Augmented Case-Only Designs for Randomized Clinical Trials with Failure Time Endpoints
Augmented Case-Only Designs for Randomized Clinical Trials with Failure Time Endpoints
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DOI：
10.1111/biom.12392
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发表时间：
2016-03-01
期刊：
影响因子：
1.9
通讯作者：
Kooperberg, Charles
中科院分区：
文献类型：
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作者：
Dai, James Y.;Zhang, Xinyi Cindy;Kooperberg, Charles
在适当的假设下，通过利用遗传易感性和治疗分配之间的独立性，仅病例设计在考克斯模型中产生亚组治疗效应和基因-治疗相互作用的有效估计值。然而，它不能提供估计的遗传主要影响和基线风险，这是必要的计算绝对疾病风险。对于具有罕见失败时间终点的两组、安慰剂对照试验，我们考虑使用来自两组的对照随机样本（如经典病例队列抽样方案）或仅使用来自活性治疗组的对照随机样本来增强仅病例设计。后一种设计的动机是疫苗试验，以经济有效地利用资源和标本，使宿主遗传学和疫苗诱导的免疫反应可以同时在更大的参与者中进行研究。我们表明，这些设计可以识别所有参数的考克斯模型和有效的情况下，只有估计可以纳入一个两步的插件程序。模拟结果和数据示例表明，在经典病例队列设计中纳入仅病例估计量可提高所有估计参数的精度;仅在活性治疗组中进行采样控制可达到相似的效率水平。
Under suitable assumptions and by exploiting the independence between inherited genetic susceptibility and treatment assignment, the case-only design yields efficient estimates for subgroup treatment effects and gene-treatment interaction in a Cox model. However it cannot provide estimates of the genetic main effect and baseline hazards, that are necessary to compute the absolute disease risk. For two-arm, placebo-controlled trials with rare failure time endpoints, we consider augmenting the case-only design with random samples of controls from both arms, as in the classical case-cohort sampling scheme, or with a random sample of controls from the active treatment arm only. The latter design is motivated by vaccine trials for cost-effective use of resources and specimens so that host genetics and vaccine-induced immune responses can be studied simultaneously in a bigger set of participants. We show that these designs can identify all parameters in a Cox model and that the efficient case-only estimator can be incorporated in a two-step plug-in procedure. Results in simulations and a data example suggest that incorporating case-only estimators in the classical case-cohort design improves the precision of all estimated parameters; sampling controls only in the active treatment arm attains a similar level of efficiency.