Diagnostic and economic value of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 in gastrointestinal cancers

Table 1 The six schemes and examination prices in economic analysis

Item	Description
Schemes	Scheme 1 Gastrointestinal endoscopy for all people without blood tests
	Scheme 2 Both of gastroscopy and colonoscopy when blood tests were positive
	Scheme 3 Gastroscopy first when blood tests were positive, and then colonoscopy when the result of gastroscopy was negative
	Scheme 4 Colonoscopy first when blood tests were positive, and then gastroscopy when the result of colonoscopy was negative
	Scheme 5 Only gastroscopy when blood tests were positive
	Scheme 6 Only colonoscopy when blood tests were positive
Examination prices	CEA, $4.64; CA19-9, $7.25; CA72-4, $7.25
	Gastroscopy & biopsy, $87.99
	Colonoscopy, $57.98; biopsy after colonoscopy, $32.62

The prices of gastroscopy and colonoscopy did not include that of intravenous anesthesia. The costs of all examinations were from Zhongshan Hospital in 2019. All costs were converted to United States dollars. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4.

Table 2 The clinical characteristics of subjects with and without gastric cancer, colorectal cancer and gastrointestinal cancers

	Age median (quartile)	P value	Male, n (%)	Female, n (%)	P value
Gastric cancer	61 (51, 68)	< 0.001	268 (68.4)	124 (31.6)	0.084
Non-gastric cancer	48 (42, 56)		20831 (64.2)	11634 (35.8)
Colorectal cancer	62 (55, 70)	< 0.001	522 (58.5)	370 (41.5)	< 0.001
Non-colorectal cancer	48 (42, 55)		20577 (64.4)	11388 (35.6)
Gastrointestinal cancer	62 (53, 69)	< 0.001	816 (62.4)	491 (37.6)	0.170
Non-gastrointestinal cancer	48 (42, 55)		20283 (64.3)	11267 (35.7)

The P value was calculated with the Wilcoxon test for age and chi-square test for sex. The bold font indicates that the P value was less than 0.05.

Table 3 The number and proportions of diseases in the gastroscopy, colonoscopy and pathological examination groups

Examination	Disease	No.	%
Gastroscope (without pathological examination)	Esophagitis	2887	8.8%
	Esophageal erosion	88	0.3%
	Esophageal ulcer	30	0.1%
	Esophageal protuberant lesion	491	1.5%
	Esophageal non-protuberant lesion	77	0.2%
	Barrett’s esophagus	66	0.2%
	Bile reflux	1344	4.1%
	Gastric atrophy	45	0.1%
	Gastric erosion	12457	37.9%
	Gastric hemorrhage	1117	3.4%
	Gastric ulcer	1088	3.3%
	Gastric protuberant lesion	3329	10.1%
	Gastric non-protuberant lesion	225	0.7%
	Duodenitis	1473	4.5%
	Duodenal erosion	26	0.1%
	Duodenal ulcer	1548	4.7%
	Duodenal protuberant lesion	666	2.0%
	Duodenal non-protuberant lesion	31	0.1%
Colonoscopy (without pathological examination)	Colorectitis	653	2.0%
	Colorectal erosion	29	0.1%
	Colorectal ulcer	99	0.3%
	Colorectal protuberant lesion	7312	22.3%
	Colorectal non-protuberant lesion	36	0.1%
Pathological examination	Esophageal mucositis	398	1.2%
	Esophageal dysplasia	44	0.1%
	Esophageal adenoma	1	< 0.1%
	Esophageal hyperplastic polyp	2	< 0.1%
	Esophageal glandular hyperplasia	4	< 0.1%
	Chronic atrophic gastritis	1809	5.5%
	Gastric dysplasia	308	0.9%
	Gastric adenoma	13	< 0.1%
	Gastric hyperplastic polyps	117	0.4%
	Gastric glandular hyperplasia	761	2.3%
	Gastric juvenile polyps	1	< 0.1%
	Duodenal mucositis	276	0.8%
	Duodenal dysplasia	24	0.1%
	Duodenal adenoma	12	< 0.1%
	Duodenal hyperplastic polyps	10	< 0.1%
	Duodenal gland hyperplasia	31	0.1%
	Colorectal mucositis	2206	6.7%
	Colorectal high-grade intraepithelial neoplasia	330	1.0%
	Colorectal low-grade intraepithelial neoplasia	3364	10.2%
	Colorectal adenoma	3707	11.3%
	Colorectal hyperplastic polyps	1037	3.2%
	Colorectal inflammatory polyps	13	< 0.1%
	Colorectal gland hyperplasia	567	1.7%
	Colorectal juvenile polyps	3	< 0.1%
	Peutz-Jeghers polyps	5	< 0.1%
	Familial polyposis coli	3	< 0.1%
	Esophageal cancer	57	0.2%
	Gastric cancer	392	1.2%
	Duodenal cancer	25	0.1%
	Small intestine cancer	4	< 0.1%
	Colorectal cancer	892	2.7%
	Liver cancer	127	0.4%
	Pancreatic cancer	47	0.1%
	Gallbladder cancer	20	0.1%
	Bile duct cancer & ampulla cancer	10	< 0.1%
	Lung cancer	129	0.4%
	Breast cancer	55	0.2%
	Ovarian cancer	57	0.2%
	Uterine malignancy	28	0.1%
	Kidney cancer	37	0.1%
	Prostate cancer	28	0.1%
	Bladder Cancer	17	0.1%
	Leukemia	1	< 0.1%
	Lymphoma	29	0.1%
	Other malignant tumors	15	< 0.1%

