Bayesian Network Models for Genetics and Metabolomics Studies of Fetal Programming

项目摘要 遗传学和代谢组学数据的综合建模需要仔细规范复杂的 依赖性，特别是当研究相关临床的胎儿编程的潜在机制时， 母亲及其新生儿的表型。最近为确定"基因决定的代谢型"所作的努力 使用经典的全基因组关联研究方法，提供了遗传学和 代谢组学数据;然而，为了准确地表征遗传和代谢对胎儿的贡献， 发展，需要更复杂的模型。本研究的目的是发展贝氏网路 与母亲临床表型相关的遗传学和代谢组学数据的令人信服的综合模型， 他们的新生儿在网络中，节点表示感兴趣的组学特征，边表示关系 其中。贝叶斯网络在节点之间构建一系列有向关系，其中变量 由“子”节点表示的节点是以其“父”节点为条件来描述的。我们假设 母亲和新生儿的代谢分型将提供一组候选基因-代谢物关系， 对临床表型共同贡献可以在贝叶斯网络中被简约地建模，贝叶斯网络还 整合基因型和代谢物之间的依赖性。为了开发网络模型，我们将使用现有的 高血压和不良妊娠的母亲/新生儿对的遗传学和代谢组学数据 结果（HAPO）研究。HAPO是一项国际性的观察性研究，涉及超过23，000名孕妇 2000年至2006年，他们的新生儿，证明了母亲的葡萄糖水平之间的正相关， 在怀孕期间和新生儿出生体重和肥胖。HAPO Metabolomics是一项由NIH资助的 对北方欧洲人、非洲-加勒比人、墨西哥-美国人和泰国人母亲/新生儿对的调查 涉及母体和哺乳动物的靶向和非靶向气相色谱/质谱分析的祖先 新生儿脐带血血清HAPO遗传学研究涉及HAPO母亲/新生儿的全基因组基因分型 在同一个四个祖先群体中。HAPO代谢组学中约有1400对母子对 和HAPO遗传学研究。使用这些数据，我们将应用一个全面的代谢分型管道， 为综合模型确定候选基因-代谢物关系。然后我们将开发和应用 贝叶斯网络模型，以统一母亲和新生儿代谢型结合复杂 母亲和新生儿基因型和代谢谱之间的依赖性。这些拟议的分析将 通过将代谢型整合到贝叶斯网络模型中来增强现有的代谢型分析方法， 已知临床表型的母体和胎儿遗传和代谢基础的表征 协会.所提出的方法也将更广泛地适用于不同组学数据的整合 相关的个人。

Project Summary Integrated modeling of genetics and metabolomics data demands careful specification of complex dependencies, particularly when investigating mechanisms underlying fetal programming of related clinical phenotypes in mothers and their newborns. Recent efforts to identify `genetically determined metabotypes' using classic genome wide association study approaches have provided initial links between genetics and metabolomics data; however, to accurately characterize genetic and metabolic contributions to fetal development, more sophisticated models are required. The goal of this study is to develop Bayesian network models for cogent synthesis of genetics and metabolomics data related to clinical phenotypes for mothers and their newborns. In networks, nodes represent omics features of interest and edges represent relationships among them. Bayesian networks construct a series of directed relationships among nodes in which a variable represented by a `child' node is described conditional on its `parent' nodes. It is our hypothesis that metabotyping in mothers and newborns will provide a set of candidate gene-metabolite relationships whose joint contribution to clinical phenotype(s) can be parsimoniously modeled in Bayesian networks that also incorporate dependencies among genotypes and metabolites. To develop network models, we will use existing genetics and metabolomics data for mother/newborn pairs from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO was an international, observational study involving >23,000 pregnant mothers and their newborns from 2000-2006 that demonstrated a positive association between maternal glucose levels during pregnancy and newborn birth weight and adiposity. HAPO Metabolomics is an ongoing NIH-funded investigation of mother/newborn pairs of Northern European, Afro-Caribbean, Mexican-American and Thai ancestry involving targeted and non-targeted gas-chromatography/mass-spectrometry profiling of maternal and newborn cord serum. HAPO Genetics studies involved genome-wide genotyping for HAPO mother/newborn pairs in the same four ancestry groups. ~1400 mother/child pairs are represented in both HAPO Metabolomics and HAPO Genetics studies. Using these data, we will apply a comprehensive metabotyping pipeline to identify candidate gene-metabolite relationships for integrated models. We will then develop and apply Bayesian network models to unify maternal and newborn metabotypes in conjunction with complex dependencies among maternal and newborn genotypes and metabolic profiles. These proposed analyses will augment existing metabotyping approaches by integrating metabotypes into Bayesian network models for fuller characterization of maternal and fetal genetic and metabolic underpinnings of known clinical phenotype associations. The proposed methods will also be more broadly applicable to integration of diverse omics data for related individuals.