Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model

doi:10.3748/wjg.v22.i16.4168

Advanced Search

BPG is committed to discovery and dissemination of knowledge

Home / Archive / Volume 22, Issue 16

This Article

Academic Content and Language Evaluation of This Article

CrossCheck and Google Search of This Article

Academic Rules and Norms of This Article

Supplementary Materials of This Article

Citation of this article

Corresponding Author of This Article

Research Domain of This Article

Article-Type of This Article

Open-Access Policy of This Article

Times Cited Counts in Google of This Article

Number of Hits and Downloads for This Article

Total Article Views (7182)

All Articles published online

The chart showing PDF series, WORD series, HTML series, Figures (1-5) series, Tables (1-7) series.

Item

Count

PDF

594

WORD

271

HTML

3432

Figures (1-5)

167

Tables (1-7)

167

Sum=4631

Publishing Process of This Article

The chart showing Browse series, Download series.

Item

Count

Browse

1015

Download

1536

Sum=2551

Apr 28, 2016 (publication date) through Apr 26, 2024

Times Cited of This Article

Times Cited (2)

Journal Information of This Article

Publication Name

World Journal of Gastroenterology

ISSN

1007-9327

Publisher of This Article

Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Case Control Study

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 value
Age, mean ± SD (range)	56.7 ± 7.7^a (29-80)	54.01 ± 8.3^b (27-66)	40.54 ± 8.82^c (22-61)	33.37 ± 11^d (19-62)	< 0.001
Gender
Male	152^a (79)	67^a (70)	78^a (81)	21^b (22)	< 0.001
Female	40 ^a (21)	29^a (30)	18^a (19)	74^b (78)	< 0.001
Smoker
Yes	75^a (39)	26^ab (27)	20^b (21)	3^c (3)	< 0.001
No	117^a (61)	70^ab (73)	76^b (79)	92^c (97)	< 0.001
DM
Yes	43^a (22)	22^a (23)	8^b (8)	0^c (0)	< 0.001
No	149^a (78)	74^a (77)	88^b (92)	95^c (100)	< 0.001
HCV Ab
Present	168^a (88)	90^a (94)	96^b (100)	0^c	< 0.001
Absent	24^a (12)	6^a (6)	0^b (0)	95^c (100)	< 0.001
HBs Ag
Present	0 (0)	0 (0)	0 (0)	0 (0)	0.57
Absent	191 (100)	96 (100)	96 (100)	95 (100)	0.57
Ascites
Yes	86^a (45)	75^b (78)	0^c (0)	0^c (0)	< 0.001
No	106^a (55)	21^b (22)	96^c (100)	95^c (100)	< 0.001
Child score
A	69^a (36)	12^b (12)			< 0.001
B	69^a (36)	27^a (28)
C	49^a (28)	57^b (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	51^a	60^a	54^a	22^b
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	77^a	46.5^b	39.5^b	27^c
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	1.7^a	2.86^b	0.84^c	0.8^c
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	3.1^a	2.5^b	4.2^c	4.5^d
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	152^a	17.95^b	4.6^c	0^d

^a-dGroups bearing different initials are significantly different. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; AFP: α-fetoprotein; DM: Diabetes mellitus; T-Bil: Total bilirubin.

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 value
Proteosome,
median	0.8^a	0.17^b	0.4^c	0.16^d	< 0.001
mean ± SD	0.91 ± 0.6	0.25 ± 0.25	0.68 ± 0.58	0.18 ± 0.3	< 0.001
range	0.13-1.87	0.12-1.67	0.09-1.83	0.01-2.22
IL-8,
median	107^a	55^a	36.5^b	47^b	< 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	1072.5^a	892^b	510.5^c	473^c	< 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	6785^a	7011.5^b	5948.5^c	3190.5^d	< 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	10.1^a	7.95^b	7.85^b	6.8^c	< 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

^a-dGroups bearing different initials are significantly different. IL-8: Interleukin-8; sTNF-RII: Soluble tumor necrosis factor receptor II; sICAM-1: Soluble intercellular adhesion molecule-1.

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
Proteosome	1	0.000	0.000	0.000	0.000
IL-8	0.240¹	1	0.233¹	0.184¹	0.141¹
IL-8	0.000	1	0.000	0.000	0.003
sICAM-1	0.240¹	0.233¹	1	0.547¹	0.222¹
sICAM-1	0.000	0.000	1	0.000	0.000
sTNF-RII	0.185¹	0.184¹	0.547¹	1	0.264¹
sTNF-RII	0.000	0.000	0.000	1	0.000
β-catenin	0.230¹	0.141¹	0.222¹	0.264¹	1
β-catenin	0.000	0.003	0.000	0.000	1

¹Correlation is significant at the 0.01 level (2-tailed). IL-8: Interleukin-8; sTNF-RII: Soluble tumor necrosis factor receptor II; sICAM-1: Soluble intercellular adhesion molecule-1.

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

Method 1 is based on multi-class classifier and Method 2 is based on binary-class classifier. HCV group: Include LC and CHC groups; Disease group: HCC, CHC and LC groups. CHC: Chronic hepatitis C; LC: Liver cirrhosis; AFP: α-fetoprotein; HCV: Hepatitis C virus.

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

BT_Y: Best cut off computed using Youden statistics, TP: True positive; TN: True negative; FP: False positive; FN: False negative; Sen: Sensitivity; Spec: Specificity; Acc: Accuracy; PPV: Positive predictive value; NPV: Negative predictive value; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus.

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]

The values between brackets were the P values for the corresponding term parameter in the model respectively. Terms with P value < 0.05 are considered significant. The first P value was for overall model.

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

CHC: Chronic hepatitis C; LC: Liver cirrhosis; AFP: α-fetoprotein; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus.; sICAM-1: Soluble intercellular adhesion molecule; sTNF: Soluble tumor necrosis factor.

Citation: Zekri ARN, Youssef ASED, Bakr YM, Gabr RM, Ahmed OS, Elberry MH, Mayla AM, Abouelhoda M, Bahnassy AA. Early detection of hepatocellular carcinoma co-occurring with hepatitis C virus infection: A mathematical model. World J Gastroenterol 2016; 22(16): 4168-4182
URL: https://www.wjgnet.com/1007-9327/full/v22/i16/4168.htm
DOI: https://dx.doi.org/10.3748/wjg.v22.i16.4168