EHR-based Genomic Discovery and Implementation

项目摘要 在本申请中，我们建议在eMERGE前三个阶段的工作基础上开发和 验证15种常见疾病的多基因风险评分（PRS），并将其与临床风险评分相结合， 家族史，为2500人（35%非欧洲血统）建立全面的风险概况。我们将 开发表型分析算法，以确定15种疾病的病例和对照，并确定临床风险 通过从电子健康记录（EHR）中提取相关变量，对每种疾病进行评分。接下来，使用 现有的eMERGE基因型和表型数据（n= 105，000）且可公开获得（TopMed、AoU、MVP， UKBB）数据集，我们将使用新方法计算候选基因座或全基因组PRS，以使其适应 特定种族/民族群体。经确认的PRS将与家族史和临床风险评分相结合， 建立全面的风险档案。我们以前曾将这种方法应用于冠心病， 使我们能够很好地将其扩展到另外14种常见疾病。评估生产者责任计划在 前瞻性队列，我们将招募来自罗切斯特MN的参与者（1800名成人和200名青少年）， 凤凰城AZ（500名西班牙裔成年人）。DNA将被送往CLIA认证的基因组检测，我们将 计算人种/种族特定PRS。将向参与者和提供者报告个性化的风险估计 并放置在EHR中，与临床决策支持（CDS）相关联，其中包括基于指南的风险- 管理信息。对于患有以下至少一种疾病的风险显著较高的参与者， 15种疾病（估计占队列的25%），结果将亲自披露，然后评估 结果包括新的测试命令，风险降低措施，并在可修改的风险因素的变化。在 此外，我们亦会研究返回生产者责任计划对经济、行为及社会心理的影响。我们的重点 PRS将基因组医学带给人们，我们将继续与Mountain Park建立伙伴关系。 健康中心，一个为凤凰城AZ的低收入，少数民族社区服务的健康中心，以解决人们的担忧 关于基因组医学背景下的健康差异。我们的具体目标包括：1）利用现有的 105，000名eMERGE参与者的基因型和EHR数据以及其他公开数据集， 验证15种常见疾病的PRS; 2）部署新方法，将PRS整合到EHR中，并与 CDS结合了基于指南的临床建议，并开发了可扩展的披露方法 3）招募2500人，使用密集SNP阵列进行CLIA基因分型， 返回包括PRS在内的综合风险概况; 4）评估临床、成本/利用和心理社会 返回结果后的结果。

PROJECT SUMMARY In this application we propose to build on our work in the previous three phases of eMERGE to develop and validate polygenic risk scores (PRS) for 15 common diseases and combine these with clinical risk scores and family history to create comprehensive risk profiles for 2500 individuals (35% non-European ancestry). We will develop phenotyping algorithms to identify cases and controls for the 15 diseases and ascertain clinical risk scores for each disease by extracting relevant variables from the electronic health record (EHR). Next, using existing eMERGE genotype and phenotype data (n=105,000) and publicly available (TopMed, AoU, MVP, UKBB) datasets, we will calculate candidate loci or genome wide PRS using novel methods to adapt these to specific racial/ethnic groups. Validated PRS will be combined with family history and clinical risk scores to create comprehensive risk profiles. We have previously applied such methodology for coronary heart disease, positioning us well to expand this to 14 additional common diseases. To assess the utility of PRS in a prospective cohort, we will recruit participants from Rochester MN (1800 adults and 200 adolescents) and Phoenix AZ (500 adults of Hispanic ethnicity). DNA will be sent for CLIA-certified genomic testing and we will calculate race/ethnicity specific PRS. Individualized risk estimates will be reported to participants and providers and placed in the EHR with linkage to clinical decision support (CDS) that includes guideline-based risk- management information. For participants who are at significantly higher risk for developing at least 1 of the 15 diseases (estimated 25% of the cohort), results will be disclosed in-person followed by assessment of outcomes including new tests ordered, risk reduction measures, and changes in modifiable risk factors. In addition we will examine the economic, behavioral and psychosocial implications of returning PRS. Our focus on PRS brings genomic medicine to the population and we will continue our partnership with Mountain Park Health Center, a FQHC serving low-income, minority communities across Phoenix AZ, to address concerns about health disparities in the context of genomic medicine. Our specific aims include: 1) Utilize extant genotype and EHR data on 105,000 eMERGE participants as well as other publicly available datasets to validate PRS for 15 common diseases; 2) Deploy novel methods for integrating PRS in the EHR with linkage to CDS that incorporates guideline based clinical recommendations and develop scalable methods for disclosing PRS results to participants; 3) Enroll 2500 persons to undergo CLIA genotyping using dense SNP arrays and return comprehensive risk profiles that include PRS; 4) Assess clinical, cost/utilization and psychosocial outcomes following return of results.