From the Department of Mathematics and Statistics, Boston University, Boston, MA.
Center for Biostatistics in AIDS Research, Harvard T.H. Chan School of Public Health, Boston, MA.
Epidemiology. 2021 May 1;32(3):412-420. doi: 10.1097/EDE.0000000000001339.
Mediation analysis, which started in the mid-1980s, is used extensively by applied researchers. Indirect and direct effects are the part of a treatment effect that is mediated by a covariate and the part that is not. Subsequent work on natural indirect and direct effects provides a formal causal interpretation, based on cross-worlds counterfactuals: outcomes under treatment with the mediator set to its value without treatment. Organic indirect and direct effects avoid cross-worlds counterfactuals, using so-called organic interventions on the mediator while keeping the initial treatment fixed at treatment. Organic indirect and direct effects apply also to settings where the mediator cannot be set. In linear models where the outcome model does not have treatment-mediator interaction, both organic and natural indirect and direct effects lead to the same estimators as in the original formulation of mediation analysis. Here, we generalize organic interventions on the mediator to include interventions combined with the initial treatment fixed at no treatment. We show that the product method holds in linear models for organic indirect and direct effects relative to no treatment even if there is treatment-mediator interaction. Moreover, we find a product method for binary mediators. Furthermore, we argue that the organic indirect effect relative to no treatment is very relevant for drug development. We illustrate the benefits of our approach by estimating the organic indirect effect of curative HIV treatments mediated by two HIV persistence measures, using data on interruption of antiretroviral therapy without curative HIV treatments combined with an estimated or hypothesized effect of the curative HIV treatments on these mediators. See video abstract at http://links.lww.com/EDE/B796.
中介分析始于 20 世纪 80 年代中期，被应用研究人员广泛使用。间接效应和直接效应是被协变量中介的治疗效应的一部分，也是不受中介影响的治疗效应的一部分。随后关于自然间接和直接效应的研究提供了一种基于跨世界反事实的正式因果解释：在将中介设置为无治疗时进行治疗的情况下的结果。有机间接和直接效应避免了跨世界反事实，在保持初始治疗固定在治疗的情况下，对中介进行所谓的有机干预。有机间接和直接效应也适用于无法设置中介的情况。在线性模型中，结果模型没有治疗-中介相互作用，有机和自然间接和直接效应都导致与中介分析的原始公式相同的估计量。在这里，我们将中介的有机干预推广到包括与初始治疗固定在无治疗时的干预相结合的干预。我们表明，即使存在治疗-中介相互作用，产品方法也适用于线性模型中的有机间接和直接效应。此外，我们还发现了一种用于二进制中介的乘积方法。此外，我们认为相对于无治疗的有机间接效应对于药物开发非常重要。我们通过使用中断抗逆转录病毒治疗而没有治愈性 HIV 治疗的数据，并结合对这些中介物的治愈性 HIV 治疗的估计或假设效果，来估计由两种 HIV 持续存在测量介导的治疗性 HIV 治疗的有机间接效应，来说明我们方法的好处。请观看视频摘要，网址为 http://links.lww.com/EDE/B796。
