{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T17:27:13Z","timestamp":1792690033777,"version":"4.5.0"},"reference-count":15,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T00:00:00Z","timestamp":1720742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023331","name":"LEO Pharma","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023331","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Reverse causation is a challenge in many drug-cancer associations, where the cancer symptoms are potentially mistaken for drug indication symptoms. However, tools to assess the magnitude of this type of bias are currently lacking. We used a simulation-based approach to investigate the impact of reverse causation on the association between the use of topical tacrolimus and cutaneous T-cell lymphoma (CTCL) in a multinational, population-based study using topical corticosteroids (TCS) as comparator.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We used a multistate model to simulate patients\u2019 use over time of a first- (TCS) and second-line treatment (topical tacrolimus), onset of atopic dermatitis (indication for drugs) and CTCL (the studied outcome). We simulated different scenarios to mimic real-life use of the two treatments. In all scenarios, it was assumed that there was no causal effect of the first- or second-line treatment on the occurrence of CTCL. Simulated data were analysed using Cox proportional hazards models.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>The simulated hazard ratios (HRs) of CTCL for patients treated with tacrolimus vs. TCS were consistently above 1 in all 9 settings in the main scenario. In our main analysis, we observed a median HR of 3.09 with 95% of the observed values between 2.11 and 4.69.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>We found substantial reverse causation bias in the simulated CTCL risk estimates for patients treated with tacrolimus vs. TCS. Reverse causation bias may result in a false positive association between the second-line treatment and the studied outcome, and this simulation-based framework can be adapted to quantify the potential reverse causation bias.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0304145","type":"journal-article","created":{"date-parts":[[2024,7,12]],"date-time":"2024-07-12T17:26:23Z","timestamp":1720805183000},"page":"e0304145","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Reverse causation bias: A simulation study comparing first- and second-line treatments with an overlap of symptoms between treatment indication and studied outcome"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8929-1761","authenticated-orcid":true,"given":"Christian Bjerreg\u00e5rd","family":"\u00d8land","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lise Skov","family":"Ranch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0031-5726","authenticated-orcid":true,"given":"Tea","family":"Skaaby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Delvin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henny Bang","family":"Jakobsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0261-616X","authenticated-orcid":true,"given":"Christian Bressen","family":"Pipper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,7,12]]},"reference":[{"issue":"2","key":"pone.0304145.ref001","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1002\/pds.4145","article-title":"New use of prescription drugs prior to a cancer diagnosis: Use of Prescription Drugs Prior to Cancer Diagnosis","volume":"26","author":"A Potteg\u00e5rd","year":"2017","journal-title":"Pharmacoepidemiology and Drug Safety"},{"issue":"9","key":"pone.0304145.ref002","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1002\/pds.5083","article-title":"Time-related biases in pharmacoepidemiology","volume":"29","author":"S Suissa","year":"2020","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"6","key":"pone.0304145.ref003","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.jaad.2015.02.1116","article-title":"Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis","volume":"72","author":"L Legendre","year":"2015","journal-title":"Journal of the American Academy of Dermatology"},{"issue":"6","key":"pone.0304145.ref004","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1007\/s11899-016-0353-y","article-title":"T-cell Lymphoma Epidemiology: the Known and Unknown","volume":"11","author":"A Phan","year":"2016","journal-title":"Curr Hematol Malig Rep"},{"issue":"6","key":"pone.0304145.ref005","article-title":"Epidemiology and Etiology of Leukemia and Lymphoma","volume":"10","author":"JAB Bispo","year":"2020","journal-title":"Cold Spring Harb Perspect Med"},{"issue":"12","key":"pone.0304145.ref006","doi-asserted-by":"crossref","DOI":"10.2340\/00015555-3510","article-title":"Prevalence and Incidence of Atopic Dermatitis: A Systematic Review","volume":"100","author":"S Bylund","year":"2020","journal-title":"Acta Derm Venereol"},{"key":"pone.0304145.ref007","article-title":"Mycosis fungoides and Sezary syndrome: 2019 update on diagnosis, risk-stratification, and management","author":"AC Hristov","year":"2019","journal-title":"American journal of hematology"},{"issue":"1","key":"pone.0304145.ref008","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/ajh.24233","article-title":"Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management","volume":"91","author":"RA Wilcox","year":"2016","journal-title":"American journal of hematology"},{"issue":"4","key":"pone.0304145.ref009","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1172\/JCI24826","article-title":"Immunopathogenesis and therapy of cutaneous T cell lymphoma","volume":"115","author":"EJ Kim","year":"2005","journal-title":"J Clin Invest"},{"key":"pone.0304145.ref010","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.2147\/CLEP.S331287","article-title":"Long-Term Risk of Skin Cancer and Lymphoma in Users of Topical Tacrolimus and Pimecrolimus: Final Results from the Extension of the Cohort Study Protopic Joint European Longitudinal Lymphoma and Skin Cancer Evaluation (JOELLE)","volume":"13","author":"A Arana","year":"2021","journal-title":"Clin Epidemiol"},{"key":"pone.0304145.ref011","unstructured":"Lawless. 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