ORIGINAL RESEARCH published: 10 March 2022 doi: 10.3389/fneur.2022.828525 Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: Edited by: Edoardo Malfatti, Hôpitaux Universitaires Henri A Rasch Analysis Approach Mondor, France Anna G. Mayhew 1*, Meredith K. James 1 , Ursula Moore 1 , Helen Sutherland 1 , Reviewed by: Marni Jacobs 2,3 , Jia Feng 2 , Linda Pax Lowes 4 , Lindsay N. Alfano 4 , Robert Muni Lofra 1 , Matthias Boentert, University Hospital Münster, Germany Laura E. Rufibach 5 , Kristy Rose 6 , Tina Duong 7,8 , Luca Bello 9 , Irene Pedrosa-Hernández 10 , Luc Laberge, Scott Holsten 11 , Chikako Sakamoto 12 , Aurélie Canal 13 , Cégep de Jonquière, Canada Nieves Sánchez-Aguilera Práxedes 14 , Simone Thiele 15 , Catherine Siener 16 , Bruno Vandevelde 17 , Brittney DeWolf 7 , Elke Maron 18 , Heather Gordish-Dressman 2,3 , *Correspondence: Anna G. Mayhew Heather Hilsden 1 , Michela Guglieri 1 , Jean-Yves Hogrel 13 , Andrew M. Blamire 19 , anna.mayhew@newcastle.ac.uk Pierre G. Carlier 20 , Simone Spuler 21 , John W. Day 22 , Kristi J. Jones 6 , Diana X. Bharucha-Goebel 23,24 , Emmanuelle Salort-Campana 17 , Alan Pestronk 16 , † Decreased Maggie C. Walter 15 , Carmen Paradas 25 , Tanya Stojkovic 13 , Madoka Mori-Yoshimura 26 , Elena Bravver 11† , Jordi Díaz-Manera 27,28 , Elena Pegoraro 9 , Jerry R. Mendell 4 on behalf of Specialty section: The Jain COS Consortium and Volker Straub 1 This article was submitted to 1 Neuromuscular Disorders and The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University Peripheral Neuropathies, and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 2 Center for Translational Science, a section of the journal Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, DC, United States, 3 Frontiers in Neurology Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, DC, United States, 4 The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States, 5 The Jain Foundation, Seattle, Received: 03 December 2021 WA, United States, 6 The Children’s Hospital at Westmead, The University of Sydney, Sydney, NSW, Australia, 7 Cooperative Accepted: 31 January 2022 International Neuromuscular Research Group (CINRG), Children’s National Health System, Washington, DC, United States, Published: 10 March 2022 8 Lucile Salter Packard Children’s Hospital at Stanford, Neurology, Palo Alto, CA, United States, 9 Department of Citation: Neuroscience, University of Padova, Padua, Italy, 10 Physical Medicine and Rehabilitation, Hospital de la Santa Creu i Sant Mayhew AG, James MK, Moore U, Pau, Barcelona, Spain, 11 Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Sutherland H, Jacobs M, Feng J, Charlotte, NC, United States, 12 Department of Physical Rehabilitation, National Center Hospital, National Center of Lowes LP, Alfano LN, Muni Lofra R, Neurology and Psychiatry Tokyo, Tokyo, Japan, 13 Institut de Myologie, AP-HP, GH Pitié-Salpêtrière, Paris, France, 14 Rufibach LE, Rose K, Duong T, Neurorehabilitation Unit, Rehabilitation Hospital Universitario Virgen del Rocío Sevilla, Seville, Spain, 15 Department of Bello L, Pedrosa-Hernández I, Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University of Munich, Munich, Germany, 16 Department of Neurology, Holsten S, Sakamoto C, Canal A, Washington University School of Medicine, St. Louis, MO, United States, 17 Service des Maladies Neuromusculaire et de la Sánchez-Aguilera Práxedes N, SLA, Hôpital de La Timone, Marseille, France, 18 ELAN-PHYSIO, Praxis für Physiotherapie Maron, Berlin, Germany, 19 Thiele S, Siener C, Vandevelde B, Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom, 20 DeWolf B, Maron E, AIM & CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, Paris, France, 21 Charite Muscle Gordish-Dressman H, Hilsden H, Research Unit, Experimental and Clinical Research Center, A Joint Cooperation of the Charité Medical Faculty and the Max Guglieri M, Hogrel J-Y, Blamire AM, Delbrück Center for Molecular Medicine, Berlin, Germany, 22 Department of Neurology and Neurological Sciences, Stanford Carlier PG, Spuler S, Day JW, University School of Medicine, Stanford, CA, United States, 23 Department of Neurology Children’s National Health System, Jones KJ, Bharucha-Goebel DX, Washington, DC, United States, 24 National Institutes of Health (NINDS), Bethesda, MD, United States, 25 Neuromuscular Salort-Campana E, Pestronk A, Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Sevilla, Spain, 26 Department Walter MC, Paradas C, Stojkovic T, of Neurology, National Center Hospital, National Center of Neurology and Psychiatry Tokyo, Tokyo, Japan, 27 Centro de Mori-Yoshimura M, Bravver E, Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain, 28 Neuromuscular Disorders Unit, Díaz-Manera J, Pegoraro E, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Mendell JR and Straub V (2022) Assessing the Relationship of Patient Reported Outcome Measures With Dysferlinopathy is a muscular dystrophy with a highly variable functional disease Functional Status in Dysferlinopathy: A progression in which the relationship of function to some patient reported outcome Rasch Analysis Approach. Front. Neurol. 