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This complex disease course makes it challenging to define target estimands for clinical trials. While composite endpoints are routinely adopted, recent innovations involving the win ratio and other methods based on ranking the disease course have received considerable attention. We emphasize the usefulness of multistate models for addressing challenges arising in complex diseases, along with the simplicity and interpretability that come from defining utilities to synthesize evidence of treatment effects on different aspects of the disease process. Robust variance estimation based on the infinitesimal jackknife means that such methods can be used as the basis of primary analyses of clinical trials. We illustrate the use of utilities for the assessment of bleeding outcomes in a trial of cancer patients with thrombocytopenia.<\/jats:p>","DOI":"10.1002\/sim.70269","type":"journal-article","created":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T14:09:33Z","timestamp":1760450973000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Specification of Estimands for Complex Disease Processes Using Multistate Models and Utility Functions"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0872-0374","authenticated-orcid":false,"given":"Alexandra","family":"B\u00fchler","sequence":"first","affiliation":[{"name":"Department of Statistics and Actuarial Science University of Waterloo  Waterloo Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Statistics and Actuarial Science University of Waterloo  Waterloo Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jerald F.","family":"Lawless","sequence":"additional","affiliation":[{"name":"Department of Statistics and Actuarial Science University of Waterloo  Waterloo Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,14]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_10_2_1","DOI":"10.1183\/13993003.00627-2020"},{"doi-asserted-by":"publisher","key":"e_1_2_10_3_1","DOI":"10.1093\/annonc\/mdi162"},{"doi-asserted-by":"publisher","key":"e_1_2_10_4_1","DOI":"10.1056\/NEJM198809153191104"},{"unstructured":"ICH E9 Steering Committee \u201cICH E9 (R1): Addendum to Statistical Principles for Clinical Trials on Choosing Appropriate Estimands and Defining Sensitivity Analyses in Clinical Trials \u201d Paper Presented at International Conference on Harmonization (2019).","key":"e_1_2_10_5_1"},{"doi-asserted-by":"publisher","key":"e_1_2_10_6_1","DOI":"10.1002\/sim.9675"},{"doi-asserted-by":"publisher","key":"e_1_2_10_7_1","DOI":"10.1182\/blood-2005-05-1938"},{"doi-asserted-by":"publisher","key":"e_1_2_10_8_1","DOI":"10.1056\/NEJMoa1603827"},{"doi-asserted-by":"publisher","key":"e_1_2_10_9_1","DOI":"10.1002\/pst.2167"},{"doi-asserted-by":"publisher","key":"e_1_2_10_10_1","DOI":"10.1016\/j.jchf.2017.04.013"},{"doi-asserted-by":"publisher","key":"e_1_2_10_11_1","DOI":"10.1002\/ejhf.3253"},{"doi-asserted-by":"publisher","key":"e_1_2_10_12_1","DOI":"10.1002\/9781118033005"},{"doi-asserted-by":"publisher","key":"e_1_2_10_13_1","DOI":"10.1093\/biostatistics\/kxv050"},{"doi-asserted-by":"publisher","key":"e_1_2_10_14_1","DOI":"10.1001\/jama.289.19.2554"},{"doi-asserted-by":"publisher","key":"e_1_2_10_15_1","DOI":"10.1002\/sim.5436"},{"doi-asserted-by":"publisher","key":"e_1_2_10_16_1","DOI":"10.1080\/19466315.2021.1927824"},{"doi-asserted-by":"publisher","key":"e_1_2_10_17_1","DOI":"10.1080\/19466315.2024.2395404"},{"unstructured":"A.B\u00fchler R. 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