Case Control Study
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©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 28, 2016; 22(16): 4168-4182
Published online Apr 28, 2016. doi: 10.3748/wjg.v22.i16.4168
Table 1 Clinical data of the studied groups n (%)
HCC (n = 192) Cirrhotic (n = 96) Non-cirrhotic (n = 96) Control (n = 95) P valueAge, mean ± SD (range) 56.7 ± 7.7a (29-80) 54.01 ± 8.3b (27-66) 40.54 ± 8.82c (22-61) 33.37 ± 11d (19-62) < 0.001 Gender Male 152a (79) 67a (70) 78a (81) 21b (22) < 0.001 Female 40 a (21) 29a (30) 18a (19) 74b (78) Smoker Yes 75a (39) 26ab (27) 20b (21) 3c (3) < 0.001 No 117a (61) 70ab (73) 76b (79) 92c (97) DM Yes 43a (22) 22a (23) 8b (8) 0c (0) < 0.001 No 149a (78) 74a (77) 88b (92) 95c (100) HCV Ab Present 168a (88) 90a (94) 96b (100) 0c < 0.001 Absent 24a (12) 6a (6) 0b (0) 95c (100) HBs Ag Present 0 (0) 0 (0) 0 (0) 0 (0) 0.57 Absent 191 (100) 96 (100) 96 (100) 95 (100) Ascites Yes 86a (45) 75b (78) 0c (0) 0c (0) < 0.001 No 106a (55) 21b (22) 96c (100) 95c (100) Child score A 69a (36) 12b (12) < 0.001 B 69a (36) 27a (28) C 49a (28) 57b (60) ALT, mean 64.79 ± 52.737 63.6 ± 42.54 63.41 ± 44.22 21.84 ± 5.04 < 0.001 (range) (5-395) (6-290) (10-223) (11-33) median 51a 60a 54a 22b AST, mean 94.39 ± 105.61 53.91 ± 31.72 47.53 ± 29.04 26.68 ± 5.07 < 0.001 (range) (16-1155) (16-176) (8-167) ( 15-37) median 77a 46.5b 39.5b 27c T-Bil, mean 2.4 ± 2.63 3.25 ± 2.51 0.88 ± 0.49 0.79 ± 0.16 < 0.001 (range) (0.3-25.8) (0.2-19.7) (0.3-5) (0.5-1.1) median 1.7a 2.86b 0.84c 0.8c Albumin, mean 3.02 ± 0.63 2.55 ± 0.51 4.28 ± 0.4 4.45 ± 0.34 < 0.001 (range) (1.8-4.8) (1.7-4.3) (3.2-5.4) (3.8-5.2) median 3.1a 2.5b 4.2c 4.5d AFP, mean 3933.25 ± 16142 35.21 ± 40.1 18.19 ± 29.62 < 0.001 (range) (1.5-114170) (1.7-190) (0.65-112) 0 median 152a 17.95b 4.6c 0d
Table 2 Levels of the studied serological markers in different investigated groups
HCC (n = 192) Cirrhotic (n = 96) Non-Cirrhotic (n = 96) Control (n = 95) P valueProteosome, median 0.8a 0.17b 0.4c 0.16d < 0.001 mean ± SD 0.91 ± 0.6 0.25 ± 0.25 0.68 ± 0.58 0.18 ± 0.3 range 0.13-1.87 0.12-1.67 0.09-1.83 0.01-2.22 IL-8, median 107a 55a 36.5b 47b < 0.001 mean ± SD 518.19 ± 656.23 552.9 ± 732.2 283.76 ± 442.7 238.8 ± 431.6 range 14-1837 14-1811 8-1734 3-1719 sICAM-1, median 1072.5a 892b 510.5c 473c < 0.001 mean ± SD 1034.73 ± 372.7 978.17 ± 540.17 570 ± 287 493 ± 188 range 79-2419 31-2838 46-1654 37-1078 sTNF-RII, median 6785a 7011.5b 5948.5c 3190.5d < 0.001 mean ± SD 7058.31 ± 1338.78 6984.5 ± 626.8 5456 ± 1531.7 3400 ± 1519 range 3250-12776 4351-9919 1772-9403 495-7157 β-catenin, median 10.1a 7.95b 7.85b 6.8c < 0.001 mean ± SD 11.26 ± 5.49 9.34 ± 5.13 8.81 ± 4.07 7.5 ± 3.2 range 4.3-55.4 5.0-49.2 3.8-41.6 4.3-28.4
