论文标题
将因果推理的仪器变量方法连接到估算框架
Connecting Instrumental Variable methods for causal inference to the Estimand Framework
论文作者
论文摘要
因果推断方法鉴于最近发表的有关估计和敏感性分析的附录,在临床试验中,临床试验对国际统一委员会的E9指南中的估计和灵敏度分析的增长越来越重要。 E9附录强调需要说明随机后或“交流式”事件,这些事件可能会在试验的结论中可能影响治疗效果估计的解释。仪器变量(IV)方法已在经济学,流行病学和学术研究中用于“因果推理”,但直到现在的制药行业环境中都少。在本教程论文中,我们回顾了因果推断的基本工具,包括图形图和潜在结果,以及iv分析可以放置的几个概念框架。我们详细讨论了如何将这些方法映射到E9附录中引入的治疗政策,主要层和假设的“估算策略”,并使用标准回归模型提供了它们实施的详细信息。特别关注讨论每个估计策略的假设以保持一致,可以在多大程度上进行经验测试的程度以及敏感性分析,在该程度上可以放松特定的假设。我们通过应用所描述的方法来模拟数据结束,以密切匹配两个最近的药物试验,以进一步激励和阐明这些想法
Causal inference methods are gaining increasing prominence in pharmaceutical drug development in light of the recently published addendum on estimands and sensitivity analysis in clinical trials to the E9 guideline of the International Council for Harmonisation. The E9 addendum emphasises the need to account for post-randomization or `intercurrent' events that can potentially influence the interpretation of a treatment effect estimate at a trial's conclusion. Instrumental Variables (IV) methods have been used extensively in economics, epidemiology and academic clinical studies for `causal inference', but less so in the pharmaceutical industry setting until now. In this tutorial paper we review the basic tools for causal inference, including graphical diagrams and potential outcomes, as well as several conceptual frameworks that an IV analysis can sit within. We discuss in detail how to map these approaches to the Treatment Policy, Principal Stratum and Hypothetical `estimand strategies' introduced in the E9 addendum, and provide details of their implementation using standard regression models. Specific attention is given to discussing the assumptions each estimation strategy relies on in order to be consistent, the extent to which they can be empirically tested and sensitivity analyses in which specific assumptions can be relaxed. We finish by applying the methods described to simulated data closely matching two recent pharmaceutical trials to further motivate and clarify the ideas