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Polygenic risk scores (PRS) are an emerging tool to predict the clinical phenotypes and outcomes of individuals. Validation and transferability of existing PRS across independent datasets and diverse ancestries are limited, which hinders the practical utility and exacerbates health disparities. We propose PRSmix, a framework that evaluates and leverages the PRS corpus of a target trait to improve prediction accuracy, and PRSmix+, which incorporates genetically correlated traits to better capture the human genetic architecture. We applied PRSmix to 47 and 32 diseases/traits in European and South Asian ancestries, respectively. PRSmix demonstrated a mean prediction accuracy improvement of 1.20-fold (95% CI: [1.10; 1.3]; P-value = 9.17 × 10 -5 ) and 1.19-fold (95% CI: [1.11; 1.27]; P-value = 1.92 × 10 -6 ), and PRSmix+ improved the prediction accuracy by 1.72-fold (95% CI: [1.40; 2.04]; P-value = 7.58 × 10 -6 ) and 1.42-fold (95% CI: [1.25; 1.59]; P-value = 8.01 × 10 -7 ) in European and South Asian ancestries, respectively. Compared to the previously established cross-trait-combination method with scores from pre-defined correlated traits, we demonstrated that our method can improve prediction accuracy for coronary artery disease up to 3.27-fold (95% CI: [2.1; 4.44]; P-value after FDR correction = 2.6 × 10 -4 ). Our method provides a comprehensive framework to benchmark and leverage the combined power of PRS for maximal performance in a desired target population., Competing Interests: CONFLICT OF INTEREST P.N. reports grants from Allelica, Amgen, Apple, Boston Scientific, Genentech, and Novartis, is a consultant to Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, HeartFlow, Novartis, Genentech, and GV, scientific advisory board membership to Esperion Therapeutics, Preciseli, and TenSixteen Bio, is a scientific co-founder of TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. Others declare no conflict of interest.

Innovative service delivery models are needed to increase access to genetics specialists. Electronic consultation (e-Consult) programs can connect clinicians with specialists. At Massachusetts General Hospital, an e-Consult service was created to address genomics-related questions. In its first year, the e-Consult service triaged 153 requests and completed 122 in an average of 3.2 days. Of the 95 e-Consults with actionable recommendations, there was documentation that most ordering clinicians followed through (82%). A variety of providers used the service, although the majority (77%) were generalists. E-Consult models should be considered as one way to increase access to genetics care., Competing Interests: Conflicts of Interest: The authors have no relevant conflicts of interest to disclose.