Table 4 Correlation analysis of biomarker levels

	Correlation coefficient			P value
	CEA and CA19-9	CEA and CA72-4	CA19-9 and CA724-4	CEA and CA19-9	CEA and CA72-4	CA19-9 and CA724-4
Whole	0.245	-0.005	-0.046	< 0.001	0.359	< 0.001
Gastric cancer	0.291	0.048	0.022	< 0.001	0.342	0.657
Colorectal cancer	0.385	0.2	0.169	< 0.001	< 0.001	< 0.001
Gastrointestinal cancer	0.354	0.164	0.134	< 0.001	< 0.001	< 0.001

P values and correlation coefficients were calculated with Pearson correlation analysis or Spearman correlation analysis. The bold font indicates that the P value was less than 0.05. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4.

Table 5 The biomarker levels, comparisons between subjects with and without diseases and area under the curves of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4

Disease	No.	CEA			CA19-9			CA72-4
		Median (quartile) (μg/L)	P value	AUC	Median (quartile) (kU/L)	P value	AUC	Median (quartile) (kU/L)	P value	AUC
Whole	32857	1.67 (1.13, 2.41)	-	-	8.50 (5.60, 13.50)	-	-	1.60 (1.05, 3.20)	-	-
Esophagitis	3137	1.88 (1.29, 2.72)	< 0.001	0.566	8.60 (5.70, 13.50)	0.439	0.504	1.60 (1.10, 3.40)	0.001	0.518
Esophageal erosion	109	1.84 (1.40, 2.90)	0.007	0.575	8.30 (5.00, 15.00)	0.938	0.498	1.50 (1.10, 3.20)	0.644	0.487
Esophageal ulcer	30	1.73 (0.90, 2.29)	0.818	0.488	7.90 (5.73, 10.38)	0.166	0.573	1.59 (1.10, 3.95)	0.572	0.470
Barrett’s esophagus	66	1.91 (1.21, 3.01)	0.095	0.559	8.95 (6.25, 12.70)	0.565	0.520	1.95 (1.10, 3.98)	0.306	0.536
Bile reflux	1344	1.65 (1.07, 2.43)	0.435	0.506	8.90 (5.60, 14.73)	0.121	0.512	1.60 (1.10, 3.30)	0.130	0.512
Gastric erosion	13094	1.78 (1.22, 2.57)	< 0.001	0.555	8.60 (5.70, 13.70)	0.006	0.509	1.60 (1.00, 3.20)	0.748	0.499
Gastric ulcer	1091	1.98 (1.41, 2.98)	< 0.001	0.598	8.40 (5.50, 14.40)	0.646	0.496	1.60 (1.00, 3.20)	0.789	0.498
Gastric hemorrhage	1125	1.68 (1.12, 2.46)	0.492	0.506	8.70 (5.80, 14.50)	0.092	0.515	1.60 (1.10, 3.40)	0.331	0.509
Chronic atrophic gastritis	1839	1.90 (1.32, 2.89)	< 0.001	0.578	9.20 (6.00, 14.90)	< 0.001	0.535	1.70 (1.10, 3.40)	< 0.001	0.528
Gastric xanthoma	100	1.65 (1.13, 2.41)	0.935	0.498	10.35 (6.45, 15.18)	0.072	0.552	1.80 (1.20, 3.43)	0.111	0.546
Gastrointestinal stromal tumor	48	1.56 (1.09, 2.69)	0.903	0.505	7.80 (5.78, 13.41)	0.614	0.521	1.50 (1.10, 2.23)	0.683	0.517
Gastric hyperplastic polyps	117	1.71 (1.14, 2.89)	0.282	0.529	11.20 (7.00, 22.72)	< 0.001	0.612	1.70 (1.10, 2.40)	0.964	0.501
Gastric glandular hyperplasia	761	1.57 (1.09, 2.29)	0.050	0.521	9.50 (6.00, 15.00)	< 0.001	0.543	1.70 (1.10, 3.80)	0.010	0.527
Colorectitis	2592	1.83 (1.25, 2.70)	< 0.001	0.552	8.70 (5.70, 14.30)	0.014	0.515	1.60 (1.10, 3.40)	0.034	0.513
Colorectal erosion	167	1.72 (1.17, 2.73)	0.198	0.529	8.80 (5.95, 13.90)	0.495	0.515	1.60 (1.00, 3.10)	0.788	0.494
Colorectal ulcer	107	1.54 (1.03, 2.61)	0.658	0.512	9.10 (6.30, 16.90)	0.069	0.551	1.70 (1.09, 2.80)	0.859	0.495
Colorectal hemorrhage	36	1.57 (1.12, 3.14)	0.799	0.488	9.05 (5.73, 13.75)	0.550	0.529	1.25 (0.90, 1.95)	0.061	0.590
