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This study aims to identify the optimal use of muscle fat fraction biomarkers in DMD clinical trials through a quantitative disease\u2010drug\u2010trial modeling and simulation approach. We simultaneously developed two multivariate models quantifying the longitudinal associations between 6\u2010minute walk distance (6MWD) and fat fraction measures from vastus lateralis and soleus muscles. We leveraged the longitudinal individual\u2010level data collected for 10\u2009years through the ImagingDMD study. Age of the individuals at assessment was chosen as the time metric. After the longitudinal dynamic of each measure was modeled separately, the selected univariate models were combined using correlation parameters. Covariates, including baseline scores of the measures and steroid use, were assessed using the full model approach. The nonlinear mixed\u2010effects modeling was performed in Monolix. The final models showed reasonable precision of the parameter estimates. Simulation\u2010based diagnostics and fivefold cross\u2010validation further showed the model's adequacy. The multivariate models will guide drug developers on using fat fraction assessment most efficiently using available data, including the widely used 6MWD. The models will provide valuable information about how individual characteristics alter disease trajectories. We will extend the multivariate models to incorporate trial design parameters and hypothetical drug effects to inform better clinical trial designs through simulation, which will facilitate the design of clinical trials that are both more inclusive and more conclusive using fat fraction biomarkers.<\/jats:p>","DOI":"10.1002\/psp4.13021","type":"journal-article","created":{"date-parts":[[2023,8,3]],"date-time":"2023-08-03T11:59:25Z","timestamp":1691063965000},"page":"1437-1449","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Multivariate modeling of magnetic resonance biomarkers and clinical outcome measures for Duchenne muscular dystrophy clinical trials"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9179-0735","authenticated-orcid":false,"given":"Sarah","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca J.","family":"Willcocks","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael J.","family":"Daniels","sequence":"additional","affiliation":[{"name":"Department of Statistics University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Francisco","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deok Yong","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy University of Florida  Orlando Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William T.","family":"Triplett","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison M.","family":"Barnard","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela J.","family":"Conrado","sequence":"additional","affiliation":[{"name":"e\u2010Quantify LLC  La Jolla California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8406-0961","authenticated-orcid":false,"given":"Varun","family":"Aggarwal","sequence":"additional","affiliation":[{"name":"Critical Path Institute  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ramona","family":"Belfiore\u2010Oshan","sequence":"additional","affiliation":[{"name":"Critical Path Institute  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Terina N.","family":"Martinez","sequence":"additional","affiliation":[{"name":"Critical Path Institute  Tucson Arizona USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenn A.","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Physiology and Aging University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Rooney","sequence":"additional","affiliation":[{"name":"Advanced Imaging Research Center Oregon Health &amp; Science University  Portland Oregon USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krista","family":"Vandenborne","sequence":"additional","affiliation":[{"name":"Department of Physical Therapy University of Florida  Gainesville Florida USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,8,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2014-2044"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2019_256"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-019-09642-7"},{"key":"e_1_2_11_5_1","doi-asserted-by":"crossref","unstructured":"Deflazacort eteplirsen and golodirsen for duchenne muscular dystrophy: effectiveness and value. Final Evidence Report (Posted August 15 2019 & Updated April 22 2022).https:\/\/icer.org\/wp\u2010content\/uploads\/2020\/10\/Corrected_ICER_DMD\u2010Final\u2010Report_042222.pdf.","DOI":"10.24926\/iip.v10i4.2337"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.26161"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(17)32160-8"},{"key":"e_1_2_11_8_1","unstructured":"FischerR.Join the fight. End Duchenne. 2018 Annual Conference Polling Report Parent Project Muscular Dystrophy.https:\/\/www.parentprojectmd.org\/wp\u2010content\/uploads\/2018\/11\/PPMD\u2010Conference\u2010Polling\u2010Final\u2010Report\u20102018.pdf."},{"key":"e_1_2_11_9_1","unstructured":"U.S. Food and Drug Administration.Duchenne muscular dystrophy and related dystrophinopathies: developing drugs for treatment guidance for industry (FDA\u20102015\u2010D\u20101884).2018."},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000009244"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09481-z"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000009012"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0128915"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000000775"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24599"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194283"},{"key":"e_1_2_11_17_1","volume-title":"Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Duchenne and Becker Muscular Dystrophy","author":"Committee for Medicinal Products for Human Use (CHMP)","year":"2015"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009012"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.13121948"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0106435"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9112-5"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-008-9094-4"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12753"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e318225ab2e"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0027127"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781118784860"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000002147"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000008939"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2015.05.006"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2014.01.015"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000012724"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/forestscience\/19.1.2"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/jxb\/10.2.290"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0000000000201163"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph14080798"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-019-09642-7"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-022-03257-3"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12973"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13021","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T10:22:43Z","timestamp":1697624563000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,27]]},"references-count":38,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/psp4.13021"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13021","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,27]]},"assertion":[{"value":"2023-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-24","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}