Unraveling the Complexities of COPD: Modeling COPD Outcomes and Phenotype Associations Using Electronic Health Records

揭示慢性阻塞性肺病的复杂性：使用电子健康记录对慢性阻塞性肺病结果和表型关联进行建模

• 批准号: 9983171
• 负责人: Victoria Martucci
• 金额: $ 5.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9983171
• 关键词: Academic Medical Centers; Address; Adult; Affect; Algorithms; Asthma; Biological; Biomedical Research; Bipolar Disorder; Candidate Disease Gene; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Code; Complex; DNA; Data; Development; Diagnosis; Disease; Disease Outcome; Disease model; Electronic Health Record; Family; Gene Expression; Gene Expression Profile; Genetic; Genetic Risk; Genomics; Genotype; Goals; Gold; Heterogeneity; Individual; Investigation; K-Series Research Career Programs; Knowledge; Lead; Learning; Link; Location; Lung diseases; Malignant neoplasm of lung; Measures; Medical History; Mentors; Morbidity - disease rate; Outcome; Participant; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Population; Predictive Value; Prevalence; Public Health; Records; Reporting; Research; Resources; Respiratory Signs and Symptoms; Respiratory physiology; Risk; Scientist; Spirometry; Symptoms; System; Testing; Tissues; Training; United States; Variant; base; biobank; bioinformatics tool; biomedical informatics; career; case control; comorbidity; disease diagnosis; disease heterogeneity; disease phenotype; disorder prevention; experience; experimental study; genetic association; genetic epidemiology; genetic predictors; genetic variant; genome wide association study; genome-wide; genomic locus; improved; innovation; insight; mortality; novel; phenotyping algorithm; polygenic risk score; precision medicine; screening; training opportunity; transcriptome

Project Summary This project proposes to investigate the genetics of chronic obstructive pulmonary disease (COPD) using germline DNA linked to electronic health records (EHR) to discover new insights into the pathogenesis of the disease. COPD is the third leading cause of mortality worldwide and in the U.S., affecting 6.3% of the U.S. population. COPD is difficult to diagnose and highly heterogeneous in its presentation, with individuals experiencing different symptoms, complications, and outcomes. We intend to fill key gaps in our knowledge about COPD with this project. We hypothesize that combining a strategy that interrogates clinical characteristics (phenotypes) in the EHR of a large population with in-depth genomic analysis of the germline DNA will allow us to make a significant contribution to understanding the genetic factors associated with COPD. While various mechanisms for development and progression of COPD have been proposed, the biological mechanisms remain poorly understood. Genome-wide association studies have uncovered genetic associations with COPD, but there is little information about the biological pathways affected by these variants. By testing the association between multiple variants or gene expression and COPD, we hope to gain greater insights into the pathogenesis of this disease. Vanderbilt University Medical Center (VUMC) is an ideal location for Ms. Martucci's training given the unique resources available. VUMC has developed a de-identified EHR with over 2.1 million adult participants, with 220,000 individuals providing germline DNA. Over 22,000 individuals have had their DNA genotyped using the Illumina MEGA genome-wide array. By leveraging bioinformatics tools, this project will develop an algorithm for COPD within EHR, build genetic risk scores for COPD, and identify gene expression changes associated with COPD. Ms. Martucci will be mentored by experts in the fields of pulmonary disease and genetic epidemiology (Dr. Melinda Aldrich) and statistical genetics (Dr. Nancy Cox). In Aim 1, we will build an algorithm to identify COPD within the Vanderbilt EHR. Aim 2 will focus on building genetic risk scores for COPD and related phenotypes to investigate COPD pathogenesis and heterogeneity. In Aim 3, we will investigate gene expression changes associated with COPD and reduced lung function. The planned project will provide novel information that has the potential to lead to precision medicine discoveries for disease prevention, diagnosis, and management. The integrated rigorous research and clinical training experience gained from this career development award will enhance Ms. Martucci's potential to develop into a productive independent physician-scientist with a focus on biomedical research in pulmonary disease.

项目摘要 该项目建议使用使用慢性阻塞性肺疾病（COPD）的遗传学 与电子健康记录（EHR）相关的种系DNA，以发现对有关该发病机理的新见解 疾病。 COPD是全球和美国死亡率的第三大主要原因，影响美国6.3％ 人口。 COPD很难诊断和高度异质性，个人 经历不同的症状，并发症和结果。我们打算在我们的知识中填补关键空白 关于这个项目的COPD。我们假设结合了询问临床的策略 大量人口的EHR的特征（表型），对深度基因组分析的特征（表型） 种系DNA将使我们能够为理解遗传因素做出重大贡献 与COPD相关。尽管COPD的发展和发展的各种机制已经 提出的，生物学机制仍然很少了解。全基因组关联研究 发现与COPD的遗传关联，但关于生物途径的信息很少 受这些变体的影响。通过测试多种变体或基因表达与COPD之间的关联， 我们希望对这种疾病的发病机理有更多的了解。范德比尔特大学医学中心 鉴于可用的独特资源，（VUMC）是Martucci女士培训的理想场所。 vumc有 开发了一个被取消识别的EHR，拥有超过210万成人参与者，有22万个人提供 种系DNA。超过22,000个人使用Illumina大型基因组对DNA进行了基因分型 大批。通过利用生物信息学工具，该项目将在EHR中为COPD开发算法，构建 COPD的遗传风险评分，并确定与COPD相关的基因表达变化。 Martucci女士威尔 受肺部疾病和遗传流行病学领域的专家（Melinda Aldrich博士）和 统计遗传学（Nancy Cox博士）。在AIM 1中，我们将构建一种算法来识别Vanderbilt中的COPD EHR。 AIM 2将着重于为COPD和相关表型建立遗传风险评分，以调查COPD 发病机理和异质性。在AIM 3中，我们将研究与COPD相关的基因表达变化 并降低肺功能。计划的项目将提供有可能导致的新型信息 预防疾病，诊断和管理的精确医学发现。综合严格的 该职业发展奖获得的研究和临床培训经验将增强女士。 Martucci有潜力发展为生产性独立医师科学家，重点是生物医学 肺部疾病的研究。