Colorectal cyst	41	1.53 (0.93, 2.70)	0.455	0.534	9.20 (6.50, 13.70)	0.321	0.545	1.40 (1.10, 2.40)	0.353	0.542
Colorectal adenoma	3707	1.91 (1.29, 2.84)	< 0.001	0.578	9.04 (6.00, 14.70)	< 0.001	0.532	1.60 (1.10, 3.30)	0.010	0.513
Colorectal hyperplastic polyps	1037	1.88 (1.31, 2.75)	< 0.001	0.565	8.70 (5.90, 13.70)	0.065	0.517	1.60 (1.00, 3.20)	0.379	0.492
Colorectal gland hyperplasia	567	1.87 (1.35, 2.62)	< 0.001	0.560	8.30 (5.45, 13.45)	0.308	0.512	1.50 (1.10, 3.30)	0.687	0.505
Esophageal cancer	57	2.34 (1.30, 3.78)	< 0.001	0.645	9.40 (6.40, 20.00)	0.114	0.560	2.00 (1.20, 4.20)	0.073	0.568
Gastric cancer	392	2.15 (1.35, 4.13)	< 0.001	0.625	10.30 (5.70, 20.23)	< 0.001	0.577	2.00 (1.10, 5.70)	< 0.001	0.570
Colorectal cancer	892	3.25 (1.78, 11.55)	< 0.001	0.736	13.30 (7.10, 33.45)	< 0.001	0.649	2.30 (1.20, 5.90)	< 0.001	0.598
Liver cancer	127	4.27 (2.15, 7.46)	< 0.001	0.786	17.30 (7.40, 39.15)	< 0.001	0.674	1.60 (1.15, 3.75)	0.070	0.547
Pancreatic cancer	47	3.20 (1.98, 9.63)	< 0.001	0.771	99.60 (16.95, 307.15)	< 0.001	0.830	3.10 (1.35, 9.60)	< 0.001	0.680
Lung cancer	129	4.25 (2.15, 16.67)	< 0.001	0.787	12.10 (8.20, 25.50)	< 0.001	0.668	3.40 (1.40, 9.00)	< 0.001	0.660
Breast cancer	55	2.39 (1.44, 6.06)	< 0.001	0.654	15.60 (8.30, 27.20)	< 0.001	0.693	2.10 (1.20, 4.70)	0.022	0.589
Ovarian cancer	57	1.78 (1.08, 5.63)	0.228	0.546	21.85 (8.50, 130.50)	< 0.001	0.718	6.40 (1.50, 17.70)	< 0.001	0.698
Thyroid cancer	74	1.71 (1.06, 2.48)	0.936	0.497	9.90 (6.80, 15.28)	0.067	0.562	1.70 (1.03, 3.08)	0.874	0.495
Kidney cancer	37	2.37 (1.16, 3.70)	0.015	0.615	10.60 (7.70, 17.46)	0.039	0.598	2.20 (1.40, 5.20)	0.050	0.593
Malignant tumors (except thyroid cancer)	1955	2.65 (1.49, 6.70)	< 0.001	0.692	12.00 (6.80, 28.30)	< 0.001	0.636	2.20 (1.20, 5.90)	< 0.001	0.589

The bold font of the P value indicates that the P value was less than 0.05 in the Wilcoxon test. The bold font of the area under the curve (AUC) indicates that the AUC value was greater than 0.7. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; AUC: Area under the curve.

Table 6 Correlation analysis and linear regression analysis of biomarker levels and clinical characteristics

		Age			Gender
		P value	Correlation coefficient	Regression coefficient	P value	Correlation coefficient	Regression coefficient
CEA	Whole	< 0.001	0.227	0.176	< 0.001	0.236	0.004
	With malignant tumors	< 0.001	0.231	0.263	< 0.001	0.144	-2.965
	Without malignant tumors	< 0.001	0.195	0.041	< 0.001	0.248	0.472
CA19-9	Whole	< 0.001	0.135	1.076	< 0.001	-0.070	-1.400
	With malignant tumors	< 0.001	0.111	1.898	0.356	-0.021	-
	Without malignant tumors	< 0.001	0.113	0.269	< 0.001	-0.071	-2.482
CA72-4	Whole	< 0.001	0.084	0.076	< 0.001	-0.043	-0.927
	With malignant tumors	0.064	0.042	-	0.814	-0.005	-
	Without malignant tumors	< 0.001	0.069	0.052	< 0.001	-0.044	-0.773

The bold font indicates that the P value was less than 0.05. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4.

