Genetics

SC25 sampling often matches full-cohort performance for rare pediatric outcomes in simulations

In Monte Carlo simulations of 100,000 children with an exemplar rare condition, SC25 sampling largely matched full-cohort (FC) results for medium and large effects. SC25 deviations versus FC in p-values were generally ≤5% for medium effects and ≤2% for large effects across outcomes. Small effect sizes produced low power across all designs and reduced precision for some DGMs, limiting inference for modest effects. Authors conclude SC25 offers a cost-effective design when whole-population data are unavailable, but generalizability beyond the exemplar condition is uncertain. 1

ML-derived PRS for diabetic retinopathy interacts with lifestyle; healthy behavior lowers risk

In 91,691 UK Biobank participants, a 182-locus ML-driven PRS conferred 37% higher incident DR risk for high versus low genetic risk (HR 1.37). An unfavorable lifestyle increased DR risk by 49% versus a favorable lifestyle (HR 1.49), independent of genetic risk. High genetic risk plus an unfavorable lifestyle more than doubled DR risk (HR 2.09); conversely, high-risk individuals with a favorable lifestyle had 44% lower risk (HR 0.56). Findings replicated in an independent diabetic cohort, supporting lifestyle counseling regardless of genetic background. 2

Cascade genetic testing uptake for Lynch syndrome is suboptimal at roughly half of relatives

Meta-analysis of 18 studies (4,939 probands; 10,461 relatives) found 42% engaged in genetic counseling and 46% underwent cascade testing. Uptake was higher in female and first-degree relatives than in male and more distant relatives. Overall utilization remains inadequate for population-level case finding of Lynch syndrome. Authors call for targeted interventions to improve equitable cascade testing among at-risk relatives. 3