physical activity and incident hypertension. se-response: Do Strong evidence demonstrates an inverse dose-response relationship between physical activity and incident hypertension among adults with normal blood pressure . Two meta-analyses investigated the relationship of physical activity and incident hypertension among adults with normal 56 55, 56 blood pressure. et al quantified the dose-response relationship between physical Of these, Liu . Among activity and incident hypertension among adults with normal blood pressure (Figure F5-3) 330,222 adults with normal blood pressure, after 2 to 20 years of follow up, 67,698 incident cases of hypertension occurred (20.5% of the sample) . The risk of hypertension was reduced by 6 percent 0.96) at 10 MET-hours per week of leisure-time light, moderate, and vigorous (RR=0.94; 95% CI: 0.92- physical activity (LMVPA) among adults with normal blood pressure . The protective effect increased by about 6 percent for each further increase of 10 MET-hours per week . For adults with 20 MET hours per wee k of leisure-time LMVPA, the risk of hypertension was reduced by 12 percent ( RR=0.88 ; 95% CI: 0.83- 0.92); and for those for 60 MET-hours per week of leisure-time LMVPA, the risk of hypertension was RR ; 95% . The relationship between leisure-time physical reduced by 33 percent ( CI: 0.58-0.78) =0.67 activity and incident hypertension was linear, with no cutoff of benefit, and slightly weaker with =0.91 ; 95% . These same CI: 0.89-0.93) BMI adjustment 6) than without ( RR CI: 0.92-0.9 (RR=0.94; 95% dose-response trends were seen for total physical activity such that for each 50 MET-hours per week increase in total physical activity, the risk of hypertension was reduced by 7 percent (RR=0.93 ; 95% CI: 0.88-0.98); and for 64.5 MET-hours per week of total physical activity, the risk of hypertension was . The relationship between total physical activity and incident hypertension was reduced by 10 percent . The authors linear, with no cutoff of benefit, and slightly stronger with than without BMI adjustment acknowledged their meta-analysis was limited by the considerable variety of physical activity self-report questionnaires used in the primary level studies. -15 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

331 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Figure F5-3. Inverse Relationship Between Incident Hypertension and Leisure-Time Physical Activity, by MET-Hours per Week Among Adults with Normal Blood Pressure 56 Source: Adapted from data found in Liu et al., 2017. The available evidence is insufficient to determine whether a dose-response relationship exists between physical activity and incident hypertension among adults with prehypertension, as the magnitude and . precision of the effect cannot be ascertained from findings that are too scarce to synthesize Evidence on Specific Factors : The available evidence is insufficient to determine Demographic characteristics and weight status whether the relationship between physical activity and blood pressure varies by age, sex, race/ethnicity, . socioeconomic status, or weight status among adults with prehypertension and normal blood pressure In the few instances where age, sex, race/ethnicity, socioeconomic status, and weight status were examined as moderators of the blood pressure response to physical activity, the findings were too disparate to synthesize because they were often not reported separately by blood pressure classification but were reported for the overall sample that included adults with hypertension, prehypertension, and normal blood pressure . Three meta-analyses found age not to be a significant moderator of the blood pressure response to 48 , 56 47, physical activity, but two of these contained samples with mixed blood pressure levels, and the other did not stratify analyses by age . One meta-analysis reported that men exhibited blood pressure reductions twice as large as did women following aerobic exercise training among samples with mixed 56 48 and another found no difference by sex. blood pressure levels, Race/ethnicity was poorly reported, 55, 53, 56 the samples prima rily included White and some and when reported in three of the meta-analyses, -16 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

332 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain . Three meta-analyses reported the weight status of their samples, which ranged from Asian participants 47 , 51, 53 Among a large sample of 330,222 adults with normal blood normal weight to overweight. 56 Liu et al found that the inverse dose-response pressure who were followed for 2 to 20 years, relationship between leisure-time physical activity and incident hypertension was slightly weaker with -0.93), but these CI: 0.89 ; 95% (RR=0.94 ; 95% CI: 0.92-0 .96) than without BMI adjustment ( RR =0.91 analyses were not stratified by BMI . These authors also found that the relationship between total physical activity and incident hypertension was slightly stronger with than without BMI adjustment, but 48 these analyses were also not stratified by BMI . Cornelissen and Smart found the systolic blood pressure reductions resulting from aerobic exercise training tended to be larger with greater ( β1=0.49, P= 0.08) than less ( β1=0 .45, P =0.06) weight loss among a sample of 5,223 adults with mixed blood pressure levels . Therefore, no conclusions can be made regarding the influence of age, sex, race/ethnicity, socioeconomic status, or weight status on the relationship between physical activity and . blood pressure 60 The African Americans have the highest prevalence of hypertension of any ethnic group in the world. progression from prehypertension to hypertension is also faster among African Americans than 11 Whites. African Americans are more likely to have their hypertension identified and treated, but less ntrolled than are Whites, despite using more antihypertensive likely to have their hypertension co 61- 63 iew, surprisingly little published research in the form of meta- medications. As verified by this rev analyses and systematic reviews exists on the association between physical activity and incident hypertension among African Americans . There are findings, however, from recent original studies, such as the Jackson Heart Study, that may also inform the association between physical activity and incident 64 hypertension in African Americans. Strong evidence demonstrates the magnitude of the blood pressure Resting blood pressure level: response to physical activity varies by resting blood pressure level, with greater benefits occurring . Of the six meta-analyses among adults with prehypertension than with normal blood pressure examining blood pressure classification as a moderator of the blood pressure response to physical , 51, 47- 49 , 54 53 , 53 48 , 49, 51 activity, found four that the greatest blood pressure reductions occurred amon g samples with hypertension (5 to 8 mmHg, 4 to 6 percent of resting blood pressure level) followed by samples with prehypertension (2 to 4 mmHg, 2 to 4 percent of resting blood pressure level), and normal blood pressure (1 to 2 mmHg, 1 to 2 percent of resting blood pressure level) (see online Supplemental 65, 66 adults with prehyp . Consistent with the law of initial values, Table 2) ertension experience blood -17 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

333 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain pressure reductions from exercise training that are about 2 to 4 times greater than the blood pressure reductions that occur among adults with normal blood pressure . Blood pressure reductions of this magnitude may be sufficient to reduce the resting blood pressure of some of the samples with prehypertension into normotensive ranges . They also may be sufficient to reduce the risk of coronary heart disease by 4 to 5 percent and stroke by 6 to 8 percent among adults with normal blood pressure 8, 58 , 59 and prehypertension. , 56 , 53 51 47- The frequency of physical activity was reported in seven meta-analyses, and ranged Frequency: from 0 to 7 days per week . However, no conclusions can be made about the influence of frequency on the blood pressure response to physical activity because the findings were too scarce and too disparate to synthesize. 47- 56 The intensity of physical activity was reported in all meta-analyses, Intensity: and ranged from low to vigorous intensity . However, no conclusions can be made regarding the influence of intensity on the blood pressure response to physical activity as the magnitude and precision of the effect could not be determined from findings that were too scarce to synthesize. , 56 , 54 51 48- s, The time of the exercise session was reported in six meta-analyse and ranged from 12 to Time: , 53 52 47, conclusions can be made . Time was not disclosed in three meta-analyses. 63 minutes However, no regarding the influence of time on the blood pressure response to physical activity, as the magnitude and precision of the effect could not be determined from a lack of findings on the time of the exercise session. All chronic (i.e., training) meta-analyses reported the duration of the physical activity Duration: -51, , 54 53 47 onclusions can be made intervention, and they ranged from 4 to 52 weeks. However, no c regarding the influence of duration on the blood pressure response to physical activity as the magnitude and precision of the effect could not be determined from findings that were too scarce to synthesize. Type (Mode): Moderate evidence indicates the relationship between resting blood pressure level and the blood pressure response to physical activity does not vary by type (i.e., aerobic, dynamic resistance, . Three meta-analyses examined the blood pressure response to aerobic combined) of physical activity 48- 50 three meta-analyses e exercise training, xamined the blood pressure response to resistance exercise 53 52 47, alysis examined the blood pressure response to training (one acute one meta-an and two chronic), 51 combined aerobic and resistance exercise training (also referred to as concurrent exercise training), 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5 -18

334 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 54 and one meta-analysis examined the blood pressure response to isometric resistance training. 48 examined aerobic exercise training performed, on average, at moderate to Cornelissen and Smart vigorous intensity for 40 minutes per session 3 days per week for 16 weeks and reported systolic/diastolic blood pressure reductions of -8.3 (95% CI: -10.7 to -6.0)/-5.2 (95% CI: -6.9 to -3.4), -4.3 ( 95% CI: -7.7 to -0.9)/-1.7 (95% CI: -2.7 to -0.7), and -0.8 (95% CI: -2.2 to +0.7)/-1.1 ( 95% CI: -2.2 to -0.1) mmHg among adults with hypertension, prehypertension, and normal blood pressure, respectively 53 examined dynamic resistance training performed, on average, at (Figure F5- 4). MacDonald et al moderate intensity for 32 minutes per session 3 days per week for 14 weeks, which approximates 90 minutes of moderate intensity or 45 minutes of vigorous intensity physical activity per week, and reported systolic/diastolic blood pressure changes of -5.7 (95% CI: -9.0 to -2.7)/-5.2 (95% CI -8.4, -1.9), - 3.0 (95% CI: -5.1 to - 1.0)/-3.3 (95% CI: -5.3 to -1.4), and 0.0 (95% CI: -2.5 to 2.5)/-0.9 (95% CI: -2.1 to 2.2) mmHg among adults with hypertension, prehypertension, and normal blood pressure, respectively . 51 examined combined aerobic and dynamic resistance exercise training performed, on Corso et al average, at moderate intensity for 58 minutes per session 3 days per week for 20 weeks and reported systolic/diastolic blood pressure changes of -5.3 (95% CI -6.4 to -4.2)/-5.6 (95% CI -6.9 to -3.8), -2.9 (95% CI -3.9 to -1.9)/-3.6 (95% CI -5.0 to -0.2), and +0.9 (95% CI 0.2 to 1.6)/-1.5 (95% CI -2.5 to -0.4) mmHg among adults with hypertension, prehypertension, and normal blood pressure, respectively. Figure F5-4. Blood Pressure Response to 16 Weeks of Aerobic Exercise Training 48 Source: Adapted from data found in Cornelissen and Smart, 2013. 54 Carlson et al investigated the blood pressure response to 4 or more weeks of isometric resistance training at 30 percent to 50 percent maximal voluntary contraction with 4 contractions held for 2 minutes with 1 to 3 minutes of rest between contractions among adults with hypertension (N=61) and -19 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

335 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain normal blood pressure (N=162) . Systolic, diastolic, and mean arterial blood pressure were reduced among the adults with hypertension, all of whom were on medication, by -4.3 (95% CI: -6.6 to -2.2)/-5.5 (95% CI: -7.9 to -3.3)/-6.1 (95% CI: -8.0 to -4.0) mmHg, and by -7.8 (95% CI: -9.2 to -6.4)/-3.1 (95% CI: -3.9 ly. Carlson to -2.3)/-3.6 (95% CI: -4.4 to -2.7) mmHg among adults with normal blood pressure, respective 54 were unable to explain the larger reductions in systolic blood pressure among the adults with et al normal blood pressure compared to adults with hypertension, and the reverse pattern of blood pressure response for diastolic blood pressure and mean arterial pressure. The sample size of the meta-analysis 54 investigating isometric resistance training was much smaller than the sample size of by Carlson et al 51 48 53 and combined the meta-analyses investigating aerobic, . For dynamic resistance, exercise training these reasons, any conclusions made about the blood pressure benefits of isometric resistance training should be made with caution included in this report . It also should be noted that the existing literature on physical activity and blood pressure has examined aerobic, resistance, and combined types of . physical activity Collectively, these findings indicate the blood pressure response to aerobic, dynamic resistance, and combined types of physical activity elicit blood pressure reductions of 2 to 4 mmHg (2 to 4 percent of resting blood pressure level) among adults with prehypertension and 1 to 2 mmHg (1 to 2 percent of resting blood pressure level) among adults with normal blood pressure, independent of type (mode) . These blood pressure reductions are about 2 to 4 times greater among adults with prehypertension than normal blood pressure . These blood pressure benefits occurred at about 6 MET hours per week of . moderate- to-vigorous physical activity All meta-analyses that examined the blood pressure response to How physical activity was measured: physical activity included interventions that were structured by the frequency, intensity, time, duration, and type (mode) of physical activity, but the details of these features of the physical activity interventions were not well disclosed . None of these meta-analyses reported any physical activity . No conclusions can be made regarding measure outside of the structured physical activity intervention how physical activity was measured, as the magnitude and precision of the effect could not be determined from findings that were too scarce to synthesize. For additional details on this body of evidence, visit: online Supplementa ry Tables S-F5- 1 and S-F5- 2 https://health.gov/paguidelines/second-edition/report/supplementary-material.aspx for the and Evidence Portfolio. -20 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

336 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Comparing 2018 Findings with the 2008 Scientific Report The 2008 Scientific Report concluded that both aerobic and dynamic resistance exercise training of to-vigorous intensity produced small but clinically important reductions in systolic and moderate- diastolic blood pressure in adults, with the evidence more convincing for aerobic than dynamic 1 . First, the 2018 resistance exercise. The 2018 Scientific Report extends these findings in four ways Scientific Report provides strong evidence that physical activity reduces blood pressure among adults with prehypertension and normal blood pressure . Second, it provides strong evidence of an inverse dose-response relationship between leisure-time physical activity and incident hypertension among adults with normal blood pressure . Third, due to an accumulating amount of highly consistent evidence over the past decade, the 2018 Scientific Report provides strong evidence demonstrating the magnitude of the blood pressure response to physical activity is greater among adults with prehypertension than . Fourth, reflecting on the accumulating evidence over the past decade, the with normal blood pressure 2018 Scientific Report indicates aerobic and dynamic resistance exercise may be equally effective in reducing blood pressure at a lower volume of physical activity. Public Health Impact Hypertension is the most common, costly, and preventable cardiovascular disease risk factor. According to the JNC 7 blood pressure classification scheme, by 2030 it is estimated that nearly 40 percent of adults in the United States will have hypertension and almost an equal amount will have prehypertension . Due to the clinically important role of physical activity in the prevention of hypertension, adults with normal blood pressure and prehypertension are encouraged to engage in at least 90 minutes per week or more of moderate intensity or at least 45 minutes per week or more of . vigorous intensity aerobic and/or dynamic resistance physical activity, or some combination of these Because there appears to be no cut off to the amount of physical activity that confers benefit, even greater amounts of physical activity should be encouraged. These recommendations are particularly important for African Americans to reduce the high disease burden of hypertension among this population group. Question 3: In adults without diabetes, what is the relationship between physical activity and type 2 diabetes? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? ion, intensity, type (mode), and how : frequency, durat Does the relationship vary based on c) physical activity is measured? -21 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

337 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Sources of evidence : Systematic reviews, meta-analyses, pooled analysis Conclusion Statements Strong evidence demonstrates a significant relationship between a higher volume of physical activity PAGAC Grade: Strong. and lower incidence of type 2 diabetes . Strong evidence demonstrates that an inverse curvilinear dose-response relationship exists between the volume of physical activity and incidence of type 2 diabetes, with a decreasing slope at higher levels of physical activity. PAGAC Grade: Strong. Moderate evidence indicates no effect modification by weight status. An inverse relationship exists between a higher volume of physical activity and lower incidence of type 2 diabetes for people who have normal weight, overweight, or obesity . PAGAC Grade: Moderate. Limited evidence suggests that the relationship between a higher volume of physical activity and lower PAGAC Grade: Limited. incidence of type 2 diabetes is not influenced by age, sex, or race/ethnicity. Insufficient evidence is available to determine whether the relationship between physical activity and the incidence of type 2 diabetes varies by socioeconomic status. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity and the incidence of type 2 diabetes varies by the frequency, intensity, duration, or type of physical activity, PAGAC Grade: Not assignable. or how physical activity is measured. Review of the Evidence 67 -73 74- 77 four systematic reviews, The evidence base comprised seven meta-analyses, and one pooled -78 78 68- 71 , 73 Ten d analysis. of the articles inclu ded only cohort studies, one included cohort an 72 67 The number and one included cohort, experimental, and case-control studies. experimental studies, of studies included in each review ranged from 2 to 81, with a median of 8.5. For the eight reviews for which data on number of participants were provided, the total number ranged from 4,550 to about 67 300,000, with a median of 140,000. All reviews except one, which had no age restrictions, included only adults. Mean age was not commonly provided; the three studies for which it was provided reported 72 68, 78 a mean age of 50 years. Alm and 52 ost all physical activity behavior was self-reported leisure-time moderate- to-vigorous, though a few studies included other domains (i.e., occupational, transportation, -22 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

338 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 67, 68 , 71 , 77 household). Seven reviews provided risk estimates for at least three doses of physical activity, , 76 , 74 67- 69, 71 , 73 enabling an assessment of dose-response. Evidence on the Overall Relationship 78 67- 73 74- 77 reported an inverse relationship systematic reviews, All meta-analyses, led analysis and the poo 67, 70 , 72 between volume of physical activity and the incidence of type 2 diabetes . Three meta-analyses, 77 78 and the pooled analysis one systematic review, provided quantitative estimates of the reduction in risk comparing participants engaging volume of physical activity with participants engaging in in “high” “low” represented by “high” and “low” was volume of physical activity. The volume of physical activity not provided. I t is expected that “high” is at or near the target zone recommended in the 2008 Scientific Report for moderate- to-vigorous physical activity (i.e., 150 to 300 minutes per week of moderate intensity physical activity, 75 to 150 minutes per week of vigorous intensity physical activity, or an 1 and “low” is at or near zero equivalent combination) to-vigorous physical activity. reported moderate- The estimated relative risks and 95% confidence interval for these four studies were: 0.65 (95% CI: 0.59- 67 0.71) for total physical activity and 0.74 (95% CI: 0.70-0.79) for leisure-time physical activity ; 0.69 (95% 70 CI: 0.58-0.83) without adjustment for BMI and 0.83 (95% CI: 0.76-0.90) with adjustment for BMI ; odds 72 78 77 ratios of 0.53 (95% CI: 0.40-0.70) ; and 0.45 (95% CI: 0.31-0.77). Warburton et al, a systematic review including 20 pertinent cohort studies, reported that all 20 studies found an inverse relationship between volume of moderate- to-vigorous physical activity and risk of type 2 diabetes, and that comparing the highest with the least active participants, the average risk reduction was 42 percent . These findings suggest that a reasonable estimate of the reduction in type 2 diabetes associated with 150 to 300 minutes per week of moderate to vigorous physical activity would be about 25 to 35 percent. Dose-response: Five of the meta-analyses provided estimates for at least three levels of moderate- to- 67 ed vigorous physical activity (Figure F5 -5). Aune et al report here was evidence of a nonlinear that “t P association between MET-hours per week of leisure-time physical activity and type 2 diabetes ( nonlinearity <0.0001), with a slightly more pronounced reduction in risk at low levels of activity than at high levels. ” 68 calculated of 1.0 for 150 or more minutes per week of moderate- Cloostermans et al OR to-vigorous physical activity, OR of 1.08 (95% CI: 1.04-1.13) for more than 0 to less than150 minutes per week of moderate- to-vigorous physical activity, and OR of 1.23 (95% CI: 1.04-1.39) for 0 minutes per week of 68 values have been divided by 1.23 in moderate- to-vigorous physical activity. All the Cloostermans et al Figure F5-5, below, to match the orientation of the other meta-analyses (i.e., lowest activity group is the 69 Huai et al referent group with relative risk of 1.0). calculated hazard ratios for participants grouped -23 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

339 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain into those with low (HR=1.0), moderate (HR=0.79 ; 95% CI: 0.70-0.89), and high (HR=0.69; 95% CI: 0.61- 73 . Wahid et al 0.78) volumes of physical activity provided relative risk estimates of 0.77 (95% CI: 0.71- 0.84) at 6 MET-hours per week and 0.74 (95% C Is not provided) at 11.25 MET-hours per week. The dose- response curves from these four reviews are shown in Figure F5-5. The shape of the dose-response curve for the fifth review that provided estimates for at least three levels of physical activity is similar to 71 The curve is not included because the units for the curves from the four studies shown in Figure F5-5. 71 volume of physical activity are incompatible with the other studies. Kyu et al combined and extrapolated domain-specific moderate- to-vigorous physical activity into total MET-minutes per week of MVPA and, using <600 MET-minutes per week as the referent value, reported risk reductions of 14 percent for 600 to 3,999 MET-minutes per week, 25 percent for 4,000 to 7,999 MET-minutes per week, 77 . In a systematic review, and 28 percent for 8,000 or more MET-minutes per week Warburton et al reported that the majority (84%) of the 20 included studies revealed incremental reductions in the risk for type 2 diabetes with increasing activity/fitness levels. Figure F5-5. Dose-response Curves for Moderate- to-Vigorous Physical Activity and Relative Risk of Type 2 Diabetes 73 68 69 Source: Adapted from data found in Cloostermans et al., 2015, Aune et Wahid et al., 2016, Huai et al., 2016, 67 al., 2015. These findings indicate an inverse curvilinear relationship between volume of moderate- to-vigorous physical activity and the reduction in risk of type 2 diabetes, with a decreasing slope at higher levels of physical activity. This indicates that less active individuals who add a certain amount of physical activity to a larger extent than more to their daily routine reduce their risk of developing type 2 diabetes -24 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

