Burden of adult neurofibromatosis 1: development and validation of a burden assessment tool

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1 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand https://doi.org/10.1186/s13023-019-1067-8 RESEARCH Open Access Burden of adult neurofibromatosis 1: development and validation of a burden assessment tool 3 4 1 1 2* , Mireille Bourlier , Aline Bourgeois , Mohammed Bennani , , Charles Taieb Marie-Laure Armand 2,5 1 , Pierre Wolkenstein and along with the French national network on rare skin diseases Christine Bodemer (FIMARAD) Abstract Background: Neurofibromatosis Type 1 (NF1) is a common genetic neurocutaneous disease, with an autosomal dominant inheritance mode. Quality of life has been shown impaired in NF1, due to severe complications, cosmetic features, and uncertainty about the disorder. This study sought to develop a self-administered questionnaire in French to assess the burden of NF1 Methods: (BoN), then translate and linguistically and cross-culturally validate it into American English, standardized methodology applied, as outlined in the report. Results: Based on several discussions with NF1 patients, a 17-item conceptual questionnaire was first produced. Of the 91 NF1 adult patients who responded to the conceptual questionnaire, 65 (64.6% females) were accessible. Subsequent confirmatory analyses generated a 15-item questionnaire grouped into four domains, demonstrating internal consistency (Cronbach ’ s alpha: 091), discriminant validity, and high reliability. The BoN was likewise shown to significantly correlate with other validated questionnaires, such as Dermatology Life Quality Index, Perceived Stress Scale, and SF12 mental score, indicating good external validity. BoN is a specific tool for assessing the burden that NF1 generates on many practical aspects of the Conclusions: . Given the increasing relevance that regulatory ” patient daily activities, beyond the notion of quality of life authorities attribute to patient-reported outcomes, the BoN questionnaire provides such supplementary information while accounting for the burden of NF1 patients in the broadest sense. Neurofibromatosis type 1, NF1, Von Recklinghausen ’ s disease, Individual disease burden, Quality of life, Keywords: Questionnaire 1:3500 individuals worldwide, yet with wide – 1:2000 Background phenotypical variability [ 4 – 6]. The germline NF1 muta- Neurofibromatosis Type 1 (NF1) is the most common tion rate proves ten-fold higher than that observed in autosomal dominant neurocutaneous disease, caused by other inherited disease genes [ 7]. mutations in the NF1 tumor suppressor gene, located in Establishing the correct NF1 diagnosis may prove 1]. This gene encodes a region on chromosome 17ql1.2 [ challenging [ 8]. NF1 patients are at increased risk of a common protein, namely neurofibromin, which is an developing various tumors, and their life-expectancy is essential negative regulator of Ras cellular proliferation decreased by 10 years as compared to the general popu- pathways [ 2, 3]. Disease prevalence is estimated at lation [ 9]. With skin lesions as the most noticeable disease manifestation, NF1 may affect many organs, and [email protected] * Correspondence: 2 psychiatric and psychological disorders are likewise com- FIMARAD, French rare diseases Healthcare Network: rare dermatologic disease, CHU Paris - Hôpital Necker-Enfants Malades, 149 rue de Sèvres, mon [ 10, 11]. Around 20% of patients display dysthymia 75743 Paris, France and 7% depressed mood, with a heightened risk of Full list of author information is available at the end of the article Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 © The Author(s). 2019 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

2 Page 2 of 8 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand suicide [ Exploratory phase 12]. Anxiety and personality disorders are simi- The initial step involved several one-to-one interviews larly observed, and cognitive disorders may last into between the dermatologist, psychologist, social worker, adulthood, thereby impacting smooth integration into and expert in patient-reported outcomes with patients work [ 13]. Quality of life (QoL) was shown impaired in suffering from NF1 to comprehensively collect the pa- NF1 patients, especially in severe disease cases [ 14]. tients ’ perceptions and complaints. By analyzing these “ The concept of burden has taken a central role in ” interviews, the most relevant concepts were identified. A 15], and specifically in case of skin evaluating care [ semi-structured questionnaire was