Background: Although the role of radon gas in lung carcinogenesis is well-known, relatively little is known about radon’s role in the pathogenesis or epidemiology of cerebrovascular disease. Methods: We therefore identified postmenopausal women without a history of stroke at the 1993-1998 screening visit of the Women’s Health Initiative Clinical Trials and Observational Study (WHI CT and OS). We linked their geocoded addresses to U.S. Environmental Protection Agency (EPA)-predicted, county-level, indoor, screening radon gas concentrations classified as follows: Zone 3 (<2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (>4 pCi/L). We identified incident strokes based on physician-reviewed, classified, and adjudicated medical records. We measured time from screening to the earliest stroke or censoring date (02/28/20). We used Cox proportional hazards models to estimate radon-related risk of stroke on an attained-age scale as a hazard ratio (HR) and 95% confidence interval (CI), adjusting for WHI design, race/ethnicity, education, homemaker status, U.S. Census region, neighborhood socioeconomic status, smoking, alcohol intake, sodium intake (g/day), 2005 Healthy Eating Index, recreational physical activity (MET-hr/wk), body mass index (kg/m 2 ), systolic blood pressure (mm Hg), as well as history of diabetes, hypercholesterolemia, atrial fibrillation, and deep vein thrombosis/pulmonary embolism. Results: Among 158,906 women (mean, standard deviation [SD] age = 63.1 [7.2] years; 83% white; 9% black; 4% Hispanic; 4% other), we identified 6,979 incident strokes over a mean [SD] follow-up period of 9.3 [5.6] person-years, i.e. 3.41 strokes / 1,000 person-years. The proportion of women with incident stroke was 1.38%, 1.72%, and 1.30% in EPA Radon Zones 3, 2, and 1, respectively. Corresponding incidence rates by EPA Radon Zone were 3.33, 3.43 and 3.49 per 1,000 person-years. Relative to women in Zone 3, those in Zones 2 and 1 had higher adjusted risks of incident stroke: HR (95% CI) = 1.07 (1.00, 1.14) and 1.15 (1.07 , 1.24). Conclusion: Radon gas is a pervasive carcinogen that also may increase susceptibility to a societally burdensome form of cerebrovascular disease, thereby highlighting the potential value of targeted testing, radon-safe construction, and mitigation in stroke prevention.
Background: Young to middle-aged U.S. adults are burdened by the obesity, opioid, and COVID-19 epidemics. However, the ability to detect cardiovascular disease (CVD) manifestations of population-wide changes in risk factors within contemporary cohorts in young to middle adulthood is unknown. Objective: To assess inter-rater reliability of death certificate (DC), obituary, coroner/medical examiner (CME) autopsy report, and hospital record abstraction in young to middle adulthood. Setting: The National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative school-based sample of 20,745 U.S. adolescents in grades 7-12 (1994-1995) followed for the last 26 years and aged 37-45 years in 2020. Methods: We traced all participants, identified decedents, then collected DCs, obituaries, CME autopsy reports, and hospital records ≤ 1 month before death dates. Among a random sample of 28 decedents and an oversample of 28 hospitalized decedents enriched 3:1 for CVD, two trained and certified staff used an electronic data entry system to abstract data needed for outcome classification from the four information sources following standardized, item-by-item instructions. We measured item-specific reliability of categorical data abstraction as the agreement between abstractors (%) and prevalence- and bias-adjusted kappa coefficient ( PABAK ). We measured reliability of interval-scale data (e.g. creatinine; troponin; creatinine kinase; CK-MB; pro-BNP concentrations) as an intra-class correlation coefficient (ICC). Results: We identified 578 (2.8%) participants who were deceased through December 2020. Of those, 577 (99.8%) had high scoring National Death Index matches uniquely identifying decedents in 44 U.S. states. We collected and abstracted 531 (92%), 445 (77%), 178 (66%), and 95 (39%) of their DCs, obituaries, CME autopsy reports, and hospital records. CVD was the underlying cause of death in 10% (95% confidence interval [CI]: 8%-13%) of decedents. Mean, item-specific agreement (95% CI) was 0.86 (0.84-0.89), 0.90 (0.87-0.93), 0.93 (0.92-0.95), and 0.94 (0.92-0.95) for each source. The corresponding mean, item-specific PABAK (95% CI) was 0.83 (0.80-0.86), 0.86 (0.83-0.90), 0.92 (0.90-0.94) and 0.91 (0.89-0.93). The mean, biomarker-specific ICC (95% CI) was 0.96 (0.95-0.98). Conclusion: Overall, CVD was a major cause of mortality and reliability of abstraction was excellent across a range of measures. Ongoing investigation of deaths, and as needed, targeted staff retraining and improvement of abstraction protocol will enable high quality studies of CVD emergence within this large, nationally representative U.S. cohort. Such studies will provide generalizable insight into the biological mechanisms underlying cardiovascular manifestations and thereby inform understanding of changing CVD burden in the U.S. population.
Background: Clonal hematopoiesis of indeterminate potential (CHIP) occurs when there is expansion of leukocyte clones in the blood due to mutations in hematopoietic stem cells. CHIP is associated with a high risk of hematologic malignancy and increased risk of cardiovascular disease (CVD). Although the environmental risk factors for CHIP remain poorly understood, radon is a ubiquitous mutagen and may deliver non-negligible doses of α-radiation to bone marrow that trigger CHIP development. Methods: We conducted a cross-sectional study of 10,495 postmenopausal women without hematologic malignancy from the Women’s Health Initiative clinical trials and observational study (mean age: 69 years; 82% white; 9% African American; 4% Hispanic/Latina; 3% Asian). Using blood from the 1993-1998 screening visit or a subsequent annual visit, and whole genome sequence data from the Trans-Omics for Precision Medicine project, we identified CHIP using the GATK Mu TECT2 somatic variant caller, a pre-specified list of leukemogenic driver mutations in 74 genes, and a threshold variant allele fraction > 0.02. We linked geocoded participant addresses at the time of blood draw to county-level, indoor, screening radon concentrations that were predicted by the Environmental Protection Agency (EPA) in 1993 using data on indoor radon, geology, aerial radioactivity, soil parameters, and foundation types. Radon exposure was classified as follows: Zone 3 (< 2 pCi/L), Zone 2 (2-4 pCi/L), and Zone 1 (> 4 pCi/L), the level at which EPA recommends remediation. We estimated the radon-related risk of CHIP as an odds ratio (OR, 95% CI) using logistic regression with and without adjustment for study design, participant sampling, age, race/ethnicity, smoking, and other sociodemographic / behavioral covariates. Results: We identified CHIP in 887 (8.5% of) participants. 3106 (29.6%), 3982 (37.9%), and 3407 (32.5%) had Zone 3, 2, and 1 radon exposures. The corresponding percentage of participants with CHIP across zones was 7.6%, 8.6%, and 9.1%. Relative to participants in Zone 3, those in Zones 2 and 1 had a higher adjusted risk of CHIP: OR (95% CI) = 1.13 (0.95, 1.35) and 1.24 (1.03, 1.48). Conclusion: Risk of CHIP was positively associated with indoor radon concentrations in this cross-sectional study of post-menopausal women. Longitudinal study of temporally integrated, in-home radon exposures, incident CHIP, and CVD would help confirm this novel radon-CHIP association and place it in context.
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