Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations.
Niall J LennonLeah C KottyanChristopher KachulisNoura Abul-HusnJosh AriasGillian BelbinJennifer E BelowSonja BerndtWendy K ChungJames J CiminoEllen Wright ClaytonJohn J ConnollyDavid CrosslinOzan DikilitasDigna R Velez EdwardsQiPing FengMarissa FisherRobert FreimuthTian Genull nullnull nullJoseph T GlessnerAdam GordonCandace GuiducciHakon HakonarsonMaegan HardenMargaret HarrJoel HirschhornClive J HoggartLi HsuRyan IrvinGail P JarvikElizabeth W KarlsonAtlas KhanAmit KheraKrzysztof KirylukIftikhar KulloKatie LarkinNita LimdiJodell E LinderRuth LoosYuan LuoEdyta MalolepszaTeri ManolioLisa J MartinLi McCarthyJames B MeigsTesfaye B MershaJonathan MosleyBahram NamjouNihal PaiLorenzo L PesceUlrike PetersJosh PetersonCynthia A ProwsMegan J PuckelwartzHeidi RehmDan M RodenElisabeth A RosenthalRobb RowleyKonrad Teodor SawickiDan SchaidTara SchmidlenRoelof SmitJohanna SmithJordan W SmollerMinta ThomasHemant TiwariDiana ToledoNataraja Sarma VaitinadinDavid VeenstraTheresa L WalunasZhe WangWei-Qi WeiChunhua WengGeorgia WiesnerYin XianyongEimear KennyPublished in: medRxiv : the preprint server for health sciences (2023)
Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.
Keyphrases
- type diabetes
- healthcare
- prostate cancer
- chronic kidney disease
- risk assessment
- primary care
- atrial fibrillation
- clinical practice
- insulin resistance
- heart failure
- young adults
- quality improvement
- public health
- chronic obstructive pulmonary disease
- gene expression
- dna methylation
- glycemic control
- end stage renal disease
- cardiovascular events
- climate change
- percutaneous coronary intervention
- coronary artery disease
- heavy metals
- cystic fibrosis
- body mass index
- weight gain
- allergic rhinitis
- social media
- high fat diet induced