then elaborated 16]. In 2010, the World Health Organization diseases [ comprising specific themes in a question/answer format, Global Disease Burden , ” “ first introduced the concept of including closed-ended questions with a choice of prede- particularly useful for quantifying population health and termined answers, as well as open-ended questions determining action priorities [ 17]. The focus has mean- allowing unrestricted answers. The final choice of ques- individual disease burden ” while been switched to ,a “ tions was made by the working group. disability “ ” in the concept designed to assess disease broadest sense, including psychological, social, eco- nomic, and physical features. Such individual disease Development phase burden was already investigated in skin diseases like During this phase, the conceptual questionnaire was 19], hereditary psoriasis [ 18], infantile hemangioma [ administered to a sample of subjects suffering from the 20], atopic dermatitis [ 21], and vitiligo [ 22]. ichthyosis [ disease. An exploratory factor analysis was conducted to 23] have developed a disease-specific Ferner et al. [ highlight the underlying constructs, assigning each item questionnaire to measure QOL in people with NF1 to its respective domain, with orthogonal varimax (INF1-QOL) that is suitable as an assessment tool in rotation performed to verify whether the hypothetical clinical practice and in clinical trials. The aim of our constructs were interrelated. work is to assess the burden and the impact that the s internal consistency ’ To evaluate the questionnaire NF1 generates on many practical aspects of the patient and confirm its reliability, the item homogeneity in each daily activities in addition to the notion of quality of life. dimension was tested using Cronbach ’ s alpha coefficient “ reference cen- As part of their research activities, the [25]. Higher order factor confirmatory analysis was per- network has elaborated and ters for rare skin disorders ” formed to confirm that the dimensions created could be validated a French questionnaire designed to assess the combined into one single score. PROC CALIS proced- burden of NF1 on patients suffering from the condition, ’ s ure, SAS 9.4, was employed. The criteria for the model B urden o termed f eurofibromatosis (BoN). This paper N goodness-of-fit were defined as a Bentler comparative fit describes the different steps involved. index > 0.90, and Bentler-Bonett non-normed fit index 26], with root mean square error of approxima- > 0.90 [ tion (RMSEA) close to 0.05 or at the very least less than Methods 0.08. The self-administered BoN questionnaire was developed using standard methodology comprising three phases, namely exploratory, development, and validation [ 24]. External validity This questionnaire was developed by a multidisciplinary To assess the questionnaire s external validity, all partici- ’ working group comprising experts in questionnaire de- pants were asked to complete three previously validated sign/development, such as healthcare professionals like ermatology Life self-administered questionnaires: the D physicians and psychologists, experts in NF1, such as Quality Index [DLQI] questionnaire, social workers and dermatologists, as well as experts in The DLQI questionnaire is the first dermatology-spe- QoL and patient-reported outcomes. cific instrument designed to assess the impact of skin The questionnaire was conventionally created in a diseases on patient QoL [ 27, 28]. Intended for adults question and answer format. Response modalities were and patients aged over 16 years, DLQI has proven a sim- determined via consensus among the experts, and took ple, practical, and validated questionnaire that grades ” ” never “ the form of a 6-point Likert scale: (0), “ rarely – QoL, the DLQI score being the sum of all scores (0 30), (4), and (1), “ sometimes ” (2), “ often ” (3), “ very often ” with high scores reflecting poor QoL. “ ” (5). To limit missing data, we also consid- constantly The PSS is the most widely used psychological instru- ” not applicable “ ered a (0). Instructions in the preamble ment for measuring the perception of stress. Composed state that the questions relate to the previous 30 days. , PSS measures never of 10 items rated from “ ” ” to “ often Subjects from the age of 15 could complete the ques- the degree to which situations in one ’ s life are perceived ” not concerned tionnaire and had the option to indicate “ 29, 30]. The total score ranges from 10 to as stressful [ for non-applicable questions. 50, and the higher the score, the higher the stress.

