Measuring Disease Severity in Duchenne and Becker Muscular Dystrophy

Medical investigations use a wide variety of outcome indicators that are often not comparable. It can be challenging to integrate results across multiple studies that do not share a common metric. Some conditions such as Duchenne and Becker muscular dystrophy have a predictable course of disease progression. Severity can be inferred from a patient's medical history. This paper describes the development of a disease severity measure using common markers of disease progression. Rasch modeling was used to estimate severity using dichotomous events that indicate disease progression. Caregivers of 34 young men with Duchenne or Becker muscular dystrophy completed structured interviews about their care and medical history. Interview questions included surgeries (tendon release, scoliosis, tracheostomy), respiratory equipment (assisted ventilation, cough assist devices), and the use of other medical equipment (e.g., braces, walkers, wheelchairs, transfer boards, hospital beds). The resulting measure had a reliability of .83. The correlation between the severity measure and the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was .68. Preliminary results and item calibrations are provided for the severity measure that can be estimated from caregiver reports or administrative data. DOI:10.2458/azu_jmmss_v1i1_davis

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Measuring Disease Severity in Duchenne and Becker Muscular Dystrophy

Journal of Methods and Measurement in the Social Sciences ◽

10.2458/azu_jmmss_v1i1_p8-18 ◽

2010 ◽

Vol 1 (1) ◽

pp. 8

Author(s):

Melinda F. Davis ◽

Katalin H. Scherer ◽

Timothy M. Miller ◽

F. John Meaney

Keyword(s):

Muscular Dystrophy ◽

Medical History ◽

Disease Progression ◽

Disease Severity ◽

Rating Scale ◽

Becker Muscular Dystrophy ◽

Assisted Ventilation ◽

Structured Interviews ◽

Course Of Disease ◽

Outcome Indicators

Medical investigations use a wide variety of outcome indicators that are often not comparable. It can be challenging to integrate results across multiple studies that do not share a common metric. Some conditions such as Duchenne and Becker muscular dystrophy have a predictable course of disease progression. Severity can be inferred from a patient's medical history. This paper describes the development of a disease severity measure using common markers of disease progression. Rasch modeling was used to estimate severity using dichotomous events that indicate disease progression. Caregivers of 34 young men with Duchenne or Becker muscular dystrophy completed structured interviews about their care and medical history. Interview questions included surgeries (tendon release, scoliosis, tracheostomy), respiratory equipment (assisted ventilation, cough assist devices), and the use of other medical equipment (e.g., braces, walkers, wheelchairs, transfer boards, hospital beds). The resulting measure had a reliability of .83. The correlation between the severity measure and the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was .68. Preliminary results and item calibrations are provided for the severity measure that can be estimated from caregiver reports or administrative data. DOI:10.2458/azu_jmmss_v1i1_davis

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Measuring Disease Severity in Duchenne and Becker Muscular Dystrophy

Journal of Methods and Measurement in the Social Sciences ◽

10.2458/v1i1.76 ◽

2010 ◽

Vol 1 (1) ◽

pp. 8 ◽

Cited By ~ 2

Author(s):

Melinda F. Davis ◽

Katalin H. Scherer ◽

Timothy M. Miller ◽

F. John Meaney

Keyword(s):

Muscular Dystrophy ◽

Medical History ◽

Disease Progression ◽

Disease Severity ◽

Rating Scale ◽

Becker Muscular Dystrophy ◽

Assisted Ventilation ◽

Structured Interviews ◽

Course Of Disease ◽

Outcome Indicators

Medical investigations use a wide variety of outcome indicators that are often not comparable. It can be challenging to integrate results across multiple studies that do not share a common metric. Some conditions such as Duchenne and Becker muscular dystrophy have a predictable course of disease progression. Severity can be inferred from a patient's medical history. This paper describes the development of a disease severity measure using common markers of disease progression. Rasch modeling was used to estimate severity using dichotomous events that indicate disease progression. Caregivers of 34 young men with Duchenne or Becker muscular dystrophy completed structured interviews about their care and medical history. Interview questions included surgeries (tendon release, scoliosis, tracheostomy), respiratory equipment (assisted ventilation, cough assist devices), and the use of other medical equipment (e.g., braces, walkers, wheelchairs, transfer boards, hospital beds). The resulting measure had a reliability of .83. The correlation between the severity measure and the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was .68. Preliminary results and item calibrations are provided for the severity measure that can be estimated from caregiver reports or administrative data. DOI:10.2458/azu_jmmss_v1i1_davis