340 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain physically active individuals who add the same amount of physical activity to their daily routine. The absolute risk of the more physically active individuals remains below that of the less active individuals ; their relative reduction in risk per unit of added physical activity is merely lower. Two of the articles included statistically significant risk reduction estimates for volumes of physical activity below the 68, 73 confirming that benefit current target of 150 to 300 minutes per w eek of moderate- to-vigorous, accrues below the target zone. Evidence on Specific Factors Physical activity, weight status, and risk of type 2 diabetes : The relationship between physical activity, weight status, and risk of type 2 diabetes is complicated because weight status affects risk of type 2 diabetes and physical activity affects risk of type 2 diabetes and weight status (for more details on this relationship see Question 1 in this chapter). When populations are stratified by BMI, higher levels of physical activity are associated with reduced risk of type 2 diabetes at all strata of BMI. For example, in a joint analysis of three physical activity behavior groups (low = 0 minutes per w ee k of self-reported ee moderate- k, high = ≥150 min utes per w ee k) and BMI to-vigorous, middle = >0 to <150 minutes per w 2 strata, among individuals with overweight (25 to <30 kg/m ), the hazard ratio for the high active group was 2.26 (95% CI: 1.74 – 2.93), the middle active group was 2.45 (95% CI: 1.87 – 3.20), and the low active 2 group was 2.86 (95% CI: 1.93 – 4.22). Among individuals with obesity (≥ 30 kg/m ), the hazard ratio for the 11.43), – 8.84), the middle active group was 6.93 (95% CI: 4.20 – was 6.13 (95% CI: 4.25 high active group 68 – 15.89). Similar findings are reported in the systematic and the low active group was 7.43 (95% CI: 3.47 74 review by Fogelholm. Evidence also suggests that the combination of low levels of physical activity and high levels of adiposity, usually assessed as BMI, is a stronger risk factor for type 2 diabet es than one would expect if they were 75 acting independently of each other. Qin et al identified five articles that provided enough information . for them to calculate estimates of the “biological interaction ” The “attributable portion(s) due to 82 83 79 80 81 biological interaction” were 46 22 percent, percent, 42 percent, and 5 percent. 29 percent, The analyses indicate that a substantial portion of the reduction in risk for type 2 diabetes (median value 29% of the five studies) is due to the combined effect of physical activity and adiposity. Given this interaction and the known contribution of obesity to the risk of developing type 2 diabetes, it is not surprising that adjusting for BMI reduces the magnitude of the risk reduction attributable to 67, 70 68 , 70 , 76 , 77 Jeon et al in a high versus low comparison, report a ed physical activity. For example, -25 F5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

341 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain relative risk of 0.69 (95% CI: 0.58-0.83) without adjustment for BMI and a relative risk of 0.83 (95% CI: 0.76-0.90) with adjustment for BMI . Age, sex, race/ethnicity, socioeconomic status: Although the importance of weight status as a risk factor for type 2 diabetes was uniformly acknowledged in these reports, the studies provide little information about demographic factors such as age, sex, or race/ethnicity. Information in a few suggest age, sex, and race/ethnicity have little or no impact on the relationship between physical activity and , 78 68 67, type 2 diabetes. No conclusion could be made about the impact of socioeconomic status because none of the studies provided information about this variable. Type of physical activity: The physical activity of interest in these papers was largely restricted to moderate- to-vigorous aerobic physical activity. The Subcommittee was unable to draw a conclusion because the studies provided no information about whether frequency, duration, intensity, type of physical activity, or the way physical activity was measured had any influence on the relationship between physical activity and the incidence of type 2 diabetes. https://health.gov/paguidelines/second- For additional details on this body of evidence, visit: for the Evidence Portfolio. edition/report/supplementary-material.aspx Comparing 2018 Findings with the 2008 Scientific Report 1 concluded that “approximately 30 minutes of moderate intensi ty exercise at The 2008 Scientific Report 1 This least 5 days per week provides a substantial (25% to 36%) reduction in the risk of type 2 diabetes ” . evidence review confirms that estimate and expands on the previous findings by providing evidence for an inverse curvilinear dose-response association, demonstrating that risk reductions accrue at levels physical activity, and to-vigorous below the target range of 150 to 300 minutes per w eek of moderate- providing evidence of an interaction, but no effect modification, between physical activity and weight status. Public Health Impact Currently about 9.4 percent of the U.S. adult population has type 2 diabetes, with associated annual 13 12, The evidence presented direct medical costs and lost productivity of about $245 billion per year. to-vigorous physical activity here confirms that about 150 to 300 minutes per week of moderate- reduces the risk of developing type 2 diabetes by 25 to 35 percent. This applies to people with normal weight, overweight, or obesity. Given that less than half of the U.S. population currently participates in to-vigorous physical activity, the potential reduction in 150 minutes or more per week of moderate- -26 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

342 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 84 incidence and costs of type 2 diabetes is substantial. Moreover, the fact that physical activity reduces of excessive weight gain means that the reduction in risk could be even greater because the risk excessive weight is an independent risk factor for type 2 diabetes . NEEDS FOR FUTURE RESEARCH 1. Conduct longitudinal research on lower exposure levels of physical activity to allow for an enhanced understanding of the dose-response associations between physical activity and weight gain, hypertension, and type 2 diabetes across a wider spectrum of exposure. on the effect of physical activity less than 150 Only limited evidence is currently available Rationale: . Thus, limited minutes per week on prevention of weight gain, hypertension, and type 2 diabetes currently available to inform whether lower amounts of physical activity can be effective data are e is important and will inform public health for preventing these conditions . Having this knowledg recommendations regarding the minimum physical activity exposure that can be effective for preventing weight gain or the development of obesity, hypertension, and type 2 diabetes. Conduct large research trials with ample sample sizes to allow for stratum-specific analyses to 2. determine whether the influence of physical activity on the prevention of weight gain, hypertension, and type 2 diabetes varies by age, sex, race/ethnicity, socioeconomic status, or initial weight status. Rationale: Only limited evidence is currently available on whether the influence of physical activity on weight gain or risk of hypertension or type 2 diabetes varies by age, sex, race/ethnicity, socioeconomic status, weight status . Moreover, little is known about whether the influence of physical activity varies when the exposure to physical activity is consistent across individuals with . Having this information will inform public health different demographic characteristics recommendations regarding whether physical activity exposure to prevent weight gain needs to vary by age, sex, race/ethnicity, socioeconomic status, weight status, and other demographic characteristics, and may allow for more precise individual-level physical activity recommendations . Thus, adequately designed and statistically powered studies are needed to allow for comparisons across the various strata of demographic characteristics to examine whether the influence of physical activity varies by these factors. -27 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

343 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain Conduct experimental research on varying intensities (light, moderate, and vigorous) of physical 3. activity, while holding energy expenditure constant, to determine the independent effects of physical activity intensity on weight gain, hypertension, and type 2 diabetes. Rationale: Limited evidence is available on whether the influence of physical activity on weight gain , hypertension, or type 2 diabetes is consistent across intensities (light, moderate, vigorous) when total energy expenditure is held constant, and only limited evidence is available on the influence of . This information will inform public health light-intensity physical activity on weight gain recommendations regarding whether the emphasis to prevent weight gain, hypertension, or type 2 diabetes should be on total volume of physical activity regardless of intensity, or whether the emphasis needs to be on volume of physical activity that is performed at a specific intensity. es energy intake and eating behavior Conduct observational and experimental research that quantifi 4. to determine whether these factors influence the association between physical activity and weight gain. Rationale: The majority of the studies examined regarding weight gain either did not report that diet and eating behavior were measured or considered in the analysis . Given that both dietary factors, primarily energy intake, and energy expenditure from physical activity can influence body weight regulation, it is important to understand whether the physical activity exposure necessary to limit weight gain will vary based on diet or eating behavior patterns. 5. Within research that is conducted, disclose the standard criteria and methods that were used to determine the blood pressure status of the study sample to better isolate samples with hypertension from those with normal blood pressure and prehypertension, and report results separately by blood pressure classification. Rationale: Strong evidence demonstrates the magnitude of the blood pressure response to physical activity varies by resting blood pressure, with greater benefits occurring among adults with . However, study samples often include mixed samples prehypertension than normal blood pressure of adults with hypertension, prehypertension, and normal blood pressure, and findings are frequently not reported separately by blood pressure classification . Consistent with the law of initial . In addition, values, this practice underestimates the blood pressure benefits of physical activity samples with prehypertension are underrepresented as they are often mixed with samples with -28 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

344 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain hypertension. Reporting findings by blood pressure classification will inform public health recommendations on the magnitude and precision of the blood pressure reductions that result from physical activity among adults with normal blood pressure and prehypertension. 6. Conduct randomized controlled trials to examine the influence of types of physical activity other than aerobic, dynamic resistance, or combined aerobic and dynamic resistance physical activity on blood pressure and other health outcomes among adults with normal blood pressure and prehypertension. Limited evidence on these topics is available among adults with normal blood pressure Rationale: . Gaining this information will inform the public health recommendations on and prehypertension . the types of physical activity that optimize blood pressure benefit 7. Conduct experimental research that examines both the acute (i.e., short-term or immediate, referred to as postexercise hypotension) and the chronic (i.e., long-term or training) blood pressure response to physical activity among adults with prehypertension and normal blood pressure. Rationale: Insufficient evidence exists on the acute blood pressure response to physical activity despite primary-level reports suggesting a close relationship between the blood pressure response to acute and chronic exercise . Developing a better understanding of acute blood pressure responses will inform public health recommendations on possible behavioral strategies to increase adherence to physical activity for blood pressure benefit . 8. Conduct observational and experimental research examining the relationship between physical Guideline for the Prevention, Detection, Evaluation and activity and blood pressure using the 2017 57 new blood pressure classification scheme. Management of High Blood Pressure in Adults Rationale: The literature that was reviewed to answer this question was based upon The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High 8 Blood Pressure (JNC 7) blood pressure classification scheme. The new guideline increases the number of people with hypertension, eliminates the category of prehypertension, and adds the category of elevated blood pressure . The relationship between physical activity and blood pressure according to this new blood pressure classification scheme remains to be determined. -29 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

345 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain REFERENCES 1. Physical Activity Guidelines Advisory Committee. elines Advisory Committee Physical Activity Guid Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. 2. National Institutes of Health, National Heart, Lung, and Blood Institute. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults the evidence report. Obes — Res . 1998;6(suppl 2):51S-209S. doi:10.1002/j.1550-8528.1998.tb00690.x. 3. Jensen MD, Ryan DH, Apovian CM, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. . 2014;63(25 Pt J Am Coll Cardiol B):2985-3023. doi:10.1016/j.jacc.2013.11.004. 4. Yang L, Colditz GA. Prevalence of overweight and obesity in the United States, 2007-2012. JAMA Intern Med . 2015;175(8):14 12 -1413. doi:10.1001/jamainternmed.2015.2405. 5. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in obesity among adults in the United States, 2005 to 2014. JAMA . 2016;315(21):2284-2291. doi:10.1001/jama.2016.6458. 6. Benjamin EJ, Blaha MJ, Chiuve SE, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2017 Update: a report from the American . 2017;135(10):e146- Circulation Heart Association. 03. doi:10.1161/CIR.0000000000000485. e6 7. World Health Organization. A Global Brief on Hypertension: Silent Killer, Global Public Health Crisis . Geneva, Switzerland: World Health Organization; 2013. 8. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung,and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National . Hypertension Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. 2003;42(6):1206-1252. . 9. Staessen JA, Wang JG, Birkenhager WH. Outcome beyond blood pressure control? Eur Heart J 2003;24(6):504-514. . Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P. The burden of adult hypertension in the 10 . 2004;44(4):398-404. United States 1999 to 2000: a rising tide. Hypertension 11 . Egan BM. Physical activity and hypertension: knowing is not enough; we must apply. Willing is not enough; we must do-von Goethe. Hypertension . 2017;69(3):404-406. doi:10.1161/HYPERTENSIONAHA.116.08508. . Centers for Disease Control and Prevention. 12 National Diabetes Statistics Report, 2017: Estimates of Diabetes and Its Burden in the United States . Atlanta, GA: Centers for Disease Control and Prevention, U.S. Department of Health and Human Services; 2017. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed December 29, 2017. -30 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

346 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 13 . American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Car e . 2013;36(4):1033-1046. doi:10.2337/dc12-2625. 14 . Adair LS, Gultiano S, Suchindran C. 20-year trends in Filipino women's weight reflect substantial secular and age effects. J Nutr . 2011;141:667-673. doi:10.3945/jn.110.134387. 15 . Basterra-Gortari FJ, Bes-Rastrollo M, Pardo-Fernandez M, et al. Changes in weight and physical Med Sci Sports Exerc . 2009;41:516-522. activity over two years in Spanish alumni. doi:10.1249/MSS.0b013e318188607c. . Bea JW, Cussler EC, Going SB, Blew RM, Metcalfe LL, Lohman TG. Resistance training predicts 6-yr 16 body composition change in postmenopausal women. Med Sci Sports Exerc . 2010;42:1286-1295. doi:10.1249/MSS.0b013e3181ca8115. 17 . Blanck HM, McCullough ML, Patel AV, et al. Sedentary behavior, recreational physical activity, and 7- year weight gain among postmenopausal U.S. women. Obesity . 2007;15:1578-1588. 18 . Botoseneanu A, Liang J. The effect of stability and change in health behaviors on trajectories of body . 2012;67:1075- mass index in older Americans: a 14-year longitudinal study. J Gerontol A Biol Sci Med Sci 1084. doi:10.1093/gerona/gls073. . Brien SE, Katzmarzyk PT, Craig CL, Gauvin L. Physical activity, cardiorespiratory fitness and body mass 19 index as predictors of substantial weight gain and obesity: the Canadian physical activity longitudinal Can J Public Health study. . 2007;98:121-124. . Brown WJ, Kabir E, Clark BK, Gomersall SR. Maintaining a healthy BMI: data from a 16-year study of 20 young Australian women. Am J Prev Med . 2016;51:e165-e178. doi:10.1016/j.amepre.2016.09.007. 21 . Chiriboga DE, Ma Y, Li W, et al. Gender differences in predictors of body weight and body weight change in healthy adults. Obesity . 2008;16:137-145. doi:10.1038/oby.2007.38. 22 . Colchero MA, Caballero B, Bishai D. The effect of income and occupation on body mass index among women in the Cebu Longitudinal Health and Nutrition Surveys (1983-2002). . Soc Sci Med 2008;66(9):1967-1978. doi:10.1016/j.socscimed.2008.01.008. . de Munter JS, Tynelius P, Magnusson C, Rasmussen F. Longitudinal analysis of lifestyle habits in 23 relation to body mass index, onset of overweight and obesity: results from a large population-based cohort in Sweden. Scand J Public Health . 2015;43:236-245. 24. Drenowatz C, Gribben N, Wirth MD, et al. The association of physical activity during weekdays and J Obes . 2016;8236439. weekend with body composition in young adults. http://dx.doi.org/10.1155/2016/8236439 . 25. Drenowatz C, Hill JO, Peters JC, Soriano-Maldonado A, Blair SN. The association of change in physical . 2017;71(3):377- activity and body weight in the regulation of total energy expenditure. Eur J Clin Nutr 382. doi:10.1038/ejcn.2016.228. 26 . French SA, Mitchell NR, Hannan PJ. Decrease in television viewing predicts lower body mass index at . 2012;44(5):415-422. 1-year follo J Nutr Educ Behav w-up in adolescents, but not adults. doi:10.1016/j.jneb.2011.12.008. -31 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

347 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 27 . Gebel K, Ding D, Bauman AE. Volume and intensity of physical activity in a large population-based cohort of middle-aged and older Australians: prospective relationships with weight gain, and physical Prev Med function. . 2014;60:131-133. doi:10.1016/j.ypm. 28 . Gradidge PJ, Norris SA, Micklesfield LK, Crowther NJ. The role of lifestyle and psycho-social factors in predicting changes in body composition in black South African women. PloS One . 2015;10:e0132914. https://doi.org/10.1371/journal.pone.0132914 . . Hamer M, Brunner EJ, Bell J, et al. Physical activity patterns over 10 years in relation to body mass 29 index and waist circumference: the Whitehall II cohort study. Obesity . 2013;21: E755-E761. doi:10.1002/oby.20446. 30 . Hankinson AL, Daviglus ML, Bouchard C, et al. Maintaining a high physical activity level over 20 years and weight gain. . 2010;304:2603-2610. doi: 10.1001/jama.2010.184 3. JAMA 31 . Hillemeier MM, Weisman CS, Chuang C, Downs DS, McCall-Hosenfeld J, Camacho F. Transition to J Womens Health . 2011;20:703-710. overweight or obesity among women of reproductive age. doi:10.1089/jwh.2010.2397. Kaikkonen JE, Mikkila V, Juonala M, et al. Factors associated with six-year weight change in young 32. and middle-aged adults in the Young Finns Study. . 2015;75:133-144. Scand J Clin Lab Invest doi:10.3109/00365513.2014.992945. Kelly MC, Latner JD. Evaluating patterns of weight and body composition change among college 33. women. Eat Behav . 2015;17:157-162. doi: 10.1016/j.eatbeh.2015.01.016. JAMA Lee IM, D jousse L, Sesso HD, Wang L, Buring JE. Physical activity and weight gain prevention. . 34. 2010;303:1173-1179. doi: 10.1001/jama.2010.312. 35. MacInnis RJ, Hodge AM, Dixon HG, et al. Predictors of increased body weight and waist circumference for middle-aged adults. Public Health Nutr . 2014;17:1087-1097. doi:10.1017/S1368980013001031. Moholdt T, Wisloff U, Lydersen S, Nauman J. Current physical activity guidelines for health are 36. insufficient to mitigate long-term weight gain: more data in the fitness versus fatness debate (The HUNT . 2014;48:1489-1496. d. Br J Sports Med study, Norway). 37. Mortensen LH, Siegler IC, Barefoot JC, Gronbaek M, Sorensen TI. Prospective associations between . 2006;14:1462-1471. doi:10.1038/oby.2006.166. sedentary lifestyle and BMI in midlife. Obesity 38. Parsons TJ, Manor O, Power C. Physical activity and change in body mass index from adolescence to mid-adulthood in the 1958 British cohort. Int J Epidemiol . 2006;35:197-204. 39 . Rosenberg L, Kipping-Ruane KL, Boggs DA, Palmer JR. Physical activity and the incidence of obesity in young African Am J Prev Med . 2013;45:262-268. doi:10.1016/j.amepre.2013.04.016. -American women. . Shibata AI, Oka K, Sugiyama T, Salmon JO, Dunstan DW, Owen N. Physical activity, television viewing 40 Med Sci Sports Exerc time, and 12-year changes in waist circumference. . 2016;48:633-640. doi: 10.1249/MSS.0000000000000803. -32 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

348 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 41 . Sims ST, Larson JC, Lamonte MJ, et al. Physical activity and body mass: changes in younger versus older postm enopausal women. Med Sci Sports Exerc . 2012 Jan;44(1):89-97. doi: 10.1249/MSS.0b013e318227f906. 42. Sjosten N, Kivimaki M, Singh-Manoux A, et al. Change in physical activity and weight in relation to retirement: the French GAZEL Cohort Study. BMJ Open . 2012;2:e000522. doi: 10.1136/bmjopen-2011- 000522. 43 . Smith KJ, Gall SL, McNaughton SA, et al. Lifestyle behaviours associated with 5-year weight gain in a . 2017;17:54. BMC Public Health prospective cohort of Australian adults aged 26-36 years at baseline. y. doi:10.1186/s12889-016-3931- 44. Williams PT, Thompson PD. Dose-dependent effects of training and detraining on weight in 6406 runners during 7.4 years. Obesity . 2006a;14:1975-1984. 45. Williams PT, Wood PD. The effects of changing exercise levels on weight and age-related weight Int J Obes (Lond) gain. . 2006b;30:543-551. 46. Williams, PT. Maintaining vigorous activity attenuates 7-yr weight gain in 8340 runners. Med Sci Sports Exerc . 2007;39:801-809. doi:10.1249/mss.0b013e31803349b1. 47 . Cornelissen VA, Fagard RH, Coeckelberghs E, Vanhees L. Impact of resistance training on blood pressure and other cardiovascular risk factors: a meta-analysis of randomized, controlled trials. . 2011;58(5):950 – 958. doi:10.1161/HYPERTENSIONAHA.111.177071. Hypertension . Cornelissen VA, Smart NA. Exercise training for blood pressure: a systematic review and meta- 48 analysis. . 2013;2(1):e004473. doi:10.1161/JAHA.112.004473. J Am Heart Assoc 49 . Fagard RH, Cornelissen VA. Effect of exercise on blood pressure control in hypertensive patients. Eur J Cardiovasc Prev Rehabil . 2007;14(1):12 – 17. 50. Murtagh EM, Nichols L, Mohammed MA, et al. The effect of walking on risk factors for cardiovascular disease: an updated systematic review and meta-analysis of randomised control trials. Prev Med . 2015;72:34 – 43. doi:10.1016/j.ypmed.2014.12.041. . Corso LM, Macdonald HV, Johnson BT, et al. Is concurrent training efficacious antihypertensive 51 2406. – Med Sci Sports Exerc . 2016;48(12):2398 therapy? A meta-analysis. . Casonatto J, Goessler KF, Cornelissen VA, Cardoso JR, Polito MD. The blood pressure-lowering effect 52 of a single bout of resistance exercise: a systematic review and meta-analysis of randomised controlled – trials. Eur J Prev Cardiol . 2016;23(16):1700 1714. 53. MacDonald HV, Johnson BT, Huedo-Medina TB, et al. Dynamic resistance training as stand-alone antihypertensive lifestyle therapy: a meta-analysis. J Am Heart Assoc . 2016;5(10): e003231. doi:10.1161/JAHA.116.003231. 54 . Carlson DJ, Dieberg G, Hess NC, Millar PJ, Smart NA. Isometric exercise training for blood pressure . 2014;89(3):327 – 334. Mayo Clin Proc management: a systematic review and meta-analysis. doi:10.1016/j.mayocp.2013.10.030. -33 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

