Region‐based association tests for sequencing data on survival traits
Region‐based association tests for sequencing data on survival traits
复制标题
基于区域的关联测试，用于生存特征测序数据
作者：
Li;D. Bowden;Y. Chiu
基于家族的设计中包含受影响的受试者和疾病相关变异，可增加识别功能性罕见变异的统计功效。然而，很少有罕见的变异分析方法可用于家族设计中的事件发生时间性状，并且没有一种适用于X染色体。我们开发了新的基于谱系的负担和核心关联检验，用于事件发生时间结局，对谱系数据进行右删失，称为FamRATS（基于家族的生存性状罕见变异关联检验）。采用考克斯比例风险模型将事件发生时间特征与罕见变异相关联，灵活性涵盖所有范围和多个变异的折叠。此外，还研究了拟定检验和四种现有检验违反比例风险假设的稳健性，包括传统的基于人群的考克斯比例模型以及家庭数据的负荷、核和平方和统计量（SSQ）检验。所提出的检验可应用于大规模全基因组测序数据。它们适用于广泛的错误指定的考克斯模型下的实际使用，以及基于人群、基于谱系或混合设计。在我们广泛的模拟研究和数据示例中，我们表明，所提出的内核测试是所提出的负担测试和现有的四种罕见变异生存关联测试中最强大和最稳健的选择。当应用于糖尿病心脏研究时，拟议的测试发现1号染色体上JAK1基因的外显子组变体与全外显子组分析中2型糖尿病发病年龄的相关性最显著。
Family‐based designs enriched with affected subjects and disease associated variants can increase statistical power for identifying functional rare variants. However, few rare variant analysis approaches are available for time‐to‐event traits in family designs and none of them applicable to the X chromosome. We developed novel pedigree‐based burden and kernel association tests for time‐to‐event outcomes with right censoring for pedigree data, referred to FamRATS (family‐based rare variant association tests for survival traits). Cox proportional hazard models were employed to relate a time‐to‐event trait with rare variants with flexibility to encompass all ranges and collapsing of multiple variants. In addition, the robustness of violating proportional hazard assumptions was investigated for the proposed and four current existing tests, including the conventional population‐based Cox proportional model and the burden, kernel, and sum of squares statistic (SSQ) tests for family data. The proposed tests can be applied to large‐scale whole‐genome sequencing data. They are appropriate for the practical use under a wide range of misspecified Cox models, as well as for population‐based, pedigree‐based, or hybrid designs. In our extensive simulation study and data example, we showed that the proposed kernel test is the most powerful and robust choice among the proposed burden test and the existing four rare variant survival association tests. When applied to the Diabetes Heart Study, the proposed tests found exome variants of the JAK1 gene on chromosome 1 showed the most significant association with age at onset of type 2 diabetes from the exome‐wide analysis.
影响因子：
9.8
作者：
Zawistowski, Matthew;Gopalakrishnan, Shyam;Zollner, Sebastian
通讯作者：
Zollner, Sebastian
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
影响因子：
2.1
作者：
Lee, Seunggeun;Wu, Michael C.;Lin, Xihong
通讯作者：
Lin, Xihong