High-risk symptoms and quantitative faecal immunochemical test accuracy: Systematic review and meta-analysis

Table 1 Characteristics of the studies included in the meta-analysis

Test	Study, Year	Demographic characteristics				CRC	AN	SCL	Exclusion criteria			Symptoms, %
		N	Age,	Sex,	Area				IBD	OB	AD	AnS	WeL	AbPa	Hem	ChBo	Co	Di	An
			m/md	W%		%	%	%
Mixed cohorts
OC-S	Rozen, 2010[17]	1682	63.7	49.6	IL	1.2	8.9	0	yes	yes	yes	23	NA	NA	0	NA	NA	NA	NA
OC-S	Mc Donald, 2012[20]	280	631	59.6	UK (S)	2.1	NA	21.4	NA	no	no	NA	NA	NA	NA	NA	NA	NA	NA
OC-S	Ou, 2013[21]	694	59.51	55.9	CN	0.4	6.1	NA	yes	yes	no	NA	NA	NA	NA	NA	NA	NA	NA
OC-S	van Turenhout, 2014[18]	3022	59.7	55.0	NL	2.3	12.3	NA	yes	yes	no	44	2.9	11.7	0	18.1	3	4.2	0
OC-S	Symonds, 2016[23]	1381	64.11	50.6	AU	4.8	17.2	NA	no	no	no	34.8	NA	NA	NA	NA	NA	NA	NA
HM-J	Woo, 2005[19]	85	561	52.9	KR	7.1	NA	NA	NA	no	no	49.4	0	15.3	4.7	1.2	0	17.6	4.7
HM-Ja	Auge, 2016[22]	208	631	55.8	ES	1.0	14.0	NA	yes	yes	yes	NA	NA	NA	0	NA	NA	NA	NA
FOB Gold®	Auge, 2018[30]	487	62	51.2	ES	2.5	14.6	NA	no	no	yes	54.2	NA	NA	NA	NA	NA	NA	NA
100% Symptomatic cohorts
OC-S	Mowat, 2016[26]	750	641	54.7	UK (S)	3.7	NA	13.6	no	no	no	100	0.9	11	34.2	42.8	NA	16.8	8.9
OC-S	Rodriguez-Alonso, 2015[25]	1003	NA	46.8	ES	3.0	13.3	23.4	yes	no	no	100	19	36.4	34.2	NA	12.1	23.5	8.8
OC-S	Cubiella, 2014 (DC)[29]	1567	66.9	48.6	ES	13.7	26.7	29.5	no	no	no	100	24.5	43.8	59.9	57.2	14.5	22.2	34.8
OC-S	Cubiella, 2017 (VC)[31]	715	64.4	53.3	ES	9.4	21.1	25.3	no	no	no	100	NA	NA	54	47.9	NA	NA	NA
HM-J	Parente, 2012[24]	280	67	43.9	IT	16.8	47.2	0	yes	no	no	100	11.1	17.9	26.1	23.9	NA	NA	15
HM-Ja	Godber, 2016[27]	484	591	60.1	UK (S)	2.3	NA	9.3	no	no	no	100	1.7	18.8	15.9	39.7	NA	NA	4.8
HM-Ja	Widlack, 2017[28]	430	671	51.0	UK (E)	5.6	NA	NA	no	no	no	100	15.8	30	43	64.2	NA	NA	17.2

¹Age is expressed as median; AbPa: Abdominal pain; AD: Antithrombotic discontinuity; An: Anaemia; AN: advanced neoplasia; AnS: Any symptom; AU: Australia; CN: China; Co: Constipation; CRC: Colorectal cancer; ChBo: Change in bowel habit; DC: Derivation cohort; Di: Diarrhoea; ES: Spain; HM-J: HM-JACK^®; HM-Ja: HM-JACKarc^®; Hem: Haematochezia; IBD: Inflammatory bowel disease; IL: Israel; IT: Italy; KR: South Korea; m: mean; md: median; NA: Non-available; NL: Netherlands; OC-S: OC-Sensor^®; OB: Overt bleeding; SCL: Significant colonic lesion; UK (E): United Kingdom (England); UK (S): United Kingdom (Scotland); VC: Validation cohort; W%: Women%; WeL: Weight loss.

