Journal of Controlled Release, Год журнала: 2024, Номер 378, С. 294 - 305
Опубликована: Дек. 17, 2024
Язык: Английский
The American Journal of Human Genetics, Год журнала: 2024, Номер 111(7), С. 1431 - 1447
Опубликована: Июнь 21, 2024
Язык: Английский
Процитировано
14
Human Reproduction Update, Год журнала: 2024, Номер 30(5), С. 529 - 557
Опубликована: Май 28, 2024
The genetic composition of embryos generated by in vitro fertilization (IVF) can be examined with preimplantation testing (PGT). Until recently, PGT was limited to detecting single-gene, high-risk pathogenic variants, large structural and aneuploidy. Recent advances have made genome-wide genotyping IVF feasible affordable, raising the possibility screening for their risk polygenic diseases such as breast cancer, hypertension, diabetes, or schizophrenia. Despite a heated debate around this new technology, called embryo (PES; also PGT-P), it is already available patients some countries. Several articles studied epidemiological, clinical, ethical perspectives on PES; however, comprehensive, principled review emerging field missing.
Язык: Английский
Процитировано
11
Nature Communications, Год журнала: 2024, Номер 15(1)
Опубликована: Июль 25, 2024
Abstract A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence detailed longitudinal electronic health records (EHRs) > 700k Finns and Estonians. We found that a high generalized PRS (PRS GGE ) increased (GGE) (hazard ratio [HR] 1.73 per standard deviation [SD]) across lifetime within 10 years after unspecified seizure event. The effect was significantly larger on idiopathic epilepsies, females earlier onset. Analogously, more modest focal burden associated with non-acquired (NAFE). outline the potential specific PRSs to serve as first
Язык: Английский
Процитировано
5
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 26, 2024
Abstract Importance Polygenic risk scores (PRSs) for coronary artery disease (CAD) are a growing clinical and commercial reality. Whether existing provide similar individual-level assessments of liability is critical consideration implementation that remains uncharacterized. Objective Characterize the reliability CAD PRSs perform equivalently at population level predicting risk. Design Cross-sectional Study. Setting All Us Research Program (AOU), Penn Medicine Biobank (PMBB), UCLA ATLAS Precision Health Biobank. Participants Volunteers diverse genetic backgrounds enrolled in AOU, PMBB, with available electronic health record genotyping data. Exposures from previously published new developed separately testing cohorts. Main Outcomes Measures Sets prediction were identified by comparing calibration discrimination (Brier score AUROC) generalized linear models prevalent using Bayesian analysis variance. Among performing scores, agreement between estimates was tested intraclass correlation (ICC) Light’s Kappa, measures inter-rater reliability. Results 50 calculated 171,095 AOU participants. When included model CAD, 48 had practically equivalent Brier AUROCs (region practical equivalence = 0.02). Across these 84% participants least one both top bottom quintile. Continuous individual predictions poor, an ICC 0.351 (95% CI; 0.349, 0.352). Agreement two statistically moderate, 0.649 0.646, 0.652). used to evaluate consistency assignment high-risk thresholds, did not exceed 0.56 (interpreted as ‘fair’) across scores. Repeating among 41,193 PMBB 50,748 yielded different sets which also lacked strong agreement. Conclusions Relevance three biobanks, performed produced unreliable estimates. Approaches must consider potential discordant otherwise indistinguishable
Язык: Английский
Процитировано
1
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 30, 2024
The transferability of polygenic scores across population groups is a major concern with respect to the equitable clinical implementation genomic medicine. Since genetic associations are identified relative mean, inevitably differences in disease or trait prevalence among social strata influence relationship between PGS and risk. Here we quantify magnitude PGS-by-Exposure (PGSxE) interactions for seven human diseases (coronary artery disease, type 2 diabetes, obesity thresholded body mass index waist-to-hip ratio, inflammatory bowel chronic kidney asthma) pairs 75 exposures White-British subset UK Biobank study (n=408,801). Across 24,198 PGSxE models, 746 (3.1%) were significant by two criteria, at least three-fold more than expected chance under each criterion. Predictive accuracy significantly improved high-risk including interaction terms effects as large those documented low ancestries. predominant mechanism PGS×E shown be amplification presence adverse such polyunsaturated fatty acids, mediators obesity, determinants ill health. We introduce notion proportion needed benefit (PNB) which cumulative number treat range show that typically this halved 70
