Estimating Malaria Vaccine Efficacy in the Absence of a Gold Standard Case Definition: Mendelian Factorial Design
成果类型：
Article
署名作者：
Hasegawa, Raiden B.; Small, Dylan S.
署名单位：
University of Pennsylvania
刊物名称：
JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION
ISSN/ISSBN：
0162-1459
DOI：
10.1080/01621459.2020.1863222
发表日期：
2022
页码：
1466-1481
关键词：
摘要：
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, for example, 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 rate 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. Our method can be applied in vaccine and prevention trials of other childhood diseases that have no gold-standard case definition and known genetic risk factors. for this article are available online.