Structural Limitations of Early–Late Treatment Comparisons Under Target Trial Emulation: A Simulation Study

Vollständiger Abstract

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Abstract Early versus Late (E–L) treatment initiation comparisons, which are prone to immortal time bias, are widely considered amenable to causal inference through target trial emulation (TTE) using clone–censor–weighting (CCW). However, whether standard CCW yields a well-defined causal estimand for the E–L comparison under ideal implementation conditions has not been formally examined. We conducted a structural simulation study to evaluate CCW-based TTE for E–L comparisons. The design varied along three dimensions: treatment-initiation mechanisms (random versus baseline-confounded timing), benefit–harm structures governing delayed-treatment harm and post-treatment benefit, and five distinct E–L initiation-window configurations. We implemented CCW as conventionally recommended and summarized estimated 12-month marginal risk ratios across settings. Depending on the placement and structure of the initiation windows, estimated risk ratios exhibited systematic window-dependent variation, including direction reversals across window specifications, even in settings where the true marginal causal contrast was 1 by design. These patterns were not consistently explained by weight instability or lack of support overlap. Our findings indicate that, in E–L comparisons, the window-defined strategy contrast estimated using CCW-based TTE can be strongly shaped by risk accumulated before treatment initiation under the specified windows, underscoring the need for caution when interpreting E–L analyses.