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Latent process model of the 6-minute walk test in Duchenne muscular dystrophy

A Bayesian approach to quantifying rare disease progression

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Abstract

Duchenne muscular dystrophy (DMD) is a rare X-linked genetic pediatric disease characterized by a lack of functional dystrophin production in the body, resulting in muscle deterioration. Lower body muscle weakness progresses to non-ambulation typically by early teenage years, followed by upper body muscle deterioration and ultimately death by the late twenties. The objective of this study was to enhance the quantitative understanding of DMD disease progression through nonlinear mixed effects modeling of the population mean and variability of the 6-min walk test (6MWT) clinical endpoint. An indirect response model with a latent process was fit to digitized literature data using full Bayesian estimation. The modeling data set consisted of 22 healthy controls and 218 DMD patients from one interventional and four observational trials. The model reasonably described the central tendency and population variability of the 6MWT in healthy subjects and DMD patients. An exploratory categorical covariate analysis indicated that there was no apparent effect of corticosteroid administration on DMD disease progression. The population predicted 6MWT began to rise at 1.32 years of age, plateauing at 654 meters (m) at 17.2 years of age for the healthy population. The DMD trajectory reached a maximum of 411 m at 8.90 years before declining and falling below 1 m at age 18.0. The model has potential to be used as a Bayesian estimation and posterior simulation tool to make informed model-based drug development decisions that incorporate prior knowledge with new data.

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Notes

  1. The elements in the \({\varvec{\theta }}_{prior}\) mean vector and diagonal vector of the variance-covariance matrix are, row-wise, as follows: \(\theta _1\), \(\theta _2\), \(\theta _3\), \(\theta _4\), \(\theta _5\), \(\theta _6\). The elements in the \({\varvec{\varOmega }}_{prior,DMD}\) matrix are, row-wise, as follows: \(\omega ^2_{K_{out,DMD}}\); \(\omega _{K_{out,DMD}-K_{in,DMD}}\); \(\omega ^2_{K_{in,DMD}}\); \(\omega _{K_{\alpha }-K_{out,DMD}}\); \(\omega _{K_{\alpha }-K_{in,DMD}}\); \(\omega ^2_{K_{\alpha }}\)

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Acknowledgements

Thanks to the scientists at Metrum Research Group for support and advisement during this analysis. We acknowledge the researchers and patients from the included literature studies, and thank them for contributing to public data sharing in the rare disease therapeutic area.

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  1. Metrum Research Group, Tariffville, CT, 06081, USA

    Janelle L. Lennie, John T. Mondick & Marc R. Gastonguay

  2. University of Connecticut, Storrs, CT, 06268, USA

    Janelle L. Lennie & Marc R. Gastonguay

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Lennie, J.L., Mondick, J.T. & Gastonguay, M.R. Latent process model of the 6-minute walk test in Duchenne muscular dystrophy. J Pharmacokinet Pharmacodyn 47, 91–104 (2020). https://doi.org/10.1007/s10928-020-09671-7

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