Gilbert Peter B, Blette Bryan S, Shepherd Bryan E, Hudgens Michael G
Department of Biostatistics, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington, 98109, U.S.A.
Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, 27599, U.S.A.
J Causal Inference. 2020;8(1):54-69. doi: 10.1515/jci-2019-0022. Epub 2020 Jul 25.
While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, markers measuring immune response to vaccination were strongly correlated with infection. This finding generated the hypothesis that some marker-defined vaccinated subgroups were partially protected whereas others had their risk increased. This hypothesis can be assessed using the principal stratification framework (Frangakis and Rubin, 2002) for studying treatment effect modification by an intermediate response variable, using methods in the sub-field of principal surrogate (PS) analysis that studies multiple principal strata. Unfortunately, available methods for PS analysis require an augmented study design not available in HVTN 505, and make untestable structural risk assumptions, motivating a need for more robust PS methods. Fortunately, another sub-field of principal stratification, survivor average causal effect (SACE) analysis (Rubin, 2006) - which studies effects in a single principal stratum - provides many methods not requiring an augmented design and making fewer assumptions. We show how, for a binary intermediate response variable, methods developed for SACE analysis can be adapted to PS analysis, providing new and more robust PS methods. Application to HVTN 505 supports that the vaccine partially protected individuals with vaccine-induced T-cells expressing certain combinations of functions.
虽然HVTN 505试验表明，与安慰剂相比，所测试的疫苗在预防HIV感染方面没有整体疗效，但衡量疫苗免疫反应的标志物与感染密切相关。这一发现产生了一个假设，即一些由标志物定义的接种疫苗亚组受到了部分保护，而其他亚组的风险则增加了。可以使用主分层框架（弗兰加基斯和鲁宾，2002年）来评估这一假设，该框架用于研究中间反应变量对治疗效果的修正，采用主替代（PS）分析子领域中研究多个主层的方法。不幸的是，现有的PS分析方法需要HVTN 505中没有的增强研究设计，并且做出了无法检验的结构风险假设，这就促使人们需要更稳健的PS方法。幸运的是，主分层的另一个子领域，即幸存者平均因果效应（SACE）分析（鲁宾，2006年）——它研究单个主层中的效应——提供了许多不需要增强设计且假设较少的方法。我们展示了，对于二元中间反应变量，为SACE分析开发的方法如何能够适用于PS分析，从而提供新的、更稳健的PS方法。应用于HVTN 505的数据支持了该疫苗对具有疫苗诱导的表达某些功能组合的T细胞的个体具有部分保护作用。
