Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois, USA.
Affiliate of City of Hope, Translational Genomics Research Institute, Phoenix, Arizona, USA.
J Med Genet. 2022 Mar;59(3):243-247. doi: 10.1136/jmedgenet-2020-107286. Epub 2020 Dec 21.
SNP-based polygenic risk scores have recently been adopted in the clinic for risk assessment of some common diseases. Their validity is supported by a consistent trend between their and disease risk in populations. However, for clinical use at the individual level, the reliability of is necessary considering they are directly used to calculate remaining lifetime risk.
We assessed the reliability of polygenic score values to estimate prostate cancer (PCa), breast cancer (BCa) and colorectal cancer (CRC) risk in three incident cohorts from the UK Biobank (n>500 000).
Cancer-specific Genetic Risk Score (GRS), a well-established population-standardised polygenic risk score, was calculated.
A systematic bias was found between estimated risks (GRS values) and observed risks; β (95% CI) was 0.67 (0.58-0.76), 0.74 (0.65-0.84) and 0.82 (0.75-0.89), respectively, for PCa, BCa and CRC, all significantly lower than 1.00 (perfect calibration), p<0.001. After applying a correction factor derived from a training data set, the β for corrected GRS values in an independent testing data set were 1.09 (1.05-1.13), 1.00 (0.88-1.12) and 1.08 (0.96-1.21), respectively, for PCa, BCa and CRC.
Assessing the calibration of polygenic risk scores is necessary and feasible to ensure their reliability prior to clinical implementation.
基于 SNP 的多基因风险评分最近已在临床中用于评估某些常见疾病的风险。它们在人群中的与疾病风险之间存在一致的趋势，支持了它们的有效性。然而，对于个体水平的临床应用，考虑到它们直接用于计算剩余寿命风险， 需要评估多基因评分值的可靠性。
我们评估了多基因评分值在英国生物库（n>500000）中的三个发病队列中估计前列腺癌（PCa）、乳腺癌（BCa）和结直肠癌（CRC）风险的可靠性。
计算了特定癌症的遗传风险评分（GRS），这是一种成熟的基于人群的标准化多基因风险评分。
发现估计风险（GRS 值）与观察风险之间存在系统性偏差；β（95%CI）分别为 0.67（0.58-0.76）、0.74（0.65-0.84）和 0.82（0.75-0.89），均显著低于 1.00（完美校准），p<0.001。在应用从训练数据集导出的校正因子后，在独立测试数据集校正 GRS 值的β分别为 1.09（1.05-1.13）、1.00（0.88-1.12）和 1.08（0.96-1.21），用于 PCa、BCa 和 CRC。
在临床实施之前，评估多基因风险评分的校准情况是必要且可行的，以确保其可靠性。
