High Dimensional Mediation Analysis for DNA Methylation Markers Mediating Cardiovascular Health Metrics and Cardiovascular Diseases

表观遗传学和人类疾病研究的最新进展促使了 研究DNA甲基化在多大程度上介导环境暴露对健康的影响 结果。随着新的和先进的技术，表观基因组DNA甲基化数据（EWAS） 成为大规模、基于人群的表观遗传学研究的标准，同时引入新的 在调解分析中使用高维数据所特有的方法学挑战。由于这些 挑战，以前关于表观遗传介导效应的研究通常被迫集中在候选人上。 （基因特异性）甲基化标记物。对这一领域的更系统的研究将继续停滞不前，直到迫切需要 满足了对EWAS中介分析适当和特定的分析方法的需求。 我们建议开发和应用新的分析方法，高维中介分析方法 用于表观基因组DNA甲基化研究。我们将整合高维筛选和模型 选择方法纳入传统的中介分析框架。我们还将解决复杂的 在进行这种类型的数据分析的实际问题，特别是：DNA甲基化的分组效应 健康结果的标记，以及甲基化标记之间的普遍高度相关性。最后我们将 编制和分发一套方便用户的软件，以协助实施拟议的 方法. 我们将使用年轻人冠状动脉风险发展的数据来测试我们提出的方法。 研究（CARDIA）是一项大型纵向研究，使用EWAS数据检查风险因素， 发展，以及临床和亚临床心血管疾病的决定因素。我们的发现可能会导致 对DNA甲基化介导环境暴露影响的机制的新见解 健康结果。它也可能为针对这些甲基化的新干预措施的开发提供信息 标志物和改善疾病的预防和治疗。

Recent advances in the study of epigenetics and human diseases have prompted a substantial increase in research on the extent to which DNA methylation mediates the effects of environmental exposures on health outcomes. With new and advancing technologies, epigenome-wide DNA methylation data (EWAS) have become the standard for large, population-based epigenetic studies while simultaneously introducing new methodological challenges unique to the use of high-dimensional data in mediation analyses. Due to these challenges, previous studies on epigenetic-mediated effects were generally forced to focus on candidate (gene-specific) methylation markers. More systematic research into this area will remain stalled until the urgent need for analytical methods appropriate and specific to EWAS mediation analysis is met. We propose to develop and apply new analytical approaches to high-dimensional mediation analysis methods for epigenome-wide DNA methylation studies. We will integrate high-dimensional screening and model selection methods into the traditional mediation analysis framework. We will also address sophisticated practical issues in conducting this type of data analysis, specifically: grouping effects of DNA methylation markers on health outcomes, and the generally high correlation among methylation markers. Finally, we will compile and disseminate a user-friendly software package to facilitate implementation of the proposed methods. We will test our proposed methods using data from the Coronary Artery Risk Development in Young Adults Study (CARDIA), a large longitudinal study with available EWAS data that examines the risk factors, development, and determinants of clinical and subclinical cardiovascular disease. Our discoveries may lead to new insights into the mechanisms by which DNA methylation mediates the effects of environmental exposures on health outcomes. It may also inform the development of new interventions targeting these methylation markers and improving the prevention and treatment of disease.