Bias-reduced methods in Genetic Epidemiology

我的研究领域是遗传流行病学中的生物统计学方法。这项拟议的研究是基于对复杂人类特征的遗传基础的调查，事实证明，这比最初认为的要微妙得多。过去对常见疾病与基因组中数百万种常见基因变异之间的关联的研究已经发现了许多在疾病发生和发展中发挥作用的基因，但这些发现只是冰山一角。最近的研究旨在更深入地研究常见疾病的复杂遗传结构，需要强大的统计方法来应对罕见的遗传变异，找到基因与环境暴露之间的相互作用，并衡量基因直接作用于疾病风险的程度，或通过中间疾病状态间接作用的程度。我建议的研究可以总结如下：*病例对照数据的惩罚似然方法：为了研究罕见的变异关联，我们需要预测变量的回归方法，这些变量主要是零。我对罕见变异的工作重点是从病例对照数据中推断遗传效应的惩罚似然方法。*GxE从病例-父母三人组的稳健推断：在病例-父母三人组设计中，遗传变异是在受影响的儿童(病例)及其父母身上测量的。还可以收集儿童在环境中的暴露情况。病例-父母三人组设计给出了对遗传效应的正确推断，即使在跨多个种族群体汇集数据的研究中也是如此。然而，Shih et al.(2011)的研究表明，当被分析的遗传基因座(测试基因座)不是因果关系，而是与因果关系相关，并且这种相关性因种族而异时，从病例-父母三人组数据推断GxE可能是有偏见的。我正在开发从病例-亲本三元组数据中推断GxE的方法，这些方法对这种群体分层偏见是健壮的。*中介分析的健壮方法：中介可以被认为是基因和疾病之间因果路径上的中间疾病状态。例如，一个基因对冠心病的影响可能是通过血脂水平来调节的。中介分析将暴露效应分解为估计的直接和间接成分。然而，在存在不可测量的混杂变量的情况下，这种效应估计容易产生偏差，例如人口分层。在我关于GxE稳健推断的工作的基础上，我计划开发对人口分层偏见稳健的中介分析方法。

My area of research is biostatistical methods in genetic epidemiology. The proposed research is motivated by investigations of the genetic basis of complex human traits, which has proven to be more subtle than initially thought. Past studies of associations between common diseases and millions of common genetic variants across the genome have uncovered many genes that play a part in disease onset and progression, but these findings are just the tip of the iceberg. Recent studies that aim to delve deeper into the complex genetic architecture of common diseases require robust statistical methods able to cope with rare genetic variants, find interactions between genes and environmental exposures, and measure the extent to which a gene acts directly to increase disease risk, or acts indirectly, through an intermediate disease state. My proposed research can be summarized as follows.******Penalized likelihood methods for case-control data: To study rare variant associations we require regression methods for predictor variables that are predominantly zeros. The focus of my work for rare variants is on penalized likelihood methods for inference of genetic effects from case-control data.******Robust inference of GxE from case-parent trios: In the case-parent trio design genetic variants are measured on affected children (cases) and their parents. Environmental exposures on the child may also be collected. The case-parent trio design gives correct inference of genetic effects, even in studies that pool data across multiple ethic groups. However, Shi et al. (2011) have shown that showed that inference of GxE from case-parent trio data can be biased when the genetic locus being analyzed (the test locus) is not causal, but is correlated with a causal locus and this correlation varies from one ethnic group to another. I am developing methods for inference of GxE from case-parent trio data that are robust to such population stratification bias.******Robust methods for mediation analysis: Mediators can be thought of as intermediate disease states on the causal path between a gene and a disease. For example, the effect of a gene on coronary heart disease may be mediated by lipid levels. Mediation analysis decomposes the exposure effect into estimated direct and indirect components. However, such effect estimates are prone to bias in the presence of unmeasured confounding variables, such as population stratification. Building on my work on robust inference of GxE, I plan to develop methods for mediation analysis that are robust to population stratification bias.***********