3 Page 3 of 8 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand The SF12 is a short version of the SF-36, namely a Results Conceptual phase generic instrument to measure population health [ 31], with a physical composite score and mental composite Over the preceding 12 months, the psychologist and score calculated based on 12 questions, and the higher co-author conducted discussions with 45 NF1 patients the score, the better the physical and the mental quality on a one-to-one basis concerning their complaints and of life, respectively. distresses. Combined with the work of the social worker, Concurrent validity was established by calculating this research resulted in the description of the patients ’ Pearson correlations between the BoN and the other perceptions in an initial verbatim. Several one-on-one three validated questionnaires. The data were analyzed discussions between dermatologist, psychologist, social using SAS software Version 9.4 (SAS Institute, Cary, worker and expert in patient-reported outcomes contrib- NC, USA), with the significance level set at 0.05. uted to consolidate this initial wording, with eventually 17 items forming the conceptual questionnaire. Test-retest analysis To assess reproducibility, a test-retest analysis was con- ducted, with a group of subjects asked to complete the Development and validation phase questionnaire twice, with at least a 10-day interval Study population in-between. Patients were selected with the support of the French association of patients with neurofibromatosis, which proposed the questionnaire to previously diagnosed Translation, cross-cultural adaptation, and cognitive patients. NF1 is a rare skin disease, and working with debriefing the Association Neurofibromatoses et Recklinghausen While the original BoN questionnaire was developed in ensured broad recruitment over the territory to guaran- French, previously-validated methodology was applied to teed a reasonably diversity of patients in terms of geo- generate an US English-language version, involving graphical location, age and sociological status. Overall, cross-cultural validation [ 32]. The nine steps involved 91 patients were contacted of whom 65 responded to are summarized in Table 1. A number of changes could the conceptual questionnaire. Among the respondents, be implemented throughout the validation process, so as 64.6% were women (Table 2). to further improve the initial idiomatic draft. ’ s mean age was 47.74 years ±17.06 (43.47 – The cohort Principles of Good Practice for the Translation and Table 1 52.00). Some 44.4% of patients stated that they were Cultural Adaptation Process for Patient-Reported Outcomes cohabiting, 59.7% exerted a job, and 21.53% were retired, (PRO) Measures while 47,69% had been to higher level education. Almost Stage Détails all were covered under the French national health insur- Preparation Evaluation of the source text from a ance, with 78.7% covered under the chronic conditions linguistic and cultural point of view scheme. including definition of concepts NF1 diagnosis was made by a family physician in Forward translation into the required Forward translations 25.9% of cases, a dermatologist in 38.9%, and another target language by two independent translators specialist in 35.2%. The family physician was involved in Reconciliation Comparison of the two forward managing the disease in 35.4% of cases, and the derma- translations to provide the best adaption tologist in 75.4%. Altogether, 71.7% of patients stated and produce a draft version of the text they were satisfied with their current treatment, and Back translation Translation of the draft forward 20% used self-medication. translation back into the targeted language without reference to the original language Table 2 Description of the study population Comparison of the original text and Back-translation review Men Women the back translation to verify that the n = 42 (64.62%) = 23 (35.38%) n meaning of the draft translation is equivalent to source 48.87 Age 47.12 Analysis of the back-translation review Analysis and implementation 39.13% Live alone 28.57% of back-translation review report to verify if there are changes 56.52% Higher level education 42.86% report required to the draft forward Diagnosis delay, if occurred (years) 10.83 13.28 Clinical review and cognitive debriefing Pilot testing living in a rural area 30.43% 14.29% Review of the results from the cognitive Review of cognitive debriefing or clinical review to identify debriefing or clinical 40.48% living in a mid size city 47.83% translation modifications necessary for review results 42.86% 17.39% living in a large size city improvement

