Global significance test based on quantile regression with applications to genomic studies of Alzheimer’s disease

基于分位数回归的全局显着性检验及其在阿尔茨海默病基因组研究中的应用

• 批准号: 10303743
• 负责人: Qi Zheng
• 金额: $ 25.71万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303743
• 关键词: Affect; Age-Years; Aging; Alzheimer' s Disease; Awareness; Biological; Biomedical Research; Brain Diseases; Cause of Death; Cohort Studies; Complex; Confounding Factors (Epidemiology); Data; Data Analyses; Dementia; Development; Dimensions; Disease; Disease regression; Elderly; Etiology; Evaluation; Foundations; Gene Expression; Gene Expression Profiling; Genes; Genetic Predisposition to Disease; Genomics; Goals; Heritability; Joints; Light; Linear Regressions; Memory; Methods; Modeling; Neurodegenerative Disorders; Pattern; Phenotype; Play; Probability; Procedures; Public Health; Quantitative Trait Loci; Research Personnel; Role; Sampling; Single Nucleotide Polymorphism; Standardization; Testing; Therapeutic; Tissue-Specific Gene Expression; United States; base; biological research; differential expression; disease phenotype; flexibility; follow-up; genome-wide; genomic data; genomic tools; high dimensionality; improved; innovation; insight; multidimensional data; neglect; novel; religious order study; research and development; response; risk variant; statistics; theories; tool; user-friendly

Project Summary/Abstract Alzheimer's disease (AD) is one of the leading causes of death for the elderly with no current cure. Genomics studies, such as mapping expression quantitative trait loci (eQTL) and differential gene expressions, play a critical role in understanding the biological mechanisms of AD and developing potential therapeutic treatments. In genomics studies, there has been growing awareness that the covariates (e.g., quantitative gene expression) may have changing effects on the distribution of responses (e.g., disease phenotypes) reflecting a heterogeneous covariates-response association. Those heterogeneous associations shed insight on scientific discoveries and entail significant implications but are often neglected by most existing analysis procedures confined to a narrow aspect of the response distribution (e.g., standard linear regression focusing on the mean or quantile regression at a single quantile level). Thus, the development of valid and efficient hypothesis tests to detect heterogeneous associations is of great value to genomics studies of complex diseases such as AD. This proposal aims to develop several quantile regression-based global significance tests, which utilize all information across a well-chosen region of quantile levels and provide researchers with evaluations of the overall impacts of covariates on the response. Inspired by our preliminary data analysis on the two studies of aging and dementia, namely Religious Orders Study (ROS) and Memory and Aging Project (MAP), we will first propose a global significance test to thoroughly evaluate covariates' impact across all quantile levels of the response variable (Aim 1). Then motivated by high-dimensional genomics data of AD in ROS/MAP, we will further develop two global significance tests for high-dimensional responses and covariates data, respectively (Aim 2). Moreover, we will apply the proposed tests in Aims 1-2 to the genomics data generated by ROS/MAP to identify eQTL and differentially expressed genes that can be used to prioritize risk genes of AD for identifying developing potential treatments (Aim 3). We will also provide a user-friendly R package to implement the proposed tests. The innovation of our proposal is three-fold. (i) By evaluating the impacts of covariates on responses across the entire quantile domain, the proposed global significance tests have a superior power to identify heterogeneous covariates-response associations compared to alternative methods. (ii) As the proposed tests neither impose any stringent model assumption nor require additional splines smoothing or re-sampling or shrinkage estimation, they can be broadly implemented in large-scale genomics data. (iii) Our proposed test in Aim 2 will serve as a useful tool for detecting heterogeneous associations between covariates and multiple responses. The successful completion of this project will facilitate detecting heterogeneous associations and the subsequent scientific discoveries in AD genomics studies for developing treatments. Moreover, our tests can be applied to a broad scope of biomedical fields, resulting in a fruitful avenue for promoting public health.

项目总结/文摘