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Better understanding and quantifying the impact of factors affecting NASH and fibrosis is essential to inform a clinical study design. We developed a population Markov model to describe the transition probability between fibrosis stages and mortality using a unique clinical nonalcoholic fatty liver disease cohort with serial biopsies over 3 decades. We evaluated covariate effects on all model parameters and performed clinical trial simulations to predict the fibrosis progression rate for external clinical cohorts. All parameters were estimated with good precision. Age and diagnosis of type 2 diabetes (T2D) were found to be significant predictors in the model. Increase in hepatic steatosis between visits was the most important predictor for progression of fibrosis. Fibrosis progression rate (FPR) was twofold higher for fibrosis stages 0 and 1 (F0\u20101) compared to fibrosis stage 2 and 3 (F2\u20103). A twofold increase in FPR was observed for T2D. A two\u2010point steatosis worsening increased the FPR 11\u2010fold. Predicted fibrosis progression was in good agreement with data from external clinical cohorts. Our fibrosis progression model shows that patient selection, particularly initial fibrosis stage distribution, can significantly impact fibrosis progression and as such the window for assessing drug efficacy in clinical trials. Our work highlights the increase in hepatic steatosis as the most important factor in increasing FPR, emphasizing the importance of well\u2010defined lifestyle advise for reducing variability in NASH progression during clinical trials.<\/jats:p>","DOI":"10.1002\/psp4.13052","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T06:50:14Z","timestamp":1695711014000},"page":"2038-2049","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Markov model of fibrosis development in <scp>nonalcoholic<\/scp> fatty liver disease predicts fibrosis progression in clinical cohorts"],"prefix":"10.1002","volume":"12","author":[{"given":"Jane","family":"Kn\u00f6chel","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology &amp; Safety Sciences, R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linn\u00e9a","family":"Bergenholm","sequence":"additional","affiliation":[{"name":"DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9282-9136","authenticated-orcid":false,"given":"Eman","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-739X","authenticated-orcid":false,"given":"Stergios","family":"Kechagias","sequence":"additional","affiliation":[{"name":"Department of Health, Medicine, and Caring Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Hansson","sequence":"additional","affiliation":[{"name":"Translational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8368-5775","authenticated-orcid":false,"given":"Mathias","family":"Liljeblad","sequence":"additional","affiliation":[{"name":"Translational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrik","family":"Nasr","sequence":"additional","affiliation":[{"name":"Department of Health, Medicine, and Caring Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3023-9878","authenticated-orcid":false,"given":"Bj\u00f6rn","family":"Carlsson","sequence":"additional","affiliation":[{"name":"Translational Science and Experimental Medicine, Research and Early Development Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&amp;D, AstraZeneca  Gothenburg Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mattias","family":"Ekstedt","sequence":"additional","affiliation":[{"name":"Department of Health, Medicine, and Caring Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3712-0255","authenticated-orcid":false,"given":"Sebastian","family":"Ueckert","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Quantitative Pharmacology Clinical Pharmacology &amp; 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