4 Page 4 of 8 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand There was no diagnostic delay for 36.9% of the pa- Dimension 1, with five questions on concentration  tients. For those who did experience diagnostic delay, and learning problems; the waiting period was long, since 139.9 months  Dimension 2, with five questions on the way (11.65 years) on average separated the first disease others look at them and the anxiety they feel signs from definite diagnosis. About one-third of pa- about the future; tients (30.8%) were offered psychological treatment,  Dimension 3, with three questions on life with the and 16.9% had actually received it. Overall, 67% of disease; the respondents were in contact with a patients Dimension 4, with two questions on sexuality;  association. Dimension 5, with two questions on acceptance  and pain. Confirmatory analysis revealed two questions not to Internal validity be relevant, which were thus removed, resulting in a Principal component factor exploratory analysis was 15-item questionnaire, with four dimensions: performed on the 17-item questionnaire. The correl- ation matrix was previously generated, and the maximum value was 0.8. For all items, neither the  Dimension 1, with five questions on concentration “ ” exceeded answer always never “ ” nor the answer and learning problems; 20%. Standardized regression coefficients were all > Dimension2,withfivequestionsonthewayothers  1: Table S1), and each group of 0.4 (Additional file look at them and the anxiety they feel about the future; questions was assigned a dimension, with five dimen-  Dimension 3, with three questions on life with the 3): sions as follows (Table disease;  Dimension 4, with two questions on sexuality. Table 3 Loading of the questions on the factors after rotation Factor2 Factor4 Factor5 Factor3 Factor1 0.09071 0.00039 0.88400 − Do you think that your concentration problems 0.11713 0.09955 have had a negative impact on your work? − 0.09345 0.06042 0.30780 0.88148 Do you think that your concentration problems 0.05582 have restricted your daily activities? During your education, do you think that you 0.10511 0.06509 0.79896 − 0.00429 0.21201 had learning difficulties because of your NF1? 0.44034 0.26651 − 0.03789 0.06598 0.73315 Do you think that your concentration problems have hindered your inclusion in society? Have you had any difficulties in asking for help? 0.01459 0.60144 0.03367 0.57266 0.10930 0.17472 0.01365 Have you perceived your NF1 as a physical disability? 0.12939 0.88082 0.09128 0.01311 0.05429 0.31858 0.75423 Because of your NF1, has the way other people 0.09864 look at you caused you to suffer? 0.63127 − 0.19180 Has your NF1 affected which clothes you choose 0.34293 − 0.03823 0.41378 to wear? 0.33170 0.05902 0.26411 0.62787 0.38068 Have you felt that you have no control over what − is happening to you? 0.32267 0.09847 0.28498 Are you sometimes afraid of the future because 0.53923 0.55738 of your NF1? 0.14724 0.87805 0.06822 0.04185 0.16269 Has the paperwork in connection with your NF1 been difficult? Have you felt that your socio-economic status may 0.02013 0.03600 0.62411 0.31203 0.47696 be directly linked to your NF1? 0.51316 − 0.00448 Have you felt the need to justify yourself? 0.35859 0.31300 0.34404 0.18588 0.14253 − Do you think your NF1 has made you shyer? 0.81264 0.13130 0.16481 0.00112 0.04124 − 0.26387 0.30992 Has your NF1 hindered your sexuality? 0.75537 0.10323 Have you succeeded in managing (or dealing with) 0.00897 0.82165 − 0.01640 0.11954 your NF1 pain? − 0.0229 − 0.0461 0.16370 0.81977 0.01270 Have you come to terms with the administrative difficulties that you have encountered?