Table 7 The biomarker levels and categorical regression analysis of each stage of gastric cancer and colorectal cancer

		Gastric cancer		Colorectal cancer
		Median (quartile)	Quatization	Median (quartile)	Quatization
CEA (μg/L)	CIS	1.74 (1.45, 2.18)	-0.983	2.04 (1.17, 2.32)	-1.695
	Stage I	1.78 (1.29, 2.79)	-0.983	2.30 (1.45, 4.10)	-1.252
	Stage II	2.16 (1.07, 4.03)	-0.835	3.42 (2.13, 9.26)	-0.680
	Stage III	2.37 (1.31, 5.78)	-0.176	3.28 (2.00, 8.21)	-0.680
	Stage IV	3.79 (1.76, 29.1)	1.346	10.1 (2.57, 57.4)	1.168
CA19-9 (kU/L)	CIS	8.60 (5.05, 12.7)	-1.138	8.66 (6.18, 13.2)	-0.963
	Stage I	9.25 (5.88, 14.4)	-1.138	9.50 (6.20, 14.1)	-0.963
	Stage II	7.73 (5.53, 16.8)	-1.138	12.4 (7.38, 28.8)	-0.812
	Stage III	12.2 (5.63, 37.7)	0.842	13.1 (7.33, 23.0)	-0.790
	Stage IV	11.8 (5.08, 28.7)	0.903	28.9 (10.5, 216.4)	1.192
CA72-4 (kU/L)	CIS	1.50 (0.90, 3.50)	-1.203	1.50 (1.00, 2.03)	-1.550
	Stage I	1.80 (1.20, 4.33)	-0.977	1.70 (1.10, 3.20)	-1.060
	Stage II	1.90 (1.18, 4.30)	-0.789	2.10 (1.20, 3.81)	-0.818
	Stage III	2.10 (1.30, 4.63)	-0.164	1.95 (1.10, 4.21)	-0.679
	Stage IV	4.10 (1.00, 12.0)	1.340	4.75 (1.50, 15.2)	1.182

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; CIS: Carcinoma in situ.

Table 8 Diagnostic efficiencies of gastric cancer, colorectal cancer and gastrointestinal cancers at the traditional and best cut-off values

		Gastric cancer			Colorectal cancer			Gastrointestinal cancers
		CEA	CA19-9	CA72-4	CEA	CA19-9	CA72-4	CEA	CA19-9	CA72-4
	AUC	0.625	0.577	0.570	0.736	0.649	0.598	0.705	0.627	0.590
Traditional cut-off value	Cut-off value	5.0	37.0	6.0	5.0	37.0	6.0	5.0	37.0	6.0
	DOR	6.083	5.089	2.220	14.854	11.895	2.376	12.459	10.367	2.337
	Sensitivity	0.227	0.140	0.240	0.377	0.241	0.249	0.323	0.210	0.243
	Specificity	0.954	0.969	0.876	0.961	0.974	0.878	0.963	0.975	0.879
	Youden index	0.181	0.109	0.115	0.338	0.215	0.127	0.286	0.185	0.122
	Accuracy	0.945	0.959	0.868	0.945	0.954	0.861	0.938	0.945	0.854
	PPV	0.056	0.052	0.023	0.212	0.204	0.054	0.266	0.261	0.077
	NPV	0.990	0.989	0.990	0.982	0.979	0.977	0.972	0.968	0.966
	PLR	4.927	4.516	1.927	9.640	9.269	2.034	8.759	8.400	2.012
	NLR	0.810	0.888	0.868	0.649	0.779	0.856	0.703	0.810	0.861
Best cut-off value	Cut-off value	2.6	16.3	3.8	2.8	20.7	2.0	2.5	19.6	3.4
	DOR	2.687	2.233	2.038	6.345	4.825	1.933	4.419	3.872	2.068
	Sensitivity	0.423	0.324	0.349	0.558	0.361	0.566	0.556	0.339	0.375
	Specificity	0.785	0.823	0.791	0.834	0.895	0.597	0.779	0.883	0.775
	Youden index	0.209	0.147	0.141	0.392	0.256	0.163	0.335	0.222	0.150
	Accuracy	0.781	0.817	0.786	0.827	0.881	0.596	0.770	0.861	0.759
	PPV	0.023	0.022	0.020	0.086	0.088	0.038	0.094	0.107	0.065
	NPV	0.991	0.990	0.990	0.985	0.980	0.980	0.977	0.970	0.968
	PLR	1.972	1.833	1.675	3.363	3.445	1.405	2.519	2.900	1.667
	NLR	0.734	0.821	0.822	0.530	0.714	0.727	0.570	0.749	0.806

The best cut-off value referred to the threshold when the Youden index was the largest. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; AUC: Area under the curve; DOR: Diagnostic odds ratio; PPV: Positive predictive value; NPV: Negative predictive value; PLR: Positive likelihood ratio; NLR: Negative likelihood ratio.

