EHR-based Genomic Discovery and Implementation (Supplement)

项目总结 由于常见疾病的病因复杂且多因素，估计其风险是具有挑战性的。 常见疾病造成了巨大的卫生保健负担，因此，即使在 风险估计的准确性可能会产生重大影响。完善风险分层的一个有希望的途径是 将遗传风险、临床变量和环境因素的测量纳入综合风险 配置文件。通过提供正交和增量信息，多基因风险评分(Prs)可以提高风险。 对常见疾病的预测，这些疾病共同造成了大部分死亡和发病率 全世界。 要告知在临床环境中使用PRS，需要有关于以下临床效用的证据 将PRS与其他危险因素相结合，用于疾病风险预测。随机对照试验证明 在延长生存或改善生活质量方面的临床应用通常是不可行的，主要是 由于所需的时间、巨大的费用，以及可能需要在 审判仍在进行中。在没有这样的试验的情况下，需要一个分析框架来收集 适当的证据。作为本次行政补充申请的一部分，我们将进行系统的 评价PRS临床应用于常见疾病风险的科学状况的证据综述 以冠心病(CHD)为例进行评估。我们的系统评估将基于 ACCE(分析效度、临床效度、临床效用、伦理、法律和社会影响)框架。 由于基因分型的分析有效性已经确立，我们的重点放在‘..CCE’成分上。系统化的 综述将对以下方面的证据进行整理：1)PRS治疗冠心病(PRSCHD)的临床有效性；2)PRSCHD的临床实用性 利用初级保健中心进行风险评估；包括净重分类改进、综合甄别 改进(IDI)和结果变化(过程、中间和临床)；3)伦理、法律、社会 在临床环境中使用PRSCHD的意义。

PROJECT SUMMARY Estimating risk for common diseases is challenging because of their complex and multifactorial etiology. Common diseases pose an enormous health care burden, therefore even modest improvements in the accuracy of risk estimates could have a substantial impact. A promising avenue for refining risk stratification is to incorporate measures of genetic risk, clinical variables, and environmental factors, into comprehensive risk profiles. By providing orthogonal and incremental information, polygenic risk scores (PRS) could improve risk prediction for common diseases, which are collectively responsible for most of the mortality and morbidity worldwide. To inform use of PRS in the clinical setting there is need for an evidence base on the clinical utility of integrating PRS with other risk factors, for disease risk prediction. Randomized control trials to demonstrate the clinical utility of a PRS in prolonging survival or improving the quality of life, are generally infeasible, mainly because of time needed, significant expense, and the possibility that the PRS may need updating while the trials are still ongoing. In the absence of such trials, an analytical framework is needed to collect the appropriate evidence. As part of this administrative supplement application, we will conduct systematic evidence reviews assessing the state of the science on the clinical utility of PRS for common disease risk assessment, using coronary heart disease (CHD) as an example. Our systematic review will be based on the ACCE (analytic validity, clinical validity, clinical utility, and ethical, legal, and social implications) framework. Since analytic validity of genotyping is established, our focus is on the ‘..CCE’ components. The systematic reviews will collate evidence for the following: 1) clinical validity of PRS for CHD (PRSCHD); 2) clinical utility of using PRSCHD for risk assessment; including net reclassification improvement (NRI), integrated discrimination improvement (IDI), and change in outcomes (process, intermediate and clinical); 3) ethical, legal, social implications of using PRSCHD in the clinical setting.