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Methods for Pathway Modeling with Application to Folate

应用于叶酸的通路建模方法

基本信息

批准号：
8651489
负责人：
Duncan C. Thomas
金额：
$ 53.4万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-16 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651489
关键词：
Alcohols American Association of Cancer Research Applications Grants Aspirin Bayesian Analysis Biochemical Pathway Biological Biological Markers Blood Cancer Family Cancer Prevention Trial Candidate Disease Gene Carbon Carcinoma Case-Control Studies Colorectal Colorectal Adenoma Colorectal Cancer Complex Computer Simulation DNA Methylation DNA Repair Data Data Set Databases Diet Dietary intake Differential Equation Dimensions Disease Environment Environmental Risk Factor Enzyme Kinetics Epidemiologist Epidemiology Epithelial Evolution Family Family Study Family-Based Registry Fiber Folate Folic Acid Genes Genetic Polymorphism Genetic Programming Genomics Genotype Glutathione Goals Graph Haplotypes Hepatic Homocysteine Homocystine Human Individual Intake Joints Knowledge Literature Logistic Regressions Longitudinal Studies Markov Chains Measurement Measures Mediating Metabolic Pathway Metabolism Methionine Methods Metric Mitochondria Modeling Molecular Epidemiology Observational Study Ontology Parents Pathway interactions Phase Polyps Population Study Prevention Randomized Randomized Controlled Trials Reaction Research Personnel Riboflavin Role Sampling Scheme Siblings Single Nucleotide Polymorphism Staging Statistical Methods Structure Techniques Testing Thinking Time Triad Acrylic Resin Uncertainty Ursodeoxycholic Acid Variant Vitamin B6 Wheat Bran adenoma analytical method base carcinogenesis case control cohort colon cancer family registry design disorder risk enzyme activity epidemiology study folic acid metabolism forest gene interaction genetic association genome wide association study genome-wide improved insight interest novel strategies pharmacokinetic model population based prototype public health relevance randomized trial research study symposium thymidylate trait

项目摘要

DESCRIPTION (provided by applicant): An important challenge in the field of molecular epidemiology is to develop methods for studying multiple gene and multiple environmental factors as interacting factors contributing to disease. The overall goal of this proposal is to develop novel approaches to this problem, using folate metabolism as an important candidate pathway in colorectal carcinogenesis and as a prototype for other candidate biochemical and metabolic pathways, and to apply them to several datasets on colorectal cancer and colorectal adenomas. We have the following specific aims: 1. Develop a modeling framework incorporating biological understanding about the structure of a complex pathway, illustrated by folate metabolism. This will involve extensions to our differential equations model for folate metabolism, using the predictions of this in silico model to derive prior covariates for our hierarchical modeling framework, and developing an integrated approach allowing for model uncertainty. These various methods will be illustrated and contrasted with purely exploratory methods using data from the Colon Cancer Family Registry (C-CFR) folate study, an adenoma case-control study, and a randomized adenoma prevention trial. 2. Extend this framework to exploit biomarker measurements of intermediate metabolite concentrations and enzyme activity rates on a subsample of subjects. We will develop analytical methods and explore optimal sampling schemes stratifying on various combinations of disease, exposure, and genotypes that are available on an entire study population. These approaches will be illustrated with already available data on homocysteine levels in the adenoma case-control, additional biomarkers that will be measured in a pending C-CFR grant application, and two longitudinal studies. 3. Organize biological knowledge for the folate pathway into a formal ontology. We will develop systematic methods for extracting prior covariates from an ontology for use in our hierarchical modeling framework, and will explore ways of incorporating information on evolution of pathways across species. 4. Extend this candidate pathway approach to the genome-wide scale. We will explore methods for inferring pathways from genome-wide data and for using genome-wide association data to inform pathway-based analyses. These methods will be applied to data from the ongoing C-CFR GWAS. The four example datasets we propose were chosen in part to illustrate a range of designs, including family-based, population-based case-control, longitudinal, and randomized trial.

描述（由申请人提供）：分子流行病学领域的一个重要挑战是开发研究多基因和多种环境因素作为导致疾病的相互作用因素的方法。该提案的总体目标是开发解决该问题的新方法，利用叶酸代谢作为结直肠癌发生中的重要候选途径，并作为其他候选生化和代谢途径的原型，并将其应用于结直肠癌和结直肠腺瘤的多个数据集。我们有以下具体目标： 1. 开发一个建模框架，结合对复杂途径结构的生物学理解，以叶酸代谢为例。这将涉及叶酸代谢微分方程模型的扩展，使用计算机模型的预测来导出我们的分层建模框架的先验协变量，并开发一种允许模型不确定性的集成方法。我们将使用来自结肠癌家族登记 (C-CFR) 叶酸研究、腺瘤病例对照研究和随机腺瘤预防试验的数据来说明这些不同的方法，并将其与纯粹的探索性方法进行对比。 2. 扩展该框架以利用受试者子样本的中间代谢物浓度和酶活性率的生物标志物测量。我们将开发分析方法并探索最佳抽样方案，对整个研究人群中可用的疾病、暴露和基因型的各种组合进行分层。这些方法将通过腺瘤病例对照中同型半胱氨酸水平的现有数据、将在待决的 C-CFR 拨款申请中测量的其他生物标志物以及两项纵向研究来说明。 3. 将叶酸途径的生物学知识组织成正式的本体。我们将开发系统方法，从本体中提取先验协变量，用于我们的分层建模框架，并将探索整合跨物种路径进化信息的方法。 4. 将这一候选途径方法扩展到全基因组范围。我们将探索从全基因组数据推断通路的方法，以及使用全基因组关联数据为基于通路的分析提供信息的方法。这些方法将应用于正在进行的 C-CFR GWAS 的数据。我们选择的四个示例数据集部分是为了说明一系列设计，包括基于家庭、基于人群的病例对照、纵向和随机试验。