Язык: Английский
Процитировано
1
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown
Опубликована: Ноя. 27, 2023
Abstract A diagnosis of epilepsy has significant consequences for an individual but is often challenging in clinical practice. Novel biomarkers are thus greatly needed. Here, we investigated how common genetic factors (epilepsy polygenic risk scores, [PRSs]) influence detailed longitudinal electronic health records (EHRs) > 360k Finns spanning up to 50 years individuals’ lifetimes. Individuals with a high generalized PRS (PRS GGE ) FinnGen had increased (GGE) (hazard ratio [HR] 1.55 per standard deviation [SD]) across their lifetime and after unspecified seizure events. Effect sizes PRSs were comparable effect clinically curated data supporting our EHR-derived diagnoses. Within 10 seizure, the rate was 37% when 2 SD compared 5.6% < –2 SD. The even larger on subtypes idiopathic (IGE) (HR 2.1 ). We further report significantly effects females younger age groups. Analogously, found more modest focal burden associated non-acquired (NAFE). specifically comparison >2000 independent diseases while NAFE also other than such as back pain. show that specific have good discriminative ability first event i.e. circumstances where prior probability outlining potential serve diagnosis.
Язык: Английский
Процитировано
2
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Окт. 8, 2024
Abstract Electronic health record (EHR)-based phenotype risk scores (PheRS) leverage individuals’ trajectories to infer disease risk. Similarly, polygenic (PGS) use genetic information estimate While PGS generalizability has been previously studied, less is known about PheRS transferability across healthcare systems and whether provide complementary PGS. We trained predict the onset of 13 common diseases with high burden in a total 845,929 individuals (age 32-70) from 3 biobank-based studies Finland (FinnGen), UK (UKB) Estonia (EstB). The were based on elastic-net models, incorporating up 242 diagnoses captured EHR 10 years before baseline. Individuals followed for maximum 8 years, during which incidence was observed. calculated each using recent publicly available results genome-wide association studies. All significantly associated interest. different biobanks utilized partially distinct diagnoses, reflecting differences medical code usage countries. Even large variability prevalence various most UKB or EstB transferred well FinnGen without re-training. only moderately correlated (Pearson’s r ranging 0.00 0.08), models including both improved prediction compared alone 8/13 diseases. able identify subset at high-risk better than disease. Our indicate that EHR-based capture largely independent additive benefits prediction. Furthermore, many transfer between EHRs. Given availability EHR, can tool stratification.
Язык: Английский
Процитировано
0
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 5, 2024
Abstract Randomized controlled trials (RCTs) are the gold standard for evaluating efficacy and safety of medical interventions but ethical, practical, financial limitations often necessitate decisions based on observational data. The increasing volume such data has prompted regulatory bodies to rely more real-world evidence, primarily obtained through trial emulations. This study explores how genetic can improve design both emulated traditional trials. We successfully four major cardiometabolic RCTs within FinnGen (N=425 483) showed reduced differences in polygenic scores (PGS) between arms track improved consequently residual confounding. Complementing these results with simulations, we show that PGS cannot be directly used adjust or unmeasured Instead, propose an approach uses instruments confounding detection apply this identify likely confounders Empareg emulation. Finally, our suggest emulations inform practical application RCTs, potentially improving statistical power. Such prognostic enrichment strategies need assessed a trial-relevant population, that, 2 out 4 trials, association outcomes general population was different from what observed included trial. In conclusion, work shows information These contribute establishment promising new era genetically-informed clinical
Язык: Английский
Процитировано
0
Journal of Controlled Release, Год журнала: 2024, Номер 378, С. 294 - 305
Опубликована: Дек. 17, 2024
Язык: Английский
Процитировано
0