5 Page 5 of 8 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand Correlations between the scores Table 5 s uni-dimensionality was confirmed The questionnaire ’ by higher order factor analysis (Additional file 2: Table Pearson correlation coefficients, N =65 Prob > |r| under H0: Rho = 0 S2). The practical goodness-of-fit indices were accept- DLQI 0.69930 able, with a Bentler comparative fit index of 0.9521 and <.0001 a Bentler-Bonett non-normed fit index of 0.9355. The 0.72643 PSS model appears well adjusted and well fitted, offering the <.0001 possibility to group the four dimensions into one single 0.57650 − SF12 -MCS score. All dimensions were found well correlating with <.0001 the overall score (Table 4). SF12 -Physical − 0.26242 Cronbach ’ s alpha coefficient was 0.91 for the entire 0.0347 questionnaire, reflecting its excellent internal coherence, PCS DLQI D Physical ermatology Life Quality Index Perceived Stress Scale, , PSS while intradimensional coherences exhibiting good Composite Score /SF12, MCS Mental Composite Score /SF12 reliability. performed in which retranslation of the draft question- naire into the original language and comparison of the ori- External validity ginal questionnaire against the version obtained from The BoN questionnaire highly correlated with the back-translation was done to check whether the overall Dermatology Life Quality Index (DLQI), Perceived Stress meaning of the reconciled translation matched that of the 5). The Scale (PSS), and SF12 mental scores (Table source document. Afterwards, to allow pilot testing of the correlation coefficients between BoN and validated questionnaire, an analysis of the back-translation and s ’ questionnaires were relatively high, confirming BoN implementation of the back-translation review report was external validity; the correlation with the SF12 physical performed. Finally, before correction and finalization, a score proved the weakest. review of cognitive debriefing was performed. Cognitive debriefing did not result in any major However, from this US English version, an adequate ’ wording. changes to the questions validation in the US patients is still required. Both versions are presently available (Table 6). Test-retest analysis The test-retest reliability was obtained on 23 evaluable subjects (Day 1 and Day 10), demonstrating good repro- BoN scoring ducibility. The intraclass correlation of each dimension The BoN can be expressed as a total score between 0 was > 0.85 for each domain. and 75, where 0 represents no impact and 75 the highest possible impact. The total score is obtained by summing Translation and cultural adaptation up the scores for each of the 15 questions. In our patient The original BoN French version was translated, then cohort, the mean BoN score obtained was 28.42 linguistically and culturally validated in US English. (±16.87), the mean score for men being 22.48 (±16.47) While the original BoN questionnaire was developed versus 31.67 (±16.38) for women ( < 0.001). The Sha- p in French, previously validated methodology was applied piro test of normality for the BoN score provided a in order to generate an US English-language version, p -value of 0.15, meaning that the hypothesis that the involving linguistic and cross-cultural validation 21. This data are normally distributed can-not be rejected. rigorous process comprises a meticulous 9-step procedure The respondents evaluated disease severity on a visual and was meant to refine the translation while taking into analog scale between 1 and 5, with 1 being low severity account nuances of the source document. Briefly, source and 5 very high severity. The subjects were divided into text evaluation from a linguistic and cultural perspective, three groups, namely low severity (scores of 1 and 2), including a clear definition of various concepts, was first moderate severity (3), and high severity (4 and 5). The carried out. In a second step, a separate translation of the BoN score of the low severity group was 17.6 (±11.9), text into US English by two independent translators was while that of the moderate severity group was 29.3 made. A comparison of the two translations with subse- (±14.4), and that of the high severity group 45.5 (±18.2), quent text optimization aiming to produce a preliminary the BoN score differences statistically significant. Table 7 draft questionnaire was then performed. Further, a compares BoN score evolution according to severity, to back-translation and back-translation review were the evolution of the other validated scores. The mean BoN score was calculated for subjects who s alpha for the four dimensions Table 4 ’ Cronbach stated that they experienced diagnostic delay versus Factor 3 Factor 1 Factor 2 Factor 4 those who did not. BoN score for patients reporting a 0.78 0.62 Standardized 0.90 0.86 α diagnostic delay was 30.3 (±15.4) versus 23 (±13.9) for

