Population-Wide Genomic Screening: Clinical Outcomes, Economic Value, and Ethics Considerations in Familial Hypercholesterolemia

Abstract

Population-wide genomic screening is one of the great promises of precision medicine with opportunities to improve patient health outcomes, lower healthcare costs, and prevent disease. This dissertation examines population-wide genomic screening effects, economics, and ethics through the use case of familial hypercholesterolemia (FH) and bundled genomic screening. In Chapter 1, we performed a longitudinal statistical analysis estimating the effect of disclosure of pathogenic genetic variants for FH on individuals’ low-density lipoprotein (LDL) cholesterol levels and trajectories. We used electronic health records from individuals with variants from FH associated genes (LDLR, APOB, and PCSK9) identified in a cohort of more than 190,000 patients within the Geisinger MyCode Community Health Initiative. When individuals in the United States with an FH variant receive their genetic return of results (ROR), there may be a reduction in their LDL cholesterol levels and LDL cholesterol level trajectories over time attributable to ROR, suggestive of a beneficial clinical effect. As interest in population genetic screening implementation continues to grow, future studies should aim to include larger populations affected by FH and improved study designs for better insight into the true effect sizes of ROR on LDL cholesterol. Chapter 2 builds on this analysis, utilizing a decision-analytic model to estimate the clinical and economic outcomes of population-wide FH genomic screening versus no genomic screening in age-based cohorts from 20 to 80 years old. We found that population FH screening is not cost-effective at current genomic screening costs. However, reducing genomic testing costs or including FH testing within a broader multiplex screening panel may improve clinical and economic value. Finally, Chapter 3 evaluates at what age a bundled population genomic screen should take place from a utilitarian and principlist perspective. Our analysis found that a pragmatic approach considers engaging in a utilitarian analysis first due to the likelihood that health systems may have to weigh their actions in a very similar manner. Principlism can support and supplement analyses undertaken with a utilitarian perspective by identifying areas of concern based on discordance from proposed age recommendations. However, it is apparent that no matter what age a bundled population genomic screen takes place, there are going to be explicit and implicit trade-offs between conditions, dimensions, and principles.