External Validation of Risk Prediction Models Incorporating Common Genetic Variants for Incident Colorectal Cancer Using UK Biobank

Abstract

The aim of this study was to compare and externally validate risk scores developed to predict incident colorectal cancer (CRC) that include common genetic variants (single nucleotide polymorphisms, SNPs), with or without established lifestyle/environmental (questionnairebased/classical/phenotypic) risk factors. We externally validated 23 risk models from a previous systematic review in 443,888 participants aged 37-73 from the UK Biobank cohort who had 6 year prospective follow-up, no prior history of CRC and data for incidence of CRC through linkage to national cancer registries. There were 2,679 (0.6%) cases of incident CRC. We assessed model discrimination using the Area Under the Curve (AUC) and relative risk calibration. The AUC of models including only SNPs increased with the number of included SNPs and was similar in men and women: the model by Huyghe with 120 SNPs had the highest AUC of 0.62(95%CI 0.59-0.64) in women and 0.64(95%CI 0.61-0.66) in men.Adding phenotypic risk factors without age improved discrimination in men but not in women. Adding phenotypic risk factors and age increased discrimination in all cases (p<0.05), with the best performing models including SNPs, phenotypic risk factors and age having AUCs between 0.64-0.67 in women and 0.67-0.71 in men. Relative risk calibration varied substantially across the models. Among middle-aged people in the UK, existing polygenic risk scores discriminate moderately well between those who do and do not develop colorectal cancer over six years. Consideration should be given to exploring the feasibility of incorporating genetic and lifestyle/environmental information in any future stratified CRC screening program.

The Costs and Benefits of Risk Stratification for Colorectal Cancer Screening Based On Phenotypic and Genetic Risk: A Health Economic Analysis

“…However, higher ranking risk scores with AUROCs of above 0.65 are likely to promote QALY gains in addition to cost-savings, and result in CRC incidence and mortality reductions. In external validation within a UK cohort, the risk score by Huyghe with 120 SNPs had an AUROC of 0.62 (95% CI 0.61-0.64) in both women and men (16), which is close to this level, although the performance of this score could not be evaluated independently within our model. It is important to note that discrimination of risk scores may differ considerably between cohorts from different countries, and scores that perform well in a UK population may not rank as highly in non-European populations, indicating that there may be a need for different risk scores with high discrimination for different populations of interest.…”

“…Previously we reviewed published risk scores and externally validated them against UK Biobank data to determine which scores have the best discrimination within a UK population (16,17). The aim of the analysis presented here was to use the best-performing risk scores including phenotypic and genetic risk as the basis for determining the age at which FIT screening should start, then to estimate the cost-effectiveness, clinical benefits and resource impact of risk-stratification, compared with current screening strategies, from the English NHS perspective.…”

The Polygenic Score Catalog as an open database for reproducibility and systematic evaluation

“…Diagnosis of colorectal cancer was performed using data linkage to the UK's national cancer and death registries. Cases of colorectal cancer were identified using previously used ICD codes in UKB 44 : ICD9: 153.0 -153.9, 154.0, 154.1, 154.8 ICD10: C18.0 -C18.9, C19, C20, C21.8 For each colorectal cancer diagnosis or death we recorded the date and age of the event. colorectal cancer events were defined as the first event of colorectal cancer, and participants were censored after the last cancer registry linkage date (2016-03-31).…”

The Polygenic Score Catalog: an open database for reproducibility and systematic evaluation

“…Diagnosis of colorectal cancer was performed using data linkage to the UK’s national cancer and death registries. Cases of colorectal cancer were identified using previously used ICD codes in UKB 44 :…”