349 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain . Huai P, Xun H, Reilly KH, Wang Y, Ma W, Xi B. Physical activity and risk of hypertension: a meta- 55 cohort studies. Hypertension . 2013;62(6):1021 – 1026. analysis of prospective doi:10.1161/HYPERTENSIONAHA.113.01965. Liu X, Zhang D, Liu Y, et al. Dose-response association between physical activity and incident 56. hypertension: a systematic review and meta-analysis of cohort studies. Hypertension . 2017;69(5):813 – 820. doi:10.1161/HYPERTENSIONAHA.116.08994. Whelton PK, Carey RM, Aronow WS, et al. 2017 57. ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . November 2017:pii:HYP.0000000000000066. doi:10.1161/HYP.0000000000000066. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of 58. cardiovascular disease: meta-analysis of 147 randomized trials in the context of expectations from prospective epidemiological studies. BMJ . 2009;338:b1665. doi:10.1136/bmj.b1665. 59. Whelton PK, He J, Appel LJ, et al. National High Blood Pressure Education Program Coordinating Committee. Primary prevention of hypertension: clinical and public health advisory from The National . 2002;288(15):1882-1888. High Blood Pressure Education Program. JAMA . 2017;35(2):234-239. J Hypertens . Rayner BL, Spence JD. Hypertension in blacks: insights from Africa. 60 doi:10.1097/HJH.0000000000001171. Mozaffarian D, Benjamin EJ, Go AS, et al. American Heart Association Statistics Committee and 61. Stroke Statistics Subcommittee. Heart disease and stroke statistics — 2015 update: a report from the American Heart Association. Circulation . 2015;131(4):e29- e3 22. doi:10.1161/CIR.0000000000000152. 62. Whelton PK, Einhorn PT, Muntner P, et al. Research needs to improve hypertension treatment and Hypertension control in African Americans. . 2016;71(1):68:00-00. doi:10.1161/HYPERTENSIONAHA.116.07905. 63 . Carnethon MR, Pu J, Howard G, et al. American Heart Association Council on Epidemiology and Prevention; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Functional Genomics and Translational Biology; Stroke Council. Cardiovascular health in African Americans: a scientific statement from the American 00. doi.org/10.1161/CIR.0000000000000534. Heart Association. Circulation . 2017;136(21):00 – 64. Diaz KM, Booth JN, Seals SR, et al. Physical activity and incident hypertension in African Americans: the Jackson Heart Study. Hypertension . 2017;69(3):421-427. doi:10.1161/HYPERTENSIONAHA.116.08398. . 65. Wilder J. The law of initial value in neurology and psychiatry; facts and problems. J Nerv Ment Dis 1957;125(1):73-86. Pescatello LS, MacDonald HV, Ash GI, et al. Assessing the existing professional exercise 66. Mayo recommendations for hypertension: a review and recommendations for future research priorities. Clin Proc . 2015;90(6):801-812. doi:10.1016/j.mayocp.2015.04.008. -34 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

350 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 67 . Aune D, Norat T, Leitzmann M, Tonstad S, Vatten LJ. Physical activity and the risk of type 2 diabetes: a systematic revi ew and dose-response meta-analysis. Eur J Epidemiol . 2015;30(7):529-542. doi:10.1007/s10654-015-0056-z. 68 . Cloostermans L, Wendel-Vos W, Doornbos G, et al. Independent and combined effects of physical activity and body mass index on the development of type 2 diabetes — a meta-analysis of 9 prospective 3. cohort studies. Int J Behav Nutr Phys Act . 2015:147. doi:10.1186/s12966-015-0304- . Huai P, Han H, Reilly KH, Guo X, Zhang J, Xu A. Leisure-time physical activity and risk of type 2 69 diabetes: a meta-analysis of prospective cohort studies. Endocrine . 2016;52(2):226-230. doi:10.1007/s12020-015-0769- 5. 70 . Jeon CY, Lokken RP, Hu FB, van Dam RM. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review. Diabetes Care . 2007;30(3):744-752. doi:10.2337/dc06-1842. 71. Kyu HH, Bachman VF, Alexander LT, et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ . 2016;354:i3857. doi:10.1136/bmj.i3857. Merlotti C, Morabito A, Pontiroli AE. Prevention of type 2 diabetes; a systematic review and meta- 72. . 2014;16(8):719-727. Diabetes Obes Metab analysis of different intervention strategies. doi:10.1111/dom.12270. 73. Wahid A, Manek N, Nichols M, et al. Quantifying the association between physical activity and cardiovascular disease and diabetes: a systematic review and meta-analysis. . J Am Heart Assoc 2016;5(9). pii:e002495. doi:10.1161/JAHA.115.002495. 74 . Fogelholm M. Physical activity, fitness and fatness: relations to mortality, morbidity and disease risk factors. A systematic review. Obes Rev . 2010;11(3):202-221. doi:10.1111/j.1467-789X.2009.00653.x. 75. Qin L, Knol MJ, Corpeleijn E, Stolk RP. Does physical activity modify the risk of obesity for type 2 diabetes: a review of epidemiological data. Eur J Epidemiol . 2010;25(1):5-12. doi:10.1007/s10654-009- 9395- y. 76 . Reiner M, Niermann C, Jekauc D, Woll A. Long-term health benefits of physical activity — a systematic review of longitudinal studies. BMC Public Health . 2013;813. doi:10.1186/1471-2458- 13 -813. 77. Warburton DE, Charlesworth S, Ivey A, Nettlefold L, Bredin SS. A systematic review of the evidence for Canada's Physical Activity Guidelines for Adults. Int J Behav Nutr Phys Act . 2010;7:39. doi:10.1186/1479-5868-7- 39. 78. Xu F, Wang Y, Ware RS, et al. Joint impact of physical activity and family history on the development of diabetes among urban adults in Mainland China: a pooled analysis of community-based prospective cohort studies. Asia Pac J Public Health . 2015;27(2):NP372-381. doi:10.1177/1010539512443700. 79 . Hu G, Lindström J, Valle TT, et al. Physical activity, body mass index, and risk of type 2 diabetes in 896. – . 2004;164(8):892 Arch Intern Med patients with normal or impaired glucose regulation. -35 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

351 Part F. Chapter 5. Cardiometabolic Health and Prevention of Weight Gain 80 . Hu FB, Leitzmann MF, Stampfer MJ, Colditz GA, Willett WC, Rimm EB. Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men. Arch Intern Med . 2001;161(12):1542 – 1548. 81 . Rana JS, Li TY, Manson JE, Hu FB. Adiposity compared with physical inactivity and risk of type 2 58. – . 2007;30(1):53 Diabetes Care diabetes in women. 82 . Hu FB, Sigal RJ, Rich-Edwards JW, et al. Walking compared with vigorous physical activity and risk of – 1439. . 1999;282(15):1433 type 2 diabetes in women: a prospective study. JAMA 83. Weinstein AR, Sesso HD, Lee IM, et al. Relationship of physical activity vs body mass index with type 2 diabetes in women. JAMA . 2004;292(10):1188-1194. Office of Disease Prevention and Health Promotion. Healthy People 2020: Physical activity. 84. HealthyPeople.gov website. https://www.healthypeople.gov/2020/data-search/Search-the-Data#topic- area=3504 . Accessed January 12, 2018. -36 2018 Physical Activity Guidelines Advisory Committee Scientific Report F5

352 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease PART F. CHAPTER 6. ALL-CAUSE MORTALITY, CARDIOVASCULAR MORTALITY, AND INCIDENT CARDIOVASCULAR DISEASE Table of Contents ... Introduction -1 F6 Review of the Science ... F6 -2 Overview of Questions Addressed ... F6 -2 Data Sources and Process Used to Answer Questions F6 -3 ... -3 F6 ... Question 1. What is the relationship between physical activity and all-cause mortality? Comparing 2018 Findings with the 2008 Scientific Report ... F6 -10 Question 2. What is the relationship between physical activity and cardiovascular disease mortality? -11 F6 ... Question 3. What is the relationship between physical activity and cardiovascular disease incidence? ... F6 -15 F6 Overall Summary, Conclusions, and Public Health Impact ... -21 Needs for Future Research ... F6 -22 ... -24 References F6 INTRODUCTI ON 1 Physical Activity Guidelines Advisory Committee Report, 2008 The that the amount of concluded moderate- to-vigorous physical activity is inversely associated with all-cause mortality, cardiovascular disease (CVD) mortality, and incident CVD . All of the dose-response data used to develop the physical 2 were developed using epidemiologic data from activity targets for the 2008 Physical Activity Guidelines longitudinal cohort studies with moderate- to-vigorous physical activity as the lone physical activity exposure. F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -1

353 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease 1 relied mostly on the primary literature to perform its work on all- In 2008, the Advisory Committee . Since then, studies on the relationship of moderate- to- cause mortality, CVD mortality, and CVD . In 2008, the assessment of vigorous physical activity to these outcomes have continued to be published 1 CVD as an outcome was principally limited to coronary artery disease. Since then, studies have been . In incident heart failure published o n incident cerebrovascular disease — primarily ischemic stroke — and addition, due to the volume of conducted studies, reviews, pooled analyses, and meta-analyses with many component studies and large sample sizes now are available on the relationship of moderate- to- to all-cause mortality, CVD mortality, and CVD vigorous physical activity . The abundance of reviews permitted the Subcommittee to rely on systematic reviews, meta-analyses, and pooled analyses to perform our review. 1 to- In 2008, the Advisory Committee began to define a dose-response relationship among moderate- vigorous physical activity and both all-cause and CVD mortality as a curvilinear one, with an early decrease in risk with greater amounts of moderate- to-vigorous physical activity, and with continuing . While undertaking the current review, the benefit with still greater physical activity amounts Subcommittee believed it important to confirm whether this relationship still holds with new data, and to examine whether it extends to the various CVD outcomes of incident CVD, cerebrovascular disease (ischemic stroke), and incident heart failure. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses three major questions and related subquestions: 1. What is the relationship between physical activity and all-cause mortality? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? b) What is the relationship between physical activity and cardiovascular disease mortality? 2. Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? 3. What is the relationship between physical activity and cardiovascular disease incidence? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -2

354 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Data Sources and Process Used to Answer Questions The Exposure Subcommittee determined that systematic reviews, meta-analyses, and pooled analyses provided sufficient literature to answer all three research questions. One search and triage process was conducted for Questions 1 through 3, which covered all-cause mortality, cardiovascular disease mortality, and cardiovascular disease incidence. For complete details on the systematic literature review process, see Part E. Scientific Literature Search Methodology . Question 1. What is the relationship between physical activity and all-cause mortality? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, or socioeconomic status, and weight status? Source of Evidence : Systematic reviews, meta-analyses, pooled analyses Conclusion Statements Strong evidence demonstrates a clear inverse dose-response relationship between the amount of to-vigorous physical activity and all-cause mortality. moderate- The strength of the evidence is very unlikely to be modified by more studies of these outcomes. PAGAC Grade: Strong. Strong evidence demonstrates a dose-response relationship between physical activity and all-cause mortality. The shape of the curve is nonlinear, with the greatest benefit seen early in the dose-response relationship of moderate- to-vigorous physical activity and risk reduction has no lower relationship . The limit. Risk appears to continue to decrease with increased exposure up to at least three to five times the amounts of the lower bound of moderate- to-vigorous physical activity recommended in the 2008 Guidelines (i.e., 150 minutes per week) e new data are consistent with those used to develop the . Th PAGAC Grade: Strong. 2008 Guidelines. to-vigorous Strong evidence demonstrates that the dose-response relationships between moderate- physical activity and all-cause mortality do not vary by age, sex, race, or weight status . PAGAC Grade: Strong. Insufficient evidence is available to determine whether these relationships vary by ethnicity or socioeconomic status. PAGAC Grade: Not assignable. F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -3

355 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Review of the Evidence An initial search for systematic reviews, meta-analyses, pooled analyses, and reports identified sufficient literature to answer the research question as determined by the Subcommittee . Additional searches for original research were not needed. In data collected from 2006 to 2017, the outcomes of all-cause mortality, CVD mortality, and incident CVD were often considered in the same systematic reviews and meta-analys es. Therefore, the systematic reviews and meta-analyses contributing to the understanding of the relation of physical activity to these three outcomes had significant overlap . Similarly, many of the same studies appeared in the systematic reviews and meta-analyses identified in our searches . In this section, we deal only with . all-cause mortality A total of 12 existing reviews were included in the analysis of the relation of physical activity to all-cause 3, 4 5- 11 12 -14 7 meta-analyses, and 3 pooled analyses. mortality: 2 systematic reviews, Of these 12 reviews, 5 for these studies ranged also addressed CVD mortality and are reported later in the chapter . Follow- up from 3.8 to longer than 20 years, and up to 3.4 million participants in total were studied across these reviews and meta-analyses. 4 3 and 254. However, in The two systematic reviews included a large number of contributing studies: 121 3 only seven addressed all-cause mortality, nine addressed CVD, and three addressed stroke . Milton et al, 4 70 component studies addressed all-cause mortality, 49 addressed CVD, and 25 For Warburton et al, addressed stroke . The total numbers for each outcome were not reported . The studies covered extensive timeframes : from 1990 to 2013 and from 1950 to 2008, respectively. The meta-analyses ranged from 9 to 80 studies. Most meta-analyses covered an extensive timeframe: 5, 7, 10 8 , 11 from inception of the database to 1 year before publication, and from 1970s from 1945 to 2013, 6, 9 The pooled analyses include data from six prospective cohort studies and 1990s to 2007 and 2006. 14 12 13 Arem et al Moore et al, (used the same six cohorts) and from 11 cohorts O’Donovan et al . and to-vigorous physical The majority of the included reviews examined self-reported leisure time moderate- . Most reviews also established specific physical activity dose categories in metabolic equivalents activity of task (MET) for minutes or hours per week using quartiles or a variety of categories such as inactive and low, medium, and high levels of physical activity, or high versus low levels of physical activity. F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -4

356 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease 8 Three reviews addressed specific types of physical activity . Kelly et al studied cycling and walking. 10 studied domain-specific physical activity defined into leisure-time physical activity, Samitz et al 6 . Hamer and Chida activities of daily living, and occupational physical activity studied habitual walking only . 14 separately examined individuals who meet the physical activity guidelines in one One pooled analysis or two sessions in addition to the usual physical activity categories (inactive, insufficiently active, and 15 regularly active) . Merom et al examined dancing versus walking. Evidence on the Overall Relationship All the included reviews addressed all-cause mortality as an outcome and five of them also examined CVD mortality. to-vigorous physical activity and all- All studies reported an inverse relationship between moderate- cause mortality in a dose-response fashion as described below . There were no null studies. The pooled analysis, in which individuals meeting guidelines in one or two sessions per week and individuals meeting guidelines with three or more sessions per week were compared to an inactive group, showed no differences in the effect sizes for all-cause mortality between individuals meeting guidelines in 1 to 2 sessions per week (hazard ratio ( HR )= 0.60; confidence interval (CI): 0.45-0.82) and individuals meeting 14 CI: 0.48-0.73), compared to the inactive group. guidelines in 3 or more sessions per week (HR=0.59; 8 In the analysis by Kelly et al, . For exercise of 11.25 the effect sizes for cycling and walking were similar MET-hours per week (675 MET-minutes per week), the reduction in risk for all-cause mortality was 11 percent (95% CI: 4%-17%) for walking and 10 percent (95% CI: 6%-13%) for cycling. The shape of the dose-response relationship was modeled through meta-analysis of pooled relative risks within three exposure intervals . Consistent with other studies, the dose-response analysis showed tha t for walking or in the lowest exposure cycling, the greatest reduction in risk for all-cause mortality occurred with categories of physical activity. 6 Hamer and Chida studied the effect of walking only on both all-cause mortality and CVD mortality . The analysis included 18 prospective studies with 459,833 total participants. The Forest plots, displayed in 6 Figure F6-1, show a dose-response for amount (volume of walking) and walking pace . Hamer and Chida found walking pace to be a stronger independent predictor of all-cause mortality than volume: 48 . However, within the exposure categories the percent versus 26 percent risk reductions, respectively F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -5

357 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease studies had considerable heterogeneity . The greatest walking exposure groups averaged more than 5.2 hours per week or more than 10.7 miles per week, and the groups ranged from more than 1 hour per week to more than 2 hours per day and more than 6.0 miles per week to more than 12.4 miles per week . Walking pace was generally assessed as a relative rather than an absolute measure, although several studies defined ‘‘brisk’’ as more than 3.0 miles per hour and ‘‘moderate’’ as 2.0 to 2.9 miles per hour . Minimal walking categories averaged approximately 3 hours per week (ranging from approximately 30 minutes per week to approximately 5 hours per week) or 6.1 miles per week (ranging from approximately 3.1 miles per week to approximately 9.3 miles per week), which equated to a casual or moderate walking pace of approximately 2 miles per hour. Figure F6-1. The Association Between Walking and All-Cause Mortality in Men and Women Hazard ratio (95% CI) Authors (year) Exposure Sample size Male 11 1 Wannamethee et al (1998) Walking > 1 hour/day (0.37 4311 to 1.05) 0.62 12 Hakim et al (1998) 2 Walking > 3.2 km/day 83) 0.55 (0.37 to 0. 707 13 Walking > 1 hour/week et al (1998) 3 Bijnen 0.71 (0.68 to 0.88) 80 2 19 4 (2000) et al Davey Smith Brisk walking 0 . (0.48 to 0.63) 55 6702 24 (2004) et al Fujita 5 > 1 hour/day Walking 0 . 92 (0.80 to 1.06) 20,004 26 Walking > 2 hours/day 6a Schnohr et al (2007) 89 3204 0 . (0.69 to 1.14) 26 Brisk walking (2007) et al Schnohr (0.32 0.43 to 0.59) 6b 3204 38,934 Subtotal 0.66 to 0.83) (0.53 Female 23 Walking > 898 kcal/week to 0.82) al (0.62 (2003) 0.71 et Gregg 1 9518 24 21,159 0.72 ( 2 0.59 to 0.89) Fujita et al (2004) Walking > 1 hour/day 26 4104 to 1.10) (0.59 3a 0.81 > 2 hours/day Walking (2007) et al Schnohr 26 to 0.66) 4104 0.35 ( 0.48 3b Brisk walking et al (2007) Schnohr 27 to 1.05) (0.71 0.86 4 (2007) Walking > 10 MET-hours/day et al Matthew 67,143 0.72 Subtotal to 0.84) 106,028 (0.62 Male and female 1 0 0.73 to 1.10) (0.48 et al 1 LaCroix (1996) Walking > 4 hours/week 1645 18 2 Stessman al (2000) et to 0.50) (0.04 0.14 Walking > 4 hours/week 456 147,063 Total to 0.78) 0.68 (0.59 Test for heterogeneity χ²(13) = 31.35, p < 0.001 Test for overall effect χ²(1) = 57.86, p < 0.001 Note: Walking is favored, with a shift of the estimate to the left. These estimates are similar to the effects on cardiovascular disease mortality in Question 2, Figure F6- 4. Source: Reproduced from [Walking and primary prevention: A meta-analysis of prospective cohort studies, Hamer 6 and Chida , 42, 2008] with permission from BMJ Publishing Group Ltd. Dose-response: e dose- Every one of the 12 studies within our analysis demonstrated a significant invers response relationship with all-cause mortality across physical activity exposure groups . The uniformity and strength of these relationships led to the strength of association finding for this subquestion . The 12 uniformity of findings prompted us to highlight the two pooled analyses of Arem et al and Moore et 13 ed In these pooled analyses of six studies, combining data at the individual level allow al. an F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -6

358 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease exa mination of the strength of effects and confidence boundaries across large populations with great precision. 13 Moore et al reported a pooled analysis of the association of leisure-time physical activity with mortality during follow-up in pooled data from six prospective cohort studies in the National Cancer . The combined pooled cohort included 654,827 individuals, ages Institute Cohort Consortium 90 21 to years. Moderate- to-vigorous physical activity in MET-hours per week was used to generate adjusted survival curves (for participants ages 40 years and older), with 95% confidence intervals derived by bootstrap. The study included a median 10 years of follow-up and 82,465 deaths . Figure F6-2 shows the survival curves against several characteristics of the relationship common among the studies reporting on dose-response on all-cause mortality . The survival curve from this analysis demonstrates several important points: The beneficial effect has no lowest threshold. 1. . The slope is steepest at the lowest amounts of moderate- to-vigorous physical activity 2. 3. At least 70 percent of the potential benefit on all-cause mortality is reached by achieving 8.25 to-vigorous physical activity. MET-hours (150 minutes) per week of moderate- There is no obvious best amount. 4. 5. There is no apparent upper threshold. Benefits continue to accrue 6. as more physical activity is accrued. 2 (150-300 minutes moderate- 7. Activity volumes (amounts) up to four times the 2008 Guidelines intensity physical activity) show no evidence of increased mortality risk . F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -7

359 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Figure F6-2. Relationships of Moderate- to-Vigorous Physical Activity to All-Cause Mortality, with Highlighted Characteristics Common to Studies of This Type 13 Source: Adapted from data found in Moore et al., 2012. 12 Similarly, Arem et al reported a pooled analysis of six studies in the National Cancer Institute Cohort 13 These were Consortium (baseline collection in 1992-2003; the same studies reported i n Moore et al. population-based prospective cohorts in the United States and Europe, with self-reported physical activity analyzed in 2014 . A total of 661,137 men and women (median age, 62 years; range 21 to 98 years) and 116,686 deaths were included . Cox proportional hazards regression with cohort stratification was used to generate multivariable-adjusted hazard ratios and 95% confidence intervals. Median follow- up time was 14.2 years . The dose response-relationship from this report is shown in Figure F6-3 . Several 13 (Figure F6-2). characteristics of this dose-response relationship are reminiscent of that of Moore et al However, several differences in results are described below. F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -8