13:828525. measures (PROMs) has not been previously reported. This analysis aims to identify doi: 10.3389/fneur.2022.828525 the suitability of PROMs and their association with motor performance.Two-hundred Frontiers in Neurology | www.frontiersin.org 1 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy and four patients with dysferlinopathy were identified in the Jain Foundation’s Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy. Keywords: limb girdle muscular dystrophy, dysferlinopathy, PROMs, quality of life, clinical outcome assessments INTRODUCTION into examining PROMs in this group over time and has shown the ACTIVLIM to detect change even in a period of Dysferlinopathy is a rare, autosomal recessive muscular 6 months (14), limited work has been done on the other dystrophy caused by mutations in the DYSF gene, which encodes patient measures. the skeletal muscle protein dysferlin (1, 2). The most common The Jain Clinical Outcomes Study (COS) for dysferlinopathy clinical diagnoses associated with dysferlinopathy are limb was established to address the lack of comprehensive natural girdle muscular dystrophy type 2B (LGMDR2 dysferlin related) history data for dysferlinopathy, particularly around PROMs, and a distal posterior myopathy known as Miyoshi myopathy and to identify if these were associated with functional changes 1 MM1 (3, 4). Though onset typically occurs during young related to disease progression. The aim of the present paper adulthood, clinical presentation is inconsistent, with a wide is to evaluate the suitability and change of selected PROMs range of ages of onset, patterns of muscle weakness, and severity, from baseline up to a maximum of 4 years and to examine despite the fact that most patients share a loss of expression the association between these measures and the North Star of the dysferlin protein (1, 5–7). Likewise, disease progression Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) is variable; loss of ambulation occurs 5 to 35 years after onset (15) and the Performance of Upper Limb (PUL) (16), both as of muscle weakness, while a small number of patients remain measures of motor performance. only mildly affected for decades (8, 9). A number of factors that may influence the clinical phenotype and progression of dysferlinopathy have been proposed, including exercise and the METHODS specific mutation (5, 10, 11), though no clear pattern of decline or genotype–phenotype correlation has been established. Clinical Outcomes Study is a multicenter, international study Of key importance to developing appropriately designed of patients with a confirmed diagnosis of dysferlinopathy. clinical trials in this group and to provide support and Detailed study methods have been published previously (8, 14). appropriate management for patients is understanding the In order to be included in COS, patients were required to natural history of the disease over time, particularly its have two pathogenic mutations in DYSF, or one pathogenic impact on function, activities of daily living and ultimately mutation plus either absent dysferlin expression on immunoblot quality of life. These are generally described as Patient or <20% dysferlin monocyte expression. Each participating site Reported Outcome Measures (PROMs) or Patient Centered received local ethics approval and written informed consent Outcome Measures (PCOMs). They are deemed a necessity was obtained for all patients. The study was registered at for evaluating disease progression and the efficacy and clinical ClinicalTrials.gov (NCT01676077). meaningfulness of therapeutic interventions by experts (12) The present study includes data from 204 patients at 14 sites; and regulatory authorities (13). Although some work has gone one original site was excluded from the present analysis due to Frontiers in Neurology | www.frontiersin.org 2 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy unidimensionality the level of missing data over the 4-year period. Participants were Not acceptable Not acceptable evaluated on PROMs up to five times over the course of the Acceptable? study: baseline (visit 1), 