Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Atlanta, GA, USA.
Hum Mol Genet. 2019 Nov 21;28(R2):R143-R150. doi: 10.1093/hmg/ddz205.
Polygenic risk scores (PRSs) have become the standard for quantifying genetic liability in the prediction of disease risks. PRSs are generally constructed as weighted sum scores of risk alleles using effect sizes from genome-wide association studies as their weights. The construction of PRSs is being improved with more appropriate selection of independent single-nucleotide polymorphisms (SNPs) and optimized estimation of their weights but is rarely reflected upon from a theoretical perspective, focusing on the validity of the risk score. Borrowing from psychometrics, this paper discusses the validity of PRSs and introduces the three main types of validity that are considered in the evaluation of tests and measurements: construct, content, and criterion validity. This introduction is followed by a discussion of three topics that challenge the validity of PRS, namely, their claimed independence of clinical risk factors, the consequences of relaxing SNP inclusion thresholds and the selection of SNP weights. This discussion of the validity of PRS reminds us that we need to keep questioning if weighted sums of risk alleles are measuring what we think they are in the various scenarios in which PRSs are used and that we need to keep exploring alternative modeling strategies that might better reflect the underlying biological pathways.
多基因风险评分（PRS）已成为量化疾病风险预测中遗传易感性的标准。PRS 通常是通过使用全基因组关联研究的效应大小作为权重，对风险等位基因进行加权求和而构建的。通过更恰当地选择独立的单核苷酸多态性（SNP）和优化其权重的估计，PRS 的构建正在得到改进，但从理论角度来看，很少对其进行反思，主要关注风险评分的有效性。本文借鉴心理测量学，讨论了 PRS 的有效性，并介绍了评估测试和测量时考虑的三种主要有效性类型：结构有效性、内容有效性和标准有效性。在介绍之后，本文讨论了三个挑战 PRS 有效性的主题，即它们声称的与临床风险因素的独立性、放宽 SNP 纳入阈值的后果以及 SNP 权重的选择。对 PRS 有效性的讨论提醒我们，我们需要不断质疑加权风险等位基因总和是否在 PRS 用于的各种情况下都能测量我们认为它们在测量的内容，并且我们需要不断探索可能更好地反映潜在生物学途径的替代建模策略。
