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The limits of personalization in precision medicine: Polygenic risk scores and racial categorization in a precision breast cancer screening trial

ABSTRACT: Population-based genomic screening is at the forefront of a new approach to disease prevention. Yet the lack of diversity in genome wide association studies and ongoing debates about the appropriate use of racial and ethnic categories in genomics raise key questions about the translation of genomic knowledge into clinical practice. This article reports on an ethnographic study of a large pragmatic clinical trial of breast cancer screening called WISDOM (Women Informed to Screen Depending On Measures of Risk). Our ethnography illuminates the challenges of using race or ethnicity as a risk factor in the implementation of precision breast cancer risk assessment. Our analysis provides critical insights into how categories of race, ethnicity and ancestry are being deployed in the production of genomic knowledge and medical practice, and key challenges in the development and implementation of novel Polygenic Risk Scores in the research and clinical applications of this emerging science. Specifically, we show how the conflation of social and biological categories of difference can influence risk prediction for individuals who exist at the boundaries of these categories, affecting the perceptions and practices of scientists, clinicians, and research participants themselves. Our research highlights the potential harms of practicing genomic medicine using under-theorized and ambiguous categories of race, ethnicity, and ancestry, particularly in an adaptive, pragmatic trial where research findings are applied in the clinic as they emerge. We contribute to the expanding literature on categories of difference in post-genomic science by closely examining the implementation of a large breast cancer screening study that aims to personalize breast cancer risk using both common and rare genomic markers.

SUBMITTER: James J

PROVIDER: S-EPMC8555816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study, we present an in-depth evaluation of PRS based on multi-ancestry GWAS for five cardiometabolic phenotypes in the Penn Medicine BioBank (PMBB) followed by a phenome-wide association study (PheWAS). We examine the PRS performance across all individuals and separately in African ancestry (AFR) and EUR ancestry groups. For AFR individuals, PRS derived using the multi-ancestry LD panel showed a higher effect size for four out of five PRSs (DBP, SBP, T2D, and BMI) than those derived from the AFR LD panel. In contrast, for EUR individuals, the multi-ancestry LD panel PRS demonstrated a higher effect size for two out of five PRSs (SBP and T2D) compared to the EUR LD panel. These findings underscore the potential benefits of utilizing a multi-ancestry LD panel for PRS derivation in diverse genetic backgrounds and demonstrate overall robustness in all individuals. Our results also revealed significant associations between PRS and various phenotypic categories. For instance, CAD PRS was linked with 18 phenotypes in AFR and 82 in EUR, while T2D PRS correlated with 84 phenotypes in AFR and 78 in EUR. Notably, associations like hyperlipidemia, renal failure, atrial fibrillation, coronary atherosclerosis, obesity, and hypertension were observed across different PRSs in both AFR and EUR groups, with varying effect sizes and significance levels. However, in AFR individuals, the strength and number of PRS associations with other phenotypes were generally reduced compared to EUR individuals. Our study underscores the need for future research to prioritize 1) conducting GWAS in diverse ancestry groups and 2) creating a cosmopolitan PRS methodology that is universally applicable across all genetic backgrounds. Such advances will foster a more equitable and personalized approach to precision medicine.

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The limits of personalization in precision medicine: Polygenic risk scores and racial categorization in a precision breast cancer screening trial

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