从生存结局的RCT中识别亚组的同时推理程序：应用于AMD进展研究的分析
A Simultaneous Inference Procedure to Identify Subgroups from RCTs with Survival Outcomes: Application to Analysis of AMD Progression Studies
摘要：
随着靶向治疗的采用，而不是“一刀切”的方法，现代随机临床试验（RCT）通常旨在开发针对一个亚组患者的治疗方法。通过分析老年性黄斑变性相关眼病研究（AREDS）数据，一项研究营养补充剂在延缓眼部疾病（年龄相关性黄斑变性（AMD））进展方面的疗效的大型RCT，我们开发了一种同步推理程序，以识别和推断RCT中具有不同治疗疗效的亚组。具体来说，我们制定了多重检验问题，通过对比，并建立其同时置信区间，控制内和跨标记的多重性适当。使用真实的基因型数据进行真实的模拟，以评估各种情况下的方法性能。然后将该方法应用于AREDS以评估抗氧化剂和锌组合在延迟AMD进展中的功效。已经鉴定了包括14号染色体上的ESRRB-VASH 1在内的多个基因区域，其中亚组显示出不同的功效。我们进一步验证了我们的研究结果在一个独立的后续RCT，AREDS 2，通过发现一致的差异治疗反应的目标和非目标亚组已确定从AREDS。这种同时推理方法为在现代药物开发中自信地识别和推断亚组提供了一个步骤。
英文摘要：
With the uptake of targeted therapies, instead of the "one-fits-all" approach, modern randomized clinical trials (RCTs) often aim to develop treatments that target a subgroup of patients. Motivated by analyzing the Age-Related Eye Disease Study (AREDS) data, a large RCT to study the efficacy of nutritional supplements in delaying the progression of an eye disease, age-related macular degeneration (AMD), we develop a simultaneous inference procedure to identify and infer subgroups with differential treatment efficacy in RCTs with survival outcome. Specifically, we formulate the multiple testing problem through contrasts and construct their simultaneous confidence intervals, which control both within- and across- marker multiplicity appropriately. Realistic simulations are conducted using real genotype data to evaluate the method performance under various scenarios. The method is then applied to AREDS to assess the efficacy of antioxidants and zinc combination in delaying AMD progression. Multiple gene regions including ESRRB-VASH1 on chromosome 14 have been identified with subgroups showing differential efficacy. We further validate our findings in an independent subsequent RCT, AREDS2, by discovering consistent differential treatment responses in the targeted and non-targeted subgroups been identified from AREDS. This simultaneous inference approach provides a step forward to confidently identify and infer subgroups in modern drug development.
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