Table 3 Correlation analysis of different studied markers showing Spearman’s rho value and P value
Proteosome IL-8 sICAM-1 sTNF-RII β-catenin Proteosome 1 0.2401 0.2401 0.1851 0.2301 0.000 0.000 0.000 0.000 IL-8 0.2401 1 0.2331 0.1841 0.1411 0.000 0.000 0.000 0.003 sICAM-1 0.2401 0.2331 1 0.5471 0.2221 0.000 0.000 0.000 0.000 sTNF-RII 0.1851 0.1841 0.5471 1 0.2641 0.000 0.000 0.000 0.000 β-catenin 0.2301 0.1411 0.2221 0.2641 1 0.000 0.003 0.000 0.000
Table 4 Area under curve of individual markers vs combined one using (method 1 and 2) in different combinations of groups
Method 1 Method 2 Proteasome IL-8 sICAM-1 sTNF-RII β-catenin AFP Disease vs Control 0.979 0.992 0.834 0.612 0.825 0.951 0.768 0.923 HCC vs LC 0.841 0.962 0.911 0.576 0.585 0.424 0.718 0.804 HCC vs HCV 0.866 0.952 0.799 0.639 0.705 0.568 0.723 0.849 HCC vs Non-HCC 0.917 0.970 0.848 0.652 0.787 0.724 0.771 0.902 HCV vs Control 0.957 0.983 0.726 0.543 0.716 0.928 0.677 0.850 LC vs CHC 0.695 0.951 0.220 0.648 0.769 0.829 0.494 0.736 CHC vs Control 0.917 0.968 0.846 0.471 0.571 0.857 0.678 0.749 LC vs Control 0.990 1.000 0.637 0.597 0.825 0.981 0.676 0.924 HCC vs Control 0.998 1.000 0.927 0.672 0.917 0.970 0.846 0.986 HCC vs CHC 0.967 0.971 0.648 0.724 0.867 0.762 0.730 0.908
Table 5 Statistical measurements of the diagnostic performance for the binary classifier over different pairwise comparison of the investigated groups
AUC BT_Y Spec (%) Sen (%) Acc (%) TN TP FN FP NPV (%) PPV (%) Disease vs Control 0.992 0.764 96.8 96.0 96.2 92 312 13 3 87.6 99.0 HCC vs LC 0.962 0.655 98.8 89.1 92.3 85 156 19 1 81.7 99.3 HCC vs HCV 0.952 0.712 98.7 80.5 88.9 148 141 34 2 81.3 98.6 HCC vs Others 0.970 0.378 91.0 91.4 91.2 223 160 15 22 93.7 87.9 HCV vs Control 0.983 0.764 96.8 91.3 93.5 92 137 13 3 87.6 97.8 LC vs CHC 0.950 0.581 90.6 91.9 91.3 58 79 7 6 89.2 92.9 CHC vs Control 0.968 0.341 90.5 93.7 91.8 86 60 4 9 95.5 86.9 LC vs Control 1.000 0.500 100.0 100.0 100.0 95 86 0 0 100.0 100.0 HCC vs Control 1.000 0.500 100.0 100.0 100.0 95 175 0 0 100.0 100.0 HCC vs CHC 0.971 0.745 96.8 89.7 91.6 62 157 18 2 77.5 98.7
Table 6 Disease logistic predictive models based on binary-class classifier over different pairwise comparisons of the investigated groups
Combination Model Disease vs Control [-11 + 6.83 × Prot + (-5.99 × 10-5 ) × IL-8 + 3.12 × 10-4 × sICAM + 0.0013 × sTNF-RII + 0.172aβ-catenin + 0.283 × AFP][P values = 6.83E-10, 1.86E-05, 0.938962, 0.764414, 6.79E-08, 0.225761, 0.000818] HCC vs LC [11.33 + 7.380 × Prot + (-2.047 × 10-4 ) × IL-8 + 0.0011 × sICAM + 6.299 × 104 × sTNF + 0.26 ×β-catenin + 0.016 × AFP][P values = 3.22E-05, 7.11E-07, 0.591834, 0.041838, 0.056595, 