Serum homocysteine-based traffic light triage colonoscopy screening in colorectal cancer at-risk patients: A prospective cohort study

Table 1 Group stratification criteria

Group number	Criteria
Absence of lesion/no polyps	No pathological findings in the diagnostic colonoscopy
Low-risk lesion	Classified as low risk are those subjects who present the finding of polyps with low-risk endoscopic characteristics according to number (< 3), size (< 1 cm), endoscopic criteria of the Paris staging, and results of the pathological anatomy of the piece(s) obtained classified as adenoma
High-risk lesion	Polyps with high-risk endoscopic characteristics according to number (> 3), size (> 1 cm), endoscopic criteria of Paris staging, and pathological anatomy results of the piece(s) obtained compatible with a villous component, high-grade dysplasia, or intramucosal adenocarcinoma
Adenocarcinoma	Local and/or distant invasive adenocarcinoma

Table 2 Baseline and clinical data, n (%)

	Total (n = 301)	Colonoscopy findings				P value	Homocysteine		P value
		No polyps (n = 79)	Low-risk polyps (n = 54)	High-risk polyps (n = 107)	Adenocarcinoma (n = 61)		≤ 15 (n = 213)	> 15 (n = 88)
Age (years), median (IQR)	63.0 (57.0-67.0)	61.0 (55.0-65.0)	61.0 (57.0-65.0)	62.0 (58.5-67.0)	69.0 (63.0-79.0)	< 0.0001	62.0 (57.0-67.0)	64.0 (60.0-70.0)	0.0046
< 65	177 (58.8)	55 (69.6)	36 (66.7)	65 (60.7)	21 (34.4)	0.0001	131 (61.5)	46 (52.3)	0.1767
≥ 65	124 (41.2)	24 (30.4)	18 (33.3)	42 (39.3)	40 (65.6)		82 (38.5)	42 (47.7)
Sex						0.0001			0.0003
Female	132 (43.9)	48 (60.8)	29 (53.7)	32 (29.9)	23 (37.7)		108 (50.7)	24 (27.3)
Male	169 (56.1)	31 (39.2)	25 (46.3)	75 (70.1)	38 (62.3)		105 (49.3)	64 (72.7)
Alcohol intaking	73 (24.3)	14 (17.7)	16 (29.6)	24 (22.4)	19 (31.1)	0.2162	49 (23.0)	24 (27.3)	0.5235
Smoking	63 (20.9)	11 (13.9)	14 (25.9)	31 (29.0)	7 (11.5)	0.0139	40 (18.8)	23 (26.1)	0.2036
Diabetes	45 (15.0)	12 (15.2)	4 (7.4)	15 (14.0)	14 (23.0)	0.1349	29 (13.6)	16 (18.2)	0.4049
Hypertension	118 (39.2)	28 (35.4)	17 (31.5)	47 (43.9)	26 (42.6)	0.3735	80 (37.6)	38 (43.2)	0.4359
Obesity	95 (31.6)	26 (32.9)	19 (35.2)	33 (30.8)	17 (27.9)	0.8481	67 (31.5)	28 (31.8)	1.0000
Dyslipidemia	139 (46.2)	40 (50.6)	28 (51.9)	47 (43.9)	24 (39.3)	0.4411	104 (48.8)	35 (39.8)	0.1916
Coronaropathy	23 (7.6)	5 (6.3)	3 (5.6)	8 (7.5)	7 (11.5)	0.6598	14 (6.6)	9 (10.2)	0.3970
Chronic kidney injury	11 (3.7)	2 (2.5)	1 (1.9)	4 (3.7)	4 (6.6)	0.5979	4 (1.9)	7 (8.0)	0.0168
Family history of CRC	13 (4.3)	4 (5.1)	3 (5.6)	5 (4.7)	1 (1.6)	0.7309	9 (4.2)	4 (4.5)	1.0000
Colonoscopy findings						No significant connection			< 0.0001
No polyps	79 (26.2)	79 (100.0)	-	-	-		66 (31.0)	13 (14.8)
Low-risk polyps	54 (17.9)	-	54 (100.0)	-	-		46 (21.6)	8 (9.1)
High-risk polyps	107 (35.5)	-	-	107 (100.0)	-		73 (34.3)	34 (38.6)
Adenocarcinoma	61 (20.3)	-	-	-	61 (100.0)		28 (13.1)	33 (37.5)
Medication associated with increased Hcy	118 (39.2)	35 (44.3)	19 (35.2)	40 (37.4)	24 (39.3)	0.7109	81 (38.0)	37 (42.0)	0.6034
Medication associated with decreased Hcy	15 (5.0)	4 (5.1)	-	6 (5.6)	5 (8.2)	0.1920	5 (2.3)	10 (11.4)	0.0023
Homocysteine (µmol/L), median (IQR)	12.5 (10.8-15.5)	11.5 (9.74-13.5)	11.8 (10.8-13.3)	12.5 (10.9-16.0)	15.3 (12.4-19.3)	< 0.0001	11.3 (10.1-12.6)	17.7 (16.1-21.8)	n/c
Homocysteine						< 0.0001			n/c
≤ 15	213 (70.8)	66 (83.5)	46 (85.2)	73 (68.2)	28 (45.9)		213 (100.0)	-
> 15	88 (29.2)	13 (16.5)	8 (14.8)	34 (31.8)	33 (54.1)		-	88 (100.0)

