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

项目摘要 本项目拟采用基因芯片技术研究慢性阻塞性肺疾病（COPD）的遗传学。 生殖系DNA与电子健康记录（EHR）相关联，以发现对糖尿病发病机制的新见解。 疾病COPD是全球和美国的第三大死亡原因，影响了美国6.3%的人口 人口COPD很难诊断，其表现高度异质性，个体 经历不同的症状并发症和结果我们打算填补我们知识上的关键空白 关于慢性阻塞性肺疾病我们假设，结合一个策略，询问临床 特征（表型）在EHR的一个大的人口与深入的基因组分析， 生殖系DNA将使我们能够为理解遗传因素做出重大贡献， 与COPD有关。虽然已经研究了COPD的发展和进展的各种机制， 尽管提出了这一建议，但对生物学机制仍知之甚少。全基因组关联研究已 发现了与COPD的遗传关联，但关于生物学途径的信息很少 受这些变种的影响。通过测试多种变异或基因表达与COPD之间的关联， 我们希望对这种疾病的发病机制有更深入的了解。范德比尔特大学医学中心 （VUMC）是Martucci女士培训的理想地点，因为它拥有独特的资源。VUMC拥有 开发了一个去身份化的EHR，有超过210万成年参与者，其中22万人提供 生殖系DNA超过22，000人使用Illumina MEGA全基因组进行了DNA基因分型 阵通过利用生物信息学工具，该项目将在EHR中开发COPD的算法， COPD的遗传风险评分，并确定与COPD相关的基因表达变化。马图奇女士将 接受肺病和遗传流行病学领域专家的指导（梅林达·奥尔德里奇博士）， 统计遗传学（南希考克斯博士）。在目标1中，我们将建立一个算法来识别范德比尔特中的COPD 电子病历目标2将集中于建立COPD和相关表型的遗传风险评分，以研究COPD 发病机制和异质性。在目标3中，我们将研究与COPD相关的基因表达变化， 肺功能下降计划中的项目将提供新的信息，有可能导致 用于疾病预防、诊断和管理的精准医学发现。综合严谨 从这个职业发展奖获得的研究和临床培训经验将提高女士。 Martucci有潜力发展成为一名富有成效的独立医生-科学家，专注于生物医学 肺疾病的研究。

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.