Dealing with positivity violations in mediation analysis via weighted controlled effects, with application to assessing immune correlates of protection in antigen-experienced participants

TL;DR

This paper develops a weighted controlled effects method for causal mediation analysis in antigen-experienced populations, addressing positivity violations and applying it to COVID-19 immune response data.

Contribution

It introduces a novel weighted controlled risk approach for causal mediation analysis in populations with prior antigen exposure, extending existing frameworks.

Findings

Valid estimators demonstrated through simulation studies.

Applied to COVID-19 antibody data, revealing insights into immune correlates.

Provided R code for implementation on GitHub.

Abstract

Causal mediation analysis has become an important and increasingly used framework for evaluating candidate immune response biomarkers in vaccine research. A controlled effects approach has been proposed to estimate controlled risk curves under a counterfactual scenario in which the entire study population is vaccinated and their post-vaccination immune responses are set to a range of fixed levels. This framework performs well when the study population is antigenically na\"ive, that is, individuals have not been previously exposed to the antigen, as is common in HIV-1 vaccine research and during the early phases of the COVID-19 pandemic. However, the controlled effects framework becomes more challenging to apply in antigen-experienced populations, where prior vaccination or infection has occurred, as in the case of influenza, dengue, and more recent phases of the COVID-19 pandemic. In such settings, a key identification assumption for valid causal mediation analysis, the positivity assumption, is violated: it is no longer plausible to conceive of a hypothetical intervention that sets a post-vaccination immune marker to a fixed level below an individual's baseline immune level. In this article, we introduce a weighted controlled risk approach that targets a subpopulation for whom there is a prespecified probability of attaining a post-vaccination immune marker level. We further generalize this framework to study contrasts of controlled risks for relevant subpopulations. We demonstrate the validity of the proposed estimators through simulation studies and apply the method to reanalyze post-vaccination neutralizing antibody titers against Omicron BA.4/BA.5 as an immune correlate of COVID-19 in the Coronavirus Variant Immunologic Landscape (COVAIL) trial. R code to implement the proposed method can be found on Github: https://github.com/Qijia-He/weighted_CVE.