Statistical Method for Identifying Genetic Modifiers of Conotruncal Heart De

描述(由申请人提供)：遗传异质性是未能确定复杂疾病的遗传关联的主要原因之一。通常，患有复杂疾病的患者具有不同的表型特征，并可分为不同的亚型，这可能反映了潜在遗传机制的差异。现有的方法要么忽略了患者之间的遗传异质性，要么在检验统计中缺乏简约性和大量的自由度。在考虑遗传异质性的同时，缺乏能有效结合不同疾病亚型的关联证据的统计方法。因此，我们建议使用一种新的三阶段多项式Logistic回归模型来检验遗传关联，该模型考虑了疾病亚型之间的遗传异质性，同时减少了用于检验遗传关联的大量参数。我们计划将建议的方法应用于一项合作研究的真实数据集，目的是找到22q11DS儿童结构性心血管畸形的遗传关联。我们期望这项拟议的项目将产生一种新的强大的统计方法和相应的软件来识别复杂疾病的遗传关联，并有可能识别新的遗传变异、基因和途径，从而深入了解先天性心脏缺陷的生物学机制。

DESCRIPTION (provided by applicant): Genetic heterogeneity is one of the major reasons for failure to identify genetic associations of complex diseases. Often, patients with complex diseases have various phenotypic characteristics and can be grouped into variable subtypes, possibly reflecting differences in underlying genetic mechanisms. Existing approaches either ignore genetic heterogeneity among patients, or lack parsimony with a large number of degrees of freedom in test statistics. There is a lack of statistical approaches that can efficiently combie association evidence from varied disease subtypes while accounting for genetic heterogeneity. As such, we propose to test genetic association using a novel three-stage polynomial logistic regression model, which takes genetic heterogeneity among disease subtypes into account while reducing large number of parameters for testing genetic association. We plan to apply the proposed approach to a real dataset from a collaboration study with the goal to find genetic associations of structural cardiovascular malformations in 22q11DS children. We expect that the proposed project will yield a new powerful statistical approach and the corresponding software for identifying genetic associations of complex diseases, and has the potential to identify novel genetic variants, genes and pathways, providing an insight into biological mechanisms of congenital heart defects.