Evaluating the effect of multiple genetic risk score models on colorectal cancer risk prediction

Currently, genetic risk score (GRS) model has been a widely used method to evaluate the genetic effect of cancer risk prediction, but seldom studies investigated their discriminatory power, especially for colorectal cancer (CRC) risk prediction. In this study, we applied both simulation and real data to comprehensively compare the discriminability of different GRS models. The GRS models were fitted by logistic regression with three scenarios, including simple count GRS (SC-GRS), logistic regression weighted GRS (LR-GRS, including DL-GRS and OR-GRS) and explained variance weighted GRS (EV-GRS, including EV_DL-GRS and EV_OR-GRS) models. The model performance was evaluated by receiver operating characteristic (ROC) curves and area under curves (AUC) metric, net reclassification improvement (NRI) and integrated discrimination improvement (IDI). In real data analysis, as DL-GRS and EV_DL-GRS models were carried with serious over-fitting, the other three models were kept for further comparison. Compared to unweighted SC-GRS model, reclassification was significantly decreased in OR-GRS model (NRI = -0.082, IDI = -0.002, P < 0.05), while EV_OR-GRS model showed negative NRI and IDI (NRI = -0.077, IDI = -5.54E-04, P < 0.05) compared to OR-GRS model. Besides, traditional model with smoking status (AUC = 0.523) performed lower discriminability compared to the combined model (AUC = 0.607) including genetic (i.e., SC-GRS) and smoking factors. Similarly, the findings from simulation were all consistent to real data results. It is plausible that SC-GRS model could be optimal for predicting genetic risk of CRC. Moreover, the addition of more significant genetic variants to traditional model could further improve predictive power on CRC risk prediction.