Efficient methods for genome-wide survival analysis of early childhood caries

项目摘要 摘要幼儿龋病是我国学龄前儿童最常见的慢性病。 美国。它已被证明具有很大的遗传性，但尚不存在共识 关于ECC相关的遗传风险基因座。现有的全基因组关联研究(GWAS) ECC是稀有的，并基于使用Logistic回归的单基因座关联作图 二元性状(例如，龋齿状况)或数量性状的计数回归(例如， DMFS/DMFT/DFS/DFT)。这些方法的缺点包括对年龄的潜在错误说明 影响，没有充分利用牙齿/牙齿表面水平的龋齿寿命数据，可能会很弱 来自单个变种的信号，以及多次测试校正的负担。第一个缺点 可能会导致基于模型的关联测试产生不正确的I类错误率。其他人阻碍了 统计学上的力量。牙齿/牙面水平年龄对龋病的多位点检验或计数 DMFS/DMFT/DFS/DFT作为表型的处理可以解决上述缺点。然而，龋齿 生命过程数据不可避免地被间隔审查，因为持续监测龋病影响或 严重程度在龋病研究中是不切实际的。现有的多位点生存测试都不适用于牙齿- /牙面水平到龋齿次数或受区间约束的DMFS/DMFT/DFS/DFT计数过程 审查。这个项目的目标是开发两套基于人口的方法和 基于家庭的生存结果的遗传关联分析，解决了上述问题 缺点和区间筛选的复杂性，剖析ECC的遗传结构。这个 具体目标是1)开发两套基于集合的遗传关联测试，分别用于 多变量区间删失生存结果和面板计数结果，2)应用 两个关于ECC、龋齿的大型真实数据集的方法：全基因组 协会和基因x环境研究和Zoe 2.0，以说明方法的实用性 并发现主题知识。此外，新的方法将被编程到 R资料包将通过综合R档案网散发。成功者 该项目的完成将解决阻碍ECC基因研究的分析挑战，以及 推进基于群体和基于家庭的遗传统计方法的发展 总体生存结局的关联性分析。新方法的应用 真实数据将为ECC的遗传病因提供新的见解。

Project Summary Early childhood caries (ECC) is the most common chronic disease in preschool-age children in the United States. It has been shown to have a substantial heritability, but no consensus exists regarding ECC-associated genetic risk loci. Existing genome-wide association studies (GWAS) of ECC are scarce and were based on single-locus association mapping using logistic regression of binary traits (e.g., caries affection status) or count regression of quantitative traits (e.g., dmfs/dmft/dfs/dft). Drawbacks of those approaches include potential misspecification of the age effect, not making full use of tooth-/tooth-surface-level caries lifetime data, potentially weak signals from individual variants, and the burden of multiple testing correction. The first drawback may lead to incorrect type I error rates from model-based association tests. The others hinder statistical power. Multi-locus tests with tooth-/tooth-surface-level ages to caries or the counting process of dmfs/dmft/dfs/dft as phenotypes can address the above drawbacks. However, caries life course data are inevitably interval censored since continuous monitoring of caries affection or severity is impractical in caries research. No existing multi-locus survival tests can apply to tooth- /tooth-surface-level times to caries or the counting process of dmfs/dmft/dfs/dft subject to interval censoring. The goal of this project is to develop two suites of methods for population-based and family-based genetic association analyses of survival outcomes, which address the above drawbacks and the interval censoring complexity, to dissect the genetic architecture of ECC. The specific aims are 1) to develop two suites of set-based genetic association tests respectively for multivariate interval-censored survival outcomes and panel count outcomes and 2) to apply the methods to two large-scale real-world data sets on ECC, Dental Caries: Whole Genome Association and Gene x Environment Studies and ZOE 2.0, to illustrate the utility of the methods and discover subject matter knowledge. Additionally, the new methods will be programmed into R packages to be disseminated through the Comprehensive R Archive Network. The successful completion of this project will address analytic challenges that impede ECC genetic research, and advance the statistical methodology development for population-based and family-based genetic association analyses of survival outcomes in general. The application of the new methods to the real data will provide new insights into the genetic etiology of ECC.