Quantitative Methods for Genetic Epidemiology

描述（由申请人提供）：人类基因组序列的完成带来了关于人类基因组结构的大量信息。我们现在面临的挑战是利用这些丰富的信息，通过更好地了解人类常见疾病来改善人类健康。导致常见复杂疾病的复杂遗传和环境机制加剧了这一挑战。我们的长期目标是发展最先进的统计和定量方法来分析遗传关联研究，以提取最大数量的遗传信息。我们的短期目标是为遗传关联研究开发新的“无模型”统计方法，以便在我们获得导致疾病和对治疗反应的遗传和环境因素的知识时提供可靠而有力的方法。通过采取这一策略，我们预计我们提出的研究计划将成功地为研究界提供急需的统计方法来评估大规模基因组变异与复杂人类特征的关联。我们计划的具体目标是：1)为遗传关联研究开发非参数统计方法：基于我们最近对一类新的非参数统计的发展，我们计划扩展我们的方法，使其更强大地用于检测基因-基因相互作用，为全基因组分析创建“扫描”统计，并考虑各种特征；2)开发新的基因组扫描统计：考虑到大量候选基因，或全基因组关联研究，我们计划开发新的扫描统计来评估单倍型与各种性状的关联；3)开发系谱数据的非参数统计方法和扫描统计：目标1-2是针对不相关的主题，我们计划将这些方法扩展到系谱数据；4)开发用户友好的软件和文档：我们计划免费向科学界提供实现我们方法的用户友好的软件，包括文档完备的程序和使用示例；5)将新方法应用于合作研究：目标1-4中开发的所有方法将应用于正在进行的合作研究，以深入了解其优势和劣势，并为我们的合作研究提供潜在的临床益处。转化潜力：我们的研究计划解决了一个至关重要的科学和临床问题——优化利用大规模基因组信息来评估其在人类健康中的作用。通过发展新的定量方法，我们的研究有可能改善复杂的遗传人类疾病的诊断、预后和治疗，以及其他人类特征。

DESCRIPTION (provided by applicant): The completion of the human genome sequence has led to an immense amount of information on the structure of the human genome. We now face the challenge of using this rich information to improve human health through a better understanding of common human diseases. This challenge is intensified by complex genetic and environmental mechanisms that contribute to common complex diseases. Our long term goals are to develop state-of-the-art statistical and quantitative methods to analyze genetic association studies in order to extract the maximum amount of genetic information. Our short term goals are to develop new "model-free" statistical methods for genetic association studies, in order to provide robust, yet powerful, methods as we gain knowledge on the genetic and environmental factors that lead to disease and response to treatment. By taking this strategy, we anticipate that our proposed research plans will succeed at providing the research community with the much-needed statistical methods to evaluate the association of large scale genomic variation with complex human traits. Our planned specific aims are to: 1) Develop Nonparametric Statistical Methods For Genetic Association Studies: Based on our recent developments of a new class of nonparametric statistics, we plan to extend our methods to be more powerful for detecting gene-gene interactions, to create "scan" statistics for genome-wide analyses, and to account for a variety of traits; 2) Develop New Genomic Scan Statistics: To consider a large number of candidate genes, or a genome-wide association study, we plan to develop new scan statistics for evaluating the association of haplotypes with a variety of traits; 3) Develop Nonparametric Statistical Methods and Scan Statistics for Pedigree Data: Aims 1-2 are focused on unrelated subjects, and we plan to extend these methods to pedigree data; 4) Develop User-Friendly Software and Documentation: We plan to provide, at no charge to the scientific community, user-friendly software that implements our methods, including well-documented procedures and examples on their usage; 5) Apply New Methods to Collaborative Research Studies: All methods developed in Aims 1-4 will be applied to ongoing collaborative studies in order to gain insights to their strengths and weaknesses, and to provide potential clinical benefits for our collaborative studies. Translational Potential: Our research plans address a critically important scientific and clinical problem--to make optimal use of large-scale genomic information to evaluate its role in human health. Through development of new quantitative methods, our research has the potential to improve the diagnosis, prognosis, and treatment of complex genetic human diseases, as well as other human traits.