12 (V2), 24 (V3), 36 (V4), and for some Acceptable at 48 (V5) months. Visits took place between November 2012 Test of and March 2018. Follow-up rate was high with 163 participants (87.2%) completing all five study visits across the 14 sites. Number of pairs of dependent items Demographic and Clinical Measures Dependency Self-reported race (if allowed by the participating country) and patient gender were recorded at baseline. Age at each study visit was approximated using the visit date and patient’s year of 33 2 0 birth. Clinical diagnosis of LGMDR2, MM1, or other (consisting primarily of hyperCKemia) was recorded based on the diagnostic 8/10 (80%) 8a / 9b 16/18 (89%) 16a 20/39 (51%) 26a Number of items label given by the diagnosing clinician, as reported by patients. with good fit* Ambulatory status was defined at the point of assessment by the ability to complete a 10-m walk distance independently (gait aids / 16b / 24b permissible) as part of the physiotherapy assessment. Item fit Outcome Measures A wide range of measures were included in the study, 18/18 (100 %) including measures of function and muscle strength, in order thresholds Ordered to establish their usefulness in assessing disease progression 15/39 (38%) (30%) 3/10 over time. For this study, we examined all patients who completed the following PROMs as appropriate: ACTIVLIM, International Physical Activity Questionnaire (IPAQ), and the Psi with extremes Individualized Neuromuscular Quality of Life Questionnaire (INQoL). Nonambulant patients also completed the Egen Reliability defined as fit residual inside the recommended range (–2.50 to +2.50) a and nonsignificant v2 probability (p<0.001) b . Klassifikation (EK) scale. Assessments were conducted annually 0.95 0.95 0.76 at baseline, years 1, 2, and 3 for some at year 4. Data were also collected on motor performance at these time points (8). The ACTIVLIM is a validated patient reported outcome Overall item-trait interaction chi 2 measure of functional ability based on perceived difficulty in performing specific activities of daily living (17). Total scores 0.00 (162) 0.00 (351) 0.00 (120) value (DF) range from 0 to 36, with higher scores suggesting better function. International Physical Activity Questionnaire assesses a Person fit person’s physical activity levels using a set of seven questions and describes that activity in terms of time spent and level of −0.423 (0.576) intensity (18). There are two forms of output from scoring the −0.37 (0.883) −0.09 (1.703) TABLE 1 | Summary Rasch results for ACTIVLIM, INQoL, and EK scales. IPAQ. Results can be reported in categories (low activity levels, Mean (SD) moderate activity levels or high activity levels) or as a continuous variable (Metabolic Equivalent Task (MET) minutes a week). Individualized Neuromuscular Quality of Life Questionnaire is a quality of life measure that aims to capture the impact of key muscle disease symptoms and the impact on activities, −0.05 (1.963) −0.22 (1.737) 0.65 (3.039) independence, relationships, and body image (19). Mean (SD) Item fit The EK scale is a patient’s assessment of their “own functioning” related to daily tasks and was designed for nonambulant pediatric and adult patients with N (no. of extremes) Duchenne muscular dystrophy (DMD) and spinal Rasch summary 787 (66) = 721 muscular atrophy (20, 21). 660 (2) = 658 250 (5) = 245 The NSAD is a Rasch-developed clinician reported outcome available (ClinRO) of motor performance suitable for ambulant and nonambulant adults and children, validated in this dysferlinopathy (LGMDR2) cohort, and has been shown to be ACTIVLIM very sensitive to change over 1 year (15). INQoL The PUL scale was designed specifically to measure upper * Fit: EK limb motor performance across the spectrum of severity in Frontiers in Neurology | www.frontiersin.org 3 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy FIGURE 1 | Threshold map showing all items ordered in the ACTIVLIM Scale in order of difficulty. Threshold map for items in ranked order of difficulty according to Rasch analysis. “Impossible” labeled 1; “With difficulty” labeled 2; “Easy” labeled 3. There were no reversed thresholds. This is why the figure legend suggested that disordered thresholds will be labeled with a double asterisk but none are disordered. The implication of this is that as a person’s functional ability increases (move left to right) they would be more likely to score higher in a consistent and hierarchical way for all questions. FIGURE 2 | Person–item location distribution for the EK scale. Targeting of the patient sample (top) to the EK items (bottom). The