360 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Figure F6-3. Relationships of Moderate- to-Vigorous Physical Activity to All-Cause Mortality, with Highlighted Characteristics Common to Studies of this Type 12 Source: Adapted from data found in Arem et al., 2015. Here the relationship is carried out to a category (greater than 75 MET-hours per week) representing 2 approximately ten times the exposure of the lower end of the 2008 Guidelines (i.e., 150 minutes per week). At this greater exposure, an apparent uptick in mortality risk occurs. This possible uptick is not 13 Moore et al study that went only to about four times the Guidelines exposure. In the apparent in the 12 Arem et al pooled study of 661,137 individuals only 18,831 participants (2.8% of the total) were included in the 40 to 75 MET-hours per week category, and only 4,077 (0.62%) in the more than 75 MET- 12 hours per week category. These accounted for only 1,390 (1.2%) and 212 (0.18%) of 116,686 deaths in the combined analysis, respectively, and the error bars are large . Figure F6-3 indicates that the point estimate of risk for the greate st exposure group is the same as the estimate for those meeting the 2008 Guidelines (7.5 to 15 MET-hours per week, or 150 to 300 minutes per week) . This apparent uptick in risk 17 16, reported it in the at extreme volumes of exercise has been observed before . Paffenbarger et al Harvard Alumni Heart study for CVD (heart attack) risk, in 1978 and 1993 . However, as in these previous F6 2018 Physical Activity Guidelines Advisory Committee Scientific Report -9

361 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease the apparent rise in risk at very high amounts of moderate- to-vigorous physical activity did not reports, 12 reach the level of statistical significance. 5 In a seminal paper in 2016, examin ed the associations of sedentary behavior (sitting and Ekelund et al television watching) and physical activity (moderate- to-vigorous physical activity ) with all-cause for more Part F. Chapter 2. Sedentary Behavior mortality . See Part D. Integrating the Evidence and details on these interactions. Using 16 contributing studies, combining data across all studies to analyse the association of daily sitting time and physical activity with all-cause mortality, estimating summary hazard ratios using Cox regression, and expressing physical activity in terms of MET-hours per week of 5 moderate- to-vigorous physical activity, Ekelund et al found the same curvilinear relationships among 13 12 physical activity and all-cause mortality as observed Arem et al and Moore et al. Evidence on Specific Factors Demographic factors and weight status Most studies reported overall distributions of demographic : ) across exposure groups within individual studies in their reviews and factors (race, sex, weight status meta-analyses. Given the nature of meta-analyses — conducted at the study level versus the individual it is difficult to detect differential effects by demographic factors and weight status unless the level — specific component studies performed them within their analysis . Some studies examined subgroup 7 effects directly in their review or meta-analysis; one focused on adults older than 60 years. In such 14 studies, no subgroup effects were detected . The O’Donovan et al analysis of “weekend warrior” differential responses by sex physical activity behavior on all-cause mortality, showed no . 12, 13 permit a direct examination of the relative effects across However, the pooled analyses demographic categories . In these studies, effects are reported for strata across sex, race, and body mass index (BMI) and the aggregate event data reported according to strata . Although not directly tested in these reports, no differential effects across sex, race, or BMI strata are readily apparent . Strata for socioeconomic status and ethnicity were not reported . For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report eview of systematic reviews, meta- ’s r Compared with the 2008 Advisory Committee, this Subcommittee analyses, and pooled studies exploited the analysis of larger cohorts and provided more precision -10 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

362 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease around the effect size estimates . Our review identified the same dose-effect estimates relating moderate- to-vigorous physical activity with all-cause mortality as was described in 2008 . Given the large population sizes and heterogeneity studied, we have more confidence in the precision of these numbers as well as their generalizability to U.S. adult men and women, and populations of all races, ages, and body sizes. Question 2. What is the relationship between physical activity and cardiovascular disease mortality? Is there a dose-response relationship? If yes, what is the shape of the relationship? a) b) Does the relationship vary by age, sex, race/ethnicity, or socioeconomic status, and weight status? Systematic reviews, meta-analyses, pooled analyses Source of Evidence: Conclusion Statements Strong evidence demonstrates that a strong inverse dose-response relation exists between amount of The strength of the to-vigorous physical activity and cardiovascular disease mortality. moderate- evidence is very unlikely to be modified by more studies of this outcome. PAGAC Grade: Strong. Strong evidence demonstrates that the shape of the curve is nonlinear, with the greatest benefit seen early in the dose-response relationship . The relationship of moderate- to-vigorous physical activity and risk reduction has no lower limit. Risk appears to continue to decrease with increased exposure up to at least three to five times the amounts of moderate- to-vigorous physical activity recommended in the . The new data are consistent with those used to develop 2008 Guidelines (i.e., 150 minutes per week) the 2008 Guidelines. PAGAC Grade: Strong. Strong evidence demonstrates that these relationships do not vary by age, sex, race, or weight status . PAGAC Grade: Strong. Insufficient evidence is available to determine whether these relationships vary by ethnicity or PAGAC Grade: Not assignable. socioeconomic status. Review of the Evidence An initial search for systematic reviews, meta-analyses, pooled analyses, and reports identified sufficient literature to answer the research question as determined by the Subcommittee. Additional searches for original research were not needed. -11 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

363 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease In data collected from 2006 to 2017, the outcomes of all-cause mortality, CVD mortality, and incident CVD were often considered in the same systematic reviews and meta-analyses. Therefore, the systematic reviews and meta-analyses contributing to the understanding of the relation of physical activity to these three outcomes had significant overlap . Similarly, many of the same studies appeared in the systematic reviews and meta-analyses identified in our searches . In this section, we address only CVD mortality; however, the format and conclusions differ little from those made for all-cause mortality. A note on nomenclature is necessary here . For this discussion, CVD mortality refers to mortality attributable to CVD in its broadest sense. CVD refers to diseases beyond coronary artery disease, but does not include: • non-atheromatous or infectious valvular disease and others, such as diseases due to coronary heart disease secondary to coronary artery disease, cerebrovascular disease secondary to a cerebrovascular accident or stroke, • • heart failure of ischemic (coronary) or non-ischemic etiology. 5, 6, 18 3 three meta-analyses, A total of six existing reviews were included: one systematic review, and two 3 15 14, included ere published from 2008 to 2017. The systematic review pooled analyses. The reviews w 121 studies and a timeframe from 1983 to 2013 . The meta-analyses included a range of 16 to 36 studies 5 Hamer and from inception of the database to 2015; and covered an extensive timeframe : Ekelund et al, 18 6 from 1970s and 1980s to 2007 and 2014 respectively . The pooled analyses Chida, and Wahid et al, 15 14, included data from 11 cohorts, each from different population surveys. The majority of the included reviews examined self-reported leisure time moderate- to-vigorous physical activity . Most reviews also established specific physical activity dose categories in MET-minutes or MET- hours per week using quartiles or a variety of categories such as inactive and low, medium, and high levels of physical activity, or high versus low levels of physical activity. 14 examined a “weekend warrior” category (meeting the physical activity guidelines One pooled analysis in one or two sessions per seek) in addition to the usual physical activity categories (insufficiently active and regularly active) compared to an inactive group. Two reviews addressed specific types of physical 6 15 and habitual walking. activity: dancing 2018 Physical Activity Guidelines Advisory Committee Scientific Report -12 F6

364 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Evidence on the Overall Relationship All of the included reviews addressed CVD mortality and four of them also assessed all-cause mortality in addition to other outcomes. to- As it was for all-cause mortality, all reviews reported an inverse relationship between moderate- . The vigorous physical activity and all-cause mortality in a dose-response fashion, as described below reviews included no null studies . The pooled analysis in which individuals meeting guidelines in one or two sessions per week and individuals meeting guidelines with three or more sessions per week were compared to an inactive group, showed no differences (overlapping hazard ratios) in the effect sizes for CVD mortality (HR=0.59 to 0.60). 6 . studied walking only on both all-cause mortality and CVD mortality As noted above, Hamer and Chida The analysis included 18 prospective studies with 459,833 total participants. The Forest plots for CVD mortality are shown in in Figure F6-4 . The effect sizes and confidence intervals for all categories of walking pace and amount are reminiscent of those determined for all-cause mortality (Figure F6-1) . This to-vigorous physical activity relationship is for both is an example of how closely aligned the moderate- CVD mortality and all-cause mortality within and across studies. -13 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

365 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Figure F6-4. The Association Between Walking and Cardiovascular Mortality Risk in Men and Women Authors (year) Exposure Hazard ratio (95% CI) Sample size Male 12 Walking > 3.2 km/day (1998) et al Hakim to 1.49) (0.10 0.39 707 1 14 Hakim (1999) et al Walking >2.5 km/day 2 to 0.77) (0.24 0.43 2678 13 et al (1998) Bijnen > 1 hour/week Walking 3 to 1.05) (0.45 0.69 802 17 Sesso et al (2000) Walking > 10 km/week 4 (0.78 to 1.00) 0 .88 12,516 19 walking Brisk Davey Smith et al (2000) to 0.59) (0.37 0.47 5 6702 22 et al (2002) Tanasescu > 3.5 hours/week Walking 6a (0.73 44,452 0 .90 to 1.10) 22 Brisk walking al Tanasescu (2002) et 0.51 (0.31 to 0.84) 44,452 6b 25 7 Walking > 1 hour/day al (2005) Noda et to 1.00) (0.72 31,023 0.85 Subtotal 143,332 0.68 (0.55 to 0.85) Female 15 et 1a Manson al (1999) to 0.91) 0.65 (0.47 > 3 hours/week Walking 72,488 15 (1999) et 1b Manson al 0.64 (0.47 to 0.88) Brisk walking 72,488 16 2 Walking > 10 km/week to 1.01) 0.67 (0.45 (1999) al et Sesso 1564 20 Walking > 2 hours/week 0.48 to 0.78) (0.29 (2001 ) et al 3a Lee 39,372 20 (2001 ) 3b Lee al et Brisk walking to 0.90) (0.30 0.52 39,372 2 1 4 Walking > 3 hours/week Manson et al [ to 0.82) (0.56 2002) 0.68 73,743 23 Walking > 898 kcal/week 0.62 (0.49 to 0.78) (2003) 5 Gregg et al 9518 26 6 > 1 hour/day Walking (0.70 to 1.02) 0.84 Noda et al (2005) 42,242 27 Matthew > 10 MET-hour/day et 0.92 (0.60 to 1.40) al (2007) 7 Walking 67,143 Subtotal 417,930 0.69 to 0.77) (0.61 Male and female 10 Walking > 4 hours/week al LaCroix et (1996) 1645 0.68 (0.52 to 0.90) 1 Total 562,907 to 0.77) (0.61 0.69 Test for heterogeneity χ²(17) = 42.91, p < 0.001 Test for overall effect χ²(1) = 47.68, p < 0.001 Note: Walking is favored, with a shift of the estimate to the left. Notice the similarity of these estimates to the effects on all-cause mortality in Question 1, Figure F6-1. Source: Reproduced from [Walking and primary prevention: A meta-analysis of prospective cohort studies, Hamer 6 and Chida , 42, 2008] with permission from BMJ Publishing Group Ltd. Dose-response : Here also, the findings for the dose-response relationships between moderate- to- vigorous physical activity and CVD mortality are basically identical to those found for the relationships . to-vigorous physical activity and all-cause mortality between moderate- Every one of the 12 studies within our analysis demonstrated a significant inverse dose-response relationship with CVD mortality across physical activity exposure groups . The uniformity and strength of these relationships led to the strength of association finding for this subquestion. 18 Wahid et al used 36 studies, 33 pertaining to CVD and 3 pertaining to type 2 diabetes mellitus to model the effects of three physical activity categories (low physical activity, 0.1-11.5 MET-hours per week ; MET-hours ≥29.5 ; and high physical activity; medium physical activity, 11.5-29.5 MET-hours per week per week) in a dose-response fashion on CVD incidence and mortality, coronary heart disease incidence . For those and mortality, myocardial infarction incidence, heart failure incidence, and stroke incidence conditions for which all three categories had entries (CVD incidence, CVD mortality, stroke incidence and -14 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

366 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease CHD incidence), all but CVD mortality demonstrated a strong curvilinear dose-response relationship across categories. Evidence on Specific Factors Demographic factors and weight status : Similar to all-cause mortality, the studies providing the strongest evidence regarding subgroup moderation effects on CVD mortality were the pooled analyses 14 15 of . O’Donovan et al Merom et al Again, as for all-cause mortality, no differential effects across and sex, race, or BMI strata were readily apparent . Strata for socioeconomic status and ethnicity were not reported. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx Question 3. What is the relationship between physical activity and cardiovascular disease incidence? a) Is there a dose-response relationship? If yes, what is the shape of the relationship? b) Does the relationship vary by age, sex, race/ethnicity, socioeconomic status, or weight status? Source of evidence: Systematic reviews and meta-analyses Conclusion Statements Strong evidence demonstrates a significant relationship between greater amounts of physical activity and decreased incidence of cardiovascular disease, stroke, and heart failure. The strength of the evidence is unlikely to be modified by more studies of these outcomes. PAGAC Grade: Strong. Strong evidence demonstrates a significant dose-response relationship between physical activity and cardiovascular disease, stroke, and heart failure . When exposures are expressed as energy expenditure (MET-hours per week), the shape of the curve for incident CVD appears to be nonlinear, with the . It is unclear whether the shapes of the greatest benefit seen early in the dose-response relationship relations for incident stroke and heart failure are linear or nonlinear . There is no lower limit for the relation of MPVA and risk reduction. Risk appears to continue to decrease with increased exposure up to . PAGAC to-vigorous physical activity at least five times the current recommended levels of moderate- Grade: Strong. Insufficient evidence is available to determine whether these relationships vary by age, sex, race, PAGAC Grade: Not assignable. ethnicity, socioeconomic status, or weight status. -15 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

367 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Review of the Evidence An initial search for systematic reviews, meta-analyses, pooled analyses, and reports identified sufficient . Additional searches for literature to answer the research question as determined by the Subcommittee original research were not needed. 4 18- 26 and 9 meta-analyses. A total of 10 existing reviews were included: 1 systematic review The reviews 4 were published from 2008 to 2016 . The systematic review included 254 studies published between 1950 and 2008. The meta-analyses included a range of 12 to 43 studies. Most meta-analyses covered an extensive 25 24, 26 from 1954 and 1966 to 2007, timeframe: from database inception to 2013, and from the 1980s 18- 23 and 1990s to 2005 – 2016. The majority of included reviews examined self-reported physical activity. Different domains of physical 20 21 ; oc cupational and leisure activity were also assessed, including total ; occupational, leisure, and 24 23 transport ; and leisure physical activity only. Some reviews also established specific dose categories in , 22 21 18, , 26 MET-minutes or MET-hours per week. Other reviews used minimal or low versus moderate or 4, 19 , 24 high physical activity levels as reported in individual studies. Two meta-analyses specifically 25 26 examined tai c and walking. hi Included reviews addressed the incidence of CVD in a variety of ways . Several addressed incident 4 21 , 23, 24 , 26 , 22 19, 21 , 25 20 oke, Warburton et al coronary heart disease, and incident heart failure. incident str 18 used 33 studies to address reviewed incident stroke and coronary (ischemic) heart disease. Wahid et al CVD incidence and mortality, coronary heart disease incidence and mortality, myocardial infarction incidence, heart failure incidence, and stroke incidence . Thus, in all, six studies address ed incident coronary heart disease; five studies addressed incident stroke; and three studies addressed incident heart failure. rall Relationship Evidence on the Ove All six studies addressing incident coronary heart disease, the five studies addressing incident stroke, and the three studies addressing incident heart failure demonstrated significant dose-response inverse relationships with increased amounts of physical activity. There were no null studies. The shapes of the relationships are discussed below. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6 -16

368 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Coronary Heart Disease 23 Sattelmair et al performed a pooled sample meta-analysis of epidemiologic studies to investigate the relationship of MPVA to incident coronary heart disease . Pooled dose-response estimates were derived . Of the 33 studies initially from qualitative estimates describing low, moderate, and high physical activity selected for analysis, 9 permitted quantitative estimates of kilocalories per week of moderate- to- vigorous physical activity . Those participating in leisure-time physical activity at the lower limit of the 2 percent reduced risk of developing coronary heart disease (Relative Risk 2008 Guidelines had a 14 those reporting no leisure-time physical activity 0.09) compared with (RR)=0.86 +/- . They reported an inverse dose-response relationship similar to the curves for all-cause mortality and CVD mortality. These curves are characterized by an early decrease in risk, continued benefit with greater exposure, no lower threshold, and no upper limit (Figure F6- 5). One MET-hour per week is approximately equal to 1.05 kilocalories per kilogram (kg) per week . Therefore, for a 70 kg individual, the lower boundary of the 2008 2 for moderate- to-vigorous physical activity is achieved at 600 kilocalories per week. Guidelines f Coronary Heart Disease Figure F6-5. Plot with Spline and 95% Confidence Intervals of Relative Risk o by Kilocalories per Week of Leisure-time Physical Activity Note: Individual study results are plotted with grey lines; the thick black line shows the trend line for both sexes combined from a random spline-fit model and the thinner black lines show the 95% CI for the trend. 23 Dose response between physical Activity and Risk of Coronary Heart Disease, a Source: Sattelmair et al., 2011, 795. https://doi.org/10.1161/CIRCULATIONAHA.110.010710 Meta-Analysis, Circulation, 124: 789- -17 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

369 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease This analysis points to an important aspect of understanding how the interpretation of dose-response relationships may depend on the modeling parameters . When the dose-response relationships of the pooled studies are model ed using the qualitative exposures of low, moderate, and high physical activity, . When, however, the physical activity exposures are the dose-response relationship appears linear modeled according to MET-hours per week (Figure F6-5), the curvilinear relationship is revealed. Evidence on Specific Factors Demographic factors and weight status : As it was for previously studied outcomes in this chapter, the studies providing the strongest evidence regarding subgroup moderation effects on cardiovascular 23 mortality were the pooled analyses; particularly that of Sattelmair et al. Of the six studies dealing with 23 explicitly tested for incident CHD in our analysis, to the best of our knowledge, only Sattelmair et al . Although no interactions were reported for effect modification disease modification by specific factors =0.03); the association was P by race or BMI strata, they observed a significant interaction by sex ( stronger among women than men. Stroke and Coronary Heart Disease 21 studied the dose-response associations between total physical activity and risk of breast Kyu et al cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events using 174 studies: 43 for ischemic heart disease, and 26 for ischemic stroke. Total physical activity in MET-minutes per week . Continuous and categorical dose-responses between physical was estimated from all included studies activity and outcomes were assessed. Categorical dose-response co mpared insufficiently active (less than10 MET hours per week), low active (10 to 66 MET-hours) moderately active (67 to 133 MET-hours) and highly active (greater than or equal to 134 MET-hours) . Compared with insufficiently active individuals, the risk reduction for those in the highly active category was 25 percent (RR=0.754; 95% CI: 0.704-0.809) for ischemic heart disease and 26 percent (RR=0.736; 95% CI: 0.659-0.811) for ischemic stroke . Again, for ischemic stroke and ischemic heart disease (equivalent to coronary heart disease), the same typical curvilinear dose-response relationship is seen as for all-cause mortality and CVD mortality . However, the initial and maximal effect sizes are attenuated, so that achieving the lower bound of the 2 2008 Guidelines achieves only 36 percent reduction in initial risk for incident ischemic stroke and heart 6). failure (Figure F6- -18 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

370 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Figure F6-6. Dose-Response Relationships Between Total Physical Activity and Risk of Breast Cancer, Colon Cancer, Diabetes, Ischemic Heart Disease, and Ischemic Stroke Events Using 174 Studies (43 For Ischemic Heart Disease, and 26 For Ischemic Stroke) Note: For reference, shown are the lower end (8.5 MET-hours/week) and upper bounds (17 MET-hours/week) of the 2008 Guidelines for moderate- to-vigorous physical activity. Also indicated is the moderate- to-vigorous physical activity amount associated with normalization of the risk from greater than 8 hours per day of sedentary activity from Ekelund, 2016 (35 MET-hours/week). Source: Reproduced from [Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: Systematic review and dose-response meta-analysis for the Global Burden of 21 , 354, 2016] with permission from BMJ Publishing Group Ltd. and Ekelund et al., Disease Study 2013, Kyu et al 5 2016. Evidence on Specific Factors Demographic factors and weight status : No effect modifications by age, sex, or weight status were reported for the five reviews that studied incident ischemic stroke . Socioeconomic status and race/ethnicity were not reported in these studies. Heart Failure 22 Pandey et al studied the categorical dose-response relationships between physical activity and heart 21 these authors used generalized least- failure risk. As in the previously discussed analysis by Kyu et al, squares regression modeling to assess the quantitative relationship between physical activity (MET- minutes per w k) and heart failure risk across studies reporting quantitative physical activity estimates. ee -19 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

