Validation of the North Star Assessment for Limb-Girdle Type Muscular Dystrophies.

OBJECTIVE: The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes. METHODS: Assessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children's Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data "fit" with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity. RESULTS: The NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981-0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of rs(134) = .92). CONCLUSION: Although LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings. IMPACT: Recent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings.

Consensus Guidelines for Improving Quality of Assessment and Training for Neuromuscular Diseases.

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center's expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naïve to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings.

Remote Delivery of Motor Function Assessment and Training for Clinical Trials in Neuromuscular Disease: A Response to the COVID-19 Global Pandemic.

Clinical outcome assessments of function or strength, assessed by physical therapists, are commonly used as primary endpoints in clinical trials, natural history studies and within clinics for individuals with neuromuscular disorders. These evaluations not only inform the efficacy of investigational agents in clinical trials, but also importantly track disease trajectory to prospectively advise need for equipment, home and work modifications, and other assistive devices. The COVID-19 pandemic had a global impact on the safety and feasibility of in-person visits and assessments, necessitating rapid development of mitigation strategies to ensure ongoing collection of key clinical trial endpoints and access to expert clinical care despite travel restrictions. Physical therapists who are expert in neuromuscular disorders working across clinics, countries, and clinical trials developed initial guidelines and methods for the suitability and feasibility of performing remote evaluations. A number of Sponsors introduced amendments to their study protocols to enable remote evaluations, supported by live video streaming of the assessment to their local clinical evaluators. Similarly, application of these techniques to clinical telemedicine enabled objective evaluations for use in payer discussions, equipment procurement, and general access to expert physical therapy services. Here we report on our methodology for adapting current practices to remote testing and considerations for remote evaluations.

Assessment of disease progression in dysferlinopathy: A 1-year cohort study.

OBJECTIVE: To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year. METHODS: One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation's International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis. RESULTS: The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In nonambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint. CONCLUSION: Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials. CLINICALTRIALSGOV IDENTIFIER: NCT01676077.

Aquatic therapy for children with Duchenne muscular dystrophy: a pilot feasibility randomised controlled trial and mixed-methods process evaluation.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare disease that causes the progressive loss of motor abilities such as walking. Standard treatment includes physiotherapy. No trial has evaluated whether or not adding aquatic therapy (AT) to land-based therapy (LBT) exercises helps to keep muscles strong and children independent. OBJECTIVES: To assess the feasibility of recruiting boys with DMD to a randomised trial evaluating AT (primary objective) and to collect data from them; to assess how, and how well, the intervention and trial procedures work. DESIGN: Parallel-group, single-blind, randomised pilot trial with nested qualitative research. SETTING: Six paediatric neuromuscular units. PARTICIPANTS: Children with DMD aged 7-16 years, established on corticosteroids, with a North Star Ambulatory Assessment (NSAA) score of 8-34 and able to complete a 10-m walk without aids/assistance. Exclusions: > 20% variation between baseline screens 4 weeks apart and contraindications. INTERVENTIONS: Participants were allocated on a 1 : 1 ratio to (1) optimised, manualised LBT (prescribed by specialist neuromuscular physiotherapists) or (2) the same plus manualised AT (30 minutes, twice weekly for 6 months: active assisted and/or passive stretching regime; simulated or real functional activities; submaximal exercise). Semistructured interviews with participants, parents (n = 8) and professionals (n = 8) were analysed using Framework analysis. An independent rater reviewed patient records to determine the extent to which treatment was optimised. A cost-impact analysis was performed. Quantitative and qualitative data were mixed using a triangulation exercise. MAIN OUTCOME MEASURES: Feasibility of recruiting 40 participants in 6 months, participant and therapist views on the acceptability of the intervention and research protocols, clinical outcomes including NSAA, independent assessment of treatment optimisation and intervention costs. RESULTS: Over 6 months, 348 children were screened - most lived too far from centres or were enrolled in other trials. Twelve (30% of target) were randomised to AT (n = 8) or control (n = 4). People in the AT (n = 8) and control (n = 2: attrition because of parental report) arms contributed outcome data. The mean change in NSAA score at 6 months was -5.5 [standard deviation (SD) 7.8] for LBT and -2.8 (SD 4.1) in the AT arm. One boy suffered pain and fatigue after AT, which resolved the same day. Physiotherapists and parents valued AT and believed that it should be delivered in community settings. The independent rater considered AT optimised for three out of eight children, with other children given programmes that were too extensive and insufficiently focused. The estimated NHS costs of 6-month service were between £1970 and £2734 per patient. LIMITATIONS: The focus on delivery in hospitals limits generalisability. CONCLUSIONS: Neither a full-scale frequentist randomised controlled trial (RCT) recruiting in the UK alone nor a twice-weekly open-ended AT course delivered at tertiary centres is feasible. Further intervention development research is needed to identify how community-based pools can be accessed, and how families can link with each other and community physiotherapists to access tailored AT programmes guided by highly specialised physiotherapists. Bayesian RCTs may be feasible; otherwise, time series designs are recommended. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41002956. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 27. See the NIHR Journals Library website for further project information.