Table 2 Possibility of data extraction on the accuracy of quantitative faecal immunochemical test for haemoglobin for detecting colorectal cancer, advanced neoplasia and significant colonic lesion

Study	CRC							AN						SCL
	Threshold (U)					SxD	SD	Threshold (U)					SxD	Threshold (U)					SxD
	0	10	15	20	Other			0	10	15	20	Other		0	10	15	20	Other
Rozen, 2010[17]		x	x	x	25; 30; 40				x	x	x	25; 30; 40
Van Turenhout, 2014[18]		x	x	x	40	x
Mc Donald, 2012[20]		x							HRA						x
Ou, 2013[21]					5							5; HRA
Symonds, 2016[23]		x			60; 80		x
Auge, 2016[22]								x	x		x	30; 40	x
Woo, 2005[19]					33							3; HRA
Auge, 2018[30]		x		x	30; 40; 50; 60		x		x		x	30; 40; 50; 60			x		x	30; 40; 50; 60
Cubiella, 2014 (DC)[29]	x	x	x	x		x		x	x	x	x		x	x	x	x	x		x
Cubiella, 2016 (VC)[31]	x	x	x	x		x		x	x	x	x		x	x	x	x	x		x
Rodríguez-Alonso 2015[25]	x	x	x	x				x	x	x	x
Mowat, 2016[26]	x	x						HRA	HRA					x	x
Parente, 2012[24]				x							x
Godber, 2016[27]															x	x	x	25; 30; 35; 40
Widlack, 2017[28]																		7; HGD

AN: Advanced neoplasia; CRC: Colorectal cancer; DC: Derivation cohort; HDG: High-grade dysplasia; HRA: High risk adenoma; SCL: Significant colonic lesion; SxD and SD: Differences between sex and stage respectively can be calculated VC: Validation cohort; (U): Threshold units: μgrams of haemoglobin per gram of faeces.

Table 3 Colorectal cancer detection: Diagnostic accuracy parameters based on quantitative faecal immunochemical test for haemoglobin threshold concentration and brand (DerSimonian´s method)"

Variable	Studies (n)	Sensitivity1	I22	Specificity1	I22	Positive LR3	I22	Negative LR3	I22	Diagnostic OR3	I22	Pa
OC-Sensor, > LoD µg Hb/g faeces
All studies	4	98.2 (96.2-99.3)	0.0	35.8 (34.2-37.3)	96.1	1.55 (1.37-1.75)	94.2	0.07 (0.03-0.14)	0.0	21.41 (10.07-45.5)	0.0		0.6
OC-Sensor, ≥ 10 µg Hb/g faeces
All studies	8	90.8 (87.9-93.2)	69.7	79.9 (79.1-80.7)	99.4	4.79 (2.96-7.76)	99.1	0.15 (0.09-0.23)	52.7	31.44 (19.50-50.68)	44.7		0.09
100% Symptomatic	4	94.4 (91.4-96.6)	0.0	65.9 (64.4-67.4)	99.3	2.97 (1.78-4.95)	99.0	0.10 (0.06-0.15)	0.0	28.49 (17.77-45.67)	0.0		0.6
Mixed patients	4	83.2 (76.5-88.6)	44.5	88.2 (87.4-89.0)	96.7	7.78 (4.72-12.82)	95.1	0.21 (0.13-0.33)	30.7	35.36 (14.19-88.10)	71.0		0.6
CRC prevalence ≥ 2.5%	5	91.9 (88.7-94.3)	76.0	69.7 (68.5-71.0)	99.2	3.16 (1.99-5.0)	98.8	0.13 (0.07-0.25)	66.5	23.20 (14.76-36.47)	20.0		0.2
CRC prevalence < 2.5%	3	86.3 (77.7-92.5)	48.0	90.2 (89.4-91.1)	72.6	9.21 (7.23-11.74)	55.1	0.17 (0.09-0.33)	26.4	52.33 (27.23-100.58)	10.0		0.7
OC-Sensor, ≥ 15 µg Hb/g faeces
All studies	5	91.0 (87.8-93.6)	73.3	81.8 (80.9-82.7)	99.7	4.77 (2.34-9.71)	99.4	0.15 (0.09-0.25)	57.3	36.64 (20.43-65.71)	49.7		0.04
100% Symptomatic4	3	93.6 (90.2-96.0)	32.6	65.8 (64.1-67.5)	99.5	2.91 (1.46-5.78)	99.3	0.11 (0.07-0.16)	0.0	29.10 (12.74-66.46)	35.5		0.67
OC-Sensor, ≥ 20 µg Hb/g faeces
All studies	5	90.3 (86.9-93.0)	75.6(86.9-93.0)	83.4 (82.5-84.2)	99.7	5.30 (2.47-11.34)	99.4	0.15 (0.09-0.27)	67.2	39.02 (21.48-70.88)	56.1		0.04
100% Symptomatic4	3	92.9 (89.5-95.5)	26.1	68.0 (66.3-69.7)	99.5	3.14 (1.52-6.50)	99.3	0.11 (0.07-0.17)	0.0	29.81 (15.05-59.04)	29.2		0.67