371 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease Twelve prospective cohort studies with 20, 203 heart failure events among 370,460 participants (53.5% women; median follow-up, 13 years) were included. As seen in Figure F6-7, the greatest levels of physical activity were associated with significantly reduced risk of heart failure (pooled HR for highest versus lowest physical activity=0.70; 95% CI: 0.67-0.73). Compared with participants reporting no leisure-time physical activity, those who engaged in 2008 Guidelines -recommended minimum levels of 2 had modest reductions in heart failure risk (pooled k ee physical activity (500 MET-minutes per w HR=0.90; 95% CI: 0.87-0.92). Thus, only 33 percent of the maximal benefit was achieved at the 2008 2 Guidelines amount . Thus, for heart failure, it appears that the dose-response relationship is linear, and not the curvilinear relationship observed for the other outcomes discussed in this chapter. f 7. Dose-Response Relationships Between Moderate-to-Vigorous Physical Activity and Risk o Figure F6- Incident Heart Failure Note: For reference, shown are the lower end (8.5 MET-hours/week) and upper bounds (17 MET-hours/week) of to-vigorous physical activity. Also indicated is the moderate- to-vigorous physical the 2008 Guidelines for moderate- activity amount associated with normalization of the risk from greater than 8 hours per day of sedentary activity from Ekelund et al., 2016 (17 MET-hours/week). -20 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

372 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease 22 Source: Used with permission, Pandey et al., Response Relationship Between Physical Activity 2015 2016, Dose – and Risk of Heart Failure, a Meta-Analysis, Circulation, 132: 1786-1794. 5 . Lines added from Ekelund et al., 2016. https://doi.org/10.1161/CIRCULATIONAHA.115.015853 Evidence on Specific Factors Demographic factors and weight status: No effect modifications by age, sex, or weight status were reported for the two reviews that studied incident heart failure . Socioeconomic status and race/ethnicity were not reported in these studies. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx OVERALL SUMMARY, CONCLUSIONS, AND PUBLIC HEALTH IMPACT to-vigorous physical activity on atherosclerotic CVDs of coronary heart disease, The effects of moderate- . The ischemic stroke and heart failure are very similar to those of all-cause mortality and CVD mortality evidence continues to support the conclusion that increasing moderate- to-vigorous physical activity levels by even small amounts in the inactive U.S. population has the potential to have an important and substantial impact on these outcomes in the adult population. With respect to reductions in risk for these endpoints, the following points are clear: Any amount of physical activity has greater benefit than no physical activity at all; • More moderate- • to-vigorous physical activity is better than none; Meeting current moderate- to-vigorous physical activity guidelines will result in an all-cause • mortality risk reduction that is about 75 percent of the maximal benefit; • More physical activity results in greater benefit, although the incremental benefit is less; and • There is no evidence of excess risk over the maximal effect observed at about three to five times the moderate- . to-vigorous physical activity of the current guidelines When the activity is quantified by volume in terms of energy expenditure of task (MET-hours per week), these relationships seem to hold for several modes and intensities of physical activity, including walking, running, and biking. -21 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

373 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease NEEDS FOR FUTURE RESEARCH Several advances in our understanding of the relationships among physical activity and these outcomes 1 have occurred since the Physical Activity Guidelines Advisory Committee Report, 2008. Most of the literature upon which the conclusions were based used survey data and questionnaire data; physical activity exposures were assessed using self-reported estimates of time spent in aerobic continuous moderate- to-vigorous physical activity accumulated in bouts of at least ten minutes . Therefore, all other components across the physical activity spectrum – sedentary behavior, light-intensity physical activity , and any moderate- – was considered to-vigorous physical activity in bouts less than 10 minutes “baseline” physical activity . Researchers have begun to incorporate device-based measures of physical activity into their measurement armamentarium . This has permitted assessments of the relationship of activity of less than moderate- to-vigorous intensity with health outcomes; it has permitted the assessment of the effects of episodes of moderate-to-vigorous physical activity of less than 10 minutes . Physical Activity Behaviors: Steps, Part F. Chapter 1 . These issues are addressed in health outcomes on Bouts, and High Intensity Training . More research is needed in these areas: 1. Conduct research on the role of light intensity physical activities in risk reduction for all-cause mortality, cardiovascular disease mortality, and incident cardiovascular disease (coronary heart disease, stroke and heart failure) . This can most economically and efficiently be accomplished by incorporating devices (pedometers or wearables ) to measure physical activity into all clinical drug trials with all-cause mortality, cardiovascular disease mortality, or incident cardiovascular disease as outcomes. Ra to-vigorous physical activity on all- As reported in this chapter, the benefits of moderate- : tionale cause mortality, cardiovascular disease mortality, and incident cardiovascular disease (coronary . However, these studies heart disease, stroke and heart failure) are well-documented and strong ignore the effects of physical activity that are not characterized as moderate- to-vigorous in intensity (i.e., light intensity) . The development of device-based measures of physical activity (pedometers, accelerometers, and other wearables) provides the scientific imperative to begin to explore the relations of all intensities and amounts of physical activity — light- to vigorous-intensity; small to 31 27- Unfortunately, there are not enough . These studies are beginning to appear. large total amounts studies on the relation of light-intensity physical activity, total physical activity, or step counts per -22 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

374 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease day to provide enough information for meta-analyses to be performed in these areas for the outcomes of interest here . Therefore, this is a major future research need in this area. 2. Conduct research on the possibility of increased risk associated with high amounts of physical activity. Rationale : Whether high amounts (volumes) of aerobic physical exercise lead to increased cardiac morbidity or mortality is an important, yet open question . As discussed in this chapter, there is a . Recent hint in some studies of an increase in cardiovascular risk in high-volume aerobic athletes 32, 33 reports document increased coronary calcium scores in masters athletes ; however, there seem s 33 These findings may explain the hint to be a U-shaped relationship with life-long volume of training. . Clearly, this issue demands more study in of an increased cardiovascular risk in long-term athletes athletic populations. 3. Conduct research on the relative importance of the various characteristics of physical activity exposure (total volume, intensity, frequency and mode) on all-cause mortality, cardiovascular disease mortality, and incident cardiovascular disease (coronary heart disease, stroke and heart failure). Rationale The second edition of the Physical Activity Guidelines Advisory Committee Scientific : Report, continues to rely on studies of aerobic ambulatory moderate- to-vigorous physical activity , primarily collected via survey, to understand the relationship of physical activity to all-cause mortality, cardiovascular disease mortality, and incident cardiovascular disease . Underexplored are the importance of frequency and intensity relative to volume of aerobic exercise; the importance of muscle strengthening to these clinical outcomes; whether swimming, biking, and rowing contribute ly to aerobic ambulatory exercise; and what the energy expenditures to cardiovascular health equal and programs are for these aerobic activities for equivalent clinical outcomes. If we are going to prescribe exercise of all modalities as options for individuals who want to exercise for health, we need better understanding of the relative contributions of a general range of options. -23 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

375 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease REFERENCES 1. Physical Activity Guidelines Advisory Committee. Physical Activity Guid elines Advisory Committee Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. 2. U.S. Department of Health and Human Services. 2008 Physical Activity Guidelines for Americans . Washington, DC: U.S. Department of Health and Human Services; 2008. 3. Milton K, Macniven R, Bauman A. Review of the epidemiological evidence for physical activity and . 2014;9(4):369-381. Glob Public Health health from low- and middle-income countries. 0/17441692.2014.894548. doi:10.108 4. Warburton DE, Charlesworth S, Ivey A, Nettlefold L, Bredin SS. A systematic review of the evidence for Canada’s Physical Ac tivity Guidelines for Adults. Int J Behav Nutr Phys Act . 2010;7:39. doi:10.1186/1479- 5868-7-39. 5. Ekelund U, Steene-Johannessen J, Brown WJ. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonized meta-analysis of data from more than 1 million men and women. Lancet . 2016;388:1302-1310. doi:10.1016/S0140-6736(16)30370- 1. 6. Hamer M, Chida Y. Walking and primary prevention: a meta-analysis of prospective cohort studies. Br Med . 2008;42(4):238-243. J Sports to-vigorous physical activity 7. Hupin D, Roche F, Gremeaux V, et al. Even a low-dose of moderate- matic revie 60 years: a syste reduces mortality by 22% in adults aged ≥ w and meta-analysis. Br J Sports Med . 2015;49(19):1262-1267. doi:10.1136/bjsports-2014-094306. 8. Kelly P, Kahlmeier S, Götschi T, et al. Systematic review and meta-analysis of reduction in all-cause mortality fro m walking and cycling and shape of dose response relationship. Int J Behav Nutr Phys Act . 2014;11:132. doi:10.1186/s12966-014-0132- x. 9. Löllgen H, Böckenhoff A, Knapp G. Physical activity and all-cause mortality: an updated meta-analysis with different intensity categories. Int J Sports Med . 2009;30(3):213-224. doi:10.1055/s-0028-1128150. . Samitz G, Egger M, Zwahlen M. Domains of physical activity and all-cause mortality: systematic 10 . 2011;40(5):1382-1400. review and dose-response meta-analysis of cohort studies. Int J Epidemiol doi:10.1093/ije/dyr112. 11. Woodcock J, Franco OH, Orsini N, Robert I. Non-vigorous physical activity and all-cause mortality: . 2011;40(1):121-138. systematic review and meta-analysis of cohort studies. Int J Epidemiol doi:10.109 3/ije/dyq104. 12 . Arem H, Moore SC, Patel A, et al. Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA Intern Med . 2015;175(6):959-967. 1/jamainternmed.2015.0533. doi:10.100 13. Moore SC, Patel AV, Matthews CE. Leisure time physical activity of moderate to vigorous intensity and mortality: a large pooled cohort analysis. PLoS Med . 2012;9(11):e1001335. doi:10.1371/journal.pmed.1001335. -24 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

376 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease 14. O’Donovan G, Lee IM, Hamer M, Stamatakis E. Association of “weekend warrior” and other leisure time physical activity patterns with risks for all-cause, cardiovascular disease, and cancer mortality. JAMA Intern Med . 2017;177(3):335-342. doi:10.1001/jamainternmed.2016.8014. 15. Merom D, Ding D, Stamatakis E. Dancing participation and cardiovascular disease mortality: a pooled analysis of 11 population-based British cohorts. Am J Prev Med . 2016;50(6):756-760. doi:10.1016/j.amepre.2016.01.004. 16. e Paffenbarger RS Jr, Wing AL, Hyde RT. Physical activity as an index of heart attack risk in colleg alumni. Am J Epidemiol . 1978;108(3):161-175. 17. Paffenbarger RS Jr, Hyde RT, Wing AL, Hsieh CC. Physical activity, all-cause mortality, and longevity of N Engl J Med . 1986;314(10):605-613. college alumni. 18. Wahid A, Manek N, Nichols M, et al. Quantifying the association between physical activity and cardiovascular disease and diabetes: a systematic review and meta-analysis. J Am Heart Assoc . 2016;5(9):e002495. doi:10.1161/JAHA.115.002495. Diep L, Kwagyan J, Kurantsin-Mills J, Weir R, Jayam-Trouth A. Association of physical activity level 19. . J Womens Health (Larchmt) and stroke outcomes in men and women: a meta-analysis. 2010;19(10):1815-1822. doi:10.1089/jwh.2009.1708. . Echouffo-Tcheugui JB, Butler J, Yancy CW, Fonarow GC. Association of physical activity or fitness with 20 Circ Heart Fail . 2015;8(5):853-861. ystematic review and meta-analysis. incident heart failure: a s doi:10.1161/CIRCHEARTFAILURE.115.002070. 21. Kyu HH, Bachman VF, Alexander LT, et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ . 2016;354:i3857. doi:10.1136/bmj.i3857. 22. Pandey A, Garg S, Khunger M, et al. Dose-response relationship between physical activity and risk of . 2015;132(19):1786-1794. heart failure: a meta-analysis. Circulation doi:10.1161/CIRCULATIONAHA.115.015853. 23 . Sattelmair J, Pertman J, Ding EL, Kohl HW, Haskell W, Lee IM. Dose response between physical . 2011;124(7):789-795. Circulation activity and risk of coronary heart disease: a meta-analysis. doi:10.1161/CIRCULATIONAHA.110.010710. 24 . Sofi F, Capalbo A, Cesari F, Abbate R, Gensini GF. Physical activity during leisure time and primary prevention of coronary heart disease: an updated meta-analysis of cohort studies. Eur J Cardiovasc Prev Rehabil . 2008;15(3):247-257. doi:10.1097/HJR.0b013e3282f232ac. 25 . Zheng G, Huang M, Liu F, Li S, Tao J, Chen L. Tai chi chuan for the primary prevention of stroke in . middle-aged and elderly adults: a systematic review. Evid Based Complement Alternat Med 2015;2015:742152. doi:10.1155/2015/742152. 26 . Zheng H, Orsini N, Amin J, Wolk A, Nguyen VT, Ehrlich F. Quantifying the dose-response of walking in Eur J Epidemiol reducing coronary heart disease risk: meta-analysis. . 2009;24(4):181-192. 9. doi:10.1007/s10654-009-9328- -25 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

377 Part F . Chapter 6. All-cause Mortality, Cardiovascular Mortality, and Incident Cardiovascular Disease 27 . Bennett DA, Du H, Clarke R, et al. China Kadoorie Biobank Study Collaborative Group. Association of . JAMA Cardiol physical activ ity with risk of major cardiovascular diseases in Chinese men and women. 2017;2(12):1349-1358. doi:10.1001/jamacardio.2017.4069. 28 . Buchner DM, Rillamas-Sun E, Di C, et al. Accelerometer-measured moderate to vigorous physical activity and incidence rates of falls in older women. J Am Geriatr Soc . 2017;65(11):2480-2487. doi:10.1111/jgs.14960. 29. to-vigorous physical LaMonte MJ, Lewis CE, Buchner DM, et al. Both light intensity and moderate- activity measured by accelerometry are favorably associated with cardiometabolic risk factors in older women: the Objective Physical Activity and Cardiovascular Health (OPACH) Study. . J Am Heart Assoc 2017;6(10). pii:e007064. doi:10.1161/JAHA.117.007064. 30. LaMonte MJ, Buchner DM, Rillamas-Sun E, et al. Accelerometer-measured physical activity and mortality in women aged 63 to 99. J Am Geriatr Soc . November 2017. doi:10.1111/jgs.15201. Lee IM, Shiroma EJ, Evenson KR, Kamada M, LaCroix AZ, Buring JE. Accelerometer-measured physical 31. activity and sedentary behavior in relation to all-cause mortality: the Women's Health Study. . Circulation November 2017. pii:CIRCULATIONAHA.117.031300. doi:10.1161/CIRCULATIONAHA.117.031300. Merghani A, Maestrini V, Rosmini S, et al. Prevalence of subclinical coronary artery disease in 32. . 2017;136(2):126-137. masters endurance athletes with a low atherosclerotic risk profile. Circulation doi:10.1161/CIRCULATIONAHA.116.026964. . Aengevaeren VL, Mosterd A, Braber TL, et al. Relationship between lifelong exercise volume and 33 coronary atherosclerosis in athletes. . 2017;136(2):138-148. Circulation doi:10.1161/CIRCULATIONAHA.117.027834. -26 2018 Physical Activity Guidelines Advisory Committee Scientific Report F6

378 Physical Activity Considerations for Selected Populations • Part F. Chapter 7. Youth • Part F. Chapter 8. Women Who are Pregnant or Postpartum • Part F. Chapter 9. Older Adults • Part F. Chapter 10. Individuals with Chronic Conditions

379 Part F. Chapter 7. Youth PART F. CHAPTER 7. YOUTH Table of Contents ... F7-1 Introduction Review of the Science ... F7-2 Overview of Questions Addressed ... F7-2 Data Sources and Process Used to Answer Questions ... F7-2 ... Question 1. In children younger than age 6 years, is physical activity related to health outcomes? . F7-3 Question 2. In children and adolescents, is physical activity related to health outcomes? ... F7-6 Question 3: In children and adolescents, is sedentary behavior related to health outcomes? ... F7-14 F7-18 ... ... Needs for Future Research ... F7-21 References ... INTR ODUCT ION included a physical activity recommendation for Physical Activity Guidelines for Americans The 2008 1 That guideline was based on the conclusion in the Physical children and adolescents, ages 6 to 17 years. that strong evidence demonstrated that, in Activity Guidelines Advisory Committee Report, 2008 children and adolescents, higher levels of physical activity are associated with multiple beneficial health outcomes, including cardiorespiratory and muscular fitness, bone health, and maintenance of healthy 2 weight status. The 2018 Physical Activity Guidelines Advisory Committee, in establishing the parameters of its work, opted to examine new evidence addressing the relationships between physical activity and health outcomes in school-aged youth Subcommittee considered two issues . In addition, the that were not examined by the 2008 Committee: 1) the association between physical activity and health outcomes in children younger than age 6 years, and 2) the association between sedentary behavior and health outcomes in children and adolescents. F7-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

380 Part F. Chapter 7. Youth REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses three major questions and related subquestions : 1. In children younger than age 6 years, is physical activity related to health outcomes? a) What is the relationship between physical activity and adiposity or weight status? b) What is the relationship between physical activity and bone health? What is the relationship between physical activity and cardiometabolic health? c) d) Are there dose-response relationships? If so, what are the shapes of those relationships? e) Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? 2. In children and adolescents, is physical activity related to health outcomes? a) What is the relationship between physical activity and cardiorespiratory and muscular fitness? b) What is the relationship between physical activity and adiposity or weight status? Does physical activity prevent or reduce the risk of excessive increases in adiposity or weig ht status? What is the relationship between physical activity and cardiometabolic health? c) d) What is the relationship between physical activity and bone health? Are there dose-response relationships? If so, what are the shapes of those relationships? e) f) Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? 3. In children and adolescents, is sedentary behavior related to health outcomes? a) What is the relationship between sedentary behavior and cardiometabolic health? What is the relationship between sedentary behavior and adiposity or weight status? b) c) What is the relationship between sedentary behavior and bone health? Are there dose-response relationships? If so, what are the shapes of those relationships? d) e) Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? Data Sources and Process Used to Answer Questions In considering the evidence linking physical activity to health outcomes in school-aged youth, the Subcommittee based its review on systematic reviews and meta-analyses that had examined longitudinal studies of the relationships between physical activity and the following health outcomes: cardiorespiratory and muscular fitness, adiposity or weight status, bone health, and cardiometabolic health . In most cases, the systematic reviews and meta-analyses included primary research articles . Many of those studies had employed objective, device-based measures of physical published since 2006 . activity In the past decade, a substantial volume of research has examined physical activity and its relationship . Accordingly, the Subcommittee opted to examine to health factors in children younger than age 6 years this relationship initially including only systematic reviews and meta-analyses. However, the reviews F7-2 2018 Physical Activity Guidelines Advisory Committee Scientific Report

381 Part F. Chapter 7. Youth provided insufficient information, so the Subcommittee conducted a de novo search of the primary research literature . Only studies using longitudinal designs were included, and the following three indicators of he alth were considered: adiposity or weight status, bone health, and cardiometabolic health . Almost all of the relevant studies focused on children ages 3 to 5 years. In addition, over the past decade researchers and professionals in multiple fields have expressed . concern regarding the potential impact of high levels of sedentary behavior on children’s health Accordingly, the Subcommittee opted to examine the evidence regarding the relationship between sedentary behavior and selected health outcomes . That examination relied on systematic reviews and meta-analyses, several of which have summarized studies with longitudinal designs . For bone health, the review of evidence focused on the primary research literature. Question 1. In children younger than age 6 years, is physical activity related to health outcomes? What is the relationship between physical activity and adiposity or weight status? a) b) What is the relationship between physical activity and bone health? What is the relationship between physical activity and cardiometabolic health? c) Are there dose-response relation d) ships? If so, what are the shapes of those relationships? e) Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? Original research studies Source of evidence: Conclusion Statements Strong evidence demonstrates that higher amounts of physical activity are associated with more favorable indicators of bone health and with reduced risk for excessive increases in body weight and adiposity in children ages 3 to 6 years. PAGAC Grade: Strong. Subquestions Strong evidence demonstrates that higher amounts of physical activity are associated with a reduced risk of excessive increases in body weight and adiposity in children ages 3 to 6 years. PAGAC Grade: Strong. Strong evidence demonstrates that higher amounts of physical activity are associated with favorable PAGAC Grade: Strong. indicators of bone health in children ages 3 to 6 years. Insufficient evidence is available to determine the effects of physical activity on cardiometabolic risk factors in children under 6 years of age. PAGAC Grade: Not assignable. F7-3 2018 Physical Activity Guidelines Advisory Committee Scientific Report

382 Part F. Chapter 7. Youth Insufficient evidence is available to determine the dose-response relationship between physical activity and health effects in children younger than 6 years of age. PAGAC Grade: Not assignable. insufficient evidence is available to determine whether the relationship between physical activity and health effects in children younger than 6 years of age is moderated by age, sex, race/ethnicity, weight status, or socioeconomic status. PAGAC Grade: Not assignable. Review of the Evidence Evidence on the Overall Relationship The conclusion that higher amounts of physical activity are associated with beneficial health outcomes in children younger than 6 years of age was based on the conclusions for two subquestions . Specifically, it was concluded that strong evidence demonstrated that higher amounts of physical activity are associated with favorable indicators of bone health and reduced risk of excessive increases in body weight and adiposity in children ages 3 to 6 years. The evidence supporting these conclusions is summarized below . Evidence on Specific Factors The conclusion that higher levels of physical activity are associated with : adiposity Body weight and reduced risk for excessive increases in body weight and adiposity was based primarily on the findings of 3- 16 14 studies. All these studies used prospective observational study designs, and they employed device- . Twelve of the based measures of physical activity 14 studies found negative associations between 3- 10, 12- 15 physical activity and weight and/or adiposity measured at follow- up. Although the evidence indicated a benefit of greater amounts of physical activity, it was not sufficient to identify a particular dose of physical activity that was needed to provide benefits . Bone health : The Subcommittee’s conclusion regarding the positive effects of physical activity on measures of bone health in children younger than age 6 years was supported by the findings of 10 17- 26 research articles based on four separate studies. These included a mix of randomized controlled of-the-art bone imaging trials and prospective observational studies . All the studies used state- . Several types of physical activity were found to be associated with bone health, including procedures gymnastics and other bone-strengthening activities, such as jumping and hopping. Total physical activity . as assessed by accelerometry also was found to be positively associated with measures of bone health F7-4 2018 Physical Activity Guidelines Advisory Committee Scientific Report

