Randomization for the susceptibility effect of an infectious disease intervention

TL;DR

This paper demonstrates that standard randomized trial designs may mislead conclusions about an infectious disease intervention's effectiveness due to interference and contagion effects, highlighting the need for careful analysis.

Contribution

The paper reveals that the commonly used direct effect measure can fail to indicate the true susceptibility effect in contagious disease trials, using a novel probabilistic coupling approach.

Findings

Direct effect may not reflect the true susceptibility effect in contagious settings

Randomization can lead to misleading inferences about intervention efficacy

Structural and probabilistic methods clarify transmission dynamics

Abstract

Randomized trials of infectious disease interventions, such as vaccines, often focus on groups of connected or potentially interacting individuals. When the pathogen of interest is transmissible between study subjects, interference may occur: individual infection outcomes may depend on treatments received by others. Epidemiologists have defined the primary causal effect of interest -- called the "susceptibility effect" -- as a contrast in infection risk under treatment versus no treatment, while holding exposure to infectiousness constant. A related quantity -- the "direct effect" -- is defined as an unconditional contrast between the infection risk under treatment versus no treatment. The purpose of this paper is to show that under a widely recommended randomization design, the direct effect may fail to recover the sign of the true susceptibility effect of the intervention in a randomized trial when outcomes are contagious. The analytical approach uses structural features of infectious disease transmission to define the susceptibility effect. A new probabilistic coupling argument reveals stochastic dominance relations between potential infection outcomes under different treatment allocations. The results suggest that estimating the direct effect under randomization may provide misleading inferences about the effect of an intervention -- such as a vaccine -- when outcomes are contagious.