Identifying and Estimating Causal Direct Effects Under Unmeasured Confounding

TL;DR

This paper develops methods to identify and estimate causal direct effects in observational studies even when unmeasured confounding exists, relaxing traditional assumptions and providing robust estimation strategies.

Contribution

It introduces relaxed identification conditions for the natural direct effect under unmeasured confounding and proposes flexible, multiply robust estimators for practical application.

Findings

Derived conditions for identifying natural direct effects with unmeasured confounding.

Proposed multiply robust estimators that do not rely on restrictive modeling assumptions.

Illustrated strategies for evaluating effects in vaccine studies with unobserved confounders.

Abstract

Causal mediation analysis provides techniques for defining and estimating effects that may be endowed with mechanistic interpretations. With many scientific investigations seeking to address mechanistic questions, causal direct and indirect effects have garnered much attention. The natural direct and indirect effects, the most widely used among such causal mediation estimands, are limited in their practical utility due to stringent identification requirements. Accordingly, considerable effort has been invested in developing alternative direct and indirect effect decompositions with relaxed identification requirements. Such efforts often yield effect definitions with nuanced and challenging interpretations. By contrast, relatively limited attention has been paid to relaxing the identification assumptions of the natural direct and indirect effects. Motivated by a secondary aim of a recent non-randomized vaccine prospective cohort study (NCT05168813), we present a set of relaxed conditions under which the natural direct effect is identifiable in spite of unobserved baseline confounding of the exposure-mediator pathway; we use this result to investigate the effect mediated by putative immune correlates of protection. Relaxing the commonly used but restrictive cross-world counterfactual independence assumption, we discuss strategies for evaluating the natural direct effect in non-randomized settings that arise in the analysis of vaccine studies. We revisit prior studies of semi-parametric efficiency theory to demonstrate the construction of flexible, multiply robust estimators of the natural direct effect and discuss efficient estimation strategies that do not place restrictive modeling assumptions on nuisance functions.