383 Part F. Chapter 7. Youth The evidence was not sufficient to identify a particular dose of physical activity that was needed to produce benefits, however . Very few studies have examined the relationship between physical activity and Cardiometabolic health: 9, 27, 28 indicators of cardiometabolic health in children younger than age 6 years. Accordingly, this subquestion was graded as Not Assignable . Dose-response Few studies of physical activity and health in children younger than age 6 years have : been designed in a manner that allows examination of dose-response relationships . Therefore, this subquestion was graded as Not Assignable . Demographic factors and weight status : The studies on physical activity and health in children younger than age 6 years have rarely been designed in a manner that provided for examination of the potential modifying effects of demographic characteristics, such as sex, age, race/ethnicity, weight status, and . . Accordingly, this subquestion was graded as Not Assignable socioeconomic status For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- edition/report/supplementary-material.aspx for the Evidence Portfolio. Comparing 2018 Findings with the 2008 Scientific Report The 2008 Scientific Report included the overall conclusion that “physical activity provides important 2 The scientific literature that was cited as supporting that health benefits for children and adolescents”. conclusion was limited to studies on children ages 5 to 19 years . This age range was selected because . However, the scientific literature at that time included few studies on children younger than age 6 years in the intervening decade, a substantial amount of research has focused on physical activity and its relationship with health in children younger than 6 years, particularly those ages 3 to 5 year s. Accordingly, this literature was systematically reviewed, and it supports the conclusions presented above . These conclusions, by focusing on the early childhood developmental period, extend the scope of the 2018 Committee’s work to an age range younger than that addressed by the 2008 Scientific Report. Public Health Impact Approximately 13 million children, representing more than 4 percent of the U.S. population, are younger The evidence summarized above demonstrates that higher amounts of physical than age 6 years. . It is noteworthy that the beneficial activity are associated with better health indicators in this age group effects were documented for adiposity and bone health, two health characteristics that are known to F7-5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

384 Part F. Chapter 7. Youth 29, 30 enabling and encouraging young children to be track into later life. Accordingly, efforts aimed at more physically active, especially activities facilitating bone health and avoidance of excessive weight gain, would be expected to have a positive impact on the future health of the nation. As noted above, the existing literature demonstrates that higher doses of physical activity, as compared with lower doses, provide important health benefits in children ages 3 to 5 years. However, that literature does not provide extensive information on dose-response relationships, nor does it suggest a dose range that . In lieu of more direct evidence on dose-response would serve as a suitable public health target relationships, the Subcommittee concluded that important public health benefits would result if children, who fall below the median level for device-based measured total physical activity, increased their activity to at least that median . Descriptive epidemiologic studies, using device-based measures of physical activity, have observed that the median time spent in light-, moderate-, or vigorous-intensity 31 physical activity approximates three hours per day in children ages three to five years. Further, because bone-strengthening and muscle-strengthening activities provide important benefits to bone health, the Subcommittee concludes that these young children would benefit from regular participation in activities like gymnastics that involve jumping, leaping, and landing . Question 2. In children and adolescents, is physical activity related to health outcomes? a) What is the relationship between physical activity and cardiorespiratory and muscular fitness? b) What is the relationship between physical activity and adiposity or weight status? Does physical activity prevent or reduce the risk of excessive increases in adiposity or weight? What is the relationship between physical activity and cardiometabolic health? c) What is the relationship between physical acti vity and bone health? d) e) Are there dose-response relationships? If so, what are the shapes of those relationships? f) Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? Sources of evidence: Systematic reviews, meta-analyses Conclusion Statements Strong evidence demonstrates that, in children and adolescents, higher amounts of physical activity are associated with more favorable status for multiple health indicators, including cardiorespiratory and muscular fitness, bone health, and weight status or adiposity. PAGAC Grade: Strong. Moderate evidence indicates that physical activity is positively associated with cardiometabolic health in Moderate. PAGAC Grade: children and adolescents. F7-6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

385 Part F. Chapter 7. Youth Subquestions Strong evidence demonstrates that increased moderate- to-vigorous physical activity increases cardiorespiratory fitness and that increased resistance exercise increases muscular fitness in children and adolescents. PAGAC Grade: Strong. Strong evidence demonstrates that higher levels of physical activity are associated with smaller PAGAC Grade: Strong. increases in weight and adiposity during childhood and adolescence. Moderate evidence indicates that physical activity is positively associated with cardiometabolic health in PAGAC children and adolescents in general; the evidence is strong for plasma triglycerides and insulin. Grade: Moderate. Strong evidence demonstrates that children and youth who are more physically active than their peers have higher bone mass, improved bone structure, and greater bone strength. PAGAC Grade: Strong . Insufficient evidence is available to determine the do se-response relationship between physical activity and health effects during childhood and adolescence. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between physical activity and health effects in youth is moderated by age, sex, race/ethnicity, weight status or socioeconomic status. PAGAC Grade: Not assignable. Review of the Evidence The conclusion that higher amounts of physical activity are associated with beneficial health outcomes in youth was based on the conclusions for four subquestions. Specifically, the Subcommittee concluded that strong evidence demonstrates that higher amounts of physical activity are associated with increased cardiorespiratory and muscular fitness, smaller age-related increases in body weight and adiposity, and higher bone mass, improved bone structure, and greater bone strength. Moderate evidence indicated that physical activity is positively associated with indicators of cardiometabolic health. The evidence supporting these conclusions is summarized below. It is important to note that, in most cases, the evidence available to address this question was based on a review of research on rs, when children ages 6 years and above. However, relevant research on children younger than 6 yea available, was also considered. F7-7 2018 Physical Activity Guidelines Advisory Committee Scientific Report

386 Part F. Chapter 7. Youth Cardiorespiratory and Muscular Fitness 32- 37 38-46 Six meta-analyses, and nine systematic rev iews were identified that examined the association 40, 45 between physical activity and cardiorespiratory fitness. Two reviews included muscular fitness outcomes. Overall, the reviews included publications from inception of the database through 2016. Reviews were focused on the impact of a variety of physical activity intervention or program types on 41- 43 32 cardiorespiratory fitness outcomes, including afterschool programs, school-based interventions, 38, 44, 46 33- 37, 40, 45 39 exercise training or aerobic exercise programs, xergaming active transportation, ; and e 37, 40 included interventions from any setting. Reviews focused on interventions among two reviews children and adolescents ages 2 to 18 years; most studies focused on children and adolescents between the ages of 6 and 18 years. Evidence on the Overall Relationship All identified reviews concluded that physical activity positively affects measures of cardiorespiratory fitness. The strongest evidence for the impact of physical activity on cardiorespiratory fitness was for organized group-based programs that included specific exercise prescriptions among youth. A meta- analysis of afterschool interventions that included a component designed to promote physical activity identified a pooled effect size from six relevant studies of 0.16 (range -0.23 to 0.86; 95% confidence 32 Systematic reviews did not provide effect sizes but were consistent with interval ( CI): 0.01-0.30). 41- 43 Organized exercise findings that school-based interventions were effective for increasing fitness. training programs were more effective for improving fitness levels than were general physical activity 33 Supervised exercise training programs; effect size 4.19 (95% CI: 3.68-4.70) vs. 3.34 (95% CI: 2.08-4.60). 34- 36 max. studies yielded 7 percent to 8 percent increases in VO 2 A single review identified associations between active transportation and health outcomes across 68 39 studies, 10 of which included fitness outcomes. Active transportation through cycling was clearly linked with improvements in cardiorespiratory fitness. The association between walking and fitness was less apparent, perhaps because of the lower intensity level of walking compared with cycling. 38, 44, 46 Findings were mixed, with Three reviews evaluated the impact o f exergaming on fitness levels. about half of included studies finding a positive impact of exergaming on some measure of fitness and the other half finding non-significant or null effects; no studies identified a negative impact of exergaming on fitness. Importantly, exergaming appears to be a feasible and acceptable strategy for F7-8 2018 Physical Activity Guidelines Advisory Committee Scientific Report

387 Part F. Chapter 7. Youth increasing light-intensity physical activity. Exergaming also appears to be feasible for increasing participation in physical activity at the lower limit of the moderate-intensity range. However, the included reviews did not provide sufficient evidence that the level of energy expended during exergaming is sufficient for increasing measures of cardiorespiratory fitness. Two systematic reviews specifically looked at musculoskeletal fitness, both of which generally concluded 40, 45 that studies including a muscle strengthening component had a positive impact on muscular fitness. Although effect sizes were not provided within the systematic reviews, results of positive outcomes for muscle-strengthening activity on at least one measure of muscular fitness were consistent. All identified reviews concluded that physical activity positively affected at least one measure of cardiorespiratory fitness. Organized group-based programs were typically implemented on 3 or more max or heart rate (HR) max. The days per week for 30 to 60 minutes, at 50 percent to 90 percent VO 2 evidence for the impact of active transportation and exergaming is less clear. Two identified reviews concluded that two or more sessions of muscle-strengthening activity weekly was effective for improving measures of muscular fitness. Specific detail on session duration, intensity, and types of exercise was not readily apparent in the information provided. Dose-response: The studies reviewed were not able to establish dose-response relationships for these modes of exercise and physical activity. Evidence on Specific Factors Demographic factors and weight status: The reviews typically focused solely on the impact of physical activity on cardiorespiratory fitness and did not specifically explore subgroup analyses or effect modifiers. Several of the studies included in the reviews focused on children with overweight or obesity. These studies generally concluded that physical activity positively affects cardiorespiratory and muscular fitness outcomes, regardless of weight status. The reviews did not provide comparisons between children with normal weight and those with overweight or obesity. Cardiometabolic Health 47 33- 36, 48-51 Nine articles including one systematic review were identified that and eight meta-analyses examined the association between physical activity and cardiometabolic health in children and adolescents. Three of the meta-analyses were exclusively concerned with the effects of physical activity 36, 49, 50 among children and adolescents with overweight or obesity. F7-9 2018 Physical Activity Guidelines Advisory Committee Scientific Report

388 Part F. Chapter 7. Youth Five out of five meta-analyses that analyzed the association between physical activity and plasma 33 , 33, 34, 36, 48, 49 33, 36, 51 alyses triglycerides reported a significant, beneficial effect. Three out of four meta-an 36, 48, 51 that analyzed the association between physical activity and plasma insulin reported a significant, beneficial effect. The results for high density lipoprotein (HDL)-cholesterol and blood pressure were not 33, 48, 49 33- 36, 48, out of six as strong, but were suggestive of a potential benefit from physical activity. Three 48, 50 49 meta-analyses reported a significant, beneficial effect of physical activity on HDL-cholesterol, two 36, 48, 50 50 out of three meta-analyses reported a significant benefit for systolic blood pressure, while one 36, 48, 50 out of three meta-analyses reported a significant benefit for diastolic blood pressure. Dose-response: Although the individual studies reviewed in the meta-analyses varied with respect to intervention duration and exercise intensity, they provided insufficient evidence to make any conclusions about dose-response associations. In general, most studies on the effects of physical activity on cardiometabolic risk factors in children were not designed to test a specific risk factor. Rather, specific risk factors were measured as one of the outcomes among many others. Thus, the children may not have had elevated levels of each risk factor at baseline, making it difficult to determine the true effects of physical activity among high-risk children (e.g., those with high blood pressure, insulin resistance) . De mographic factors and weight status: Given that only systematic reviews and meta-analyses were included in this review, limited information is available on the effects of age, sex race/ethnicity, or socioeconomic status on the association between physical activity and cardiometabolic risk factors in in children with overweight and obesity were children. Two meta-analyses reported that the effects 34 greater than in normal weight children for reductions in triglycerides and markers of insulin 51 resistance. Body Weight and/or Adiposity The Subcommittee identified a substantial number of systematic reviews and meta-analyses summarizing the scientific literature on the relationship between physical activity and weight status and/or adiposity. However, most of those articles focused on studies in which multiple exposures, often both physical activity and diet, were considered in ways that did not allow determining the independent association of physical activity with weight-related outcomes. Ten articles did focus on studies that considered the independent association of physical activity with weight-related outcomes, and these 35, 48 , 57- 59 52- 56 and meta-analyses included systematic reviews examin ing studies with both experimental F7-10 2018 Physical Activity Guidelines Advisory Committee Scientific Report

389 Part F. Chapter 7. Youth and prospective, observational study designs. When the conclusions of those articles were considered, the collective findings were deemed to be inconsistent and the evidence linking physical activity to better weight status and/or adiposity was considered to be of moderate strength. However, the consideration of evidence progressed to a third stage that involved considering only the five reviews 53- 56, 59 that focused on studies using prospective, observational study designs. The decision to focus on those reviews was based on the belief that prospective, observational study designs are particularly appropriate for an outcome such as adiposity. Observation of differential effects of physical activity doses (e.g., higher vs. lower) may require exposure for periods that are practical in observational studies bu t longer than feasible in experimental trials. When that subset of five reviews was considered, consistent evidence of an inverse association between physical activity and indicators of weight status and/or adiposity was found. The aforementioned five reviews, while concluding that higher amounts of physical Dose-response: activity provided beneficial body weight and adiposity outcomes, did not describe dose-response 53- 55, 59 One review concluded that higher intensity physical activity provided greater benefit relationships. 54 than less intense physical activity. Demographic factors and weight status: The five systematic reviews focusing on prospective observational studies gave limited attention to demographic effect modifiers. One review concluded 54 that the protective effect of physical activity on weight-related outcomes was evident in both sexes. 55, 56 as well as This protective effect was reported in reviews focusing on both children of preschool age 53, 54 older children and adolescents. Bone Health 41, 63- 66 48, 57, 60-62 The Subcommittee identified five meta-analyses Reviews and five systematic reviews. included all publications through 2016 and focused on studies among children and adolescents ages 3 to 18 years; most studies focused on children and adolescents ages 8 to 15 years, i.e., the peri-pubertal years. Intervention studies were primarily school-based. The volume of the exercise within interventions varied among the studies. However, almost all interventions included high-impact, dynamic, short duration exercise, such as hopping, skipping, jumping, and tumbling. Only two reviews considered 65, 66 observational studies. Results from the observational studies were consistent with results from the intervention studies. All reviews (systematic and meta-analyses) concluded that in youth, physical activity is positively associated with bone mass accrual and/or bone structure. F7-11 2018 Physical Activity Guidelines Advisory Committee Scientific Report

390 Part F. Chapter 7. Youth The greatest amount of evidence for the effect of physical activity on bone strength was for bone mass 60 Specker et al outcomes. In their meta-analysis, examined 22 trials (15 were randomized) and noted that the difference in annual increase in bone mass between intervention and control groups was 0.8 percent (95% CI: 0.3-1.3) for total body; 1.5 percent (95% CI: 0.5-2.5) for femoral neck; and 1.7 percent 66 (95% CI: 0.4-3.1) for spine. identified 38 reports of randomized controlled trials or clinical Weaver et al trials where exercise was used as an intervention to increase bone mass outcomes. Thirty of these reports (84%) reported statistically significant differences between exercise and control groups, ranging from approximately 1 percent to 6 percent over 6 months for total body, femoral neck, and spine. 66 Nineteen prospective longitudinal reports were also examined in the Weaver et al review. Of these, 17 reports (89%) indicated that the most active youth had significantly more bone mass when compared to less active peers. In addition to its association with bone mass, physical activity is associated with bone structure. This is important because the skeleton needs to be strong to bear loads, but at the same time light for energy- 66 65 included specific critiques and efficient movement. Of the systematic reviews, Tan et al Weaver et al 65 of studies addressing bone structure. In Tan et al, 14 intervention studies and 23 observational studies (cross-sectional and longitudinal) were examined. Studies with strong design scores showed the greatest effect in structural outcomes between intervention and control groups (3% to 4% difference). None of 66 the studies showed negative associations between physical activity and bone structure. Weaver et al examined 18 reports and noted that 8 showed positive, significant effects of exercise on bone structure outcomes. However, of the 10 reports that indicated no significant differences between exercise and control groups, 6 reports were from the same study, which did not intervene with high-impact, dynamic, 66 short duration exercise. Weaver et al also identified eight prospective observational studies; all eight studies found significant differences in bone structure favoring the most active cohort members when compared to the least active. Dose-response: Almost exclusively, intervention studies that reported positive outcomes used targeted, high-impact exercise with ground reaction forces at least three times body weight for approximately 6 months. Examples of physical activities that typically include this magnitude of ground reaction forces include volleyball, basketball, martial arts, and gymnastics. The duration and frequency of the 65, 66 interventions varied greatly, ranging from 2 to 12 sessions per week and 1 to 60 minutes per session. However, the reviewed trials were not designed to examine dose-response and no trial included multiple arms of exercise using different loading conditions. Therefore, dose-response is not F7-12 2018 Physical Activity Guidelines Advisory Committee Scientific Report

391 Part F. Chapter 7. Youth conclusively known. Limited evidence supports the osteogenic effect of resistance training and other 66 muscle-strengthening physical activity. However, dose-response information is not available. Demographic factors and weight status: The effect of physical activity on bone strength appears greatest around puberty, indicating that maturity is an effect modifier. However, very few studies focused on post-pubertal youth or pre-school children. Males and females benefit similarly from physical activity (though bone structural changes may be different between males and females). Recent reports suggest that when compared to peers of the same body weight and sex, youth with obesity have 66 weaker bones, indicating that weight status may be an effect modifier. Few studies have included children from diverse racial/ethnic groups or addressed socioeconomic status, so their effect on modifying the relationship between physical activity and bone strength is not known. For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx Comparing 2018 Findings with the 2008 Scientific Report The findings and conclusions of this report regarding the associations between physical activity and 2 health in youth are consistent with the findings reported in the 2008 Scientific Report. However, the scientific evidence supporting the conclusions in this report is substantially more robust than was the case in 2008. The evidence has been strengthened by marked increases in the quantity and quality of research on physical activity and two key health indicators, weight status and/or adiposity and bone health. Further, the evidence has been strengthened by the publication of numerous systematic reviews and meta-analyses on topics related to the impact of physical activity on health outcomes in children and adolescents. 2 The 2008 Scientific Report informed a recommendation that was included in the 2008 Physical Activity Guidelines for Americans. That recommendation called for children and adolescents ages 6 to 17 to do 60 minutes or more of moderate- to-vigorous physical activity per day. It was further recommended that, within the 60 minutes of daily physical activity, children and adolescents should engage in muscle- strengthening, bone-strengthening, and vigorous intensity physical activities at least three days per 1 As noted above, the Subcommittee’s conclusions are consistent with the conclusions of the 2008 week. Scientific Report. Accordingly, these conclusions and the evidence summaries supporting the conclusions are consistent with the physical activity recommendation for children and adolescents as included in 2008 Physical Activity Guidelines for Americans. F7-13 2018 Physical Activity Guidelines Advisory Committee Scientific Report

392 Part F. Chapter 7. Youth Public Health Impact A substantial percentage of U.S. children and youth do not meet the current federal physical activity 67 guideline. That guideline calls for daily participation in 60 or more minutes of moderate- to-vigorous physical activity as well as regular engagement in vigorous physical activity, muscle-strengthening exercise, and bone-strengthening activities. The conclusion that strong evidence demonstrates that higher amounts of physical activity are associated with better status on multiple health indicators during childhood and adolescence points to the important public health benefits that would be associated with increasing the percentage of young persons in the United States who meet physical activity guidelines. The evidence is strong that these health benefits would accrue to children and adolescents during their developmental years. Further, current evidence suggests that it is likely that many of those health benefits would carry forward into adulthood. Question 3: In children and adolescents, is sedentary behavior related to health outcomes? What is the relationship between sedentary behavior and cardiometabolic health? a) b) What is the relationship between sedentary behavior and adiposity or weight status? What is the relationship between sedentary behavior and bone health? c) d) Are there dose-response relatio nships? If so, what are the shapes of those relationships? Do the relationships vary by age, sex, race/ethnicity, weight status, or socioeconomic status? e) Sources of evidence: Systematic reviews, meta-analyses, original research articles Conclusion Statements Limited evidence suggests that greater time spent in sedentary behavior is related to poorer health outcomes in children and adolescents. PAGAC Grade: Limited. Subquestio ns Limited evidence suggests that greater time spent in sedentary behavior is related to poorer cardiometabolic health; the evidence is somewhat stronger for television viewing or screen time than for total sedentary time. PAGAC Grade: Limited. Limited evidence suggests that greater time spent in sedentary behavior is related to higher weight status or adiposity in children and adolescents; the evidence is somewhat stronger for television viewing PAGAC Grade: Limited. or screen time than for total sedentary time. F7-14 2018 Physical Activity Guidelines Advisory Committee Scientific Report

393 Part F. Chapter 7. Youth Limited evidence suggests that sedentary behavior is not related to bone health in children and adolescents. PAGAC Grade: Limited. Insufficient evidence is available to determine whether a dose-response relationship exists between greater time spent in sedentary behavior and poorer health outcomes in children and adolescents. PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether the relationship between sedentary behavior and health outcomes in youth is moderated by age, sex, race/ethnicity, or socioeconomic status. PAGAC Grade: Not assignable. Review of the Evidence Evidence Related to the Overall Question The conclusion that there is limited evidence that greater time spent in sedentary behavior is related t o poorer health outcomes in children and adolescents was based on the conclusions for three subquestions. Specifically, it was concluded that limited evidence demonstrated that greater time spent in sedentary behavior is associated with lower cardiometabolic health and less favorable weight status or adiposity, and limited evidence of no relationship between sedentary behavior and bone health. The evidence supporting these conclusions is summarized below. For Question 3, the Subcommittee relied on systematic reviews and meta-analyses, while a search was conducted for original research articles to address bone health. Evidence Related to Specific Factors Cardiometabolic risk factors: The Subcommittee obtained evidence on the relationship between sedentary time and cardiometabolic risk factors from systematic reviews and meta-analyses. The literature search identified 12 systematic reviews and meta-analyses that potentially addressed this 68- 71 question. After review of these articles, it was determined that four articles were best suited to 68 found insufficient evidence for a Chinapaw et answer the question. The systematic review by al longitudinal association between sedentary behavior and blood pressure or blood lipids in children and 69 adolescents. Tremblay et al reported that increased screen time was related to increased risk factors in children and adolescents. However, this conclusion was based on nine cross-sectional studies and only 70 69 Carson et al Tremblay et al, two longitudinal studies. Likewise, in an update of the evidence from reported that results varied across different risk factors, but TV or screen time was more closely related to risk factors than accelerometer-derived estimates of sedentary behavior. This conclusion was based F7-15 2018 Physical Activity Guidelines Advisory Committee Scientific Report