Table 9 Subgroup analysis of area under the curve for gastric cancer, colorectal cancer and gastrointestinal cancers

	Gastric cancer			Colorectal cancer			Gastrointestinal cancer
	CEA	CA19-9	CA72-4	CEA	CA19-9	CA72-4	CEA	CA19-9	CA72-4
Whole	0.625	0.577	0.570	0.736	0.649	0.598	0.705	0.627	0.590
≥ 60 years	0.585	0.521	0.544	0.701	0.614	0.577	0.675	0.592	0.572
< 60 years	0.578	0.571	0.570	0.683	0.616	0.593	0.648	0.598	0.583
HC	0.570	0.570	0.525	0.584	0.539	0.514	0.584	0.554	0.526
AC	0.595	0.544	0.547	0.724	0.637	0.577	0.696	0.615	0.571
CIS	0.551	0.478	0.542	0.540	0.536	0.526	-	-	-
Stage I	0.554	0.525	0.565	0.675	0.546	0.512	-	-	-
Stage II	0.603	0.489	0.591	0.781	0.657	0.578	-	-	-
Stage III	0.658	0.645	0.603	0.770	0.642	0.565	-	-	-
Stage IV	0.739	0.614	0.634	0.810	0.778	0.698	-	-	-

The bold font indicates that the area under the curve value was more than 0.7. CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; HC: Health checkup; AC: Active consultation; CIS: Carcinoma in situ.

Table 10 The best single biomarker and the best combination of biomarkers for gastric cancer, colorectal cancer and gastrointestinal cancers

	Best combination		Best single biomarker		P value
	Biomarkers	AUC	Biomarker	AUC
Gastric cancer	CEA + CA19-9 + CA72-4	0.653	CEA	0.625	0.067
Colorectal cancer	CEA + CA19-9	0.761	CEA	0.736	< 0.001
Gastrointestinal cancers	CEA + CA19-9	0.727	CEA	0.705	< 0.001

The bold font indicates that the P value was less than 0.05 in Delong’s test. AUC: Area under the curve; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4.

Table 11 Economic analysis of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 in several situations for gastrointestinal cancers

	Cut-off value	Proportion of endoscopy	Missed diagnosis rate	Total cost ($)	Cost per capita ($)	Total C/E ($)	C/E per capita ($)	Remarks
Non-blood test	-	1.000	0.000	3574.3	146.9	3574.3	146.9	Gold standard
CEA (μg/L)	0.0	1.000	0.000	3691.9	151.7	3691.9	151.7	Lowest cut-off value
	2.5	0.230	0.451	1718.1	38.7	3130.1	70.6	Highest youden index
	4.3	0.065	0.642	990.0	14.6	2767.1	40.7	Lowest total cost-effectiveness ratio
	5.0	0.049	0.674	903.1	12.1	2770.9	37.1	Traditional diagnostic cut-off value
	8.7	0.020	0.759	783.9	7.8	3246.2	32.2	Lowest total cost & lowest cost-effectiveness ratio per capita
CA19-9 (kU/L)	0.0	1.000	0.000	3755.4	154.3	3755.4	154.3	Lowest cut-off value & lowest total cost-effectiveness ratio
	20.0	0.121	0.665	1836.7	25.3	5485.7	75.5	Highest youden index
	36.9	0.033	0.787	1398.5	12.2	6578.5	57.5	Lowest total cost & lowest cost-effectiveness ratio per capita
	37.0	0.032	0.789	1405.2	12.2	6656.1	57.7	Traditional diagnostic cut-off value
CA72-4 (kU/L)	0.0	1.000	0.000	3755.4	154.3	3755.4	154.3	Lowest cut-off value & lowest total cost-effectiveness ratio
	3.4	0.231	0.623	2670.7	41.4	7083.5	109.7	Highest youden index
	6.0	0.126	0.756	2584.5	25.9	10605.1	106.2	Traditional diagnostic cut-off value
	10.5	0.064	0.833	2451.6	16.8	14709.6	100.7	Lowest total cost & lowest cost-effectiveness ratio per capita
CEA	5.0	0.069	0.601	1365.1	22.4	3419.2	56.1	Traditional diagnostic cut-off value in parallel
CA19-9	37.0
CEA	6.9	0.036	0.676	1309.0	17.4	4034.6	53.8	Lowest cut-off value & lowest total cost-effectiveness ratio in parallel
CA19-9	69.2
CEA	3.9	0.098	0.554	1455.6	26.7	3264.3	59.8	Lowest total cost-effectiveness ratio in parallel
CA19-9	38.1
CEA	5.0	0.012	0.862	2433.3	13.8	17661.0	100.0	Traditional diagnostic cut-off value in serial
CA19-9	37.0
CEA	5.4	0.042	0.689	1437.7	18.4	4621.3	59.1	Lowest cut-off value & lowest total cost-effectiveness ratio in serial
CA19-9	0.0
CEA	2.1	0.335	0.361	2339.4	61.4	3659.5	96.1	Lowest total cost-effectiveness ratio in serial
CA19-9	0.0
CEA	5.0	0.044	0.666	1362.9	18.7	4079.6	56.0	Traditional diagnostic cut-off value in the logistic model
CA19-9	37.0
CEA	4.9	0.052	0.641	1341.0	19.8	3732.7	55.1	Lowest cut-off value & lowest total cost-effectiveness ratio in the logistic model
CA19-9	23.2
CEA	2.0	0.213	0.436	1874.8	43.5	3321.5	77.0	Lowest total cost-effectiveness ratio in the logistic model
CA19-9	33.5

