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We propose a two-step TTE approach to create methodologically-justified evidence for these subpopulations. Using the CONFIRM trial as an illustrative example, we first emulated the trial using strict eligibility criteria, and extended the analysis to a pragmatic scenario including trial-ineligible subgroups, allowing comparison of treatment effectiveness between these two study populations. CONFIRM studied efficacy of dimethyl fumarate (DMF) and glatiramer acetate (GA) in reducing relapses in 709 relapsing-remitting multiple sclerosis (RRMS) patients. A retrospective cohort study was designed using the Swedish multiple sclerosis registry. Outcomes were the annualized relapse rate (ARR) and the probability of a relapse, adjusted for covariates and overlap weights. Using strict eligibility criteria, 288 RRMS patients were included, whereas the pragmatic scenario comprised 1831 patients. The ARR ratio for DMF versus GA was 0.78 (95%CI 0.59\u20131.05) in CONFIRM, 0.75 (95%CI: 0.44\u20131.29) in the strict scenario, and 0.58 (95% CI: 0.36\u20130.94) in the pragmatic scenario. Similarly, the hazard ratio was 0.92 (95%CI 0.70\u20131.22), 1.05 (95%CI: 0.83\u20131.33) and 0.56 (95%CI: 0.46\u20130.67), respectively.\n                    <jats:italic>Post-hoc<\/jats:italic>\n                    analysis implied existence of calendar bias. Comparable results between CONFIRM and the strict scenario were observed, while the second step demonstrates how methodological advantages of TTEs can be extended to excluded subgroups. This study can be used as guiding example for future observational studies that wish to incorporate the TTE framework, as well as embrace the wider variety in the patient population often ignored in experimental settings.\n                  <\/jats:p>","DOI":"10.1007\/s10654-026-01379-1","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T06:38:39Z","timestamp":1773815919000},"page":"841-853","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A target trial emulation of the CONFIRM study with an extension to subgroups: an example for relapsing-remitting multiple sclerosis"],"prefix":"10.1007","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7566-1776","authenticated-orcid":false,"given":"Stefan","family":"Verweij","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten J.","family":"Bijlsma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrien","family":"Oude Rengerink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hillert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Forsberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1335-7610","authenticated-orcid":false,"given":"Elena Flavia","family":"Mouresan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Glaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert James","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-7210","authenticated-orcid":false,"given":"Eelko","family":"Hak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4262-3180","authenticated-orcid":false,"given":"Peter","family":"Mol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"1379_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2024.100977","author":"E Portaccio","year":"2024","unstructured":"Portaccio E, et al. 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