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Table 1 Main characteristics of the included studies in the systematic review

From: Polygenic risk prediction models for colorectal cancer: a systematic review

First author, year [ref] Study design Study population Number of study participants Type of genetic variants used GRS computation Non-genetic factors included in the model AUC (95% CI) of model without SNPs AUC (95% CI) of SNP-enhanced model IDI; NRI
Abe M, 2017 [22] Case-control Japanese Derivation: 558 cases and 1116 controls; Replication: 547 cases and 547 controls. 11 SNPs (6 derived from GWASs in US/Europeans, 5 identified in GWASs in East Asians) Unweighted GRS    Derivation study: 0.6392; Replication study: 0.5695  
Balavarca Y, 2019 [23] Case-control German 236 non-advanced adenomas, 291 advanced CRC; 487 controls 39 SNPs Unweighted GRS; Weighted GRS using weights derived from the same study Gender, age, FH of CRC, smoking, alcohol intake, red meat consumption, use of NSAIDs, previous colonoscopy and polyps history 0.584 (0.545–0.622) Unweighted GRS: 0.636 (0.599–0.672);
Weighted GRS: 0.616 (0.579–0.654)
 
Chandler PD, 2018 [24] Cohort US 23,294 individuals, 329 CRC cases 5 SNPs Unweighted GRS     
Cho YA, 2019 [25] Case-control Korean 632 cases 1295 controls 13 SNPs Unweighted GRS; Weighted GRS using weights derived from the same study BMI, physical activity, diet, smoking, alcohol consumption.    
de Kort S, 2019 [26] Case-cohort Dutch 1907 CRC cases, 2729 subcohort members 18 SNPs Unweighted GRS Age, BMI, pant size, CRC first degree relative, smoking, nonoccupational physical activity, intake of: alcohol, meat, vegetables, fish, sweets, added sugar, saturated fats and fiber, total energy.    
Dunlop MG, 2013 [27] Case-control European descendents Genotypes alone: 39,266; In combination with other factors: 11,324; External validation case-control sets: 1563 Swedish cases and 1504 controls, 702 Finnish cases and 418 controls. 10 SNPs Unweighted GRS FH of CRC, age, gender.    
Hiraki LT, 2013 [28] Case-control European descendants 10,061 cases and 12,768 controls 4 SNPs Unweighted GRS Age, gender, center, smoking, batch effects, FH of CRC, BMI, NSAIDs use, alcohol use, dietary calcium, folate and red meat intake, sedentary status, hormone replacement therapy when possible and according to the study.    
Hosono S, 2016 [29] Case-control Japanese Derivation set: 558 cases and 1116 controls Replication set: 547 cases and 547 controls 6 SNPs Unweighted GRS Age, smoke, alcohol consumption, folate intake, BMI, FH of CRC, physical activity. Derivation study: 0.7009; Replication study: 0.5232 Derivation study: Genetic only risk score: 0.6046; Combined (genetic + traditional): 0.7167; Replication study: Genetic only: AUC 0.6391; Combined (genetic + traditional) AUC 0.6356  
Hsu L, 2015 [30] Case-control European descendants Training set: 5811 cases and 6302 controls; Validation set: 866 cases and 869 controls. 27 SNPs Unweighted GRS; Weighted GRS using weights derived from literature (results not reported) Age, gender, FH of CRC, history of endoscopic examinations Men 0.51 (0.48–0.53); Women 0.52 (0.50–0.55) Men: AUC 0.59 (0.54–0.64); Women: 0.56 (0.51–0.61)  
Huyghe JR, 2019 [31] Case-control European descendants 1439 cases and 720 controls 95 SNPs Weighted GRS using weights derived from the same study     
Ibáñez-Sanz G, 2017 [32] Case-control Spanish 1336 cases and 2744 controls. 21 SNPs Unweighted GRS; Weighted GRS using weights derived from literature and from the same study (results not reported) Alcohol consumption, BMI, physical activity, red meat and vegetables intake, NSAIDs/aspirin use, FH of CRC Environmental risk factors and family history: 0.61 (0.59–0.64) 0.63 (0.60–0.66)  
Iwasaki M, 2017 [33] Case-control Japanese men 675 cases and 675 controls 6 SNPs Weighted GRS using weights derived from the same study Age, BMI, alcohol consumption, smoking. 0.60 0.66 Significant difference in the inclusive model with a GRS compared to the non-genetic model for the IDI (0.0052; 95% CI: 0.0023–0.0081), continuous NRI (0.36; 95% CI: 0.0023–0.71), and NRI (0.26; 95% CI: 0.0039–0.43).