Development and psychometric analysis of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT).

The objective of this study was to describe the development and initial psychometric analysis of the UK English version of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a patient-reported outcome (PRO) scale designed to measure functional ability in patients with Duchenne muscular dystrophy (DMD). Item selection was made by neuromuscular specialists and a Rasch analysis was performed to understand the psychometric properties of the DMDSAT. Instrument scores were also linked to cost of illness and health-related quality of life data. The administered version, completed by 186 UK patient-caregivers pairs, included eight items in four domains: Arm function, Mobility, Transfers, and Ventilation status. These items together successfully operationalized functional ability in DMD, with excellent targeting and reliability (Person Separation Index: 0.95; Cronbach's α: 0.93), stable item locations, and good fit to the Rasch model (mean person/item fit residual: -0.21/-0.44, SD: 0.32/1.28). Estimated item difficulty was in excellent agreement with clinical opinion (Spearman's ρ: 0.95) and instrument scores mapped well onto health economic outcomes. We show that the DMDSAT is a PRO instrument fit for purpose to measure functional ability in ambulant and non-ambulant patients with DMD. Rasch analysis augments clinical expertise in the development of robust rating scales.

Detecting meaningful change using the North Star Ambulatory Assessment in Duchenne muscular dystrophy.

AIM: Clinician-reported outcome instruments such as the North Star Ambulatory Assessment (NSAA) need to be able to detect clinically important change to be suitable for clinical trials. However, in Duchenne muscular dystrophy (DMD), identifying changes in function is not straightforward. In this study, we use Rasch-transformed data to examine the responsiveness and minimal important difference (MID) of the NSAA in males with DMD receiving different corticosteroid regimes. METHOD: NSAA data were examined from 198 males (mean age at assessment was 8 y 6 mo [SD 2 y 6 mo] range 4 y-18 y; 805 assessments). Responsiveness was assessed using mean score changes (using Rasch-transformed data) between adjacent pairs of age groups, pairwise squared t-values from paired samples t-tests, and an effect size calculation. The MID was assessed using the effect size calculation and 0.5 standard deviation (SD) of mean score differences. RESULTS: Our findings revealed a difference in change scores over time between the two corticosteroid regimes. Mean NSAA person estimates were higher in the daily prednisolone group. The mean MID (0.5 SD) was 8.8 and 6.9 for the daily group and intermittent group respectively. INTERPRETATION: This study, based on Rasch-transformed NSAA data, provides an initial basis for the interpretation of clinical change in DMD over time and between corticosteroid regimes. Our proposed MIDs can be mapped back to differences in specific item content across the range of the NSAA.

Quantitative muscle MRI as an assessment tool for monitoring disease progression in LGMD2I: a multicentre longitudinal study.

BACKGROUND: Outcome measures for clinical trials in neuromuscular diseases are typically based on physical assessments which are dependent on patient effort, combine the effort of different muscle groups, and may not be sensitive to progression over short trial periods in slow-progressing diseases. We hypothesised that quantitative fat imaging by MRI (Dixon technique) could provide more discriminating quantitative, patient-independent measurements of the progress of muscle fat replacement within individual muscle groups. OBJECTIVE: To determine whether quantitative fat imaging could measure disease progression in a cohort of limb-girdle muscular dystrophy 2I (LGMD2I) patients over a 12 month period. METHODS: 32 adult patients (17 male;15 female) from 4 European tertiary referral centres with the homozygous c.826C>A mutation in the fukutin-related protein gene (FKRP) completed baseline and follow up measurements 12 months later. Quantitative fat imaging was performed and muscle fat fraction change was compared with (i) muscle strength and function assessed using standardized physical tests and (ii) standard T1-weighted MRI graded on a 6 point scale. RESULTS: There was a significant increase in muscle fat fraction in 9 of the 14 muscles analyzed using the quantitative MRI technique from baseline to 12 months follow up. Changes were not seen in the conventional longitudinal physical assessments or in qualitative scoring of the T1w images. CONCLUSIONS: Quantitative muscle MRI, using the Dixon technique, could be used as an important longitudinal outcome measure to assess muscle pathology and monitor therapeutic efficacy in patients with LGMD2I.

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network.

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.

Magnetic resonance imaging in Duchenne muscular dystrophy: longitudinal assessment of natural history over 18 months.

