Analyzing the behavior and interpreting the results of gene based tests of rare v

描述（由申请人提供）：自人类基因组测序以来的十年中，技术和计算方面的突破为了解复杂人类疾病的病因提供了前所未有的机会。值得注意的是，下一代测序成本的降低意味着研究人员现在可以获得数千个患病个体的完整基因组序列信息。然而，主要的统计问题仍然是关于使用下一代测序数据研究罕见变异对常见疾病的贡献的最佳设计和分析。许多此类问题的基础是缺乏单一标记物罕见变异相关性测试的能力，这激发了许多潜在的更强大的基于基因的测试的发展，这些测试将来自几个个体变异的证据汇总到一个单一的测试统计中。所提出的基于基因的测试在它们如何联合收割机和重量变体方面有所不同，导致对不同遗传模型下的性能差异知之甚少。目前的重点是开发一个全面的“最佳”罕见变异测试，通常是通过对模拟数据的评估。无论哪种测试--或者更有可能的是测试--成为最佳测试，将这些方法应用于真实的、不完美的序列数据，然后根据统计学上显著的测试结果推断潜在的遗传结构仍将面临一些挑战。因此，而不是专注于新的测试开发，我们的研究将集中在更深入地了解基于基因的罕见变异测试的行为，这些测试的实际应用，以及开发方法来分解重要的测试统计数据，以获得可以指导未来研究的信息。我们将特别关注各种基础疾病模型、检验统计和研究设计的相互作用。这项工作将为在未来的测序实验中成功识别罕见的风险变异并将结果转化为公共卫生实践迈出关键一步。为了实现这些目标，我们提出了以下具体目标：我们将（1）开发一种几何表示法，以更好地了解基于基因的罕见变异检测的行为（2）在存在不完善数据的情况下评估基于基因的罕见变异检测，以及（3）开发事后分析，以识别因果变异并为复制研究设计提供信息。我们将使用分析，计算和模拟方法相结合进行研究。此外，我们将执行的工作解决了NIH的R15计划的三个主要目标：（a）进行有价值的研究，将（B）加强文科学院的研究环境，研究将进行，同时（c）暴露本科生统计遗传学研究。考虑到最后一个目标，我们提案的第四个目标是在进行目标1，2和3时为本科生提供研究经验。 公共卫生相关性：寻求确定易患人类疾病的遗传变异的遗传关联研究的数量继续增长。此外，由于测序和基因分型成本的下降、新的统计技术（例如插补）和对人类基因组的理解不断加深，进行这些研究的环境正在迅速变化。拟议的研究将为遗传关联研究提供设计和分析策略，以加快研究步伐，实现全面了解常见人类疾病遗传结构的目标。

DESCRIPTION (provided by applicant): The technological and computational breakthroughs in the decade since the sequencing of the human genome have provided an unprecedented opportunity to understand the etiology of complex human diseases. Notably, the diminishing cost of next-generation sequencing means that it is now possible for researchers to obtain complete genome sequence information on thousands of diseased individuals. However, major statistical questions remain about optimal design and analysis of studies using next-generation sequencing data to study the contribution of rare variation to common diseases. At the foundation of many such questions is the lack of power for single marker rare variant tests of association, motivating the development of many potentially more powerful, gene-based tests, which aggregate evidence from several individual variants into a single test statistic. The proposed gene-based tests vary in how they combine and weight variants, leading to poorly understood differences in performance under different genetic models. Much of the current focus is on developing an all-around "best" rare variant test, typically through assessment on simulated data. Regardless of which test--or, more likely, tests--emerge as optimal, several challenges will remain toward applying these methods to real, imperfect sequence data and then inferring underlying genetic architecture based on a statistically significant test result. Ths, rather than focus exclusively on novel test development, our research will center on gaining a deeper understanding of the behavior of gene-based rare variant tests, the realistic application of these tests, and the development of methods to decompose significant test statistics to gain information that can guide future studies. We will pay specific attention to the interplay of various underlying disease models, test statistics, and study designs. This work will provide a critical step towards successfully identifying rare risk variants in future sequencing experiments and translating the results into public health practice. To achieve these goals, we propose the following specific aims: We will (1) develop a geometric representation to better understand the behavior of gene-based rare variant tests (2) evaluate gene-based rare variant tests in the presence of imperfect data and (3) develop post-hoc analyses to identify causal variants and inform replication study design. We will conduct the research using a combination of analytic, computational and simulation approaches. Additionally, the work we will perform addresses the three main goals of NIH's R15 program: (a) to conduct meritorious research that will (b) strengthen the research environment of the liberal arts college where the research will be conducted, while (c) exposing undergraduate students to statistical genetics research. With this last goal in mind, the fourth aim of our proposal is to provide research experiences to undergraduate students when conducting aims 1, 2 and 3. PUBLIC HEALTH RELEVANCE: The number of genetic association studies seeking to identify genetic variants that predispose to human diseases continues to grow. Furthermore, the environment for conducting these studies is rapidly changing due to declining sequencing and genotyping costs, new statistical technologies (e.g. imputation) and increasing understanding of the human genome. The proposed research will provide design and analysis strategies for genetic association studies in order to accelerate the pace of research towards the goal of a complete understanding of the genetic architecture of common human diseases.