Jenkins MA, 2019 [34] Case-control North American and Australian 1181 cases and 999 controls 45 SNPs Weighted GRS using weights derived from literature FH of CRC    
Jeon J, 2018 [35] case-control European descendants Training set: 4875 cases and 5291 controls Validation set: 4873 cases and 5299 controls. 63 SNPs Weighted GRS using weights derived from the same study Gender, height, body mass index, education, type 2 diabetes mellitus, smoking status, alcohol consumption, NSAID/aspirin use, regular use of postmenopausal hormones, gender- and study-specific quartiles of smoking pack-years and dietary factors, total-energy, and physical activity Men: 0.60 (0.59–0.61); Women: 0.60 (0.59–0.61) Men: 0.63 (0.62–0.64); Women: 0.62 (0.61–0.63)  
Jo J, 2012 [36] Case-control Korean 187 cases and 976 controls 3 SNPs in men, 5 SNPs in women Unweighted GRS; Weighted GRS using weights derived from the same study FH of CRC, age. Conventional risk factors alone, men: 0.692 (0.647–0.732); Conventional risk factors alone, women: 0.603 (0.569–0.637) Counted GRS plus traditional risk factors, men: 0.729 (0.682–0.767); Weighted GRS plus traditional risk factors, men: 0.719 (0.677–0.761); Counted GRS plus traditional risk factors, women: 0.650 (0.615–0.680); Weighted GRS plus traditional risk factors: 0.646 (0.612–0.674)  
Jung KJ, 2015 [37] Case-cohort Korean 173 cases and 1514 controls 7 SNPs Unweighted GRS; Weighted GRS using weights derived from the same study TRS: age, gender, smoking status, fasting serum glucose, FH of CRC 0.73 (0.69–0.78) 0.74 (0.70–0.78) The NRI (95% CI) for a prediction model with GRS compared to the model with TRS alone was 0.17 (− 0.05–0.37) for colorectal cancer, − 0.17 (− 0.33–0.21) for colon cancer, and 0.41 (0.10–0.68) for rectal cancer.
Jung SY, 2019 [38] Cohort European ancestry (women only) 6539 individuals, 472 cases developed CRC 54 SNPs   Age and % calories from saturated fatty acid    
Marshall KW, 2010 [39] Case-control North American Training set: 112 CRC and 120 controls. Validation set: 202 CRC and 208 controls (only individuals aged ≥50 years). 7 genes     Training set: AUC 0.80 (0.74–0.85); Validation set: AUC 0.80 (0.76–0.84)  
Prizment AE, 2013 [40] Cohort Caucasian 8657 individuals (205 cases) 20 SNPs Weighted GRS using weights derived from literature     
Rodriguez-Broadbent H, 2017 [41] Case-control European descendants 9254 cases and 18,386 controls 38 SNPs related to total cholesterol circulating levels, 14 SNPs related to triglyceride circulating levels, 9 SNPs related to LDL circulating levels, 43 SNPs related to HDL circulating levels      
Schmit SL, 2019 [42] Case-control European descendants Discovery stage: 36,948 cases and 30,864 controls; Replication set: 12,952 cases and 48,383 controls; Generalizability in East Asians, African Americans, and Hispanics: 12,085 cases and 22,083 controls. 76 SNPs: 67 previously published SNPs and 9 novel SNPs Weighted GRS using weights derived from the same study     
Shi Z, 2019 [43] Case-control Caucasian 387 cases and 13,427 controls 30 SNPs Weighted GRS using weights derived from literature Population-standardization    
Smith T, 2018 [44] Cohort UK Taylor model: 361,543 (1623 cases); Wells model: 286,877 (1294 cases) 41 SNPs Weighted GRS using weights derived from literature Taylor model: age-specific CRC rates and estimated RR for different degrees of FH of CRC. Wells model: age, diabetes, multi-vitamin usage, FH of CRC, education, BMI, alcohol use, physical activity, NSAIDs use, red meat intake, smoking and estrogen use (women only). Taylor model: 0.67 (0.65–0.68); Wells model: 0.68 (0.67–69) Taylor model:0.69 (0.67–0.70); Wells model: 0.69 (0.65–0.68)  
Thrift AP, 2015 [45] Case-control European descendants 10,226 cases and 10,286 controls 696 SNPs Weighted GRS using weights derived from literature     
Thrift AP, 2015 [46] Case-control European descendants 10,226 cases and 10,286 controls 77 SNPs for BMI; 47 SNPs for waist-hip ratio (WHR) Weighted GRS using weights derived from literature     
Wang HM, 2013 [47] Case-control Taiwanese 218 cases and 385 controls 16 SNPs in the short model; 26 SNPs in the full model     16-SNPs model: 0.724; 26-SNPs model: 0.734  
