Temporal dependence in exposure and hazard-based infectious disease interventions

In randomized controlled trials (RCTs) of infectious disease interventions, it is well recognized that unmeasured individual heterogeneity at baseline can induce selection bias over time, thereby complicating the interpretation of the estimated hazard ratio. The present study examines a simplified setting: RCTs consisting of homogeneous participants, with no individual heterogeneity at baseline. However, even in such an apparently ideal setting, selection bias can emerge over time due to temporal dependence in exposure, a realistic feature of infectious disease transmission. In this study, we mathematically characterize the mechanism underlying this bias and quantitatively evaluate its magnitude. Our results show that this bias should be recognized as an issue in both the design and interpretation of RCTs of infectious disease interventions.