Yu Mengxin, Jewell Nicholas P
Department of Statistics and Data Science, University of Pennsylvania, PA, United States.
Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Res Sq. 2025 Apr 29:rs.3.rs-6548614. doi: 10.21203/rs.3.rs-6548614/v1.
Test-negative designs, a form of case-cohort studies, have been commonly used to assess infectious disease interventions. Early examples of the design included the evaluation of seasonal influenza vaccines in the field. Recently, they have also been widely used to evaluate the efficacy of COVID-19 vaccines in preventing symptomatic disease for different variants. The design hinges on individuals being tested for the disease of interest; upon recruitment, such individuals are subjected to a definitive test for the presence of the disease of interest (test-positives), or not (test-negatives) along with the determination of whether the individual has been exposed to the intervention under study (e.g. vaccination). In most early TND studies, individuals were tested because they were suffering from symptoms consistent with the disease in question, and the TND was a tool to reduce confounding due to healthcare-seeking behavior. However, in many cases, such as COVID-19, and Ebola, testing results were available at healthcare facilities for individuals who presented for a variety of reasons in addition to symptoms (e.g., case contact tracing, etc.). Aggregating samples from symptomatic and asymptomatic test results leads to bias in the assessment of the efficacy of the intervention. Here we consider these issues in the context of a specific version of the ',' motivated by a vaccine trial designed to assess a new Ebola viral disease vaccine (EVD). Some participants are recruited in the usual TND fashion as they present for care suffering from symptoms consistent with an Ebola diagnosis (and are thus tested); in addition, however, any test-positive identified in this fashion leads to immediate testing for Ebola for all close contacts of the test-positive who are likely asymptomatic at that point. We examine a simple approach to estimate the common efficacy of the vaccine intervention based on these two sources of test positives and test negatives, complemented by an assessment of whether efficacy is the same for both sources. The EVD trial was not completed for the fortunate reason that the prevailing disease outbreak ended; nevertheless, the approach here will be important if this trial is ever recommenced or similar trials are conducted in the future.
检测阴性设计作为病例队列研究的一种形式，已被广泛用于评估传染病干预措施。该设计的早期实例包括对季节性流感疫苗的现场评估。最近，它们还被广泛用于评估新冠病毒疫苗针对不同变种预防有症状疾病的疗效。该设计依赖于对感兴趣疾病进行检测的个体；招募时，这些个体要接受针对感兴趣疾病是否存在的确定性检测（检测阳性），或者不接受该检测（检测阴性），同时要确定个体是否接触过所研究的干预措施（如接种疫苗）。在大多数早期的检测阴性设计研究中，个体接受检测是因为他们出现了与所讨论疾病相符的症状，而检测阴性设计是一种减少因就医行为导致的混杂因素的工具。然而，在许多情况下，如新冠病毒和埃博拉病毒感染，除了有症状个体外，因各种原因（如病例接触者追踪等）前往医疗机构的个体也能获得检测结果。将有症状和无症状检测结果的样本汇总，会导致在评估干预措施疗效时出现偏差。在此，我们结合一种特定版本的“检测阴性设计”来考虑这些问题，该版本源自一项旨在评估一种新型埃博拉病毒病疫苗（EVD）的疫苗试验。一些参与者按照常规的检测阴性设计方式被招募，因为他们因出现与埃博拉诊断相符的症状前来就医（因此接受检测）；然而，除此之外，以这种方式确定的任何检测阳性者会导致对当时可能无症状的检测阳性者的所有密切接触者立即进行埃博拉检测。我们研究了一种基于这两种检测阳性和检测阴性来源来估计疫苗干预措施总体疗效的简单方法，并评估了两种来源的疗效是否相同。幸运的是，由于当时流行的疾病疫情结束，埃博拉病毒病试验没有完成；不过，如果该试验日后重新开展或进行类似试验，这里介绍的方法将很重要。
