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Polygenic Risk Scores for Diverse Populations - Bridging Research and Clinical Care

不同人群的多基因风险评分 - 连接研究和临床护理

基本信息

批准号：
10652402
负责人：
Christopher R Gignoux
金额：
$ 246.61万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-20 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652402
关键词：
Address Adoption African American Architecture Asian Benchmarking Calibration Cardiovascular Diseases Clinical Cohort Studies Collaborations Communities Community Health Data Detection Development Diagnosis Electronic Health Record Ensure Epidemiology Ethnic group European Genetic Genetic Techniques Genetic Translation Genomic medicine Genomics Genotype Goals Health system Hispanic Improve Access Intervention Investigation Investments Latino Life Style Link Measures Medical Methods Modeling Morbidity - disease rate Participant Patients Performance Phenotype Population Population Genetics Population Heterogeneity Positioning Attribute Public Health Public Health Applications Research Publishing Race Recording of previous events Report (document)Research Research Personnel Resources Risk Risk Factors Science Structure Translating Validation Weight World Health biobank cardiovascular disorder prevention cardiovascular disorder risk clinical care clinical practice clinical prognostic clinically relevant cohort data harmonization disability epidemiology study genetic association genomic epidemiology improved individualized prevention innovation mortality multi-ethnic next generation non-genetic outreach phenotypic data polygenic risk score precision medicine prevent racial and ethnic racial and ethnic disparities risk variant secondary analysis tool trait web portal

项目摘要

Abstract Cardiovascular disease (CVD) and its risk factors impose major societal burdens and are leading causes of morbidity, mortality, and disability. Precision medicine is uniquely positioned to address CVD and its risk factors, enabled by decades of investigation and billions of dollars of investment that have established their strong underlying genetic basis. Polygenic risk scores (PRS), the aggregation of risk variants into a single score, provides one such example. Research on PRS in CVD has transitioned from estimation to examining the clinical utility; i.e., determining when and how PRS adoption will occur and how similarly conceived environmental/lifestyle risk scores (ERS) can be used clinically in concert with PRS. However, the majority of participants included in large-scale CVD research have been of European ancestry (EA), limiting the global translation of genetic associations into clinical and public health applications relevant for all populations. The PAGE consortium and others have demonstrated that EA-derived PRS are not directly translatable to racially/ethnically diverse populations. Statistical tools for PRS estimation and interpretation are founded on strong assumptions that are violated, and create bias, in the context of population structure that characterizes racially/ethnically diverse populations. These research gaps will exacerbate long-standing racial/ethnic disparities in CVD and its risk factors, underscoring the need for research that enables all groups to reap the benefits of PRS-enabled personalized prevention. In this revised application, we address the limitations previously identified in our original application by leveraging high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked electronic health records, capturing CVD and its risk factors. Through this effort, we will include over 1.5M non- European ancestry participants to develop and validate PRS for CVD-associated traits in racially/ethnically diverse populations. We will create the methods, resources, and best practices for the clinical and public health communities. This research will permit adoption and application of PRS for the detection, intervention, and treatment of CVD risk factors. Our ultimate goal is to reduce and prevent the burden of CVD in all populations. Our Specific Aims are (1) Creation of unbiased PRS: Develop and evaluate CVD PRS in combination with ERS in the large and racially/ethnically diverse PAGE study; and (2) Validation, calibration and dissemination: Externally validate and improve upon risk score models in biobanks and translate risk score models for improved access and understanding for the medical community. We will build the next generation of methods, resources, and best-practices to empower appropriate development of PRS and subsequent prediction and clinical interrogation in CVD. Deliberate focus on non-EA populations will ensure that they are not the last to benefit in the new era of genomic medicine.

摘要