The economic indicators were total cost, cost per capita and their cost-effectiveness ratios. The cut-off value with the lowest total cost equaled that of the lowest cost-effectiveness ratio per capita. In the parallel test, any positive result of carcinoembryonic antigen (CEA) or carbohydrate antigen 19-9 (CA 19-9) was considered positive, while both of the positive results of CEA and CA19-9 were considered positive in the serial test. The logistic model was CEA × 2.02 + CA19-9 × 0.06, which made the area under the curve highest. C/E: Cost-effectiveness ratio; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4.

Table 12 Subgroup analysis of economic indicators

			Scheme 2							Scheme 1
			Cut-off value	Proportion of endoscopy	Missed diagnosis rate	Total cost ($)	Cost per capita ($)	Total C/E ($)	C/E per capita ($)	Total cost & C/E ($)	Cost & C/E per capita ($)
CEA	Whole	Whole	5.0	0.049	0.674	903.1	12.1	2770.9	37.1	3574.3	146.9
		≥ 80 yr	5.0	0.258	0.543	381.8	45.6	835.9	99.8	584.4	152.7
		≥ 75 yr	5.0	0.240	0.635	472.1	41.9	1294.7	115.0	623.2	151.8
		≥ 70 yr	5.0	0.214	0.627	463.5	37.7	1242.1	101.2	691.5	150.9
		≥ 65 yr	5.0	0.174	0.634	486.4	31.6	1329.1	86.3	844.6	149.9
		≥ 60 yr	5.0	0.137	0.636	523.6	25.8	1438.6	71.0	1099.1	149.0
		≥ 55 yr	5.0	0.110	0.639	574.1	21.6	1588.8	59.8	1424.3	148.3
		≥ 50 yr	5.0	0.085	0.643	662.6	17.7	1854.8	49.6	1972.8	147.6
		≥ 45 yr	5.0	0.065	0.658	758.5	14.6	2220.9	42.7	2614.6	147.2
		≥ 40 yr	5.0	0.055	0.668	837.4	13.1	2520.1	39.4	3121.4	147.0
		≥ 35 yr	5.0	0.051	0.671	882.1	12.4	2684.9	37.8	3427.4	146.9
		≥ 30 yr	5.0	0.049	0.674	902.2	12.2	2764.8	37.3	3552.0	146.9
	HC	Whole	5.0	0.021	0.883	6834.3	7.7	58218.5	65.4	15277.9	146.1
		≥ 80 yr	5.0	0.238	0.000	446.3	42.5	446.3	42.5	1565.3	149.1
		≥ 75 yr	5.0	0.129	0.500	941.8	24.4	1883.7	48.7	2843.9	147.1
		≥ 70 yr	5.0	0.101	0.538	693.8	20.0	1503.3	43.3	2356.2	146.9
		≥ 65 yr	5.0	0.070	0.630	1046.6	15.1	2832.1	40.9	3755.2	146.6
		≥ 60 yr	5.0	0.049	0.744	1677.6	12.0	6542.7	46.7	5254.5	146.4
		≥ 55 yr	5.0	0.040	0.794	2611.7	10.5	12685.3	51.1	7474.5	146.3
		≥ 50 yr	5.0	0.033	0.824	3519.3	9.5	19989.5	53.8	9558.2	146.2
		≥ 45 yr	5.0	0.026	0.848	4577.8	8.5	30179.8	55.7	12010.0	146.2
		≥ 40 yr	5.0	0.023	0.871	5726.3	8.0	44326.1	61.8	13537.7	146.2
		≥ 35 yr	5.0	0.021	0.879	6443.2	7.8	53455.1	64.6	14572.3	146.1
		≥ 30 yr	5.0	0.021	0.881	6737.6	7.7	56396.5	64.7	15225.1	146.1
	AC	Whole	5.0	0.126	0.631	515.4	24.2	1397.6	65.5	1170.9	148.8
		≥ 80 yr	5.0	0.260	0.557	378.1	45.8	853.5	103.4	559.6	153.0
		≥ 75 yr	5.0	0.260	0.640	449.7	45.2	1249.2	125.5	547.0	152.7
		≥ 70 yr	5.0	0.256	0.634	439.0	44.4	1200.5	121.3	551.5	152.4
		≥ 65 yr	5.0	0.240	0.634	433.8	42.0	1186.4	114.8	574.1	152.0
