Huo Yanan, Yang Yang, Halloran M Elizabeth, Longini Ira M, Dean Natalie E
Gilead Sciences, Foster City, CA, USA.
Department of Statistics, Franklin College of Arts and Sciences, University of Georgia, Athens, GA, USA.
Res Sq. 2023 Dec 28:rs.3.rs-3783493. doi: 10.21203/rs.3.rs-3783493/v1.
The test-negative design (TND) is an observational study design to evaluate vaccine effectiveness (VE) that enrolls individuals receiving diagnostic testing for a target disease as part of routine care. VE is estimated as one minus the adjusted odds ratio of testing positive versus negative comparing vaccinated and unvaccinated patients. Although the TND is related to case-control studies, it is distinct in that the ratio of test-positive cases to test-negative controls is not typically pre-specified. For both types of studies, sparse cells are common when vaccines are highly effective. We consider the implications of these features on power for the TND. We use simulation studies to explore three hypothesis-testing procedures and associated sample size calculations for case-control and TND studies. These tests, all based on a simple logistic regression model, are a standard Wald test, a continuity-corrected Wald test, and a score test. The Wald test performs poorly in both case-control and TND when VE is high because the number of vaccinated test-positive cases can be low or zero. Continuity corrections help to stabilize the variance but induce bias. We observe superior performance with the score test as the variance is pooled under the null hypothesis of no group differences. We recommend using a score-based approach to design and analyze both case-control and TND. We propose a modification to the TND score sample size to account for additional variability in the ratio of controls over cases. This work expands our understanding of the data mechanisms of the TND.
检测阴性设计(TND)是一种观察性研究设计,用于评估疫苗效力(VE),该设计纳入作为常规护理一部分接受针对目标疾病进行诊断检测的个体。疫苗效力的估计方法是,用1减去接种疫苗和未接种疫苗患者检测呈阳性与检测呈阴性的校正比值比。虽然TND与病例对照研究相关,但它的不同之处在于,检测呈阳性的病例与检测呈阴性的对照的比例通常不是预先确定的。对于这两种类型的研究,当疫苗非常有效时,稀疏单元格很常见。我们考虑这些特征对TND检验效能的影响。我们使用模拟研究来探索病例对照研究和TND研究的三种假设检验程序以及相关的样本量计算。这些检验均基于一个简单的逻辑回归模型,分别是标准Wald检验、连续性校正Wald检验和计分检验。当疫苗效力较高时,Wald检验在病例对照研究和TND中表现都很差,因为接种疫苗且检测呈阳性的病例数量可能很少或为零。连续性校正有助于稳定方差,但会导致偏差。我们观察到计分检验具有更好的性能,因为在无组间差异的原假设下,方差是合并的。我们建议使用基于计分的方法来设计和分析病例对照研究和TND。我们对TND计分样本量提出了一种修正,以考虑对照与病例比例的额外变异性。这项工作扩展了我们对TND数据机制的理解。