Methods for Pathway Modeling with Application to Folate

应用于叶酸的通路建模方法

• 批准号: 8255613
• 负责人: Duncan C. Thomas
• 金额: $ 56.35万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-16 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255613
• 关键词: Alcohols; American Association of Cancer Research; Applications Grants; Aspirin; 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; Dimensions; Disease; Environment; Environmental Risk Factor; Enzyme Kinetics; Epidemiologist; Epidemiology; Epithelial; Equation; 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 Analysis; 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; computer based statistical methods; 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

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. PUBLIC HEALTH RELEVANCE: The overall goal of this project is to develop statistical methods for modeling the effects of metabolic pathways involving multiple interacting genes and environmental factors on complex human traits, incorporating biomarker measurements and leveraging ontologies generated from external biological and genomic information. Our methods will initially be developed for candidate gene studies, and later extended to a genome-wide scale. They will be applied to observational and experimental studies of folate metabolism in relation to colorectal adenomas and colorectal cancer and are expected to yield improved models for predicting individual disease risks and insight into their underlying biological mechanisms.

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个基因和多个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使用叶酸代谢作为结直肠癌的重要候选途径，并作为其他候选生物化学和代谢途径的原型，并将其应用于结直肠癌和结肠adenomas的多个数据集。我们具有以下特定目的：1。建立一个建模框架，该框架结合了对复杂途径结构的生物学理解，并由叶酸代谢说明。这将涉及叶酸代谢的微分方程模型的扩展，使用在计算机模型中的预测来为我们的分层建模框架得出先前的协变量，并开发一种允许模型不确定性的集成方法。 这些方法将使用结肠癌家族登记中心（C-CFR）叶酸研究，腺瘤病例对照研究和一项随机腺瘤预防试验的数据与纯粹的探索方法进行说明和对比。 2。扩展此框架以利用受试者子样本中中间代谢产物浓度和酶活性速率的生物标志物测量。我们将开发分析方法，并探讨在整个研究人群中可用的疾病，暴露和基因型的各种组合中分层的最佳抽样方案。这些方法将使用有关腺瘤病例对照中同型半胱氨酸水平的已经可用的数据进行说明，这些方法将在未决的C-CFR赠款应用中进行测量以及两项纵向研究。 3。将叶酸途径的生物学知识组织成正式的本体论。我们将开发系统的方法来从本体中提取先前的协变量，以用于我们的分层建模框架，并将探索整合有关跨物种途径进化的信息的方法。 4。将这种候选途径方法扩展到全基因组量表。我们将探讨从全基因组数据和使用全基因组关联数据来推断途径的方法来为基于途径的分析提供信息。这些方法将应用于正在进行的C-CFR GWAS中的数据。 我们提出的四个示例数据集是部分选择的，以说明一系列设计，包括基于家庭的，基于人群的病例对照，纵向和随机试验。 公共卫生相关性：该项目的总体目标是开发统计方法，以建模涉及多个相互作用基因和环境因素对复杂人类特征的代谢途径的影响，并结合了由外部生物学和基因组信息产生的生物标志物测量和利用的本体。我们的方法最初将用于候选基因研究，然后扩展到全基因组量表。它们将用于与结直肠腺瘤和大肠癌有关的叶酸代谢的观察和实验研究，并有望产生改进的模型，以预测个体疾病的风险并深入了解其潜在的生物学机制。