figure shows the adequate targeting between the distribution of person measurements (upper histogram) and the distribution of item locations (lower histogram). There are no ceiling/floor effects indicated by the range of the person measurements (upper histogram “blocks”) falling within the item locations (lower histogram “blocks”). Frontiers in Neurology | www.frontiersin.org 4 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy FIGURE 3 | Association between Total NSAD score and ACTIVLIM. NSAD, North Star Assessment for Limb Girdle Type Muscular Dystrophies; ACTIVLIM, Measure of Activity Limitations in Daily Living. pediatric and adult DMD, is also a Rasch-built ClinRO, and targeting of the scales by plotting item location for them has been shown to be valid and sensitive to change in DMD separately and comparing individual person–item threshold over time (22, 23). distribution maps for any significant floor or ceiling effects or gaps in the continuum of measurements in the two scales; Rasch Analysis (5) dependency, which determines if the response on one For rating scales (ACTIVLIM, INQoL, EK), Rasch analysis item influences the response on another item (this is assessed (RUMM2030 software) was conducted. Essentially, a Rasch by examining the residual correlations); and finally (6) a t- analysis examines the extent to which the observed data test of unidimensionality. Details on these methods can be (in this instance, patients’ ratings on scale items) “fit” with found elsewhere (26). predictions of those ratings from the Rasch model (which defines how a set of items should perform to generate discriminant, reliable, and valid measurements) (24). Data were entered Statistical Analysis into Rasch Unidimensional Measurement Model RUMM2030 Data were analyzed using descriptive statistics for each visit (standard version; RUMM Laboratory Pty Ltd, Perth, Australia). and the entire study. For associations, graphs (NSAD with Analyses assessed (1) item fit to the underlying construct of ACTIVLM, IPAQ and INQoL and EK with PUL) were the questionnaire (all items should lie within a fit residual generated from generalized estimating equations (GEE) based range of SD 2.5); (2) whether the scoring within each item on preliminary examination of cubic spline graphs. Spearman reflected perceived progression (ordering of thresholds); (3) correlation coefficients are presented for reference. Pseudo R2 reliability, as indicated by a Person Separation Index of more for fixed effects were estimated from generalized linear mixed than 0.8, which is equivalent to Cronbach’s alpha (25); (4) models using techniques described by Jaeger et al. (27). Frontiers in Neurology | www.frontiersin.org 5 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy FIGURE 4 | Association between total NSAD score and IPAQ. NSAD, North Star Assessment for Limb Girdle Type Muscular Dystrophies; IPAQ, International Physical Activity Questionnaire. RESULTS not including the treatment section, as only 23% of the cohort answered the questions relating to treatment and their responses Of the cohort of 204 patients, 97 were men and 107 were women. included a wide variety of management techniques which were Median age at baseline assessment was 36 years of age, range of not comparable. However, a sub-total score was calculated on all 8–86. At baseline 76% of the study cohort were ambulant. questions unrelated to treatment. For EK, a total of 208 questionnaires were reviewed over 4 Descriptive Results time points (245 for Rasch over 5 time points) in nonambulant For ACTIVLIM, a total of 733 questionnaires were reviewed over individuals. The median score was 7 (range 1–21), out of a 4 time points (787 for Rasch over 5 time points); 2% showed maximum of 30, with higher scores indicating being less able. scores under 16 and were excluded from Rasch analysis as they See Appendix A for a summary of PROM data over the would have answered a different subset of four items. Median different time points. score was 23 (range 0–36). For IPAQ, a total of 748 questionnaires were reviewed over Rasch Analysis 4 time points. Eighty-two percent of patients undertook no The results of the Rasch analysis for the three rating scales vigorous exercise, 59% undertook no moderate exercise, 40% are presented in Table 1. The data included the year 4 data did no walking exercise for more than 10 min. The mean time that were available for these Rasch analyses. The ACTIVLIM spent sitting per day was 9.4 h (SD 4.7). Twenty-four percent presented as a scale with good fit to the population with all were nonambulant. items showing ordered thresholds (Figure 1) and 89% of items For INQoL, a total of 660 questionnaires were reviewed over showing good fit with minimal dependency and an acceptable 4 time points. Total scores were calculated on a subset of items level of unidimensionality. Frontiers in Neurology | www.frontiersin.org 6 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy FIGURE 5 | Association between total NSAD score and INQoL. NSAD, North Star Assessment for Limb Girdle Type Muscular Dystrophies; INQoL, Individualized Neuromuscular Quality of Life Questionnaire. The INQoL performed less well with poor ordering of patient-centered outcomes with measures of motor performance thresholds (38%), unacceptable unidimensionality and limited can add clinical meaning to motor measures which in turn could item fit to the construct of Health Related Quality of Life be valuable within the clinical trial setting. For example, do (HRQoL), although adequate targeting was apparent with only changes in arm function measured on the PUL reflect changes a small floor effect. For the EK, ordering of the thresholds was in how easy or hard it is for an individual to wash and dress their low but items showed good fit and targeting (Figure 2) and upper body? unidimensionality was acceptable. At the beginning of COS, the choice of PROMs needed careful The ACTIVLIM was strongly associated with the NSAD total consideration as no gold standard existed for this population. score (Pseudo R2 0.68), whereas the INQoL was poorly associated The ACTIVLIM and INQoL were chosen as they had been built with the NSAD total score (Pseudo R2 0.18), as was the IPAQ using modern psychometric methods and had demonstrated Total METS (Pseudo R2 0.09). For the nonambulant population, some evidence of suitability in neuromuscular disease (17, 19). the EK was strongly associated with the PUL total score (Pseudo The IPAQ was used because activity had not been studied in R2 0.69) (Figures 3–6). the group and was felt to be a significant factor, and the EK was selected to capture “own functioning” in the nonambulant DISCUSSION patient population. The ACTIVLIM performed particularly well psychometrically in this population with adequate targeting, Findings from the present study in dysferlinopathy provide ordered thresholds, and most items fitting the construct well. The useful information on the suitability (i.e., do the scales work EK scale contained several clinically relevant items for this group; as measurement tools?) of four PROMs to capture the patient’s however, some items around respiratory insufficiency appeared opinion. In addition, understanding the relationship between to be not relevant for the nonambulant dysferlinopathy patients. Frontiers in Neurology | www.frontiersin.org 7 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy FIGURE 6 | Association between total PUL score and EK scale. EK, Egen Klassification questionnaire; PUL, Performance of Upper Limb Scale. However, the association of arm function with scores on the EK quarter of our cohort, which, for example, could result in a has been demonstrated in DMD (28) and it may be that a subset limited understanding of activity levels in this group. It may have of the items could be identified to capture function in the weaker been beneficial to review and adapt some of the PROMs prior population. The association of EK to arm function, although to testing in such a large cohort. This could have identified any strong, is not linear, which may indicate that different domains unnecessary or unsuitable questions: for example, the swallowing are captured by the individual scales. The IPAQ also did not and eating items within the EK scale. However, evidence of how correlate with functional status as measured by NSAD; however, scales work in their original format removes the concern that it is not designed specifically to capture activity and exercise changes made to it prior to full evaluation were unjustified. We in the nonambulant population and meta-analysis has shown also acknowledge that although chronic pain is recognized as that it is perhaps not capturing activity satisfactorily (18). The being a significant issue for LGMD (30), we did not specifically INQoL performed less well psychometrically, with poor ordering evaluate this area using a chronic pain questionnaire although of thresholds and limited item fit to the construct of HRQoL, patients were asked about pain during their medical assessment. although adequate targeting was apparent with only a small floor The results of this analysis have benefited the design of effect. It was not associated with functional status, although