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Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles

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Abstract

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 model variables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

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Data Availability

In accordance with our informed consent form, researchers will be required to apply for access to the data set by submitting the following information, which will be reviewed by an Executive Committee: (i) Researcher name(s) and institutional affiliation(s) and (ii) A brief proposal outlining how the data will be used. The request should be submitted to Dr. Krista Vandenborne, the Director of ImagingNMD (Email Contact: kvandenb@phhp.ufl.edu). If shared data are used in subsequent publications the original funding source (AR056973) and the ImagingNMD network will need to be acknowledged and published methodology developed during the course of the study cited, as appropriate. https://imagingnmd.org/data-sharing/.

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Acknowledgements

The authors would like to thank the DMD MR Biomarker Steering Committee members for their feedback that helped improve the study.

Funding

Research reported in this publication was supported by the NIH National Center for Advancing Translational Sciences through grant number R21TR004006, National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Heart Lung and Blood Institute through grant number R01AR056973, and the University of Florida Clinical and Translational Science Institute, which is also supported in part by the NIH National Center for Advancing Translational Sciences under award number UL1TR001427. All data were collected as part of ImagingNMD program supported by NIH grant R01AR056973. Data acquisition and storage at OHSU were supported by shared instrument grants NIH S10OD021701 and NIH S10OD018224. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA

    Deok Yong Yoon, Juan Francisco Morales & Sarah Kim

  2. Department of Statistics, University of Florida, Gainesville, FL, USA

    Michael J. Daniels

  3. Department of Physical Therapy, University of Florida, Gainesville, FL, USA

    Rebecca J. Willcocks, William T. Triplett & Krista Vandenborne

  4. Department of Physiology and Aging, University of Florida, Gainesville, FL, USA

    Glenn A. Walter

  5. Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, USA

    William D. Rooney

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  1. Deok Yong Yoon
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the DMD MR Biomarker Steering Committee

Contributions

DY, MJD, RJW, GAW, WDR, KV, and SK wrote manuscript, MJD, RJW, WDR, KV, and SK designed research, DY, RJW, WTT, JM, and SK performed research, DY, MJD, RJW, WTT, JM, GAW, WDR, KV, and SK analyzed data, and DY, RJW, WTT, JM, and SK contributed new reagents/analytical tools.

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Correspondence to Sarah Kim.

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Yoon, D.Y., Daniels, M.J., Willcocks, R.J. et al. Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles. J Pharmacokinet Pharmacodyn (2024). https://doi.org/10.1007/s10928-024-09910-1

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