EPIDEMIOLOGY OF KIDNEY STONE RECURRENCE

项目总结（见说明）： 本申请的目的是确定导致结石形成者症状性复发的关键环境和遗传因素，以及通过CT扫描验证无症状结石形成和生长作为症状性复发的替代。中心临床假设是肾结石复发可以通过电子健康记录（EHR）中的临床、实验室和放射学测量来预测。我们的中心机制假设是肾结石的基因组标记物导致结石事件发生和复发的风险增加。为了制定有效的预防肾结石复发的策略，我们计划客观地测试我们的假设，目标如下：具体目标#1：开发一种模型，利用来自综合研究的临床和实验室信息更好地预测症状性结石复发。在奥姆斯特德县一般人群中（1984年至2016年），4680例图表验证的症状性结石形成者的（住院和门诊）健康记录。具体目标#2：在我们扩展的前瞻性队列（2009年至2017年）中，使用800例结石形成者，确定尿化学、血清学和生活方式因素是否可以改善EHR中可用的临床和实验室特征以外的症状复发预测。具体目标#3：确定目标1或2中预测症状复发的模型是否也预测了我们当前前瞻性队列中300例结石形成者的影像学结石形成和生长。具体目标#4：从一般人群中取样结石形成者以鉴定致病基因。A）收集一组1500名经过仔细验证和表型分析的偶发肾结石形成者，加上1500名对照进行遗传分析。多重家庭将是这次招聘工作的重点。B）采用外显子捕获和下一代测序，筛选400验证了偶发症状性肾结石形成者在66个高钙血症候选基因中的显著变体。

PROJECT SUMMARY (See instructions): The objectives of this application are to determine the key environmental and genetic factors that lead to symptomatic recurrence among stone formers, as well as to validate asymptomatic stone formation and growth by CT scan as a surrogate for symptomatic recurrence. The central clinical hypothesis is that kidney stone recurrence can be predicted from clinical, laboratory, and radiographic measurements in the electronic health record (EHR). Our central mechanistic hypothesis is that genomic markers for kidney stones contribute to an increased risk of incident and recurrent stone events. In order to develop effective prevention strategies for kidney stone recurrence, we plan to objectively test our hypotheses with the following aims: Specific Aim #1: To develop a model to better predict symptomatic stone recurrence using clinical and laboratory information from the comprehensive (inpatient and outpatient) health records of 4680 chart validated symptomatic stone formers in the Olmsted County general population (1984 to 2016). Specific Aim #2: To determine if urine chemistries, blood serologies, and life-style factors can improve the prediction of symptomatic recurrence beyond the clinical and laboratory characteristics available in the EHR using 800 incident stone formers in our expanded prospective cohort (2009 to 2017). Specific Aim #3: To determine if models predicting symptomatic recurrence in Aims 1 or 2 also predict radiographic stone formation and growth among 300 incident stone formers in our current prospective cohort. Specific Aim #4: To sample stone formers from the general population to identify causative genes. A) Assemble a cohort of 1500 carefully validated and phenotyped incident kidney stone formers, plus 1500 controls for genetic analysis. Multiplex families will be a focus of this recruitment effort. B) Screen 400 validated incident symptomatic kidney stone formers for significant variants in 66 candidate genes for hypercalcuria, employing exon capture and next generation sequencing.