394 Part F. Chapter 7. Youth 71 on 25 cross-sectional studies and 6 longitudinal studies. Finally, Cliff et al reported that 8 out of 28 studies found a significant association between sedentary behavior and cardiometabolic outcomes in children and adolescents. In general, the limited evidence from longitudinal studies suggests a positive association between sedentary time and cardiometabolic risk factors in children and adolescents, with . somewhat stronger results for TV viewing or screen time as the exposure Weight Status or adiposity: Evidence on the relationship between sedentary time and weight status or adiposity was obtained from systematic reviews and meta-analyses. The literature search identified 12 systematic reviews and meta-analyses that potentially addressed this question. After review of these 53, 68-74 articles by two members of the Subcommittee, it was determined that eight articles were best suited to answer the question. 70 which In the most comprehensive review of sedentary behavior and adiposity published to date, included 162 studies (125 cross-sectional, 32 longitudinal, 5 case-control) the authors reported that TV or screen time and adiposity, but device-based there was a positive longitudinal association between measurements of sedentary time were not associated with adiposity. These results are supported by other systematic reviews that generally reported low levels of evidence for longitudinal associations 53, 68, 69, 71, 73 between sedentary behavior and adiposity in children and adolescents. In a systematic 72 review that focused exclusively on the early years (ages 0 to 4 years), three of four studies in toddlers reported a dose-response association between TV viewing and adiposity and two of five studies in 74 preschoolers demonstrated a significant association. Wu et al conducted a systematic review of interventions to reduce screen time, and reported no significant effect of screen time reduction on body . mass index in children, based on evidence from seven studies Bone Health: The Subcommittee obtained evidence on the relationship between sedentary time and bone health from primary research. The literature search identified four prospective observational 75- 78 studies, with sample sizes varying from 169 to 602 and age ranges from 8 to 20 years. All studies 78 used a device-based measure of sedentary time (i.e., accelerometer). Vaitkeviciute et al Ivuškāns and 75 et al used the same cohort of peri-pubescent boys and showed sedentary time was negatively associated with bone outcomes. However, the method used to construct sedentary time from . One accelerometry data likely attributed an unknown proportion of sedentary time as non-wear time 77 study used a temporal substitution statistical model and, surprisingly, reported that bone outcomes improved when levels of high physical activity intensity were held fixed and sedentary time was F7-16 2018 Physical Activity Guidelines Advisory Committee Scientific Report

395 Part F. Chapter 7. Youth 76 statistically exchanged for light-intensity physical activity time . Whereas, Gabel et al reported some negative associations and some positive associations between sedentary time and bone outcomes. Variability in bone outcomes, accelerometry-processing, and statistical approaches may have all contributed to the lack of consensus in results. The literature at this time suggests limited evidence that . there is no relationship between sedentary behavior and bone health : Few studies of sedentary behavior and health outcomes in children and adolescents Dose-Response have been designed in a manner that allows examination of dose-response relationships . Accordingly, this subquestion was graded as Not Assignable . Demographic Effect Modifiers : The studies on sedentary behavior and health outcomes in children and a manner that allowed examination of the potential modifying adolescents have not been designed in effects of demographic characteristics such as sex, age, race/ethnicity, weight status, and socioeconomic status . . Accordingly, this subquestion was graded as Not Assignable For additional details on this body of evidence, visit: https://health.gov/paguidelines/second- for the Evidence Portfolio. edition/report/supplementary-material.aspx Public Health Impact Compelling evidence demonstrates that children and adolescents in the United States spend substantial amounts of time engaged in sedentary behaviors . This evidence comes from surveillance systems using device-based assessment of time spent in sedentary behavior and from surveys documenting time spent in specific behaviors that typically involve little or no physical activity . These behaviors include television viewing and other forms of “screen time,” such as use of cell phones, tablets, and other devices for text messaging, playing video games, and other recreational pursuits . These discretionary sedentary . Analyses of data behaviors are in addition to time spent reading and studying in school and after school from NHANES have shown that U.S. children and adolescents spend 6 to 8 hours per day in sedentary behavior and that the majority spend more than 2 hours per day watching television and/or engaged 79- 81 with other types of screens. This information plus evidence that sedentary behavior causes adverse health outcomes in adults (see Part F. Chapter 2. Sedentary Behaviors for details) raises the concern that this behavior pattern may exert a negative effect on health among youth . Such an outcome could be the result of either direct effects of the sedentary behaviors, displacement of time spent in more physically active behaviors, or 69, 82, 83 both. F7-17 2018 Physical Activity Guidelines Advisory Committee Scientific Report

396 Part F. Chapter 7. Youth As noted above, currently available scientific evidence linking sedentary behavior to health outcomes in young persons is limited. Likewise, the interactive effects of sedentary behavior and physical activity on health in children and adolescents are not well understood . However, as is also noted above, the evidence linking moderate- to-vigorous physical activity to positive health outcomes is strong, and a 67 substantial portion of children and adolescents is insufficiently physically active. Accordingly, replacing some sedentary behavior with moderate- to-vigorous physical activity would improve the health of American youth. NEEDS FOR FUTURE R ESEARCH Conduct randomized controlled trials and prospective observational studies to elucidate the dose- 1. response relationships for physical activity and health outcomes, including adiposity, cardiometabolic health, and bone health in children and adolescents at each developmental stage . Few studies have been designed to directly examine dose-response relationships Rationale: between physical activity and health outcomes in young persons . This gap constitutes a major limitation in the process of identifying the types and amounts of physical activity needed to produce health benefits at each developmental stage. 2. Undertake randomized controlled trials and prospective observational studies to determine whether the health effects of physical activity during childhood and adolescence differ across groups based on sex, age, maturational status, race/ethnicity, and socioeconomic status . Few studies have been designed to directly examine the extent to which the health : Rationale effects of physical activity may differ across demographic subgroups . This gap substantially limits the ability to determine whether the dose of physical activity needed to produce health benefits varies across population sub-groups . Studies aimed at elucidating the extent to which race/ethnicity modifies the effects of physical activity on health outcomes should consider social, cultural, and . biological factors that may influence an effect modifying role of race/ethnicity Conduct experimental and prospective observational studies to examine the health effects of 3. physical activity in children and adolescents with elevated risk status based on adiposity, cardiometabolic health, and bone health. F7-18 2018 Physical Activity Guidelines Advisory Committee Scientific Report

397 Part F. Chapter 7. Youth Rationale : Most children and adolescents fall within the normal, healthy range on key health ind icators, and consequently increased physical activity is unlikely to enhance their already normal status . However, children at elevated risk may manifest improved status with increased physical with activity . A considerable volume of research has been conducted in children and adolescents ity , but more research is needed with young persons who have elevated overweight and obes cardiometabolic and bone health risk . ining and 4. Examine the effects of novel forms of physical activity, including high intensity interval tra exergaming, on health outcomes in youth . Both experimental and prospective observational studies should be conducted. Rationale : Certain forms of physical activity are particularly prevalent among children and adolescents, and more research is ne eded to determine the extent to which these forms of physical . activity affect key health outcomes 5. physical activity and examine the health effects of physical ing Develop valid instruments for measur activity in very young children between birth and 2 yea rs. Rationale : In part because of a lack of validated measures of physical activity in very young children, knowledge of the relationship between physical activity and health outcomes in children between birth and age 2 years is very limited. 6. Undertake stu dies, using longitudinal research designs, to examin e the relationship between specific forms of sedentary behavior (e.g., sitting time, screen time) and health outcomes in children and report and assessment of sede based . ntary behavior adolescents using both self - device - R ationale : Current research on the relationship between sedentary behavior and health is limited by a dearth of studies using Many studies . - measures of time spent in sedentary behavior device based indicator of sedentary behavior, but television viewing is have focused on television viewing as an Research is needed to differentiate between confounded by exposures other than sedentary time . the health effects of time spent sedentary and time spent in specific behaviors that typically include . sedentary time Conduct intervention studies to test the effects of reducing sedentary behavior on health outcomes 7. in children and adolescents. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F7 - 19

398 Part F. Chapter 7. Youth Rationale : Very few studies have examined the health effects associated with reduction of time spent in sedentary behavior among children and adolescents . The findings of such studies would inform the process of identifying the levels of time spent in sedentary behavior that may be associated with negative health outcomes . Further, these studies would determine the extent to to-vigorous which reduction of time spent in sedentary behavior influences time spent in moderate- . and light-intensity physical activity n 8. Examine the interactive effects of sedentary behavior and physical activity of varying intensities o health outcomes in children and youth . Rationale : The relationship between physical activity and health outcomes in children and . That is, youth who adolescents may be modified by amount of time spent in sedentary behavior spend large amounts of time in sedentary behavior may require higher levels of physical activity to . . Studies should be undertaken to directly examine this issue produce a particular health outcome 9. Undertake prospective observational studies to examine the effects of physical activity during . childhood and adolescence on health outcomes later in life Rationale : Large-scale cohort studies that have followed children into adulthood and have used of-the-art measures of physical activity are rare, particularly in the United States . Accordingly, state- knowledge of the long-term impact of physical activity status early in life on health outcomes later in life is very limited. Further, the findings of such studies could inform development of physical activity guidelines for individuals in transitional periods, such as early adulthood. Determine in children and adolescents the impact of genetic profiles on behavioral and physiological 10. responses to physical activity and on the health effects of physical activity. Rationale : Studies in adults have shown that the health effects of physical activity are moderated by genetic profile such that a given dose of physical activity produces widely varying effects on Our knowledge of the relationship between physical activity and health in indicators of health. . Such children and adolescents would be enriched by undertaking similar studies in young persons studies could expand knowledge of how genes and the environment may interact in influencing . indicators of health in young persons F7-20 2018 Physical Activity Guidelines Advisory Committee Scientific Report

399 Part F. Chapter 7. Youth REFERENCES 2008 Physical Activity Guidelines for Americans . 1. U.S. Department of Health and Human Services. Washington, DC: U.S. Department of Health and Human Services; 2008. https://health.gov/paguidelines/guidelines . Accessed December 29, 2017. 2. Physical Activity Guidelines Advisory Committee. Physical Activity Guidelines Advisory Committee Report, 2008 . Washington, DC: U.S. Department of Health and Human Services; 2008. 3. Roberts SB, Savage J, Coward WA, Chew B, Lucas A. Energy expenditure and intake in infants born to lean and overweight mothers. 1988;318(8):461–466. N Engl J Med. 4. Remmers T, Sleddens EF, Gubbels JS, et al. Relationship between physical activity and the development of body mass index in children. Med Sci Sports Exerc. 2014;46(1):177–184. doi:10.1249/MSS.0b013e3182a3670. 5. Moore LL, Nguyen US, Rothman KJ, Cupples LA, Ellison RC. Preschool physical activity level and change in body fatness in young children. The Framingham Children’s Study. Am J Epidemiol. 1995;142(9):982– 988. 6. Li R, O'Connor L, Buckley D, Specker B. Relation of activity levels to body fat in infants 6 to 12 months J Pediatr. of age. 7. 1995;126(3):353–357. doi:10.1016/S0022-3476(95)70447- 7. Janz KF, Kwon S, Letuchy EM, et al. Sustained effect of early physical activity on body fat mass in older Am J Prev Med. 2009;37(1):35–40. doi:10.1016/j.amepre.2009.03.012. children. 8. Jago R, Baranowski T, Baranowski JC, Thompson D, Greaves KA. BMI from 3-6 y of age is predicted by TV viewing and physical activity, not diet. Int J Obes (Lond). 2005;29(6):557–564. 9. DuRant RH, Baranowski T, Rhodes T, et al. Association among serum lipid and lipoprotein concentrations and physical activity, physical fitness, and body composition in young children. J Pediatr. 1993;123(2):185–192. 10. Berkowitz RI, Agras WS, Korner AF, Kraemer HC, Zeanah CH. Physical activity and adiposity: a longitudinal study from birth to childhood. J Pediatr. 1985;106(5):734–738. 11. Wells JC, Stanley M, Laidlaw AS, Day JM, Davies PS. The relationship between components of infant 1996;20(9):848–853. Int J Obes Relat Metab Disord. energy expenditure and childhood body fatness. 12. Klesges RC, Klesges LM, Eck LH, Shelton ML. A longitudinal analysis of accelerated weight gain in 1995;95(1):126–130. preschool children. Pediatrics. 13. Moore LL, Gao D, Bradlee ML, et al. Does early physical activity predict body fat change throughout childhood. Prev Med. 2003;37(1):10–17. 14. Sääkslahti A, Numminen P, Varstala V, et al. Physical activity as a preventive measure for coronary 2004;14(3):143–149. heart disease risk factors in early childhood. Scand J Med Sci Sports. 15. Sugimori H, Yoshida K, Izuno T, et al. Analysis of factors that influence body mass index from ages 3 to 6 years: a study based on the Toyama cohort study. 2004;46(3):302–310. Pediatr Int. F7-21 2018 Physical Activity Guidelines Advisory Committee Scientific Report

400 Part F. Chapter 7. Youth 16. Metcalf BS, Voss LD, Hosking J, Jeffery AN, Wilkin TJ. Physical activity at the government - related health outcomes: a longitudinal study (Early Bird 37). Arch Dis - recommended level and obesity 2008;93(9):772 – 777. doi: 10.1136/adc.2007.135012. Child. Erlandson MC, Kontulainen SA, Chilibeck PD, Arnold CM, Baxter - 17. - Jones AD. Bone mineral accrual in 4 to 10 year - old precompetitive, recreational gymnasts: a 4 - - J Bone Miner Res. year longitudinal study. 2011;26(6):1313 – 1320. doi:10.1002/jbmr.338. 18. Jackow ski SA, Baxter - Jones AD, Gruodyte - Raciene R, Kontulainen SA, Erlandson MC. A longitudinal study of bone area, content, density, and strength development at the radius and tibia in children 4 - 12 Osteoporos In 2015;26(6):1677 – 1690. years of age exposed to recreational gymnastics. t. - 015 doi:10.1007/s00198 3041 - 1. - 19. Janz KF, Gilmore JM, Burns TL, et al. Physical activity augments bone mineral accrual in young children: The Iowa Bone Development study. J Pediatr. 2006;148(6):793 – 799. 20. ichenberger Gilmore JM, et al. Early physical activity provides sustained bone Janz KF, Letuchy EM, E health benefits later in childhood. Med Sci Sports Exerc. 2010;42(6):1072 – 1078. doi:10.1249/MSS.0b013e3181c619b2. 21. Specker B, Binkley T. Randomized trial of physical activity and calcium supplementation on bone J Bone Miner Res. old children. - year 892. – 2003;18(5):885 mineral content in 3 - to 5 - 22. Specker B, Binkley T, Fahrenwald N. Increased periosteal circumference remains present 12 months 2004;35(6):1383 1388. Bone. – after an exercise intervention in preschool children. 23. Specker BL, Mulligan L, Ho M. Longitudinal study of calcium intake, p hysical activity, and bone mineral content in infants 6 J Bone Miner Res. 1999;14(4):569 – 576. - 18 months of age. Janz KF, Letuchy EM, Burns TL, Gilmore JM, Torner JC, Levy SM. Objectively measured physical 24. trength: Iowa Bone Development Study. Br J Sports Med. activity trajectories predict adolescent bone s – - 2014 - 093574. 1036. doi:10.1136/bjsports 2014;48(13):1032 25. Janz KF, Gilmore JM, Levy SM, Letuchy EM, Burns TL, Beck TJ. Physical activity and femoral neck bone e Development Study. Bone. 2007;41(2):216 – 222. strength during childhood: the Iowa Bon Gruodyte - 26. Raciene R, Erlandson MC, Jackowski SA, Baxter - Jones AD. Structural strength development year longitudinal hip structural at the proximal femur in 4 to 10 - year - old precompetitive gymnasts: a 4 - - ana lysis study. J Bone Miner Res. 2013;28(12):2592 – 2600. doi:10.1002/jbmr.1986. 27. Driessen LM, Kiefte - de Jong JC, Jaddoe VW, et al. Physical activity and respiratory symptoms in children: the Generation R Study. 2014;49(1):36 – 42. doi:10.10 02/ppul.22839. Pediatr Pulmonol. 28. Knowles G, Pallan M, Thomas GN, et al. Physical activity and blood pressure in primary school children: a longitudinal study. Hypertension. 2013;61(1):70 – 75. doi:10.1161/HYPERTENSIONAHA.112.201277. 29. Guo SS, Wu W, Chumlea WC, Roche AF. Predicting overweight and obesity in adulthood from body 2002;76(3):653 Am J Clin Nutr. mass index values in childhood and adolescence. 658. - 2018 Physical Activity Guidelines Advisory Committee Scientific Report F7 - 22

401 Part F. Chapter 7. Youth Gunter KB, Almstedt HC, Janz KF. Physical activity in childhood may be the key to optimizing lifespan 30. health. Exerc Sport Sci Rev. 2012;40(1):13 skeletal 21. doi:10.1097/JES.0b013e318236e5ee. - 31. Pate RR, O’Neill JR. Physical activity guidelines for young children: an emerging consensus. Arch Pediatr Adolesc Med. 2012;166(12):1095 - 1096. doi:10.1001/archpediatrics. 2012.1458. 32. - school program impact on physical activity and Beets MW, Beighle A, Erwin HE, Huberty JL. After fitness: a meta - Am J Prev Med. 2009;36(6):527 – 537. doi:10.1016/j.amepre.2009.01.033. analysis. really matter for combating childhood obesity? A 33. Clark JE. Does the type of intervention method systematic review and meta J Sports Med Phys Fitness. 2015;55(12):1524 – 1543. analysis. - Kelley GA, Kelley KS. Aerobic exercise and lipids and lipoproteins in children and adolescents: a meta - 34. randomized controlled trials. Atherosclerosis. 2007;191(2):447 – 453. analysis of doi:10.1016/j.atherosclerosis.2006.04.019. 35. - high - density lipoprotein cholesterol in Kelley GA, Kelley KS. Effects of aerobic exercise on non children and adolescents: a meta - analysis of randomized controlled trials. Prog Cardiovasc Nurs. 2008;23(3):128 – 132. score in overweight and obese children 36. Kelley GA, Kelley KS, Pate RR. Effects of exercise on BMI z - analysis. - and adolescents: a systematic review with meta - 5. doi:10.1186/1471 2014;14:22 BMC Pediatr. 2431 - 225. 14 - Saavedra JM, Escalante Y, Garcia - Hermoso A. Improvement of aerobic fitness in obese children: a 37. 2011;6(3 - analysis. Int J Pediatr Obes. - meta 4):169 – 177. doi:10.3109/17477166.2011.579975. 38. Lamboglia CM, da Silva VT, de Vasconcelos Filho JE, et al. Exergaming as a strategic tool in the fight against childhood obesity: a systematic review. J Obes. 2013;2013:438364. doi:10.1155/2013/438364. active school 39. Larouche R, Saunders TJ, Faulkner G, Colley R, Tremblay M. Associations between transport and physical activity, body composition, and cardiovascular fitness: a systematic review of 68 227. doi:10. – J Phys Act Health. 2014;11(1):206 studies. 40. - Stafford M, Becasen JS, Beets MW, Nihiser AJ, Lee SM, Fulton JE. Is physical fitness Millard associated with health in overweight and obese youth? A systematic review. Kinesiol Rev (Champaign). 2013;2(4):233 – 247. Mura G, Rocha NB, Helmich I, et al. Physical activity interventions in schools for improving lifestyle in 41. European 101. – countries. Clin Pract Epidemiol Ment Health. 2015;11(suppl 1 M5):77 doi:10.2174/1745017901511010077. - 42. Sun C, Pezic A, Tikellis G, et al. Effects of school based interventions for direct delivery of physical activity on fitness and cardiometabolic m arkers in children and adolescents: a systematic review of 2013;14(1. randomized controlled trials. Obes Rev. - 43. Dobbins M, Husson H, DeCorby K, LaRocca RL. School based physical activity programs for promoting d adolescents aged 6 to 18. physical activity and fitness in children an Cochrane Database Syst Rev. 2013;(2):CD007651. doi:10.1002/14651858.CD007651.pub2. 2018 Physical Activity Guidelines Advisory Committee Scientific Report F7 - 23