6 Page 6 of 8 (2019) 14:94 Armand et al. Orphanet Journal of Rare Diseases Table 6 Burden of adult neurofibromatosis 1 questionnaire in English US and French Do you think that your concentration problems have had a negative Pensez-vous que vos difficultés de concentration ont limité vos activités impact on your work? quotidiennes? Considérez-vous, que vos difficultés de concentration ont eu un impact Do you think that your concentration problems have restricted your daily activities? négatif dans votre travail? During your education, do you think that you had learning difficulties En raison de votre Neurofibromatose de type 1, lors de votre scolarité, ’ avez-vous rencontré des difficultés d apprentissage? because of your NF1? Do you think that your concentration problems have hindered your Pensez-vous que vos difficultés de concentration ont été un frein à votre intégration dans la société? inclusion in society? Have you had any difficulties in asking for help? Avez -vous éprouvé des difficultés à demander de l ’ aide? Have you perceived your NF1 as a physical disability? Avez-vous ressenti votre Neurofibromatose de type 1 comme un handicap physique? Because of your NF1, has the way other people look at you caused En raison de votre Neurofibromatose de type 1, le regard des autres a-t-il été pénible? you to suffer? Avez-vous eu le sentiment d Has your NF1 affected which clothes you choose to wear? avoir d ’ un destin imposé? ’ Have you felt that you have no control over what is happening Votre Neurofibromatose de type 1, a-t-elle eu une influence sur le choix des to you? vêtements que vous portez? Are you sometimes afraid of the future because of your NF1? Vous arrive-t-il, de craindre l ’ avenir en raison de votre Neurofibromatose de type 1? Les démarches administratives en lien avec votre Neurofibromatose de Has the paperwork in connection with your NF1 been difficult? type 1 ont-elles été difficiles? Have you felt that your socio-economic status may be directly linked Avez-vous eu le sentiment que votre statut social ait été directement lié à votre Neurofibromatose de type 1? to your NF1? Have you felt the need to justify yourself? Avez-vous eu le sentiment d avoir besoin de vous justifier? ’ Do you think your NF1 has made you shyer? Avez-vous pensé que votre Neurofibromatose de type 1 vous rende plus timide? Votre Neurofibromatose de type 1 a-t-elle été un obstacle (un frein) à votre Has your NF1 hindered your sexuality? sexualité? Possible answers to each question and associated score jamais “ never ” or “ not applicable ou non applicable (0) ” ” “ (0) (1) “ rarely ” (1) “ rarement ” quelques fois sometimes “ ” (2) “ (2) “ ” often (3) “ souvent ” (3) “ (4) “ very often ” (4) “ très souvent ” “ constantly ” (5) “ en permanence ” (5) Participants with more visible NF1 signs reported signifi- those without, the between-group difference being statis- cantly greater overall effects on their skin-disease-specific tically significant ( = 0.04). p QoL compared to those with more subtle manifestations. In a Spanish study on NF1 children, an extremely high Discussion frequency of cognitive disorders was reported [ 36]. In an NF1 has been associated with impaired QoL [ 33], repre- Italian survey involving 129 NF1 adult patients, cosmetic ’ senting an attack on the patients self-esteem and life- features exerted the greatest impact on QoL [ 37]. style [ 34]. In a cross-sectional study involving 176 adult The individual burden is increasingly investigated in the NF1 cases, participants experienced a significant impact healthcare domain, taking into account QoL, community in all aspects of skin-disease-specific QoL [ 35]. integration, organization of everyday life, and medical re- Table 7 Scores of validated scales according to severity 18]. With such specific question- source consumption [ PCS DLQI BoN MCS Severity N PSS naires, it is possible to directly evaluate the overarching 6.58 Low 20 24.34 44.55 52.67 45.63 19, 20, 22, 24]. Due to the burden of a particular disease [ advances in QoL research, the pharmaceutical industry, 34 25.23 5.44 46.78 44.04 45.70 Moderate medical device industry, and regulatory agencies are now 31.82 10.73 47.19 40.08 65.73 High 11 faced with complex issues related to health-related quality PSS PCS Physical Perceived Stress Scale, DLQI Dermatology Life Quality Index, of life claims [ 38]. Leidy et al. generated recommendations Mental Composite Score /SF12 Composite Score /SF12, MCS

