{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T05:57:48Z","timestamp":1790575068573,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Early vs Late (E\u2013L) treatment initiation comparisons, which are prone to immortal time bias, are widely considered amenable to causal inference through target trial emulation (TTE) using clone\u2013censor\u2013weighting (CCW). However, whether standard CCW yields a well-defined causal estimand for the E\u2013L comparison under ideal implementation conditions has not been formally examined. We conducted a structural simulation study to evaluate CCW\u2013based TTE for E\u2013L comparisons. The design varied along 3 dimensions: treatment-initiation mechanisms (random vs baseline\u2013confounded timing), benefit\u2013harm structures governing delayed-treatment harm and posttreatment benefit, and 5 distinct E\u2013L initiation-window configurations. We implemented CCW as conventionally recommended and summarized the estimated 12-month marginal risk ratios across settings. Depending on the placement and structure of the initiation windows, estimated risk ratios exhibited systematic window-dependent variation, including direction reversals across window specifications, even in settings where the true marginal causal contrast was 1 by design. These patterns were not consistently explained by weight instability or lack of support overlap. Our findings indicate that, in E\u2013L comparisons, the window-defined strategy contrast estimated using CCW\u2013based TTE can be strongly shaped by risk accumulated before treatment initiation under the specified windows, underscoring the need for caution when interpreting E\u2013L analyses.<\/jats:p>","DOI":"10.1093\/aje\/kwag208","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:43:35Z","timestamp":1787921015000},"source":"Crossref","is-referenced-by-count":0,"title":["Structural limitations of Early\u2013Late treatment comparisons under target trial emulation: a simulation study"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0479-3733","authenticated-orcid":false,"given":"Atsushi","family":"Takayama","sequence":"first","affiliation":[{"name":"Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University , Kyoto ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Center for Clinical and Translational Research, Kyushu University Hospital , Fukuoka ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7477-4071","authenticated-orcid":false,"given":"Koji","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University , Kyoto ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"issue":"18","key":"2026092801515672100_ref1","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1056\/NEJMoa0807252","article-title":"Effect of early versus deferred antiretroviral therapy for HIV on 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