The Epidemiology and Somatic Genomic Pathogenesis of Radon-Related Stroke

项目摘要/摘要 尽管中风是世界范围内导致残疾和死亡的主要因素，但既定的中风风险因素 没有完全解释观察到的负担或其发病率的空间差异。事实上，近三分之一的中风患者 是隐秘的，因此迫使人们寻找可能起重要作用的环境因素，但到目前为止， 在卒中发病机制和流行病学中的作用不充分。其中一个因素--氡--是一种 天然的无味气体，通过岩石和土壤中放射性元素的衰变而产生。气体进入 房屋通过地下室和地基裂缝，使未被识别的暴露无处不在和 在美国，吸烟是肺癌的第二大诱因，仅次于吸烟。尽管氡在肺中的作用 癌症的发生是众所周知的，但对其在发病机制和流行病学中的作用知之甚少。 脑血管疾病。然而，现有的关于氡与中风的联系的研究表明，暴露在氡中 与卒中的病理前兆和突发性卒中本身有关。他们的集体限制 尽管如此，在科学状态方面留下了很大的差距，否则可能会突出推定的手段 减少美国的氡暴露及其常见的脑血管后遗症。为了填补这一空白，我们将 因此估计：[1]缓解前后全美的家庭氡暴露(1986-2018)，[2] 时变的家庭氡暴露与意外中风之间的联系，[3]时间-- 不同的家庭氡暴露和不确定潜力的克隆性造血(CHIP)，以及[4]介导 通过芯片实现了氡与中风的关联。我们将在人口和环境多样化的地区这样做 由三个NHLBI支持的队列中的194,015名参与者组成的小组已经审查和批准了这项提议。 对准确地理编码地址的氡暴露量及其不确定性进行定量估计将 涉及国家、时空预测和两阶段交叉验证，基于时变、短期和 长期平均值、缓解前和缓解后的家庭氡浓度；家庭氡测试统计数据/政策； 和住房特征；加上时不变的航空伽马辐射、地质和土壤特征。 估计氡-射程和氡-芯片相关性还将涉及特定于队列的、多变量调整、 贝叶斯、分层、事件发生时间和Logistic回归对暴露不确定性和竞争的解释 死亡率，然后是逆方差加权随机效应荟萃分析。最后，对调解的评价 利用芯片对氡-中风的关联将涉及量化氡对中风的直接、间接和总体影响。 这种估计以前无与伦比的重点是一个可修改的风险因素，一种看似合理的机制 疾病，以及一种常见的、临床和社会负担沉重的健康后果，迄今被EPA和 世卫组织统一的氡测试和缓解政策将因此定位研究，以帮助确定 中风和其他健康后果的环境流行病学和躯体基因组发病机制 这可能导致为新的公共卫生筛查和预防努力确定可信的目标。

Project Summary/Abstract Although stroke is a major contributor to disability and mortality worldwide, established stroke risk factors have not fully explained the observed burden of or spatial variation in its incidence. Indeed, nearly a third of strokes are cryptogenic, thereby compelling a search for environmental factors that may play an important, but to date, inadequately characterized role in stroke pathogenesis and epidemiology. One such factor—radon—is a naturally occurring, odorless gas generated via decay of radioactive elements in rocks and soils. The gas enters homes through basement and foundation cracks, making unrecognized exposures both ubiquitous and the second-leading, modifiable cause of lung cancer in the US, after smoking. Although radon’s role in lung carcinogenesis is well-known, relatively little is known about its role in the pathogenesis and epidemiology of cerebrovascular disease. Yet extant studies of the radon-stroke association suggest that radon exposure is associated both with pathologic precursors of stroke and incident stroke, itself. Their collective limitations nonetheless leave a substantial gap in the state of the science that could otherwise highlight putative means of reducing radon exposures and their common cerebrovascular sequelae in the US. To fill this gap, we will therefore estimate: [1] pre- and post-mitigation home radon exposures across the US (1986-2018), [2] the association between time-varying home radon exposure and incident stroke, [3] the association between time- varying home radon exposure and clonal hematopoiesis of indeterminate potential (CHIP), and [4] mediation of the radon-stroke association by CHIP. We will do so among a demographically and environmentally diverse group of 194,015 participants in three NHLBI-supported cohorts that have reviewed and approved this proposal. Quantitatively estimating radon exposures and their uncertainties at their accurately geocoded addresses will involve a national, spatiotemporal prediction and two-stage cross-validation based on time-varying, short- and long-term mean, pre- and post-mitigation home radon concentrations; home radon testing statistics / policies; and housing characteristics; plus, time-invariant aerial gamma-radioactivity, geology, and soil features. Estimating radon-stroke and radon-CHIP associations also will involve cohort-specific, multivariable-adjusted, Bayesian, hierarchical, time-to-event and logistic regression accounting for exposure uncertainty and competing mortality, followed by inverse variance-weighted, random-effects meta-analysis. Finally, estimating mediation of the radon-stroke association by CHIP will involve quantifying direct, indirect, and total effects of radon on stroke. The previously unparalleled focus of such estimation on a modifiable risk factor, a plausible mechanism of disease, and a common, clinically and societally burdensome health outcome heretofore ignored by EPA and WHO uniform radon testing and mitigation policies will thereby position the study to help characterize the environmental epidemiology and somatic genomic pathogenesis of stroke and other health outcomes in ways that may lead to the identification of plausible targets for new public health screening and prevention efforts.