Random Field Modelling of genetic and epigenetic association underlying congenital heart defects in the presence of disease heterogeneity

项目总结/摘要 该提案是为了延长NHLBI K 01奖而提交的，题为“遗传学的随机场建模”。 和疾病异质性存在下先天性心脏缺陷的表观遗传学关联”。李明博士 是本研究的主要研究者，并且在本K 01奖项的最后一年（01/01/2018 - 12/31/2021）。 在过去的一年里，李博士的研究团队经历了大量的研究中断和额外的 新冠肺炎疫情导致的行政职责。这一扩展预计将为李博士提供 完成正在进行的K 01项目并成功过渡到未来的R 01研究所需的时间。 博士李的职业目标是成为一名独立的统计遗传学家和遗传流行病学家， 心血管疾病，特别是先天性心脏病（CHD）。在过去的三年里，李博士一直在 开发创新的生物统计方法，用于检测与风险相关的遗传和表观遗传因素 的CHD。所提出的方法正在应用于国家出生缺陷预防研究的样本 （NBDPS），有史以来最大的多中心基于人群的出生缺陷研究。到目前为止， 已经取得进展，在同行评审期刊上发表了一些重要研究结果。其他调查结果 也在主要会议上介绍，并提交出版物，但在很大程度上也经历了延误， 由于COVID-19中断。这些结果提供了对潜在的病理生理和 病因学过程，导致冠心病，也将作为一个基础，李博士提出额外的 R 01研究。未来R 01的研究将主要集中在两个方面：1）应用新开发的 生物统计方法与其他现有的NHLBI数据源，如儿科心脏基因组学联盟 （PCGC）和用于精准医学的Trans-Omics（TOPMed）;以及2）进一步开发创新的生物统计学 基于遗传、表观遗传、转录和基因组学的疾病预测和精确干预的方法。 母亲的生活方式这项研究的继续将整合NIH各机构的数据源 (i.e. NICHD和NHLBI），也可能为转化研究提供方向，从而更精确地 preconceptual咨询and interventions干预.这样的研究方向也与NHLBI的 多个特别关注通知（例如：NOT-HL-20-815）中所述的重点研究领域。

Project Summary/Abstract This proposal is submitted for an extension of the NHLBI K01 award, entitled “Random field modeling of genetic and epigenetic associations for congenital heart defects in the presence of disease heterogeneity”. Dr. Ming Li is the principal investigator of this study, and is within the final year of this K01 award (01/01/2018 – 12/31/2021). In the past year, Dr. Li’s research team has experienced substantial research interruptions and additional administrative responsibilities due to the COVID-19 pandemic. This extension is expected to provide Dr. Li the necessary time to complete the ongoing K01 projects and to make successfully transition to future R01 studies. Dr. Li’s career goal is to become an independent statistical geneticist and genetic epidemiologist in cardiovascular diseases, particularly in congenital heart defects (CHDs). In the past three years, Dr. Li has been developing innovative biostatistical methods for detecting genetic and epigenetic factors associated with the risk of CHDs. The proposed methods are being applied to samples from the National Birth Defect Prevention Study (NBDPS), the largest multi-site population-based study of birth defects ever conducted. So far, substantial progresses have been made with a number of key findings published in peer-review journals. Additional findings were also presented at the major conferences and submitted for publications, but also experienced delays largely due to COVID-19 interruptions. These results have provided insights into the underlying pathophysiological and etiological processes that result in CHDs, and will also serve as a foundation for Dr. Li to make propose additional R01 studies. The future R01 studies will mainly be focused on two aspects: 1) to apply the newly developed biostatical methods to other existing NHLBI data sources, such as the Pediatric Cardiac Genomics Consortium (PCGC) and Trans-Omics for Precision Medicine (TOPMed); and 2) to further develop innovative biostatistical methods for disease prediction and precision intervention based on the genetic, epigenetic, transcriptional and maternal lifestyle profiles. The continuation of this research will integrate data sources across NIH institutions (i.e. NICHD and NHLBI), and also may provide a direction for translational research leading to more precise preconceptional counseling and interventions. Such research directions are also consistent with NHLBI’s emphasized research areas as described in multiple notices of special interests (e.g. NOT-HL-20-815).