Rational Integration of Polygenic Risk Scores (RIPS)

项目摘要 预测常见、复杂疾病的新技术有了惊人的发展 多基因风险评分（PRS）。如果没有基于证据的理解， PRS的临床使用不太可能从高度专业化的应用中传播， 环境被更广泛地采用，并为美国提供更大的利益 人口关键的挑战包括：1）了解临床PRS对多种疾病的影响， 疾病对长期患者结果的影响，2）确定结果返回的风险阈值， 优化患者结局并提供具有成本效益的护理，3）了解PRS如何 不同人群的表现可能会影响现有的差异和随后的患者 成果。我们建议使用决策分析建模来解决这些挑战， 基于我们在这一领域的广泛工作，建立一个能够评估 单基因和临床风险背景下的PRS。我们已经创造了临床经济学 模型，以预测人群水平基因组的终身临床影响和成本效益 与三种CDC 1级疾病相关的单基因疾病风险回归筛查： 遗传性乳腺癌和卵巢癌、Lynch综合征和家族性高脂血症。的一部分 这份名为多基因风险评分的理性整合（RIPS）的提案，我们将创建模型 评估在真实的中使用PRS进行人群筛查的临床结局和经济价值- 世界设置，并适用于大量和不同的人群。建议的目的包括 1)评价关于添加PRS以告知 全面的基因组风险评估; 2）了解PRS性能的影响 乳腺癌增量临床获益和成本效益的回报风险阈值 癌症、动脉粥样硬化性心血管疾病和结肠直肠癌，以及3）发展 研究优先事项，以公平地制定和执行减贫战略， 服务不足和代表性不足的人口。

Project Summary There has been extraordinary growth in new techniques to predict common, complex disease based on polygenic risk scores (PRS). Without an understanding grounded in evidence, it is unlikely that the clinical use of PRS will propagate from highly specialized applications and environments to become adopted more broadly and provide greater benefit to the US population. Critical challenges include: 1) understanding the impact of clinical PRS for multiple diseases on long-term patient outcomes, 2) identifying risk thresholds for return of results that optimize patient outcomes and provide cost-effective care, 3) understanding how PRS performance across diverse populations may affect existing disparities and subsequent patient outcomes. We propose to address these challenges using decision analytic modeling and by building on our extensive work in this area to create a novel framework capable of assessing PRSs in the context of monogenic and clinical risks. We have already created clinical-economic models to project lifetime clinical impact and cost-effectiveness for population-level genomic screening with return of monogenic disease risks associated with three CDC Tier 1 conditions: hereditary breast and ovarian cancer, Lynch syndrome, and familial hyperlipidemia. As part of this proposal, titled Rational Integration of Polygenic Risk Scores (RIPS), we will create models to assess the clinical outcomes and economic value of population screening using PRS in real- world settings and applied to large and diverse populations. The Aims of the proposal include 1) to evaluate published and real-world evidence on the clinical value of adding PRS to inform comprehensive genomic risk assessment; 2) to understand the impact of PRS performance and return risk thresholds on incremental clinical benefit and cost effectiveness for breast cancer, atherosclerotic cardiovascular disease, and colorectal cancer, and 3) to develop research priorities for the equitable development and implementation of PRS across underserved and underrepresented populations.