Hcy: Homocysteine.

Table 3 Description of colorectal lesions found during colonoscopy, n (%)

	Total (n = 873)	No polyps (n = 84)	Low-risk polyps (n = 542)	High-risk polyps (n = 185)	Adenocarcinoma (n = 62)
Location
Left colon	552 (69.3)	5 (62.5)	353 (65.1)	146 (78.9)	48 (77.4)
Right colon	245 (30.7)	3 (37.5)	189 (34.9)	39 (21.1)	14 (22.6)
Size (mm)
< 10	570 (71.5)	6 (75.0)	542 (100.0)	21 (11.4)	1 (1.6)
≥ 10	227 (28.5)	2 (25.0)	-	164 (88.6)	61 (98.4)
Paris classification
Is	554 (69.5)	7 (87.5)	479 (88.4)	65 (35.1)	3 (4.8)
Ip	82 (10.3)	1 (12.5)	20 (3.7)	59 (31.9)	2 (3.2)
Isp	48 (6.0)	-	20 (3.7)	26 (14.1)	2 (3.2)
IIa	36 (4.5)	-	16 (3.0)	20 (10.8)	-
IIb	17 (2.1)	-	7 (1.3)	10 (5.4)	-
IIc	8 (1.0)	-	-	2 (1.1)	6 (9.7)
IIa + IIc	7 (0.9)	-	-	3 (1.6)	4 (6.5)
IIc + IIa	5 (0.6)	-	-	-	5 (8.1)
Lateral spread tumor	40 (5.0)	-	-	-	40 (64.5)
Histology
Adenocarcinoma	62 (7.8)	-	-	-	62 (100.0)
Tubulovillous adenoma	77 (9.7)	-	-	77 (41.6)	-
Tubular adenoma	502 (63.0)	-	406 (74.9)	96 (51.9)	-
Serrated adenoma	3 (0.4)	-	2 (0.4)	1 (0.5)	-
Hyperplastic	90 (11.3)	-	86 (15.9)	4 (2.2)	-
Non-retrieved specimen	44 (5.5)	-	41 (7.6)	3 (1.6)	-
Non-resected specimen	11 (1.4)	-	7 (1.3)	4 (2.2)	-
Inflammatory polyp	5 (0.6)	5 (62.5)	-	-	-
Lipoma	1 (0.1)	1 (12.5)	-	-	-
Normal colonic tissue	2 (0.3)	2 (25.0)	-	-	-
Colonoscopy without findings	76 (8.7)	76 (90.5)	-	-	-

LST: Lateral spread tumor.

