{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:02:11Z","timestamp":1790420531391,"version":"4.1.0"},"reference-count":14,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:00:00Z","timestamp":1592265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacoepidemiology and Drug"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Purpose<\/jats:title><jats:p>The case\u2010crossover design is increasingly used to evaluate the effects of chronic medications; however, as traditionally implemented in pharmacoepidemiology, with referent period preceding the outcome, it may lead to bias in the presence of persistent exposures. We aimed to evaluate the extent and magnitude of bias in case\u2010crossover analyses of chronic and persistent exposures, using simulations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We simulated cohorts with either 30\u2010day, 180\u2010day, or 2\u2010year exposure duration; and with varying degrees of persistence (10%, 30%, 50%, 70%, or 90% of patients not stopping exposure). We evaluated all scenarios under the null and the scenario with 30% persistence under varying exposure effects (odds ratios of 0.25 to 4.0). Cohorts were analyzed using conditional logistic regression that compared the odds of exposure on the outcome day to the odds of exposure on a referent day 30\u2009days prior to the outcome. We further implemented the case\u2010time\u2010control design to evaluate its ability to adjust for bias from persistence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Case\u2010crossover analyses produced unbiased estimates across all scenarios without persistent users, regardless of exposure duration. In scenarios where some patients persisted on treatment, case\u2010crossover analyses resulted in upward bias, which increased with increasing proportion of persistent users, but did not vary substantially in relation to the magnitude of the true effect. Case\u2010time\u2010control analyses removed bias in all scenarios.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Investigators should be aware of bias due to treatment persistence in unidirectional case\u2010crossover analyses of chronic medications, which can be remedied with a control group of similarly persistent noncases.<\/jats:p><\/jats:sec>","DOI":"10.1002\/pds.5031","type":"journal-article","created":{"date-parts":[[2020,6,17]],"date-time":"2020-06-17T02:54:34Z","timestamp":1592362474000},"page":"1079-1085","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Bias in case\u2010crossover studies of medications due to persistent use: A simulation study"],"prefix":"10.1002","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3336-5412","authenticated-orcid":false,"given":"Katsiaryna","family":"Bykov","sequence":"first","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7761-7090","authenticated-orcid":false,"given":"Shirley V.","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8097-8708","authenticated-orcid":false,"given":"Jesper","family":"Hallas","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacy Department of Public Health, University of Southern Denmark  Odense Denmark"},{"name":"Department of Clinical Biochemistry and Clinical Pharmacology Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9314-5679","authenticated-orcid":false,"given":"Anton","family":"Potteg\u00e5rd","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacy Department of Public Health, University of Southern Denmark  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"Maclure","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia  Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua J.","family":"Gagne","sequence":"additional","affiliation":[{"name":"Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine Brigham and Women's Hospital and Harvard Medical School  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049444"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.2330"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.aje.a115853"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1376"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-016-0278-0"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199505000-00010"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280208092346"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.960"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kww079"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001648-199605000-00003"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwu162"},{"key":"e_1_2_9_13_1","unstructured":"CarstensenB PlummerM LaaraE HillsM.Epi: A Package for Statistical Analysis in Epidemiology. R Package Version 2.37;2019.https:\/\/CRAN.R-project.org\/package=Epi."},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/EDE.0b013e31821d09cd"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.csda.2013.10.018"}],"container-title":["Pharmacoepidemiology and Drug Safety"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpds.5031","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.5031","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/pds.5031","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pds.5031","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,3]],"date-time":"2023-09-03T15:23:28Z","timestamp":1693754608000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/pds.5031"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,16]]},"references-count":14,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2020,9]]}},"alternative-id":["10.1002\/pds.5031"],"URL":"https:\/\/doi.org\/10.1002\/pds.5031","archive":["Portico"],"relation":{},"ISSN":["1053-8569","1099-1557"],"issn-type":[{"value":"1053-8569","type":"print"},{"value":"1099-1557","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,16]]},"assertion":[{"value":"2019-12-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-05-05","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-06-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}