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增长。 基于多基因风险评分(PR)。如果没有基于证据的理解，它就是 PR的临床应用不太可能从高度专业化的应用和 环境将被更广泛地采用，并为美国提供更大的好处 人口。关键挑战包括：1)了解临床PR对多个 疾病对患者长期结果的影响，2)确定返回结果的风险阈值 优化患者结局并提供经济高效的护理，3)了解 不同人群的表现可能会影响现有的差异和后续患者 结果。我们建议使用决策分析建模并通过以下方式解决这些挑战 以我们在这一领域的广泛工作为基础，创建一个能够评估 在单基因和临床风险的背景下的PRSS。我们已经创造了临床经济 预测人群水平基因组的终生临床影响和成本效益的模型 对与三种CDC第1级疾病相关的单基因疾病风险进行筛查： 遗传性乳腺癌和卵巢癌、林奇综合征和家族性高脂血症。作为以下内容的一部分 这项名为多基因风险得分(RIP)的合理集成的建议，我们将创建模型 [目的]评估在全市使用社区卫生服务进行人群筛查的临床效果和经济价值。 它适用于世界各地的环境，适用于众多不同的人群。该提案的目的包括 1)评估已发表的和真实世界的证据，说明添加PR的临床价值 全面的基因组风险评估；2)了解PRS性能的影响 并根据乳房的增量临床收益和成本效益返回风险阈值 癌症、动脉粥样硬化性心血管疾病和结直肠癌，以及3)发展 公平发展和实施减贫战略的研究优先事项 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.