		≥ 60 yr	5.0	0.219	0.624	436.5	38.9	1161.3	103.4	639.4	151.5
		≥ 55 yr	5.0	0.197	0.621	445.2	35.4	1173.3	93.4	719.0	150.9
		≥ 50 yr	5.0	0.171	0.616	471.6	31.2	1229.4	81.5	868.1	149.9
		≥ 45 yr	5.0	0.146	0.626	493.5	27.4	1319.3	73.2	1006.5	149.3
		≥ 40 yr	5.0	0.134	0.628	508.3	25.5	1367.6	68.6	1103.8	149.0
		≥ 35 yr	5.0	0.129	0.629	513.2	24.6	1383.2	66.3	1151.7	148.9
		≥ 30 yr	5.0	0.126	0.631	516.1	24.2	1400.2	65.7	1168.9	148.8
CA19-9	Whole	Whole	37.0	0.032	0.789	1405.2	12.2	6656.1	57.7	3574.3	146.9
		≥ 80 yr	37.0	0.168	0.741	494.9	33.5	1908.7	129.3	584.4	152.7
		≥ 75 yr	37.0	0.164	0.735	505.6	32.7	1906.7	123.2	623.2	151.8
		≥ 70 yr	37.0	0.137	0.761	546.5	28.5	2288.5	119.3	691.5	150.9
		≥ 65 yr	37.0	0.115	0.762	589.9	25.0	2474.1	104.7	844.6	149.9
		≥ 60 yr	37.0	0.090	0.754	633.2	21.2	2568.7	85.8	1099.1	149.0
		≥ 55 yr	37.0	0.070	0.764	736.3	18.1	3114.0	76.7	1424.3	148.3
		≥ 50 yr	37.0	0.054	0.774	913.9	15.5	4035.0	68.4	1972.8	147.6
		≥ 45 yr	37.0	0.042	0.782	1108.4	13.6	5075.1	62.4	2614.6	147.2
		≥ 40 yr	37.0	0.036	0.785	1254.6	12.7	5833.6	59.1	3121.4	147.0
		≥ 35 yr	37.0	0.033	0.789	1359.0	12.3	6434.6	58.2	3427.4	146.9
		≥ 30 yr	37.0	0.032	0.789	1398.6	12.2	6634.7	57.8	3552.0	146.9
	HC	Whole	37.0	0.014	0.917	11789.9	9.3	142719.5	112.8	15277.9	146.1
		≥ 80 yr	37.0	0.143	0.500	622.7	29.7	1245.5	59.3	1565.3	149.1
		≥ 75 yr	37.0	0.078	0.833	2187.1	18.9	13122.9	113.1	2843.9	147.1
		≥ 70 yr	37.0	0.048	0.808	1207.9	14.5	6281.3	75.3	2356.2	146.9
		≥ 65 yr	37.0	0.043	0.783	1621.1	13.8	7457.1	63.3	3755.2	146.6
		≥ 60 yr	37.0	0.032	0.808	2252.2	12.1	11711.6	62.8	5254.5	146.4
		≥ 55 yr	37.0	0.026	0.853	3855.6	11.1	26218.2	75.5	7474.5	146.3
		≥ 50 yr	37.0	0.020	0.873	5259.2	10.2	41488.9	80.5	9558.2	146.2
		≥ 45 yr	37.0	0.016	0.899	7832.3	9.6	77452.6	95.3	12010.0	146.2
		≥ 40 yr	37.0	0.014	0.909	9540.9	9.4	104950.4	103.0	13537.7	146.2
		≥ 35 yr	37.0	0.014	0.915	10937.8	9.3	128950.9	109.7	14572.3	146.1
		≥ 30 yr	37.0	0.014	0.916	11530.0	9.3	137146.2	110.7	15225.1	146.1
	AC	Whole	37.0	0.082	0.763	663.4	20.0	2793.3	84.3	1170.9	148.8
		≥ 80 yr	37.0	0.170	0.747	488.5	33.8	1929.4	133.5	559.6	153.0
		≥ 75 yr	37.0	0.180	0.731	469.9	35.2	1749.5	131.1	547.0	152.7
		≥ 70 yr	37.0	0.171	0.757	502.4	33.7	2069.9	138.9	551.5	152.4
		≥ 65 yr	37.0	0.159	0.760	503.3	32.0	2093.5	133.2	574.1	152.0
		≥ 60 yr	37.0	0.144	0.748	496.7	29.7	1967.4	117.7	639.4	151.5
		≥ 55 yr	37.0	0.126	0.753	519.6	26.9	2105.0	109.0	719.0	150.9
		≥ 50 yr	37.0	0.109	0.759	581.1	24.2	2411.0	100.4	868.1	149.9
		≥ 45 yr	37.0	0.095	0.762	620.3	21.9	2601.4	92.0	1006.5	149.3
		≥ 40 yr	37.0	0.087	0.761	644.3	20.8	2694.8	87.0	1103.8	149.0
		≥ 35 yr	37.0	0.083	0.763	659.0	20.2	2780.6	85.2	1151.7	148.9
		≥ 30 yr	37.0	0.082	0.763	663.9	20.0	2805.1	84.5	1168.9	148.8
