Importance Polygenic risk scores (PRSs) for coronary heart disease (CHD) are a growing clinical and commercial reality. Whether existing scores provide similar individual-level assessments of disease susceptibility remains incompletely characterized. Objective To characterize the individual-level agreement of CHD PRSs that perform similarly at the population level. Design, Setting, and Participants Cross-sectional study of participants from diverse backgrounds enrolled in the All of Us Research Program (AOU), Penn Medicine BioBank (PMBB), and University of California, Los Angeles (UCLA) ATLAS Precision Health Biobank with electronic health record and genotyping data. Exposures Polygenic risk for CHD from published PRSs and new PRSs developed separately from testing samples. Main Outcomes and Measures PRSs that performed population-level prediction similarly were identified by comparing calibration and discrimination of models of prevalent CHD. Individual-level agreement was tested with intraclass correlation coefficient (ICC) and Light κ. Results A total of 48 PRSs were calculated for 171 095 AOU participants. The mean (SD) age was 56.4 (16.8) years. A total of 104 947 participants (61.3%) were female. A total of 35 590 participants (20.8%) were most genetically similar to an African reference population, 29 801 (17.4%) to an admixed American reference population, 100 493 (58.7%) to a European reference population, and the remaining to Central/South Asian, East Asian, and Middle Eastern reference populations. There were 17 589 participants (10.3%) with and 153 506 participants without (89.7%) CHD. When included in a model of prevalent CHD, 46 scores had practically equivalent Brier scores and area under the receiver operator curves (region of practical equivalence ±0.02). Twenty percent of participants had at least 1 score in both the top and bottom 5% of risk. Continuous agreement of individual predictions was poor (ICC, 0.373 [95% CI, 0.372-0.375]). Light κ, used to evaluate consistency of risk assignment, did not exceed 0.56. Analysis among 41 193 PMBB and 53 092 ATLAS participants yielded different sets of equivalent scores, which also lacked individual-level agreement. Conclusions and Relevance CHD PRSs that performed similarly at the population level demonstrated highly variable individual-level estimates of risk. Recognizing that CHD PRSs may generate incongruent individual-level risk estimates, effective clinical implementation will require refined statistical methods to quantify uncertainty and new strategies to communicate this uncertainty to patients and clinicians.

中文翻译：

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评估冠心病多基因风险评分的性能和一致性。


重要性 冠心病 （CHD） 的多基因风险评分 （PRS） 是一个日益增长的临床和商业现实。现有评分是否提供类似的个体水平疾病易感性评估仍不完整。目的 表征在人群水平上表现相似的 CHD PRS 的个体水平一致性。设计、设置和参与者 对参加 All of Us 研究计划 （AOU）、Penn Medicine 生物样本库 （PMBB） 和加州大学洛杉矶分校 （UCLA） ATLAS 精准健康生物样本库的不同背景的参与者进行横断面研究，其中包含电子健康记录和基因分型数据。暴露 已发表的 PRS 和与检测样本分开开发的新 PRS 的 CHD 多基因风险。主要结局和指标 通过比较流行 CHD 模型的校准和区分来确定类似执行人群水平预测的 PRS。用组内相关系数 （ICC） 和光 κ 检验个体水平一致性。结果 共计算了 48 名 AOU 参与者的 171 095 个 PRS。平均 （SD） 年龄为 56.4 （16.8） 岁。共有 104 947 名参与者 （61.3%） 为女性。共有 35 590 名参与者 （20.8%） 与非洲参考人群基因相似，29 801 名 （17.4%） 与美国混合参考人群最相似，100 493 名 （58.7%） 与欧洲参考人群相似，其余与中/南亚、东亚和中东参考人群。有 17 589 名参与者 （10.3%） 患有 CHD，153 506 名参与者 （89.7%） 没有 CHD。当包含在普遍的 CHD 模型中时，46 个分数具有几乎相等的 Brier 分数和受试者操作员曲线下面积 （实际等效区域 ±0。02）. 20% 的参与者在最高和最低 1% 的风险中至少获得 5 分。个体预测的连续一致性较差 （ICC， 0.373 [95% CI， 0.372-0.375]）。用于评估风险分配一致性的 Light κ 不超过 0.56。对 41 193 名 PMBB 和 53 092 名 ATLAS 参与者的分析产生了不同的等效分数集，这也缺乏个体层面的一致性。结论和相关性 在人群水平上表现相似的 CHD PRS 表明个体水平的风险估计高度可变。认识到 CHD PRS 可能会产生不一致的个体水平风险估计，有效的临床实施将需要精细的统计方法来量化不确定性，并需要新的策略来将这种不确定性传达给患者和临床医生。