Abstract
BackgroundDeficits in ambulatory function progress at heterogeneous rates among individuals with Duchenne muscular dystrophy (DMD). The resulting inherent variability in ambulatory outcomes has complicated the design of drug efficacy trials and clouded the interpretation of trial results. We developed a prediction model for 1-year change in the six minute walk distance (6MWD) among DMD patients, and compared its predictive value to that of commonly used prognostic factors (age, baseline 6MWD, and steroid use).MethodsNatural history data were collected from DMD patients at routine follow up visits approximately every 6 months over the course of 2–5 years. Assessments included ambulatory function and steroid use. The annualized change in 6MWD (Δ6MWD) was studied between all pairs of visits separated by 8–16 months. Prediction models were developed using multivariable regression for repeated measures, and evaluated using cross-validation.ResultsAmong n = 191 follow-up intervals (n = 39 boys), mean starting age was 9.4 years, mean starting 6MWD was 351.8 meters, and 75% had received steroids for at least one year. Over the subsequent 8–16 months, mean Δ6MWD was -37.0 meters with a standard deviation (SD) of 93.7 meters. Predictions based on a composite of age, baseline 6MWD, and steroid use explained 28% of variation in Δ6MWD (R2 = 0.28, residual SD = 79.4 meters). A broadened prognostic model, adding timed 10-meter walk/run, 4-stair climb, and rise from supine, as well as height and weight, significantly improved prediction, explaining 59% of variation in Δ6MWD after cross-validation (R2 = 0.59, residual SD = 59.7 meters).ConclusionsA prognostic model incorporating timed function tests significantly improved prediction of 1-year changes in 6MWD. Explained variation was more than doubled compared to predictions based only on age, baseline 6MWD, and steroid use. There is significant potential for composite prognostic models to inform DMD clinical trials and clinical practice.
Highlights
Natural history data were collected from Duchenne muscular dystrophy (DMD) patients at routine follow up visits approximately every 6 months over the course of 2–5 years
Predictions based on a composite of age, baseline 6MWD, and steroid use explained 28% of variation in Δ6MWD (R2 = 0.28, residual standard deviation (SD) = 79.4 meters)
One in every 3,600 live male births is affected by Duchenne muscular dystrophy (DMD), an inherited, X-linked disease caused by mutations to the gene encoding dystrophin [1, 2]
Summary
One in every 3,600 live male births is affected by Duchenne muscular dystrophy (DMD), an inherited, X-linked disease caused by mutations to the gene encoding dystrophin [1, 2]. There is the potential for sub-maximal performance of the 6MWD test to occur at baseline or at follow-up assessments This variability has confounded the accurate measurement of treatment effects, despite efforts to homogenize trial enrollment based on age and baseline 6MWD. An improved understanding of the factors associated with biological variation in rates of 6MWD progression will be important for continued design of clinical trials and measurement of drug effects in DMD. Deficits in ambulatory function progress at heterogeneous rates among individuals with Duchenne muscular dystrophy (DMD). We developed a prediction model for 1-year change in the six minute walk distance (6MWD) among DMD patients, and compared its predictive value to that of commonly used prognostic factors (age, baseline 6MWD, and steroid use)
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