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

项目摘要/摘要 对暴露于罕见疾病干预措施的个人进行纵向随访的必要性 传染病终点对预期疗效和有效性研究构成障碍。 使用测试阴性设计(TND)的研究已经成为一种流行的替代方案。非政府组织 代表传统病例对照设计的变体：研究纳入寻求治疗的受试者 一种临床综合征，将对感兴趣的病原体检测呈阳性和阴性的人定义为 “案例”和“控制”。促进严格和可重复的评估 疫苗性能，该项目将重新评估TND的新应用，以及 从TND研究收集的数据中提供衡量干预效果的方法。 前两个目标是重温疫苗提供的预防感染的评估策略 以及防止感染进展为疾病--疫苗的两个组成部分“直接 TND研究的目的是测量“效果”。我们提出了新的框架来评估每种影响。 通过TND的扩展：通过有症状和无症状的比较 另一种是利用病例的年龄分布。我们将把这些方法应用于 评估肺炎球菌结合疫苗对疫苗血清型肺炎球菌的效力 肺炎和携带者，并重新评估已报道的轮状病毒疫苗效力差异 在高收入、中等收入和低收入国家。 在目标3中，我们将继续发展整群随机测试的统计程序- 消极的设计。这种性质的主要现场试验是利用 减少登革热传播的细菌沃尔巴克氏菌即将完成。排列- 由于聚类数目较少，因此计划进行基于推理。我们将推广这些方法 (I)允许采取单独的干预暴露措施(以人和蚊子为基础 移动性)，以及(Ii)包括设计变体，例如阶梯形楔形设计和间断设计 数据收集最近结束或正在进行的时间序列。我们也会考虑 一种新的应用于评估新的埃博拉病毒病(EVD)疫苗 刚果民主共和国。因此，该项目将贡献方法和计算 例程允许从TND研究数据进行有效推断，允许对 预防轮状病毒、肺炎球菌病、埃博拉病毒病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.