The Epidemiology and Somatic Genomic Pathogenesis of Radon-Related Stroke

项目总结/摘要 虽然中风是世界范围内残疾和死亡的主要原因，但已确定的中风风险因素 没有充分解释所观察到的发病率的负担或空间差异。近三分之一的中风 是隐源的，从而迫使寻找环境因素，可能发挥重要作用，但到目前为止， 在卒中发病机制和流行病学中的作用特征不充分。其中一个因素-氡-是 天然存在的、无味的气体，通过岩石和土壤中的放射性元素衰变产生。气体进入 房屋通过地下室和地基裂缝，使未识别的暴露无处不在， 在美国，仅次于吸烟的第二大可改变的肺癌原因。虽然氡在肺中的作用 致癌作用是众所周知的，但对其在肿瘤发病机制和流行病学中的作用知之甚少。 脑血管疾病然而，现有的氡气与中风关系的研究表明，氡气暴露是 与中风的病理前兆和中风本身有关。他们的集体局限性 然而，在科学的状态中留下了一个巨大的空白，否则可能会突出假定的方法， 减少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]缓解前后美国家庭氡暴露（1986 - 2018），[2] 随时间变化的家庭氡暴露与中风事件之间的关联，[3]时间- 不同的家庭氡暴露和不确定潜力的克隆造血（CHIP），以及[4] 氡与中风的关系。我们将在一个人口和环境多样化的国家中这样做。 NHLBI支持的三个队列中的194，015名参与者已经审查并批准了该提案。 在精确的地理编码地址，对氡暴露量及其不确定性进行定量估算， 涉及一个国家，时空预测和两个阶段的交叉验证的基础上随时间变化，短期和 长期平均、缓解前后的家庭氡浓度;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放射性、地质和土壤特征。 估计氡-中风和氡-CHIP关联还将涉及队列特异性，多变量调整， 贝叶斯、分层、至事件发生时间和逻辑回归解释了暴露不确定性和竞争性 死亡率，然后进行逆方差加权随机效应荟萃分析。最后，估计中介 通过CHIP进行的氡-中风关联将涉及量化氡对中风的直接、间接和总影响。 这种估计以前无与伦比的重点是一个可改变的风险因素，一个合理的机制， 疾病，以及一种常见的，临床和社会负担的健康结果，迄今为止被EPA忽视， 因此，世卫组织统一的氡检测和缓解政策将使研究有助于确定 中风和其他健康结果的环境流行病学和体细胞基因组发病机制， 这可能导致为新的公共卫生筛查和预防工作确定合理的目标。

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.