Broad‐ and narrow‐sense validity performance of three polygenic risk score methods for prostate cancer risk assessment

Abstract

Background Several polygenic risk score (PRS) methods are available for measuring the cumulative effect of multiple risk‐associated single nucleotide polymorphisms (SNPs). Their performance in predicting risk at the individual level has not been well studied. Methods We compared the performance of three PRS methods for prostate cancer risk assessment in a clinical trial cohort, including genetic risk score (GRS), pruning and thresholding (P + T), and linkage disequilibrium prediction (LDpred). Performance was evaluated for score deciles (broad‐sense validity) and score values (narrow‐sense validity). Results A training process was required to identify the best P + T model (397 SNPs) and LDpred model (3 011 362 SNPs). In contrast, GRS was directly calculated based on 110 established risk‐associated SNPs. For broad‐sense validity in the testing population, higher deciles were significantly associated with higher observed risk; Ptrend was 7.40 × 10−11, 7.64 × 10−13, and 7.51 × 10−10 for GRS, P + T, and LDpred, respectively. For narrow‐sense validity, the calibration slope (1 is best) was 1.03, 0.77, and 0.87, and mean bias score (0 is best) was 0.09, 0.21, and 0.10 for GRS, P + T, and LDpred, respectively. Conclusions The performance of GRS was better than P + T and LDpred. Fewer and well‐established SNPs of GRS also make it more feasible and interpretable for genetic testing at the individual level.

Calibration of polygenic risk scores is required prior to clinical implementation: results of three common cancers in UKB

“…Furthermore, because this study was limited to one specific polygenic risk score method (GRS), the generalisability of these findings to other polygenic risk score methods is unclear. However, similar findings were reported in PCa for other genome-wide polygenic risk score methods including pruning and thresholding and linkage disequilibrium prediction 14. Nonetheless, confirmation using other study populations and for other polygenic risk score methods is needed.…”

Identification of fifty-seven novel loci for abdominal wall hernia development and their biological and clinical implications: results from the UK Biobank

“…The phenomenon of multiple independent loci within the same chromosomal region is found in other diseases (e.g. 12 independent risk-associated loci at 8q24 for prostate cancer) [11]. Furthermore, the high levels of genetic correlation of polygenic architecture among hernia subtypes, especially between umbilical and ventral hernia, suggest common pathogenetic mechanisms for these subtypes.…”

“…Only independent SNPs derived from stepwise regression analysis from GWAS Stages 1 and 2 were used to calculate GRS. GRS is an odds ratio (OR)-weighted and population-standardized polygenic risk score and is calculated as: where g i stands for the genotype of SNP i in an individual (0, 1, or 2 risk alleles), OR i stands for the allelic OR of SNP i, and f i stands for the risk allele frequency of SNP i in the population [11]. The OR estimates of each SNP from Stages 1 and 2 and allele frequency from gnomAD were used.…”

Reliability of Ancestry-specific Prostate Cancer Genetic Risk Score in Four Racial and Ethnic Populations

“…Platt scaling was used to correct a systematic bias of a GRS [18] , [24] , [25] , [26] . Briefly, in each population, a logistic regression between a logarithm GRS and PCa status was performed in the training dataset (60% of randomly selected patients).…”