7 Page 7 of 8 (2019) 14:94 et al. Orphanet Journal of Rare Diseases Armand healthcare providers, improve information transfer, and to the healthcare industry for assuring that all health-re- create a real opportunity for the practitioner to better lated QoL claims be based on rigorously-designed studies understand certain issues brought up by the patient. [38]. Several developments in clinical research have led to a widespread use of questionnaires. The reason for this is the increasing relevance of patient-reported outcome data to Conclusions achieve market access. Quality of life, patient wellbeing, The BoN demonstrates feasibility, reliability, and discrimin- and patient-centered outcomes are increasingly requested ant validity. This instrument can thus be employed to 39]. by reimbursement agencies [ better understand the multidimensional nature of NF1 on ’ This report provides support for BoN s feasibility, reli- the individual burden of adult patients. This tool may simi- ability, and validity as a specific instrument designed to larlyhavearoletoplayinthedecision-makingprocess. assess the individual disease burden in adult NF1. The specificity of the BoN questionnaire is that it measures Additional files the burden and the impact that NF1 generates in a Additional file 1: Eigenvalues of the factors. (DOCX 15 kb) ’ patient s daily life. The items are directly derived from Model assessment parameters. (DOCX 17 kb) Additional file 2: discussions conducted by a psychologist with 45 patients with NF1 over a period of 1 year. This is why these items Abbreviations reflect disabilities specific to NF1 such as neurological BoN: Burden of neurofibromatosis 1; DLQI: Dermatology Life Quality Index; problems including difficulties in vision, impaired MCS-SF12: Mental Composite Score- Short Form 12; NF1: Neurofibromatosis sustained attention, or learning difficulties. Let us add type 1; PCS-SF12: Physical Composite Score- Short Form 12; PSS: Perceived Stress Scale; QoL: Quality of life; RMSEA: Root mean square error of that the burden caused by the disease on many practical approximation aspects of daily activities go beyond the notion of quality of life and are described in the very specific wording Acknowledgements expressed by the patients themselves. The authors thank the patient association for helping and supporting this project. With its 15 items and six possible answers for each, this questionnaire is relatively short, understandable and Funding easy-to-use by the patients. BoN has been proven a The project has received public funding from Fimarad (French network of rare skin disorders, Necker Hospital, Paris, France). robust tool, its internal consistency exceeding the minimum reliability criterion of 0.90. This supports Availability of data and materials using the total BoN score as a distinct measure of the The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. individual disease burden in adult NF1 patients. In our research, BoN version was able to discriminate contributions Authors ’ between low, moderate, and high disease severity, CT, MLA and AB conceived the study, participated in its design and coordination and helped drafting the manuscript. CB, PW, and MB ’ supporting the tool s discriminant validity. Consistent participated in the design of the study and conceptual phase. MB performed with our hypothesis, high BoN scores were associated the statistical analysis. All authors read, commented on, and approved the with adult patients reporting high disease severity on a final manuscript. visual analog scale, whereas low BoN scores were linked Ethics approval and consent to participate to those reporting low disease activity. The mean BoN The questionnaire construction was carried out as part of the RADICO-FARD score proved able to differentiate patients with delayed project, which obtained a favorable opinion from the Committee for the NF1 diagnosis from those with no delay. Moreover, BoN Protection of Individuals (CPP Ouest V, Rennes) on July 31, 2017. The questionnaire was proposed by the patient association, and at no time was shown to exhibit external validity, correlating well did the authors of the project or the persons in charge of the analgesia with the other validated QoL scales. statistics know the identity of the responders. Our study exhibits several limitations, the largest one There was no way to make a connection between the answers obtained and the person who answered the questionnaire. being its relatively small sample size of 65 accessible The respondents were provided with an information sheet before giving patients. In this regard, we used a Kaiser-Meyer-Olkin their consent. This information sheet as well as the consent form clearly measure to explore the sampling adequacy, and all explained the purpose of the project and guaranteed the anonymity of the responses. values were greater than 0.6, except for the 2 items that were removed. Consent for publication Another limitation is the sole use of BoN in adult pa- Not applicable. tients, as the tool has not yet been validated in children. Competing interests We hope that this BoN questionnaire will serve as a The authors declare that they have no competing interests. valuable tool for healthcare providers to better follow up ’ their patients improvement, and adjust NF1 patient sNote ’ Publisher management accordingly. This burden evaluation will Springer Nature remains neutral with regard to jurisdictional claims in likely facilitate communication between patients and published maps and institutional affiliations.

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