Core--Biostatistics

常见疾病，如心力衰竭，具有复杂的遗传和环境病因 需要复杂的统计遗传学分析方法才能理清头绪。核心C的目标是为这项SCCOR的研究人员提供高质量、高通量的统计遗传分析，以测试与心力衰竭风险、心脏功能以及对治疗和运动挑战的反应有关的肾上腺素能和钙循环特征基因的多态的临床意义。在项目1、2和3中提出了广泛的临床重要基因研究。核心C将与这些研究人员密切合作，设计、实施和分析这些研究的数据。核心C有五个主要的统计遗传学目标，以便项目1-3能够实现它们的特定目标：1)确定4,000例患者和4,000名对照(包括非拉丁裔白人、非洲裔美国人和拉丁裔)心力衰竭易感性和修饰基因的等位基因结构，2)在这个病例对照队列中进行等位基因、基因和单倍型关联研究，以及仅对死亡/移植时间和发病年龄进行病例研究，3)测试基因-基因相互作用，以确定与心力衰竭高风险相关的基因变异组合，4)统计评估特定基因的功能意义 从强化血流动力学和运动耐量试验的差异，以及5)评估药物治疗对两个潜在临床重要基因类别的心力衰竭严重程度和死亡/移植风险指标的影响。我们已经实施了排列例程来调整多次测试的p值，并将利用交叉验证方法来更准确地估计本提案中所研究的遗传变异的预测能力。

Common diseases, such as heart failure, have a complex genetic and environmental etiology that require sophisticated statistical genetics analytical approaches to untangle. The objective of Core C is to provide high quality, high throughput statistical genetic analysis to the investigators of this SCCOR in order to test for clinical significance of polymorphisms identified in genes that are involved in the adrenergic and Ca2 cycling features of heart failure risk, cardiac function and response to treatment and exercise challenges. A wide range of clinically important genetic studies have been proposed in Projects 1, 2, and 3. Core C will work closely with these investigators to design, implement, and analyze the data from these studies. There are five main statistical genetic objectives for Core C so that Projects 1-3 can achieve their Specific Aims: 1) To determine the allelic architecture of heart failure susceptibility and modification genes in 4,000 cases and 4,000 controls (includes non-Latino Whites, African-Americans, and Latinos), 2) To perform allelic, genotypic, and haplotypic association studies in this case-control cohort, as well as case-only studies of time to death/transplantation and age of onset, 3) To test gene-gene interactions to identify combinations of genetic variations that are associated with high risk of hear failure, 4) To statistically assess the functional significance of specific genetic variations from intensive hemodynamic and exercise tolerance test, and 5) To evaluate the influence of drug treatment on indicators of hear failure severity and risk of death/transplantation in two potentially clinically important genetic classes. We have implemented permutation routines to adjust p-values for multiple testing and will utilize cross-validation methods to more accurately estimate the predictive capacity of the genetic variants investigated in this proposal.