Table 4 Explanatory variables for logistic regression model of associations with risk lesions or adenocarcinoma

	OR	95%CI	P value
Age (years)	1.120	1.06-1.17	< 0.001
Sex (male)	4.030	1.48-11.1	0.007
Alcohol intaking	1.060	0.74-1.52	0.7
Smoking	1.210	0.83-1.76	0.3
Diabetes	1.170	0.73-1.88	0.5
Hypertension	0.950	0.68-1.33	0.8
Obesity	0.960	0.69-1.34	0.8
Dyslipidemia	0.760	0.54-1.05	0.1
Coronaropathy	0.940	0.52-1.73	0.8
Homocysteine (µmol/L)	1.120	1.06-1.19	< 0.001
Age (≥ 65 years old) × Hcy	0.980	0.94-1.03	0.5
Sex (male) × Hcy	0.920	0.86-0.99	0.035
Medication associated with increased Hcy × Hcy	1.000	0.97-1.02	0.7
Medication associated with decreased Hcy × Hcy	0.990	0.95-1.03	0.7

95%CI: 95% confidence interval; Hcy: Homocysteine.

Table 5 Diagnostic accuracy of homocysteine

	Hcy cut-off value	Sensitivity	Specificity	PPV	NPV	Observed agreement	AUROC
Adenocarcinoma
Overall	≥ 15.1	191/240; 79.58 (73.92-84.5)	33/61; 54.1 (40.85-66.94)	191/219; 87.21 (82.05-91.33)	33/82; 40.24 (29.56-51.66)	224/301; 74.42 (69.1-79.25)	0.706 (0.631-0.781)
< 65 years	≥ 15.1	122/156; 78.21 (70.9-84.41)	8/21; 38.1 (18.11-61.56)	122/135; 90.37 (84.1-94.77)	8/42; 19.05 (8.6-34.12)	130/177; 73.45 (66.3-79.79)	0.621 (0.496-0.747)
≥ 65 years	≥ 15.18	69/84; 82.14 (72.26-89.65)	25/40; 62.5 (45.8-77.27)	69/84; 82.14 (72.26-89.65)	25/40; 62.5 (45.8-77.27)	94/124; 75.81 (67.3-83.04)	0.755 (0.660-0.850)
Females	≥ 12.5	75/109; 68.81 (59.22-77.34)	18/23; 78.26 (56.3-92.54)	75/80; 93.75 (86.01-97.94)	18/52; 34.62 (21.97-49.09)	93/132; 70.45 (61.89-78.07)	0.780 (0.683-0.877)
Males	≥ 15.1	94/131; 71.76 (63.23-79.27)	23/38; 60.53 (43.39-75.96)	94/109; 86.24 (78.32-92.09)	23/60; 38.33 (26.07-51.79)	117/169; 69.23 (61.68-76.09)	0.653 (0.546-0.761)
Adenocarcinoma or high-risk polyps
Overall	≥ 12.26	84/133; 63.16 (54.36-71.35)	107/168; 63.69 (55.93-70.96)	84/145; 57.93 (49.46-66.07)	107/156; 68.59 (60.68-75.78)	191/301; 63.46 (57.74-68.91)	0.670 (0.609-0.730)
< 65 years	≥ 15.1	80/91; 87.91 (79.4-93.81)	31/86; 36.05 (25.97-47.12)	80/135; 59.26 (50.47-67.63)	31/42; 73.81 (57.96-86.14)	111/177; 62.71 (55.14-69.85)	0.632 (0.551-0.714)
≥ 65 years	≥ 12.16	28/42; 66.67 (50.45-80.43)	57/82; 69.51 (58.36-79.2)	28/53; 52.83 (38.64-66.7)	57/71; 80.28 (69.14-88.78)	85/124; 68.55 (59.6-76.59)	0.706 (0.610-0.802)
Females	≥ 12.46	55/77; 71.43 (60-81.15)	31/55; 56.36 (42.32-69.7)	55/79; 69.62 (58.25-79.47)	31/53; 58.49 (44.13-71.86)	86/132; 65.15 (56.37-73.23)	0.654 (0.559-0.748)
Males	≥ 14.48	44/56; 78.57 (65.56-88.41)	58/113; 51.33 (41.74-60.84)	44/99; 44.44 (34.45-54.78)	58/70; 82.86 (71.97-90.82)	102/169; 60.36 (52.56-67.78)	0.642 (0.557-0.727)

Hcy: Homocysteine; PPV: Positive predictive value; NPV: Negative predictive value; AUROC: Area under the receiver operating characteristic curve.