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Errata: Measuring Disease Severity in Duchenne and Becker Muscular Dystrophy

Journal of Methods and Measurement in the Social Sciences ◽

10.2458/v1i2.12366 ◽

2011 ◽

Vol 1 (2) ◽

Author(s):

Melinda F. Davis ◽

Katalin H. Scherer ◽

Timothy M. Miller ◽

F. John Meaney

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Muscular Dystrophy ◽

Disease Severity ◽

Muscle Weakness ◽

Respiratory Function ◽

Rating Scale ◽

Becker Muscular Dystrophy ◽

Progressive Muscle Weakness ◽

Lateral Sclerosis ◽

Disease Specific

Reports an error in Davis et al. (2010). The functional motor scale used in Davis et al. (2010) was the EK (Egen Klassifikation) Scale, rather than the Amyotrophic Lateral Sclerosis Functional Rating Scale (Steffensen et al., 2002; Cedarbaum & Stambler, 1997). Both scales are 10-item, disease-specific measures that assess mobility and respiratory function in individuals with progressive muscle weakness. This error does not change the conclusions. DOI:10.2458/azu_jmmss_v1i2_davis

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Errata: Measuring Disease Severity in Duchenne and Becker Muscular Dystrophy

Journal of Methods and Measurement in the Social Sciences ◽

10.2458/jmm.v1i2.12366 ◽

2011 ◽

Vol 1 (2) ◽

Author(s):

Melinda F. Davis ◽

Katalin H. Scherer ◽

Timothy M. Miller ◽

F. John Meaney

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Muscular Dystrophy ◽

Disease Severity ◽

Muscle Weakness ◽

Respiratory Function ◽

Rating Scale ◽

Becker Muscular Dystrophy ◽

Progressive Muscle Weakness ◽

Lateral Sclerosis ◽

Disease Specific

Reports an error in Davis et al. (2010). The functional motor scale used in Davis et al. (2010) was the EK (Egen Klassifikation) Scale, rather than the Amyotrophic Lateral Sclerosis Functional Rating Scale (Steffensen et al., 2002; Cedarbaum & Stambler, 1997). Both scales are 10-item, disease-specific measures that assess mobility and respiratory function in individuals with progressive muscle weakness. This error does not change the conclusions. DOI:10.2458/azu_jmmss_v1i2_davis

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Candidate gene modifiers of dystrophinopathy identified by the uniform application of genome-wide datasets to novel GWAS-identified loci

10.1101/2021.11.03.21265899 ◽

2021 ◽

Author(s):

Kevin M Flanigan ◽

Megan A. Waldrop ◽

Paul T. Martin ◽

Roxane Alles ◽

Diane M. Dunn ◽

...

Keyword(s):

Muscular Dystrophy ◽

Disease Progression ◽

Disease Severity ◽

Genome Wide Association Study ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Companion Paper ◽

Functional Protein ◽

Reading Frame ◽

Genome Wide

Although the major determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD) is whether their dystrophin gene (DMD) mutation disrupts the mRNA reading frame or allows expression of a partially functional protein, other genes have been proposed or demonstrated to modify the severity of disease progression. In a companion paper to this one, we describe our novel approaches to genome-wide association study (GWAS) of loss of ambulation (LOA) in the largest genome-wide search to date for loci influencing disease severity in DMD patients. Candidate regulatory SNPs that modify disease progression were identified using an evidential statistical paradigm and here we present a uniform application of recent functional genomic datasets to explore the potential functional impact of the top six candidate regions with PPLD scores of ≥0.4. The results of this analysis of the largest DMD GWAS survey to date elucidate recurrent and potentially new pathways for intervention in the dystrophinopathies.

