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; Petr Otahal; Ingrid A Cox; Barbara de Graaff; Julie A Campbell; Hasnat Ahmad; E Haydn Walters; Andrew J Palmer

doi:10.3389/fmed.2023.1157706

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 (Lausanne). 2023 Apr 11:10:1157706. doi: 10.3389/fmed.2023.1157706. eCollection 2023.

Authors

Qiang Zheng^{1

2

3}, Petr Otahal¹, Ingrid A Cox^{1

2}, Barbara de Graaff^{1

2}, Julie A Campbell¹, Hasnat Ahmad^{1

4}, E Haydn Walters^{1

2

5}, Andrew J Palmer^{1

2}

Affiliations

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.

Abstract

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 the evidence for addressing the influence of ITB in IPF and provides several recommendations to minimize ITB. Identifying the presence of ITB should be routinely considered in future IPF studies, with the time-dependent method being an optimal approach to minimize ITB.

Keywords: idiopathic pulmonary fibrosis; immortal time bias; landmark; observational research; time–dependent.

Grants and funding

This study was part of the QUality of LIfE and Costs AssociaTed with Idiopathic Pulmonary Fibrosis Study (QUIET–IPF), a project funded through the NHMRC Centre of Research Excellence in Pulmonary Fibrosis (GNT1116371) and by Foundation Partner Boehringer Ingelheim and Program Partners Roche and Galapagos. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.