EPIDEMIOLOGY OF KIDNEY STONE RECURRENCE

项目总结(见说明)： 这项应用的目的是确定导致结石形成者有症状复发的关键环境和遗传因素，并通过CT扫描验证无症状结石的形成和生长作为有症状复发的替代指标。中心的临床假设是，肾结石复发可以通过临床、实验室和电子健康记录(EHR)中的放射学测量来预测。我们的中心机制假设是肾结石的基因组标志物有助于增加发生和复发结石事件的风险。为了开发有效的预防肾结石复发的策略，我们计划客观地检验我们的假设，目标如下：具体目标1：开发一个模型，利用来自奥姆斯特县普通人群(1984至2016年)4680例图表验证的症状性结石形成者的全面(住院和门诊)健康记录中的临床和实验室信息来更好地预测症状性结石复发。具体目标#2：利用我们扩大的前瞻性队列中的800例结石患者，确定尿液化学、血液血清学和生活方式因素是否可以改善EHR提供的临床和实验室特征之外的症状性复发预测。具体目标3：确定在我们当前的前瞻性队列中，预测AIMS 1或2中症状复发的模型是否也能预测300例意外结石形成和生长的放射学结石形成和生长。具体目标4：从普通人群中抽取结石形成者样本，以确定致病基因。A)收集1500名经过仔细验证和表型的肾结石事件患者的队列，外加1500名用于基因分析的对照。多户型家庭将是此次招聘工作的重点。B)使用外显子捕获和下一代测序技术，筛选400名经过验证的事件症状性肾结石形成者，以寻找66个高钙血症候选基因中的显著变异。

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.