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403 Part F. Chapter 7. Youth Waters E, de Silva - Sanigorski A, Hall BJ, et al. In 58. terventions for preventing obesity in children. Cochrane Database Syst Rev. 2011;(12):CD001871. doi:10.1002/14651858.CD001871.pub3. 59. Wilks DC, Sharp SJ, Ekelund U, et al. Objectively measured physical activity and fat mass in children: a bias - adjusted m eta - analysis of prospective studies. PLoS One. 2011;6(2):e17205. doi:10.1371/journal.pone.0017205. 60. Specker B, Thiex NW, Sudhagoni RG. Does exercise influence pediatric bone? A systematic review. Clin Orthop Relat Res. 2015;473(11):3658 – 3672. doi:10.100 - 015 - 4467 - 7. 7/s11999 bearing exercise on bone health in girls: a - 61. Ishikawa S, Kim Y, Kang M, Morgan DW. Effects of weight - meta analysis. Sports Med. 2013;43(9):875 – 892. doi:10.1007/s40279 - 013 - 0060 - y. 62. Xu J, Lombardi G, Jiao W, Banfi G. Effects of exe rcise on bone status in female subjects, from young girls to postmenopausal women: an overview of systematic reviews and meta analyses. - Sports Med. 0. 2016;46(8):1165 1182. doi:10.1007/s40279 - 016 - 0494 - – 63. Hind K, Burrows M. Weight - bearing exercise and bone mineral accrual in children and adolescents: a 27. doi:10.1016/j.bone.2006.07.006. review of controlled trials. Bone. 2007;40:14 – - Julián 64. Cabello A, Huybrechts I, et al. Combined effects of interaction between - Almárcegui C, Gómez physical activity and n utrition on bone health in children and adolescents: a systematic review. Nutr Rev. – 2015;73(3):127 139. doi:10.1093/nutrit/nuu065. 65. Tan VP, Macdonald HM, Kim S, et al. Influence of physical activity on bone strength in children and atic review and narrative synthesis. J Bone Miner Res. adolescents: a system – 2181. 2014;29(10):2161 doi:10.1002/jbmr.2254. 66. Weaver CM, Gordon CM, Janz KF, et al. The National Osteoporosis Foundation's position statement on peak bone mass development and lifestyle factors: a systematic review and implementation recommendations. 2016 Apr;27(4):1281 – 1386. doi: 10. Osteoporos Int. 67. Troiano RP, Berrigan D, Dodd KW, Mâsse LC, Tilert T, McDowell M. Physical activity in the United States measured by accelerometer. Med Sci Sports E xerc. 2008;40(1):181 - 188. 68. Chinapaw MJ, Proper KI, Brug J, van Mechelen W, Singh AS. Relationship between young peoples' sedentary behaviour and biomedical health indicators: a systematic review of prospective studies. Obes Rev. - 789X.2011.00865.x. i:10.1111/j.1467 2011;12(7):e621 - e632. do 69. Tremblay MS, LeBlanc AG, Kho ME, et al. Systematic review of sedentary behaviour and health indicators in school - aged children and youth. Int J Behav Nutr Phys Act. 2011;8:98. doi:10.1186/1479 - 5868 - 8 - 98. 70. Carson V, Hunter S, Kuzik N, et al. Systematic review of sedentary behaviour and health indicators in - - aged children and youth: an update. Appl Physiol Nutr Metab. 2016;41(6 suppl 3):S240 school S265. doi:10.1139/apnm - 2015 - 0630. Cliff DP, Hesketh KD 71. , Vella SA, et al. Objectively measured sedentary behaviour and health and Obes Rev. analysis. - development in children and adolescents: systematic review and meta 2016;17(4):330 344. doi:10.1111/obr.12371. - 2018 Physical Activity Guidelines Advisory Committee Scientific Report F7 - 25

404 Part F. Chapter 7. Youth 72. LeBlanc AG, Spence JC, Carson V, et al. Systematic review of sedentary behaviour and health indicators in the early years (aged 0-4 years). 2012;37(4):753-772. Appl Physiol Nutr Metab. doi:10.1139/h2012-063. 73. Azevedo LB, Ling J, Soos I, Robalino S, Ells L. The effectiveness of sedentary behaviour interventions Obes for reducing body mass index in children and adolescents: systematic review and meta-analysis. 2016;17(7):623-635. doi:10.1111/obr.12414. Rev. 74. Wu L, Sun S, He Y, Jiang B. The effect of interventions targeting screen time reduction: a systematic review and meta-analysis. Medicine (Baltimore). 2016;95(27):e4029. doi:10.1097/MD.0000000000004029. 75. Ivuškāns A, Mäestu J, Jürimäe T. Sedentary time has a negative influence on bone mineral parameters in peripubertal boys: a 1-year prospective study. J Bone Miner Metab. 2015;33(1):85-92. 4. doi:10.1007/s00774-013-0556- 76. Gabel L, Macdonald HM, Nettlefold L, McKay HA. Physical activity, sedentary time, and bone J Bone Miner Res. strength from childhood to early adulthood: a mixed longitudinal HR-pQCT study. 2017;32(7):1525-1536. doi:10.1002/jbmr.3115. 77. Heidemann M, Mølgaard C, Husby S, et al. The intensity of physical activity influences bone mineral accrual in childhood: the childhood health, activity and motor performance school (the CHAMPS) study, BMC Pediatr. 2013;13:32. doi:10.1186/1471-2431- 13-32. Denmark. 78. Vaitkeviciute D, Lätt E, Mäestu J, et al. Physical activity and bone mineral accrual in boys with PLoS One. different body mass parameters during puberty: a longitudinal study. 2014;9(10):e107759. doi:10.1371/journal.pone.0107759. 79. Matthews CE, Chen KY, Freedson PS, et al. Amount of time spent in sedentary behaviors in the 2008;167(7):875-881. doi:10.1093/aje/kwm390. United States, 2003–2004. Am J Epidemiol. 80. Katzmarzyk PT, Denstel KD, Beals K, et al. Results from the United States of America’s 2016 Report 2016;13(11 suppl 2):S307–S313. Card on Physical Activity for Children and Youth. J Phys Act Health. 81. Sisson SB, Church TS, Martin CK, et al. Profiles of sedentary behavior in children and adolescents: The U.S. National Health and Nutrition Examination Survey, 2001-2006. Int J Pediatr Obes. 2009;4(4):353- 359. doi:10.3109/17477160902934777. 82. Pearson N, Braithwaite RE, Biddle SJ, van Sluijs EMF, Atkin AJ. Associations between sedentary behaviour and physical activity in children and adolescents: a meta-analysis. Obes Rev. 2014;15(8):666- 675. doi:10.1111/obr.12188. 83. Eisenmann JC, Bartee RT, Smith DT, Welk GJ, Fu Q. Combined influence of physical activity and Int J Obes (Lond). 2008;32(4):613-618. television viewing on the risk of overweight in U.S. youth. doi:10.1038/sj.ijo.0803800. F7-26 2018 Physical Activity Guidelines Advisory Committee Scientific Report

405 Part F. Chapter 8. Women Who Are Pregnant or Postpartum PART F. CHAPTER 8. WOMEN WHO ARE PREGNANT OR POSTPARTUM Table of Contents Introduction ... F8-1 ... Review of the Science F8-3 Overview of Questions Addressed ... F8-3 Data Sources and Process Used to Answer Questions ... F8-3 ... Question 1. What is the relationship between physical activity and: 1) weight gain during pregnancy; ... F8-5 and 2) weight loss during postpartum? Question 2. What is the relationship between physical activity and incidence of gestational diabetes ... F8-9 mellitus? Question 3. What is the relationship between physical activity and the incidence of (1) preeclampsia ... ... F8-13 and (2) hypertensive disorders during pregnancy? Question 4. What is the relationship between physical activity and (1) affect, (2) anxiety, and (3) depression during pregnancy and postpartum (up to one year)? ... F8-17 F8- 22 Summary of Main and Auxillary Findings Pertaining to Pregnancy-Related Health Outcomes ... ... ... Needs for Future Research F8-28 References ... F8-30 INTRODUCTION Pregnancy is a normal but unique period of life for most women . The multiple hormonal, physiologic, and biomechanical changes that occur, such as increased blood volume and heart rate, weight gain, and ll women who are pregnant should be under shift in center of gravity almost always proceed properly. A medical care to monitor the progress of pregnancy and assure the continued health of mother and fetus. This chapter is about the large majority of women whose pregnancy is proceeding normally. For them, regular engagement in physical activity of moderate intensity for 20 to 30 minutes per day on most or all F8-1 2018 Physical Activity Guidelines Advisory Committee Scientific Report

406 Part F. Chapter 8. Women Who Are Pregnant or Postpartum days of the week has been recommended during pregnancy and the postpartum period by the American 1 College of Obstetricians and Gynecologists (ACOG) in 2015 and reaffirmed in 2017. Physical Activity Guidelines for Americans recommended 150 to 300 minutes per Similarly, the 2008 week of moderate intensity aerobic physical activity during pregnancy and postpartum to be spread 2 29 percent (95% confidence interval (95% However, from 2007 to 2014 only throughout the week. CI): 24%-34%) of pregnant women at any gestation in the United States met the minimum guideline of at 3 However, when increasing the minimum guideline to least 100 minutes per week of physical activity. exercise at least 150 minutes per week, only 23% (95% CI: 15%-35%) met the guideline. Current recommendations differ markedly from 30 years ago. In 1985, an ACOG Technical Bulletin warned pregnant women to keep their heart rate below 140 beats per minute and not to exercise 4 Since then, scientific research has established not only the strenuously for more than 15 minutes. safety of moderate-intensity physical activity for women with a normal pregnancy but its benefits as well. The restrictions on heart rate and duration of physical activity have been lifted, and recommendations encouraging women with a normal pregnancy and postpartum period to participate 1, 5 and in non-contact physical activities of moderate-intensity are common both in the United States 6, 7 The normal physiologic changes occurring throughout pregnancy may make around the world. perceived exertion a better indicator of moderate intensity than heart rate parameters or estimated 1 absolute energy requirements of specific activities. On a personalized rating of perceived exertion scale of 0 to 10, where 0 is sitting and 10 is the greatest effort possible, moderate-intensity activity would be a 2 middle effort of 5 to 6. Another way to gauge moderate intensity is with a talk test, where carrying on a 8 conversation (but not singing) is still possible while doing moderate-intensity physical activity. This chapter provides some information about physical activity during the postpartum period, and considers such issues as the return toward pre-pregnancy weight and postpartum depression. The postpartum is a period during which resumption of previous lifestyle practices can be challenging. For this chapter, the postpartum period is defined as the year following delivery. The benefits and risks of muscle-strengthening physical activity and vigorous-intensity aerobic activity are two issues out of reach of the available searches performed for this Work Group. They are lightly covered by the literature pertaining to physical activity by pregnant women, yet are important to any discussion about health benefits and risks of physical activity. Muscle strengthening activity for pregnant but is Physical Activity Guidelines Advisory Committee Report, 2008 women was not addressed in the F8-2 2018 Physical Activity Guidelines Advisory Committee Scientific Report

407 Part F. Chapter 8. Women Who Are Pregnant or Postpartum 1, 5, 6 recommended in the 2015 ACOG Committee Opinion as well as in guidelines from other countries. For vigorous-intensity physical activity, the 2008 Guidelines suggested that “women who habituall y engage in vigorous-intensity aerobic activity or who are highly active can continue physical activity during pregnancy and the postpartum period, provid ed they remain healthy and discuss with their 2 health-care provider how and when activity should be adjusted over time.” Whether vigorous-intensity physical activity provides unique benefits or risks beyond its contribution to total volume of physical activity has not been well researched, although some physicians still advise against physical activity at 9 greater than 90 percent of maximum heart rate. REVIEW OF THE SCIENCE Overview of Questions Addressed This chapter addresses four major questions: 1. What is the relationship between physical activity and weight gain during pregnancy and weight loss during postpartum? What is the relationship between physical activity and the incidence of gestational diabetes 2. mellitus? 3. What is the relationship between physical activity and the incidence of (1) preeclampsia and (2) hypertensive disorders during pregnancy? 4. What is the relationship between physical activity and (1) affect, (2) anxiety, and (3) depression during pregnancy and postpartum (up to one year)? Questions 1 through 4 each have the following subquestions: a) What dose of physical activity is associated with the reported quantitative benefit or risk? Is there a dose-response relationship? If yes, what is the shape of the relationship? b) c) Does the relationship vary by age, race/ethnicity, socioeconomic status, or weight status? Data Sources and Process Us ed to Answer Questions The Work Group identified two high-quality existing reports, the Physical Activity Guidelines Advisory 5 Committee Report, 2008 and 2015 ACOG Committee Opinion on Physical Activity and Exercise During 1 that provided summaries of the science about the relationship Pregnancy and the Postpartum Period, between physical activity and health outcomes in women who are pregnant and postpartum. After decided reviewing these high-quality reports and consulting with three outside experts, the Work Group a foundation for summarizing the benefits and risks of light- to that these two documents could serve as F8-3 2018 Physical Activity Guidelines Advisory Committee Scientific Report

408 Part F. Chapter 8. Women Who Are Pregnant or Postpartum - intensity physical activity during pregnancy and the postpartum. Th Work Group also moderate e its other research questions to identify searches from other Subcommittees that could provide reviewed evidence questions related to this issue . R esearch question s unlikely to provide information to answer pertaining to pregnancy or postpartum were not considered. For example, the Committee decided that en Sev all - cause mortality or coronary artery disease would not be suitable outcomes for this age group. nent information. ommittee were considered to provide potentially perti C searches conducted by the 1. Cardiometabolic Health and Weight Management Q1: What is the relationship between physical activity and prevention of weight gain? 2. Cardiometabolic Health and Weight Management Q2: In people with normal blood pressure or pre - hyperten sion, what is the relationship between physical activity and blood pressure? : Cardiometabolic Health and Weight Management Q3 In adults without diabetes, what is the 3. relationship between physical activity and type 2 diabetes? 4. the relationship between physical activity and quality of life? What is Brain Health Q2: 5. What is the relationship between physical activity and : (1) affect, (2) anxiety, and (3) Brain Health Q3: depressed mood and depression? 6. Brain Health Q4 : What is the relationship betwee n physical activity and sleep ? 7. Aging Q2: What is the relationship between physical activity and physical function? (The search for to older age groups). this question was not restricted - or each of these seven questions, the results from the searches for systematic reviews, meta F analyses, reports were reviewed. All search results that included pooled analyses, and existing summary e title or abstract were pulled and gathered “gestation,” “postp,” “pregn,” “natal,” or “maternal” in th title, abstract, and full for Pregnancy topic . The the - text triage review process was the same as that used dvisory for other 2018 A C ommittee topic s. The Work Group rel ied on these publications as the sources of potential evidence regarding quantifiable benefits or risks and the associated dose of physical activity. Committee also The by adding “eclampsia” and completed one supplementary search activity uestion gement Q 2 search on “preeclampsia” to the Cardiometabolic Health and Weight Mana hypertension. 2018 Physical Acti vity Guidelines Advisory Committee Scientific Report F8 - 4

409 Part F. Chapter 8. Women Who Are Pregnant or Postpartum After duplicates were removed, a total of 254 articles were identified through this process. The titles were reviewed by two of the three members of the work group. A total of 122 articles were deemed potentially relevant based on the title search, and the abstracts of these papers were reviewed by two members of the Committee. Through expert consultation, two original research articles were added to the group of articles being reviewed at full text. A total of 73 articles were deemed to be potentially relevant and the full papers were retrieved and reviewed. During the full-text triage process, the Work Group originally recorded all health outcomes addressed in the articles for pregnant and postpartum women, as well as infants at birth. After reviewing the literature, the Committee decided that the available articles adequately addressed: 1) gestational weight gain (GWG) and postpartum weight loss; 2) gestational diabetes mellitus (GDM); 3) eclampsia and preeclampsia; and 4) affect, anxiety, depression . Too few reviews of quality of life, sleep, and physical function were available to provide an adequate assessment of the relationship. A wide range of potential health-related outcomes during pregnancy, delivery, and the postpartum period exist for both mother and child. Researchers commonly report not only on the outcome of their primary interest, such as gestational diabetes, but on other sometimes related outcomes, such occurrence of Cesarean section or birth weight of the infant . As a result, the review articles captured in our searches provided information on the search topic and, quite often, information on other events related to the pregnancy, delivery, or the postpartum period. The Work Group saw the opportunity to 5 compare these ancillary findings with information in the 2008 Scientific Report to determine whether the ancillary findings were consistent. The ancillary findings are summarized and discussed after presentation of the evidence pertaining to the specific questions addressed by the Work Group (see Table F8-3). During the Work Group’s review of the meta-analyses and systematic reviews, the Work Group sometimes found it necessary to examine the original research papers included in a review to determine which studies met the Committee’s requirements for inclusion. The Work Group alludes to a few of the original research articles in the text; however, these original research articles are not included in the evidence portfolio, as they were not part of the original search. Question 1. What is the relationship between physical activity and: 1 ) weight gain during pregnancy; and 2) weight loss during postpartum ? a) What dose of physical activity is associated with the reported quantitative benefit or risk? F8-5 2018 Physical Activity Guidelines Advisory Committee Scientific Report

410 Part F. Chapter 8. Women Who Are Pregnant or Postpartum Is there a dose-response relationship? If yes, what is the shape of the relationship? b) c) Does the relationship vary by age, race/ethnicity, socioeconomic status, or weight status? nce: Systematic reviews, meta-analyses, and two existing reports Sources of evide Conclusion Statements Weight Gain During Pregnancy Strong evidence demonstrates a significant inverse relationship between physical activity and weight gain during pregnancy . PAGAC Grade: Strong. Limited evidence suggests that a dose of physical activity similar to the 2015 American College of Obstetricians and Gynecologists Guidelines and the 2008 Physical Activity Guidelines for Americans is PAGAC associated with minimized weight gain and a lower risk of excess gestational weight gain. Grade: . Limited Limited evidence suggests a dose-response relationship between physical activity and gestational weight . gain. PAGAC Grade: Limited Insufficient evidence is available to determine whether the relationship between physical activity and gestational weight gain varies by age, race/ethnicity, socioeconomic status, or weight status. PAGAC . Grade: Not assignable Weight Loss During the Postpartum Period Insufficient evidence is available to determine whether physical activity is associated with weight loss during the postpartum period. PAGAC Grade: Not assignable. Insufficient evidence is available to determine what dose of physical activity is effective for weight loss . during postpartum PAGAC Grade: Not assignable. Insufficient evidence is available to determine whether a dose-response relationship exists between PAGAC Grade: Not assignable. physical activity and weight loss during postpartum . Insufficient evidence is available to determine whether any relationship between physical activity and weight loss during postpartum varies by age, race/ethnicity, socioeconomic status, or weight status. PAGAC Grade: Grade not assignable . F8-6 2018 Physical Activity Guidelines Advisory Committee Scientific Report

411 Part F. Chapter 8. Women Who Are Pregnant or Postpartum Review of the Evidence Weight Gain During Pregnancy Sources of evidence included systematic reviews, meta-analyses, and two existing reports published 10- 18 19, 20 . Nine meta-analyses, and two systematic rev iews between 2006 and 2017 were ultimately included in the Work Group’s evidence review. Nine of the reviews included only studies with 10, 11, 13-18, 20 19 experimental designs, one included only cohort studies, and one included both 10 experimental designs and cohort studies. The number of studies included in each of the reviews 17 12 ranged from 3 The specifics of the exercise interventions varied but most were similar to the to 44. 1, 2 volume recommended by 2008 Physical Activity Guidelines and the 2015 ACOG Committee Opinion. Evidence on the Overall Relationship The 11 reviews provided strong evidence that women assigned to the physical activity interventions gain kg) less weight during pregnancy than women in the control groups. Of the eight about 1 kilogram ( 10, 11, 10, 11, 13- 18 ss weight gained for the experimental group. meta-analyses, seven reported significantly le 13- 15, 17, 18 nly women with overweight or obesity and reported The other meta-analysis included o significantly lower weight gain in pregnant women with obesity, but not in those with overweight, 16 compared with women in the control groups. 10 da Silva et al The meta-analysis by reviewed 30 randomized controlled trials (RCTs). Based on a meta- analysis of 18 of those RCTs, which included 1,598 women performing a structured exercise program and 1,605 receiving standard care, the standardized mean difference (SMD) in gestational weight gain was -1.11 kg (95% confidence interval ( CI): -1.59 to -0.69), with women in the exercise group gaining less 11, 13- 1617, 18 weight than women receiving standard care. Seven other meta-analyses of RCTs reported similar standardized mean differences in gestational weight gain between exercising and control 11 16 women, ranging from -0.36 kg (95% CI: -0.64 to -0.09) ). to -2.22 kg (95% CI: -3.14 to -1.30 20 A systematic review by McDonald et al considered 21 RCTs (18 exercise only and 3 exercise and diet combined). Of the 18 exercise-only interventions in the review, only 6 were deemed “successful” based on statistically significant ( P <0.05) differences in weight gain between the exercise and control groups . 12 Han et al reported findings from However, these differences were modest in size. The meta-analysis by each of 3 RCTs because they differed sufficiently to preclude combining them for a meta-analysis. With reported that women in the more active group gained less sample sizes of 12, 83, and 84, each study weight. The differences were not statistically significant for any of the three. F8-7 2018 Physical Activity Guidelines Advisory Committee Scientific Report

412 Part F. Chapter 8. Women Who Are Pregnant or Postpartum 19 Fazzi et al considered the role of sedentary behavior on gestational One systematic review paper by weight gain. Of the three cohort studies considered, only one observed a significant relation between 21 sedentary behavior and amount of gestational weight gain, in which the “Active” group (labeled according to author ́s categorization) gained significantly less weight during the second and third trimesters than the “Sedentary” group (named according to author ́s categorization). 10, 13, 20 Several systematic reviews and meta-analyses examined the relationship between physical 22 In general, activity and “excess” weight gain (defined by the Institute of Medicine (IOM) Guidelines). women who reported physical activity during pregnancy experienced a significantly lower risk of excess weight gain compared with women who did not, with pooled effect sizes ranging from an 18 percent 10 13 lower risk (odds ratio [OR ]=0.82; 95% CI: 0.68-0.99) to 23% (OR=0.77; 95% CI: 0.66-0.88). Dose-response: The dose of