{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:01:00Z","timestamp":1789750860617,"version":"4.0.1"},"reference-count":22,"publisher":"Wiley","issue":"18-19","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA091842"],"award-info":[{"award-number":["P30CA091842"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Statistics in Medicine"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Landmark analysis establishes a fixed \u201clandmark\u201d time, including only individuals who remain event\u2010free up to that point and classifying survivors according to their treatment status at the landmark. By restarting follow\u2010up from this time, the method aims to create comparable groups presumed free from immortal time bias. Despite its simplicity and widespread use, landmark analysis has notable limitations. Under potential outcomes and piecewise proportional hazards, we derived closed\u2010form results for naive, exclusion, and landmark analyses and evaluated them via simulations. We found that landmark estimates fail to recover the target causal effect because the reference group mixes \u201cnever\u2010treated\u201d and \u201clate\u2010treated\u201d subjects. This mixture attenuates the effect size, generally biasing estimates toward the null, with the magnitude of bias depending on the true effect, treatment rate, and event rate, except under the null hypothesis. In addition, landmark analysis suffers a substantial loss of statistical power due to the exclusion of early events and the attenuation of effect estimates. Indeed, the attenuation alone can make landmark analysis perform considerably worse in power than a randomized trial with equal group sizes. Without clinical context, a small treatment effect observed in a landmark analysis may reflect bias rather than a true null effect. Therefore, caution is warranted when using landmark analysis to address immortal time bias, and time\u2010dependent regression models provide a more robust alternative.<\/jats:p>","DOI":"10.1002\/sim.70679","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T01:59:09Z","timestamp":1784858349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["On the Statistical Limitations of Landmark Analysis for Addressing Immortal Time Bias"],"prefix":"10.1002","volume":"45","author":[{"given":"Fei","family":"Wan","sequence":"first","affiliation":[{"name":"Division of Public Health Sciences Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwm324"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCOUTCOMES.110.957951"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7019"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-017-0405-6"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1080\/01621459.1977.10479903"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2020.11.010"},{"issue":"8","key":"e_1_2_10_8_1","first-page":"1521","article-title":"Immortal\u2010Time Bias in Older vs Younger Age Groups: A Simulation Study With Application to a Population\u2010Based Cohort of Patients With Colon Cancer","volume":"128","author":"Pilleron S.","year":"2023","journal-title":"British Journal of Cancer"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwi307"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyaa057"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/1475\u20106773.14376"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19820415)49:8<1544::AID-CNCR2820490806>3.0.CO;2-J"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1983.1.11.710"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35901"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.6004\/jnccn.2025.7009"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.35759"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-021-01493-6"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0037350"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1009609925212"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7178"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/03610918.2020.1722838"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0314209"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.2022"}],"container-title":["Statistics in Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.70679","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/sim.70679","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/sim.70679","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:31:11Z","timestamp":1787502671000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/sim.70679"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":22,"journal-issue":{"issue":"18-19","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/sim.70679"],"URL":"https:\/\/doi.org\/10.1002\/sim.70679","archive":["Portico"],"relation":{},"ISSN":["0277-6715","1097-0258"],"issn-type":[{"value":"0277-6715","type":"print"},{"value":"1097-0258","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"assertion":[{"value":"2025-12-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70679"}}