Estimating Malaria Vaccine Efficacy in the Absence of a Gold Standard Case Definition: Mendelian Factorial Design

TL;DR

This paper introduces a Mendelian factorial design method that uses genetic traits to estimate malaria vaccine efficacy without relying on a gold-standard case definition, addressing challenges of symptom overlap and parasitemia tolerance.

Contribution

The paper presents a novel Mendelian factorial design leveraging genetic traits to estimate vaccine efficacy without a gold-standard case definition, improving accuracy over standard methods.

Findings

Estimator performs well in simulations

Standard methods are biased under certain conditions

Combined estimator improves accuracy with weak genetic protection

Abstract

Accurate estimates of malaria vaccine efficacy require a reliable definition of a malaria case. However, the symptoms of clinical malaria are unspecific, overlapping with other childhood illnesses. Additionally, children in endemic areas tolerate varying levels of parasitemia without symptoms. Together, this makes finding a gold-standard case definition challenging. We present a method to identify and estimate malaria vaccine efficacy that does not require an observable gold-standard case definition. Instead, we leverage genetic traits that are protective against malaria but not against other illnesses, e.g., the sickle cell trait, to identify vaccine efficacy in a randomized trial. Inspired by Mendelian randomization, we introduce Mendelian factorial design, a method that augments a randomized trial with genetic variation to produce a natural factorial experiment, which identifies vaccine efficacy under realistic assumptions. A robust, covariance adjusted estimation procedure is developed for estimating vaccine efficacy on the risk ratio and incidence ratio scales. Simulations suggest that our estimator has good performance whereas standard methods are systematically biased. We demonstrate that a combined estimator using both our proposed estimator and the standard approach yields significant improvements when the Mendelian factor is only weakly protective.