INTRODUCTION: In Duchenne muscular dystrophy (DMD), fat replacement of muscle may be a useful endpoint in trials of therapy, although progression in different muscle groups is uneven. In this study we assessed the progression of fat replacement with T(1) -weighted imaging over 2 9-month periods. METHODS: Eight ambulant, corticosteroid-treated boys with DMD were imaged at 3 Tesla at 3 time-points (baseline and 9 and 18 months) with T(1) -weighted imaging to measure fat replacement. RESULTS: The greatest increase in fat content was measured in the biceps femoris long head, vastus lateralis, and rectus femoris, whereas the biceps femoris short head and gluteus maximus progressed more slowly. None of the lower leg muscles studied changed significantly. CONCLUSIONS: MRI can measure specific changes in fat replacement of muscle over time, demonstrating the variability in rates of natural progression between muscle groups and identifying those muscles suitable for use as biomarkers in clinical trials.

Development of a functional assessment scale for ambulatory boys with Duchenne muscular dystrophy.

BACKGROUND AND PURPOSE: The aims of this study were to develop a clinical assessment scale to measure functional ability in ambulant boys with Duchenne muscular dystrophy and to determine the reliability of the scale in multiple centres in the UK. METHODS: Focus groups and workshops were held with experienced paediatric neuromuscular physiotherapists to determine scale content. A manual was prepared with accompanying videos, and training sessions were conducted. A total of 17 physiotherapists from participating centres used the videos to determine inter-rater reliability. Five determined the intra-rater reliability. RESULTS: Strength of agreement for these groups based on total subject scores was very good (0.95 and ≥ 0.93 for consistency and absolute agreement, respectively). Test-retest ability was high, with perfect agreement between occasions for all but two items of the scale. CONCLUSIONS: Our study indicates that the North Star Ambulatory Assessment is practical and reliable. It takes only 10 minutes to perform and incorporates both universally used timed tests as well as levels of activities, which allow assessment of high-functioning boys with Duchenne muscular dystrophy.

Moving towards meaningful measurement: Rasch analysis of the North Star Ambulatory Assessment in Duchenne muscular dystrophy.

AIM: Reliable measurement of disease progression and the effect of therapeutic interventions in Duchenne muscular dystrophy (DMD) require clinically meaningful and scientifically sound rating scales. Therefore, we need robust evidence to support such tools. The North Star Ambulatory Assessment (NSAA) is a promising, clinician-rated scale with potential uses spanning clinical practice and clinical trials. In this study, we used Rasch analysis to test its suitability in these roles as a measurement instrument. METHOD: NSAA data from 191 ambulant boys (mean age at assessment 7 y 8 mo, SD 2 y 4 mo; range 3 y 6 mo-15 y 5 mo) with a confirmed diagnosis of DMD were examined for psychometric properties including clinical meaning, targeting, response categories, model fit, reliability, dependency, stability, and raw to interval-level measurement. All analyses were performed using the Rasch Unidimensional Measurement Model. RESULTS: Overall, Rasch analysis supported the NSAA as being a reliable (high Person Separation Index of 0.91) and valid (good targeting, little misfit, no reversed thresholds) measure of ambulatory function in DMD. One item displayed misfit (lifts head, fit residual 6.9) and there was evidence for some local dependency (stand on right/left leg, climb and descend box step right/left leg, and hop on right/left leg, residual correlations >0.40), which we provide potential solutions for in future use of the NSAA. Importantly, our findings supported good clinical validity in that the hierarchy of items within the scale produced by the analyses was supported by clinical opinion, thus increasing the clinical interpretability of scale scores. INTERPRETATION: In general, Rasch analysis supported the NSAA as a psychometrically robust scale for use in DMD clinical research and trials. This study also demonstrates how Rasch analysis is a useful instrument to detect and understand the key measurement issues of rating scales.

Reproductive health of adolescent girls perinatally infected with HIV.

OBJECTIVES: We sought to describe the reproductive health of adolescent girls perinatally infected with HIV. METHODS: We estimated the incidence of first pregnancy, genital infections, and abnormal cervical cytology for 638 girls aged 13 years and older in the Pediatric AIDS Clinical Trials Group protocol 219C. RESULTS: Thirty-eight girls became pregnant, for a first pregnancy rate of 18.8/1000 person-years; 7 of these girls had additional pregnancies (95% confidence interval [CI]=13.3, 25.7). Thirty-two pregnancies resulted in live births. All girls received antiretroviral therapy during pregnancy. One infant was HIV infected, 29 were uninfected, and 2 had unknown infection status, for a rate of mother-to-child transmission of HIV in infants with known infection status of 3.3% (95% CI=0.1, 18.6). Condylomata and trichomoniasis were the most frequent genital infections. Forty-eight (47.5%) of 101 girls with Papanicolaou test examinations had abnormal cervical cytology, including atypical cells of undetermined significance (n=18), low-grade squamous intraepithelial lesions (SIL; n=27), and high-grade SIL (n=3). Many abnormalities persisted despite intervention. CONCLUSIONS: Pregnancy rates were lower and cervical abnormalities were higher than among non-HIV-infected adolescents. These findings underscore the importance of Papanicolaou tests and promotion of safer sexual practices in this population.