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Serum creatinine as a biomarker for dystrophinopathy: a cross-sectional and longitudinal study

BMC Neurology ◽

10.1186/s12883-021-02382-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Liang Wang ◽

Min Xu ◽

Dawei Liu ◽

Yingyin Liang ◽

Pinning Feng ◽

...

Keyword(s):

Longitudinal Study ◽

Muscular Dystrophy ◽

Serum Creatinine ◽

Disease Progression ◽

Motor Function ◽

Fatty Infiltration ◽

Becker Muscular Dystrophy ◽

Cross Sectional Study ◽

Neuromuscular Disorder ◽

Cross Sectional

Abstract Background Dystrophinopathy, a common neuromuscular disorder, includes Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Many researches are currently ongoing to develop curative approaches, which results in an urgent need for biomarkers of disease progression and treatment response. This study investigated whether the serum creatinine (SCRN) level can be used as a biomarker of disease progression in dystrophinopathy. Methods We enrolled 377 male patients with dystrophinopathy and 520 male non-dystrophinopathy controls in a cross-sectional study. From this cohort, 113 follow-up patients were enrolled in a longitudinal study. Patients’ demographic information, motor function, muscle fatty infiltration, and muscle dystrophin levels were evaluated. We investigated correlations between these parameters and SCRN levels, and determined changes in SCRN levels with maturation and with motor function changes. Results Our results showed SCRN levels correlated with motor function (FDR < 0.001) and timed test results (FDR between < 0.001–0.012), as well as with muscle fatty infiltration (FDR < 0.001) and dystrophin levels (FDR = 0.015 and 0.001). SCRN levels increased with maturation in control individuals; it slowly increased with maturation in patients with BMD but decreased generally with maturation in patients with DMD. The longitudinal study further demonstrated that SCRN levels were associated with motor function. Conclusions These findings indicated that the SCRN level is a promising biomarker for assessing disease progression in dystrophinopathy and could be used as a potential outcome measure in clinical trials.

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Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in Becker Muscular Dystrophy

Neurology ◽

10.1212/wnl.0000000000012233 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012233

Author(s):

Nienke M. van de Velde ◽

Melissa T. Hooijmans ◽

Aashley S.D. Sardjoe Mishre ◽

Kevin R. Keene ◽

Zaida Koeks ◽

...

Keyword(s):

Muscular Dystrophy ◽

Disease Progression ◽

Intraclass Correlation ◽

Becker Muscular Dystrophy ◽

Knee Extension ◽

Muscle Mri ◽

Cross Sectional ◽

Functional Assessments ◽

The Difference ◽

Muscle Groups

Objective:To identify the best quantitative fat-water MRI biomarker for disease progression of leg muscles in Becker muscular dystrophy (BMD) by applying a stepwise approach based on standardized response mean (SRM) over 24 months, correlations with baseline ambulatory tests and reproducibility.Methods:Dixon fat-water imaging was performed at baseline (n=24) and 24 months (n=20). Fat fractions (FF) were calculated for three center slices and the whole muscles for 19 muscles and six muscle groups. Contractile cross sectional area (cCSA) was obtained from the center slice. Functional assessments included knee extension and flexion force, and three ambulatory tests (North Star Ambulatory Assessment (NSAA), 10-meter run, six-minute walking test). MR parameters were selected using SRM (≥0.8) and correlation with all ambulatory tests (rho≤-0.8). Parameters were evaluated based on intraclass correlation coefficient (ICC) and standard deviation (SD) of the difference. Sample sizes (SS) were calculated assuming 50% reduction in disease progression over 24 months in a clinical trial with 1:1 randomization.Results:Median whole muscle FF increased between 0.2-2.6% without consistent cCSA changes. High SRMs and strong functional correlations were found for eight FF but no cCSA parameters. All parameters showed excellent ICC (≥0.999) and similar SD of the inter-rater difference. Whole thigh three center slices FF was the best biomarker (SRM=1.04, correlations rho≤-0.81, ICC=1.00, SD=0.23%, SS=59) based on low SD and acquisition and analysis time.Conclusion:In BMD, median FF of all muscles increased over 24 months. Whole thigh three center slices FF reduced the SS by approximately 40% compared to NSAA.

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