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We established a simulation workflow to generate realistic E\u2013R datasets to assess the performance of the CoxPH model in recovering the E\u2013R ground truth in various scenarios, considering two potential reasons for the confounded E\u2013R relationship. We found that at high doses, when the pharmacological effects are largely saturated, missing important confounders is the major reason for inferring false\u2010positive E\u2013R relationships. At low doses, when a positive E\u2013R slope is the ground truth, either missing important confounders or mis\u2010specifying the interactions can lead to inaccurate estimates of the E\u2013R slope. This work constructed a simulation workflow generally applicable to clinical datasets to generate clinically relevant simulations and provide an in\u2010depth interpretation on the E\u2013R relationships with confounders inferred by the conventional CoxPH model.<\/jats:p>","DOI":"10.1002\/psp4.12859","type":"journal-article","created":{"date-parts":[[2022,8,21]],"date-time":"2022-08-21T18:44:20Z","timestamp":1661107460000},"page":"1511-1526","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Performance of Cox proportional hazard models on recovering the ground truth of confounded exposure\u2013response relationships for large\u2010molecule oncology drugs"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-2198","authenticated-orcid":false,"given":"Victor","family":"Poon","sequence":"first","affiliation":[{"name":"Modeling and Simulation Group, Department of Clinical Pharmacology Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-3599","authenticated-orcid":false,"given":"Dan","family":"Lu","sequence":"additional","affiliation":[{"name":"Modeling and Simulation Group, Department of Clinical Pharmacology Genentech, Inc.  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