Innovative Analytical Methods for DNA Methylation Age

项目摘要/摘要 随着美国人口在未来几年继续老龄化，对生物测量和生物标记物的需求 老龄化变得越来越紧迫。寻找和验证衰老的生物标记物继续吸引着研究 努力，但收效甚微。 表观遗传修饰对导致衰老的生物过程具有潜在的关键作用(Ben-Avraham et 艾尔2012年)。最近，DNA甲基化水平(DNaM)已被确定为定义 生物学年龄，如Hannum等人。(2013)和Horvath(2013)都在多个基因座结合dNaM进行量化 人类的衰老。这一“DNA甲基化年龄”预测了晚年的全因死亡(Marioni等人。2015年)。 Hannum和Horvath都应用了超高维(~485K DNA甲基化标记)变量 弹性净惩罚的选择方法(Zou和Hastie 2005)，以得出他们的表观遗传年龄指数。 然而，这些研究人员在最初的研究方法中存在一些问题。在这笔赠款中，我们建议 使用超高维DNA甲基化标记的更准确和更健壮的表观遗传年龄模型。我们 还要考虑纵向dNaM数据。我们将开发和传播一个方便用户使用的统计软件 将使研究人员能够轻松实现这些方法的包。我们将把我们的方法应用于两个 大型纵向队列研究：年轻人的冠状动脉风险发展(CARDIA)和多项 动脉粥样硬化的种族研究(MESA)。 我们的发现可能说明传统和创新风险因素背后的生物学机制 并发现更准确和可靠的生物老化标志物。潜在的临床、生活方式和 因此，可以为健康老龄化开发药物干预措施。

Project Summary/Abstract As the US population continues to age in the coming years, the need for biological measures and biomarkers of aging becomes increasingly urgent. Finding and validating biomarkers of aging continues to attract research efforts, but with limited success. Epigenetic modifications are potentially critical to the biological processes that underlie aging (Ben-Avraham et al. 2012). More recently, DNA methylation levels (DNAm) have been identified as useful tools for defining biological age, as Hannum et al. (2013) and Horvath (2013) both combined DNAm at multiple loci to quantify human aging. This “DNA methylation age” predicted all-cause mortality later in life (Marioni et al. 2015). Both Hannum and Horvath applied the ultra-high dimensional (~485K DNA methylation markers) variable selection methodology with elastic net penalty (Zou and Hastie 2005) to derive their epigenetic age indices. However, there are several issues in the original approaches by these researchers. In this grant, we propose more accurate and robust epigenetic age models using ultra-high dimensional DNA methylation markers. We also consider longitudinal DNAm data. We will develop and disseminate a user-friendly statistical software package that will enable researchers to implement these methods with ease. We will apply our methods to two large longitudinal cohort studies: the Coronary Artery Risk Development in Young Adults (CARDIA) and Multi- Ethnic Study of Atherosclerosis (MESA). Our discoveries may illustrate the biological mechanisms underlying traditional and innovative risk factors for mortality and discover more accurate and reliable markers for biological aging. Potential clinical, lifestyle, and pharmaceutical interventions can thus be developed for healthy aging.