an extension to this current study, where the quality of life it is understood that quality of life is not solely dependent measure has been replaced. More work needs to be undertaken to on functional abilities (29) and many individuals with motor understand function in relationship to these new PROMs and to impairment report high satisfaction with their lives. evaluate if change in function over time is reflected in the related This study had some limitations. Not all the measures selected PROM. Further work can also commence on refinement of some were suitable for nonambulant individuals, which made up a of the current tools such as the EK scale and IPAQ. Frontiers in Neurology | www.frontiersin.org 8 March 2022 | Volume 13 | Article 828525 Mayhew et al. PROMs in Dysferlinopathy DATA AVAILABILITY STATEMENT implementation and manuscript writing. All authors contributed to the article and approved the submitted version. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. FUNDING ETHICS STATEMENT The estimated US $4 million needed to fund this study was provided by the Jain Foundation (www.jainfoundation.org). The The studies involving human participants were reviewed and John Walton Muscular Dystrophy Research Centre is part of approved by NRES Committee, North East-Newcastle & North the MRC Centre for Neuromuscular Diseases (Grant Number Tyneside 2. Written informed consent to participate in this study MR/K000608/1). was provided by the participants’ legal guardian/next of kin. ACKNOWLEDGMENTS AUTHOR CONTRIBUTIONS Members of the Jain COS Consortium can be found in AM, MKJ, VS, LL, LA, and LR: conceptualization of the Supplementary Table 1. The Jain COS consortium would like project, methodology design, research implementation, results to thank the study participants and their families for their analysis, and manuscript writing. UM, HS, JF, RM, KR, and invaluable contribution. TD: research implementation, results analysis, and manuscript writing. MJ: results analysis and manuscript writing. HG: methodology design, research implementation, results analysis, SUPPLEMENTARY MATERIAL and manuscript writing. HH: methodology design, research implementation, and manuscript writing. NS-A, ST, CSi, BV, BD, The Supplementary Material for this article can be found EM, MG, J-YH, AB, PC, SS, JD, KJ, DB-G, ES-C, AP, MW, CP, TS, online at: https://www.frontiersin.org/articles/10.3389/fneur. MM-Y, EB, JD-M, EP, JM, LB, IP-H, SH, CSa, and AC: research 2022.828525/full#supplementary-material REFERENCES 13. Cano SJ, Hobart JC. Watch out, watch out, the FDA are about. Dev Med Child Neurol. (2008) 50:408–9. doi: 10.1111/j.1469-8749.2008.00408.x 1. Bushby K, Straub V. One gene, one or many diseases?: 14. Moore U, Jacobs M, James MK, Mayhew AG, Fernandez-Torron R, Feng simplifying dysferlinopathy. Neurology. (2010) 75:298– J, et al. 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The performance of the upper limb scores correlate with pulmonary function Copyright © 2022 Mayhew, James, Moore, Sutherland, Jacobs, Feng, Lowes, Alfano, test measures and Egen Klassifikation scores in Duchenne muscular Muni Lofra, Rufibach, Rose, Duong, Bello, Pedrosa-Hernández, Holsten, Sakamoto, dystrophy. Neuromuscul Disord. (2016) 26:264–71. doi: 10.1016/j.nmd.2016. Canal, Sánchez-Aguilera Práxedes, Thiele, Siener, Vandevelde, DeWolf, Maron, 02.015 Gordish-Dressman, Hilsden, Guglieri, Hogrel, Blamire, Carlier, Spuler, Day, Jones, 29. Bendixen RM, Senesac C, Lott DJ, Vandenborne K. Participation and quality Bharucha-Goebel, Salort-Campana, Pestronk, Walter, Paradas, Stojkovic, Mori- of life in children with Duchenne muscular dystrophy using the international Yoshimura, Bravver, Díaz-Manera, Pegoraro, Mendell and Straub. This is an open- classification of functioning, disability, and health. Health Qual Life Outcomes. access article distributed under the terms of the Creative Commons Attribution (2012) 10:43. doi: 10.1186/1477-7525-10-43 License (CC BY). The use, distribution or reproduction in other forums is permitted, 30. Stokholm RN, Handberg C, Knudsen LF. Prevalence of chronic provided the original author(s) and the copyright owner(s) are credited and that the pain in a national cohort of patients with limb-girdle muscular original publication in this journal is cited, in accordance with accepted academic dystrophy: a cross-sectional study. Disabil Rehabil. (2021) practice. No use, distribution or reproduction is permitted which does not comply 0:1–9. doi: 10.1080/09638288.2021.1998669 with these terms. Frontiers in Neurology | www.frontiersin.org 10 March 2022 | Volume 13 | Article 828525