0.000357, 0.000638] HCC vs HCV [-11.9 + 3.222 × Prot + (3.813 × 10-4 ) × IL + 0.00152 × sICAM + (6.481 × 10-4 ) × sTNF + 0.0291 ×β-catenin + 0.019 × AFP][P values = 1.39E-11, 2.63E-12, 0.231248, 0.000928, 0.000952, 5.41E-06, 5.09E-06] HCC vs Non-HCC [-12.27 + 3.3 × Prot + 0.0004 × IL + 0.00155 × sICAM + (6.803 × 10-4 ) × sTNF + 0.294 ×β-catenin + 0.02 × AFP][P values = 5.26E-13, 4.14E-13, 0.211689, 0.000767, 0.000388, 3.89E-06, 3.42E-06] HCV vs Control [-10.84 + 6.80 × Prot + (2.68 × 10-5 ) × IL-8 + 0.00017 × ICAM + 0.00126 × sTNF + 0.1742 ×β-catenin + 0.278 × AFP][P values = 1.12E-09, 1.87E-05, 0.972804, 0.875503, 9.02E-08, 0.227858, 0.000935] LC vs CHC [-10.16 + (-4.487) × Prot + 0.00134 × IL-8 + 0.0021 × sICAM + 0.0018 × sTNF + (-0.2984) ×β-catenin + 0.0217 × AFP][P values = 0.002674, 0.000351, 0.052275., 0.021958, 0.000211, 0.009838, 0.030621] CHC vs Control [-9.354 + 6.634 × Proteasome + (-0.00166) × IL-8 + (-0.00126) × sICAM + 0.001111 × sTNF + 0.208624 ×β-catenin + 0.24604 × AFP][P values = 1.40E-07, 1.64E-05, 0.2627, 0.3799, 8.55E-06, 0.1477, 0.0016] LC vs Control [-515.7 + 108.7 × Proteasome + 0.01295 × IL-8 + 0.0194 × sICAM + 0.05745 × sTNF + 4.485 ×β-catenin + 12.59 × AFP][P values = 0.997, 0.998, 0.999, 0.999, 0.998, 0.998, 0.995] HCC vs Control [-375.640 + 122.598 × Prot + (-0.0577) × IL + 0.0368 × sICAM + 0.0427 × sTNF + 1.1533 ×β-catenin + 13.584 × AFP][P values = 0.737, 0.802, 0.823, 0.917, 0.812, 0.923, 0.66] HCC vs CHC [-10.40 + 1.416 × Prot + 0.002024 × IL-8 + 0.0041 × sICAM + (4.251 × 10-4 ) × sTNF + 0.2.67 ×β-catenin + 0.0244 × AFP][P values = 1.28E-07, 0.00826, 0.01827, 5.52E-05, 0.04942, 0.00391, 0.00354]
Table 7 Final reduced disease logistic predictive models based on binary classifier with the most significant markers (achieved regression P < 0.05)
Final reduced model (with relevant terms) Best threshold Disease vs Control (-11 + 6.83 × Prot + 0.00129 × sTNF + 0.283 × AFP) 0.764 HCC vs LC (-11.3 + 7.38 × Prot + 0.00108 × sICAM + 0.2574 ×β-catenin + 0.01597 × AFP) 0.655 HCC vs HCV [-11.91 + 3.222 × Prot + 0.001518 × sICAM + (6.481 × 10-4 ) × sTNF + 0.291 ×β-catenin + 0.0193 × AFP] 0.712 HCC vs Non-HCC [-12.27 + 3.299 × Prot + 0.001548 × sICAM + (6.803 × 10-4 ) × sTNF + 0.2936 ×β-catenin + 0.0198 × AFP] 0.378 HCV vs Control (-10.84 + 6.803 × Prot + 0.00126 × sTNF + 0.2783 × AFP) 0.764 LC vs CHC [-10.16 + (-4.487) × Prot + 0.002086 × sICAM + 0.001858 × sTNF + (-0.2984) ×β-catenin + 0.02169 × AFP] 0.582 CHC vs Control (-9.353476 + 6.63414 × Prot + 0.001111 × sTNF + 0.24604 × AFP) 0.341 HCC vs CHC [-10.40 + 1.416 × Prot + 0.002024 × IL-8 + 0.004096 × sICAM + (4.251 × 10-4 ) × sTNF + 0.2567 ×β-catenin + 0.02442 × AFP] 0.745