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Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals., Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections., Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds)., Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months., Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Importance: Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches., Objective: To evaluate the population-based disease risk of clinical variants in known disease predisposition genes., Design, Setting, and Participants: This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds., Exposures: Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants)., Main Outcomes and Measures: The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured., Results: Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%])., Conclusions and Relevance: In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.

Importance: Identifying patients at risk of chronic kidney disease (CKD) progression may facilitate more optimal nephrology care. Kidney failure risk equations, including such factors as age, sex, estimated glomerular filtration rate, and calcium and phosphate concentrations, were previously developed and validated in 2 Canadian cohorts. Validation in other regions and in CKD populations not under the care of a nephrologist is needed., Objective: To evaluate the accuracy of the risk equations across different geographic regions and patient populations through individual participant data meta-analysis., Data Sources: Thirty-one cohorts, including 721,357 participants with CKD stages 3 to 5 in more than 30 countries spanning 4 continents, were studied. These cohorts collected data from 1982 through 2014., Study Selection: Cohorts participating in the CKD Prognosis Consortium with data on end-stage renal disease., Data Extraction and Synthesis: Data were obtained and statistical analyses were performed between July 2012 and June 2015. Using the risk factors from the original risk equations, cohort-specific hazard ratios were estimated and combined using random-effects meta-analysis to form new pooled kidney failure risk equations. Original and pooled kidney failure risk equation performance was compared, and the need for regional calibration factors was assessed., Main Outcomes and Measures: Kidney failure (treatment by dialysis or kidney transplant)., Results: During a median follow-up of 4 years of 721,357 participants with CKD, 23,829 cases kidney failure were observed. The original risk equations achieved excellent discrimination (ability to differentiate those who developed kidney failure from those who did not) across all cohorts (overall C statistic, 0.90; 95% CI, 0.89-0.92 at 2 years; C statistic at 5 years, 0.88; 95% CI, 0.86-0.90); discrimination in subgroups by age, race, and diabetes status was similar. There was no improvement with the pooled equations. Calibration (the difference between observed and predicted risk) was adequate in North American cohorts, but the original risk equations overestimated risk in some non-North American cohorts. Addition of a calibration factor that lowered the baseline risk by 32.9% at 2 years and 16.5% at 5 years improved the calibration in 12 of 15 and 10 of 13 non-North American cohorts at 2 and 5 years, respectively (P = .04 and P = .02)., Conclusions and Relevance: Kidney failure risk equations developed in a Canadian population showed high discrimination and adequate calibration when validated in 31 multinational cohorts. However, in some regions the addition of a calibration factor may be necessary.