The PRIMED Consortium: Reducing disparities in polygenic risk assessment

Abstract

By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities. The PRIMED Consortium was established to develop methods to improve the performance of PRSs in global populations and individuals of diverse genetic ancestry. To this end, PRIMED is aggregating and harmonizing multiple phenotype and genotype datasets on AnVIL, an interoperable secure cloud-based platform, to perform individual- and summary-level analyses using population and statistical genetics approaches. Study sites, the coordinating center, and representatives from the NIH work alongside other NHGRI and global consortia to achieve these goals. PRIMED is also evaluating ethical and social implications of PRS implementation and investigating the joint modeling of social determinants of health and PRS in computing disease risk. The phenotypes of interest are primarily cardiometabolic diseases and cancer, the leading causes of death and disability worldwide. Early deliverables of the consortium include methods for data sharing on AnVIL, development of a common data model to harmonize phenotype and genotype data from cohort studies as well as electronic health records, adaptation of recent guidelines for population descriptors to global cohorts, and sharing of PRS methods/tools. As a multisite collaboration, PRIMED aims to foster equity in the development and use of polygenic risk assessment.

Keywords: diversity; equity; polygenic risk score.

Graphical abstract

Figure 1

Overview of the PRIMED Consortium structure and investigators (A) The consortium includes study sites, coordinating center, NIH funders, committees, working groups, external advisors, affiliates, and other partner programs/consortia. (B) PRIMED investigators are located in 49 institutions across 12 countries.

Figure 2

The PRIMED common data model Each colored box represents a table, and lines represent links between tables. The subject table (purple) captures information on each subject/participant and is the linking point to the other components of the data model. The population descriptor table (orange) captures detailed population descriptor information on each subject. The phenotype dataset tables (dark pink) provide phenotype dataset metadata and provide links to the phenotype domain tables (light pink) which are tabular data files containing individual-level phenotype data for specified harmonized variables in a wide-format familiar to cohort studies; unharmonized phenotype data can be shared in tabular data files pre-harmonization. The genotype tables (blue) capture sample metadata and group samples into sets, corresponding to genotype datasets. Genotyping technology-specific dataset tables provide metadata describing key features of the genotype dataset, and file tables provide file paths to individual-level genotype data files (e.g., VCFs) linked to datasets. Genomic summary result tables (teal) include analysis tables that capture metadata about analyses that generated the GSRs and file tables provide file paths to tabular data files containing the GSR data linked to analyses.