Wang K, 2018 [48] Cohort Chinese 64 CRC cases (172 digestive cancer cases, 9636 controls) 9 SNPs    AFP level: 0.523 (0.456–0.591); CA19–9 level:0.524 (0.451–0.597); CEA level: 0.568 (0.492–0.645); AFP, CA19–9, CEA level: 0.509 (0.439–0.579) AFP level -genetic corrected: 0.524 (0.458–0.591); CA19–genetic corrected CA19–9 level: 0.525 (0.452–0.597); CEA level-genetic corrected 0.572 (0.495–0.649); AFP, CA19–9, CEA level-genetic: 0.564 (0.487–0.641)  
Weigl K, 2018 [49] Case-control German Genotype: 294 advanced neoplasms, 249 non-advanced adenomas, 500 controls Replication: 462 controls, 140 advanced adenomas, 355 non-advanced adenomas 48 SNPs (replication analyses within the TCPS with a subset of 35 SNPs of the original GRS) Unweighted GRS; Weighted GRS using weights derived from literature (results not reported) Gender, age, previous colonoscopy, physical activity, BMI Model adjusted for age and gender: 0.599; Model adjusted for age, gender, previous colonoscopy, physical activity: 0.607; Model adjusted for age, gender, previous colonoscopy, physical activity, BMI: 0.615 Model adjusted for age and gender: 0.653; Model adjusted for age, gender, previous colonoscopy, physical activity: 0.658; Model adjusted for age, gender, previous colonoscopy, physical activity, BMI: 0.665 The NRI and IDI of model including Genetic Risk Score were respectively of 0.29 (0.14–0.43) and 0.04 (0.03–0.05) when the model was adjusted for age and gender; 0.30 (0.15–0.44) and 0.04 (0.03–0.05) when adjusted for age, gender, previous colonoscopy, physical activity and 0.29 (0.14–0.43) and 0.04 (0.03–0.05) when the model was adjusted for age, gender, previous colonoscopy, physical activity, BMI.
Weigl K, 2018 [50] Case-control German 2363 cases and 2198 controls. 44 SNPs Unweighted GRS; Weighted GRS using weights derived from literature (results not reported) Gender, age, education, previous colonoscopy, smoking, hormone replacement therapy (women only), BMI, FH of CRC    
Xin J, 2018 [51] Case-control Chinese 1316 cases and 2229 controls 14 SNPs Unweighted GRS; Weighted GRS using weights derived from literature and from the same study Smoking status The highest quartile respect to the lower quartile showed an OR (95%CI) of: 2.70 (2.06–3.54) in the simple count GRS model, 2.74 (2.19–3.43) in the directed logistic regression GRS model, 2.56 (2.05–3.20) in the odds ratio weighted GRS model, 2.90 (2.32–3.63) in the explained variance weighted GRS model, 2.51 (2.01–3.14) in the explained variance weighted OR GRS model.   Model were compared among each other respect to NRI (95%CI; p-value) and IDI (95%CI; p-value): the simple-count-GRS vs. logistic regression weighted OR-GRS showed an NRI of − 0.082 (− 0.159, − 0.007; p value: 0.033) and an IDI of − 0.002 (− 0.004, − 2.33E− 04; 0.028); the simple-count-GRS vs. explained variance weighted OR-GRS showed an NRI of 0.017 (− 0.055, 0.090; 0.638) and an IDI of 2.80E− 04 (− 0.001, 0.001; 0.567); logistic regression weighted-GRS vs. explained variance weighted OR-GRS showed an NRI − 0.077 (− 0.153, − 0.001; 0.046) and an IDI of − 5.54E− 04 (− 0.001, − 3.17E− 05; 0.038). In addition, a model including only smoking factors was with a model including smoking factors and simple count GRS (SC-GRS), with an increased AUC, NRI and IDI in combined model of 0.084, 0.317 (0.225, 0.408) and 0.031 (0.023, 0.039)
Xin J, 2019 [52] Case-control Chinese Chinese studies: 2248 cases and 3173 controls; GECCO study: 4461 cases and 4140 controls Chinese studies: 19 SNPs vs. 58 SNPs; GECCO study: 19 SNPs vs. 75 SNPs Weighted GRS using weights derived from the same study Gender, age, first principal component   Chinese studies: 19 SNPs model of 0.597 (0.581–0.613), 58 SNPs model of 0.623 (0.604–0.642); GECCO study: 19 SNPs model of 0.575 (0.563–0.587), 58 SNPs model of 0.585 (0.573–0.597)  
Yeh CC, 2007 [53] Case-control Taiwanese 727 cases and 736 controls 10 SNPs   Age, education, physical activity, coffee consumption, cigarette consumption, alcohol use, staple consumption, meat, vegetable/fruit and fish/shrimp intake.    
Zhang L, 2017 [54] Case-control Chinese 369 cases and 929 controls 4 SNPs   Age, BMI, physical activity, emotion status, mental stress, cholesterol, drinking and smoking, vegetables and seafood consumption    
  1. CRC colorectal cancer, SNP single nucleotide polymorphism, ERS environmental risk score, GRS genetic risk score, TRS traditional risk score, PRS polygenic risk score, ct-DNA circulating tumor-DNA, RR relative risk, HR hazard ratio, OR odds ratio, GWAS genome-wide association study, BMI body mass index, FH family history, NSAID nonsteroidal anti-inflammatory drug