CA72-4	Whole	Whole	6.0	0.126	0.756	2584.5	25.9	10605.1	106.2	3574.3	146.9
		≥ 80 yr	6.0	0.194	0.790	676.1	37.1	3221.6	176.7	584.4	152.7
		≥ 75 yr	6.0	0.190	0.762	627.4	36.3	2641.0	152.8	623.2	151.8
		≥ 70 yr	6.0	0.180	0.755	651.5	34.8	2661.4	142.2	691.5	150.9
		≥ 65 yr	6.0	0.173	0.749	749.3	33.4	2980.7	133.0	844.6	149.9
		≥ 60 yr	6.0	0.166	0.745	933.2	32.3	3653.5	126.5	1099.1	149.0
		≥ 55 yr	6.0	0.158	0.746	1167.6	30.9	4599.8	121.6	1424.3	148.3
		≥ 50 yr	6.0	0.147	0.749	1552.7	29.1	6194.2	116.2	1972.8	147.6
		≥ 45 yr	6.0	0.139	0.753	2003.3	27.9	8106.4	112.8	2614.6	147.2
		≥ 40 yr	6.0	0.132	0.752	2293.2	26.7	9259.2	108.0	3121.4	147.0
		≥ 35 yr	6.0	0.128	0.755	2488.4	26.2	10145.7	106.7	3427.4	146.9
		≥ 30 yr	6.0	0.127	0.755	2565.2	25.9	10489.2	106.1	3552.0	146.9
	HC	Whole	6.0	0.108	0.870	18401.4	23.0	141077.7	176.0	15277.9	146.1
		≥ 80 yr	6.0	0.333	0.500	1206.6	57.5	2413.3	114.9	1565.3	149.1
		≥ 75 yr	6.0	0.190	0.667	2042.4	35.2	6127.2	105.6	2843.9	147.1
		≥ 70 yr	6.0	0.144	0.808	2375.7	28.5	12353.8	148.1	2356.2	146.9
		≥ 65 yr	6.0	0.126	0.848	4345.5	25.8	28556.3	169.7	3755.2	146.6
		≥ 60 yr	6.0	0.118	0.821	4898.1	24.5	27289.4	136.5	5254.5	146.4
		≥ 55 yr	6.0	0.119	0.843	8033.4	24.7	51212.7	157.2	7474.5	146.3
		≥ 50 yr	6.0	0.118	0.866	11985.7	24.5	89577.1	183.4	9558.2	146.2
		≥ 45 yr	6.0	0.116	0.854	13653.0	24.3	93470.7	166.2	12010.0	146.2
		≥ 40 yr	6.0	0.111	0.861	15690.0	23.5	113076.5	169.4	13537.7	146.2
		≥ 35 yr	6.0	0.109	0.866	17224.4	23.1	128608.7	172.7	14572.3	146.1
		≥ 30 yr	6.0	0.108	0.867	18051.9	23.0	135991.3	173.3	15225.1	146.1
	AC	Whole	6.0	0.177	0.733	997.5	33.8	3736.5	126.8	1170.9	148.8
		≥ 80 yr	6.0	0.183	0.797	643.0	35.6	3174.8	175.8	559.6	153.0
		≥ 75 yr	6.0	0.190	0.766	558.4	36.5	2383.4	155.8	547.0	152.7
		≥ 70 yr	6.0	0.194	0.751	539.5	37.2	2165.0	149.1	551.5	152.4
		≥ 65 yr	6.0	0.202	0.739	554.2	38.2	2126.5	146.7	574.1	152.0
		≥ 60 yr	6.0	0.212	0.736	634.8	39.7	2405.9	150.4	639.4	151.5
		≥ 55 yr	6.0	0.206	0.735	694.1	38.6	2617.8	145.6	719.0	150.9
		≥ 50 yr	6.0	0.194	0.732	793.2	36.7	2963.2	137.0	868.1	149.9
		≥ 45 yr	6.0	0.186	0.736	901.9	35.4	3410.7	133.8	1006.5	149.3
		≥ 40 yr	6.0	0.182	0.731	953.6	34.6	3547.9	128.7	1103.8	149.0
		≥ 35 yr	6.0	0.179	0.732	984.8	34.1	3674.4	127.3	1151.7	148.9
		≥ 30 yr	6.0	0.177	0.733	995.6	33.9	3723.6	126.8	1168.9	148.8

The economic indicators were total cost, cost per capita and their cost-effectiveness ratios. The units of carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4 are μg/L, kU/L, and kU/L, respectively. C/E: Cost-effectiveness ratio; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA72-4: Carbohydrate antigen 72-4; HC: Health checkup; AC: Active consultation.