Immortal time bias tends to be more pronounced in methodological studies than in empirical studies: a metaepidemiological study

Abstract

Objectives

Immortal Time Bias (ITB) is a critical challenge in observational studies estimating treatment effects, often addressed using Mantel–Byar (MB) and Landmark (LM) methods. However, the impact of ITB appears to differ between methodological and empirical studies. This study aims to investigate whether the ITB would be affected by study types and how.

Study Design and Setting

We systematically searched PubMed from January 1, 2010, to May 31, 2023, to identify empirical and methodological studies explicitly using LM or MB to address ITB. Eligible studies reported hazard ratio comparing: (i) unadjusted vs MB/LM-adjusted or (ii) MB vs LM-adjusted. We first examined estimate discrepancies across ITB-handling strategies within empirical or methodological studies, and then evaluated concordance across study types.

Results

We included 67 studies (46 empirical, 21 methodological). For unadjusted vs adjusted comparisons (58 empirical, 42 methodological), methodological studies exhibited higher rates of conclusion discordance (64.3% vs 32.8%, P = .004), and opposite effect directions (40.5% vs 15.5%, P = .010). For MB vs LM comparisons (20 empirical, 12 methodological), more frequent conclusion discordance was observed in methodological studies (41.7% vs 0%, P = .004), and other discrepancy metrics showed no significant differences between study types.

Conclusion

Our findings suggest that ITB tends to have a more pronounced impact in methodological studies, indicating that its influence may vary across different study settings. For methodological studies, it is important to clarify the critical ITB settings and the corresponding handling approaches. For empirical studies suspected of ITB, using rigorous handling strategies can enhance the robustness of treatment effect estimates.