¹Values are expressed as percentages and its 95% confidence interval;

²Values are expressed as percentages;

³Values are expressed as absolute numbers and its 95% confidence interval;

⁴The studies that comprise the 100% symptomatic subgroup also have colorectal cancer prevalence ≥ 2.5%; P^a: Significance of the threshold effect using the Spearman rank correlation (P < 0.01 is considered statistically significant). I²: Inconsistency index; LoD: Limit of detection; LR: Likelihood ratio; OR: Odds ratio; CRC: Colorectal cancer.

Table 4 Diagnostic accuracy parameters for colorectal cancer detection based on quantitative faecal immunochemical test for haemoglobin threshold concentration and brand

Brand	Threshold(µg/g faeces)	Author, year	Sensitivity1	Specificity1
Mixed cohorts
OC-Sensor®	25	Rozen, 2010[17]	60.0 (36.1-80.9)	95.2 (94.0-96.2)
OC-Sensor®	30	Rozen, 2010[17]	55.0 (31.5-76.9)	95.8 (94.7-96.7)
OC-Sensor®	40	Rozen, 2010[17]	55.0 (31.5-76.9)	96.3 (95.3-97.2)
OC-Sensor®	40	van Turenhout, 2014[18]	75.4 (63.5-84.9)	94.8 (93.9-95.6)
OC-Sensor®	60	Symonds 2016[23]	63.6 (50.9-75.1)	91.9 (90.3-93.3)
OC-Sensor®	80	Symonds 2016[23]	59.1 (46.3-71.0)	93.4 (91.9-94.7)
HM-JACK®	33	Woo, 2005[19]	50.0 (11.8-88.2)	83.5 (73.5-90.9)
FOB Gold®	10	Auge, 2018[30]	91.7 (71.5-98.5)	82.2 (79.6-84.5)
FOB Gold®	20	Auge, 2018[30]	87.5 (66.5-96.7)	86.0 (83.6-88.1)
FOB Gold®	30	Auge, 2018[30]	83.3 (61.8-94.5)	89.2 (87.0-91.1)
FOB Gold®	40	Auge, 2018[30]	83.3 (61.8-94.5)	90.3 (88.2-92.1)
FOB Gold®	50	Auge, 2018[30]	83.3 (61.8-94.5)	91.4 (89.4-93.1)
FOB Gold®	60	Auge, 2018[30]	83.3 (61.8-94.5)	91.8 (89.9-93.5)
100% Symptomatic
HM-JACK®	20	Parente, 2012[24]	61.7 (46.4-75.5)	88.8 (84.1-92.6)
HM-JACKarc®	7	Widlak, 2017[28]	84.0 (63.9-95.5)	93.1 (90.2-95.4)

¹Values are expressed as percentages and its 95% confidence interval.

