Built-in Selection Bias in Proportional Hazards Models with Omitted Covariates: Simulation Evidence and Alternative Approaches

Abstract

In time-to-event analysis, the hazard ratio (HR) derived from the Cox proportional hazards (PH) model is the most commonly used and widely reported measure for assessing treatment effects. However, hazard ratios are non-collapsible due to their inherent conditioning on survival up to each time point. As a result, they are subject to built-in selection bias in the presence of unmeasured heterogeneity arising from omitted important covariates, even when these covariates are independent of the main exposure at baseline, as is the case in randomized controlled trials. This article aims to provide an overview of key findings from the literature on how unobserved heterogeneity, due to omitted covariates that affect the outcome, can bias the estimation of the treatment hazard ratio in standard proportional hazards models, even in randomized trials where treatment is assigned independently of such covariates. Through simulations, we evaluate the extent of bias in the semi-parametric Cox PH model and parametric PH model under various scenarios of unmeasured heterogeneity. We then compare these standard models to alternative approaches that either account for this issue or are considered robust to it. These alternatives include the hazard ratio estimated from frailty models, regression parameters from an Accelerated Failure Time (AFT) model, and survival differences between treatment groups estimated nonparametrically using Kaplan-Meier curves or based on a Cox model with time-dependent effect of the exposure. We illustrate the practical relevance of the explored alternatives through a real data application to a randomized controlled trial from the Radiation Therapy Oncology Group (RTOG 9202).