Emerging methods and applications for test-negative studies of of infectious disease interventions

项目概要/摘要 需要对暴露于罕见疾病干预措施的个体进行纵向随访 传染病终点对前瞻性疗效和有效性研究构成障碍。 使用测试阴性设计（TND）的研究已成为一种流行的选择。TNDs 代表了传统病例对照设计的变体：研究招募了寻求护理的受试者， 一种临床综合征，定义那些对感兴趣的病原体检测呈阳性和阴性的人， 分别为“病例”和“对照”。为了便于对以下方面进行严格和可重复的评估， 疫苗性能，该项目将重新评估TND的新兴应用， 有助于从TND研究收集的数据中衡量干预效果的方法。 前两个目标是重新评估疫苗赋予的抗感染保护的策略 和防止感染发展为疾病--疫苗的两个组成部分“直接 TND研究旨在衡量的“影响”。我们提出了新的框架来估计每种影响 通过TND的扩展：一个是通过比较有症状和无症状的 另一个是利用案件的年龄分布。我们将这些方法应用于 评估肺炎球菌结合疫苗对疫苗血清型肺炎球菌的有效性 肺炎和携带，并重新评估轮状病毒疫苗有效性的差异 在高收入、中等收入和低收入国家。 在目标3中，我们将继续开发群集随机测试的统计程序- 消极的设计一个主要的现场试验，这种性质的载体干预利用 减少登革热传播的沃尔巴克氏菌研究已接近完成。排列- 由于簇的数量较少，因此计划基于推理。我们将扩展这些方法 (i)允许对干预暴露进行单独测量（基于人类和蚊子 移动性），以及（ii）包括设计变体，例如阶梯式楔形设计和间断式 数据收集最近结束或正在进行的时间序列。我们亦会考虑 一种新的应用，以评估针对埃博拉病毒病（EVD）的新疫苗， 刚果民主共和国因此，该项目将有助于方法和计算 允许从TND研究数据中进行有效推断的程序，允许对 针对轮状病毒、肺炎球菌病、EVD和登革热等的干预措施。

PROJECT SUMMARY/ABSTRACT The need for longitudinal follow-up of individuals exposed to interventions against rare infectious disease endpoints poses a barrier to prospective efficacy and effectiveness studies. Studies using the test-negative design (TND) have become a popular alternative. TNDs represent a variant on traditional case-control designs: studies enroll subjects who seek care for a clinical syndrome, defining those who test positive and negative for a pathogen of interest as “cases” and “controls”, respectively. To facilitate rigorous and reproducible assessments of vaccine performance, the project will re-assess emerging applications of the TND, and contribute methods to measure intervention effects from data collected by TND studies. The first two aims revisit estimation strategies for vaccine-conferred protection against infection and against the progression of infection to disease—the two components of the vaccine “direct effect” that TND studies aim to measure. We propose novel frameworks to estimate each effect through extensions of the TND: one through comparisons of symptomatic and asymptomatic persons, and another leveraging the age distribution of cases. We will apply these methods to estimate pneumococcal conjugate vaccine effectiveness against vaccine-serotype pneumococcal pneumonia and carriage, and to re-assess reported differences in rotavirus vaccine effectiveness across high, middle, and low-income countries. In Aim 3, we will continue development of statistical procedures for cluster randomized test- negative designs. A major field trial of this nature for a vector intervention utilizing the bacterium Wolbachia to reduce dengue fever transmission is nearing completion. Permutation- based inference is planned because of small numbers of clusters. We will extend such methods (i) to allow for individual measures of intervention exposure (based on human and mosquito mobility), and (ii) to include design variants such as the stepped wedge design and interrupted time series where data collection has either recently ended or is in process. We will also consider a novel application to assess a new vaccine against Ebola Virus Disease (EVD) in the Democratic Republic of the Congo. This project will thus contribute methods and computational routines to allow valid inferences from TND study data, permitting novel assessments of interventions against rotavirus, pneumococcal disease, EVD, and dengue etc.