TYPE Original Research PUBLISHED 11 April 2023 DOI 10.3389/fmed.2023.1157706 OPEN ACCESS EDITED BY Paolo Spagnolo, University of Padua, Italy REVIEWED BY Yet Khor, Monash University, Australia Iain Stewart, Imperial College London, United Kingdom *CORRESPONDENCE Andrew J. Palmer andrew.palmer@utas.edu.au † These authors share senior authorship SPECIALTY SECTION This article was submitted to Pulmonary Medicine, a section of the journal Frontiers in Medicine RECEIVED 02 February 2023 ACCEPTED 27 March 2023 PUBLISHED 11 April 2023 CITATION Zheng Q, Otahal P, Cox IA, de Graaff B, Campbell JA, Ahmad H, Walters EH and Palmer AJ (2023) The inﬂuence of immortal time bias in observational studies examining associations of antiﬁbrotic therapy with survival in idiopathic pulmonary ﬁbrosis: A simulation study. Front. Med. 10:1157706. doi: 10.3389/fmed.2023.1157706 COPYRIGHT © 2023 Zheng, Otahal, Cox, de Graaff, Campbell, Ahmad, Walters and Palmer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The inﬂuence of immortal time bias in observational studies examining associations of antiﬁbrotic therapy with survival in idiopathic pulmonary ﬁbrosis: A simulation study Qiang Zheng 1,2,3 , Petr Otahal 1 , Ingrid A. Cox 1,2 , Barbara de Graaff 1,2 , Julie A. Campbell 1 , Hasnat Ahmad 1,4 , E. Haydn Walters 1,2,5† and Andrew J. Palmer 1,2 * † 1 Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia, 2 NHMRC Centre of Research Excellence for Pulmonary Fibrosis, Camperdown, NSW, Australia, 3 Department of Anaesthesiology (High–Tech Branch), First Afﬁliated Hospital of Anhui Medical University, Hefei, Anhui, China, 4 Australian Government Department of Health and Aged Care, Tasmania (TAS) Ofﬁce, Hobart, TAS, Australia, 5 School of Medicine, University of Tasmania, Hobart, TAS, Australia Background: Immortal time bias (ITB) has been overlooked in idiopathic pulmonary ﬁbrosis (IPF). We aimed to identify the presence of ITB in observational studies examining associations between antiﬁbrotic therapy and survival in patients with IPF and illustrate how ITB may affect effect size estimates of those associations. Methods: Immortal time bias was identiﬁed in observational studies using the ITB Study Assessment Checklist. We used a simulation study to illustrate how ITB may affect effect size estimates of antiﬁbrotic therapy on survival in patients with IPF based on four statistical techniques including time-ﬁxed, exclusion, time-dependent and landmark methods. Results: Of the 16 included IPF studies, ITB was detected in 14 studies, while there were insufﬁcient data for assessment in two others. Our simulation study showed that use of time–ﬁxed [hazard ratio (HR) 0.55, 95% conﬁdence interval (CI) 0.47–0.64] and exclusion methods (HR 0.79, 95% CI 0.67–0.92) overestimated the effectiveness of antiﬁbrotic therapy on survival in simulated subjects with IPF, in comparison of the time–dependent method (HR 0.93, 95% CI 0.79–1.09). The inﬂuence of ITB was mitigated using the 1 year landmark method (HR 0.69, 95% CI 0.58–0.81), compared to the time–ﬁxed method. Conclusion: The effectiveness of antiﬁbrotic therapy on survival in IPF can be overestimated in observational studies, if ITB is mishandled. This study adds to Frontiers in Medicine 01 frontiersin.org