Table 5 OC-Sensor^® diagnostic accuracy parameters for colorectal cancer detection (Threshold 10 µg Hb/g faeces) estimated with DerSimonian vs Bivariate methods

Variable	Studies (n)	Sensitivity1	Specificity1	Positive LR2	Negative LR2	Diagnostic OR2
All studies (DS)	8	90.8 (87.9-93.2)	79.9 (79.1-80.7)	4.79 (2.96-7.76)	0.15 (0.09-0.23)	31.44 (19.50-50.68)
All studies (Bv)	8	89.6 (82.7-94.0)	80.2 (67.2-88.9)	4.52 (2.73-7.50)	0.13 (0.08-0.20)	34.85 (20.74-58.57)
100% Symptomatic (DS)	4	94.4 (91.4-96.6)	65.9 (64.4-67.4)	2.97 (1.78-4.95)	0.10 (0.06-0.15)	28.49 (17.77-45.67)
100% Symptomatic (Bv)	4	94.1 (90.0-96.6)	66.0 (47.1-80.9)	2.77 (1.69-4.55)	0.09 (0.06-0.14)	30.93 (16.09-59.45)
Mixed patients (DS)	4	83.2 (76.5-88.6)	88.2 (87.4-89.0)	7.78 (4.72-12.82)	0.21 (0.13-0.33)	35.36 (14.19-88.10)
Mixed patients (Bv)	4	85.5 (76.5-91.4)	89.3 (84.1-93.0)	8.01 (5.07-12.65)	0.16 (0.10-0.28)	49.35 (19.88-122.5)
CRC prevalence ≥ 2.5% (DS)	5	91.9 (88.7-94.3)	69.7 (68.5-71.0)	3.16 (1.99-5.0 )	0.13 (0.07-0.25)	23.20 (14.76-36.47)
CRC prevalence ≥ 2.5% (Bv)	5	91.7 (83.3-96.1)	69.3 (53.5-81.6)	2.99 (1.97-4.53)	0.12 (0.07-0.21)	24.95 (16.02-38.86)
CRC prevalence < 2.5% (DS)	3	86.3 (77.7-92.5)	90.2 (89.4-91.1)	9.21 (7.23-11.74)	0.17 (0.09-0.33)	52.33 (27.23-100.58)
CRC prevalence < 2.5% (Bv)	3	84.9 (73.4-92.0)	90.5 (89.0-91.9)	8.96 (7.63-10.53)	0.17 (0.09-0.30)	53.77 (26.99-107.11)

¹Values are expressed as percentages and its 95% confidence interval;

²Values are expressed as absolute numbers and its 95% confidence interval. Bv: Bivariate; CRC: Colorectal cancer; D: DerSimonian; LR: Likelihood ratio; OR: Odds ratio.

Table 6 Advanced neoplasia and significant colonic lesion detection: Diagnostic accuracy parameters based on quantitative faecal immunochemical test threshold concentration and brand (DerSimonian´s method)

Variable	Studies(n)	Sensitivity1	I22	Specificity1	I22	Positive LR3	I22	Negative LR3	I22	Diagnostic OR3	I22	Pa
Advanced neoplasia
OC-Sensor, > LoD µg Hb/g faeces
All studies	3	91.0 (88.7-93.0)	87.9	36.9 (35.0-38.8)	95.2	1.40 (1.35-1.45)	0.0	0.26 (0.16-0.44)	76.6	5.44 (3.48-8.48)	58	< 0.001
OC-Sensor, ≥ 10 µg Hb/g faeces
All studies	5	67.9 (65.1-70.5)	97.4	81.0 (80.0-82.0)	99.5	3.42 (1.97-5.94)	98.8	0.41 (0.30-0.57)	93.4	9.43 (8.10-10.98)	0.0	< 0.001
100% Symptomatic	3	79.7 (76.5-82.6)	94.6	67.3 (65.5-69.1)	99.4	2.43 (1.41-4.17)	98.5	0.32 (0.21-0.49)	86.5	8.67 (6.96-10.80)	5.8	< 0.001
Prevalence CRC ≥ 2.5%	4	71.7 (68.8-74.5)	97.1	76.7 (75.4-77.9)	99.5	2.96 (1.65-5.30)	98.9	0.36 (0.25-0.53)	91.8	9.29 (7.79-11.09)	9.3	< 0.001
OC-Sensor, ≥ 15 µg Hb/g faeces
All studies	5	65.0 (62.2-67.8)	97.6	83.5 (82.5-84.4)	99.6	3.90 (2.04-7.47)	99.0	0.43 (0.31-0.60)	94.2	10.06 (8.14-12.44)	42.4	< 0.001
100% Symptomatic	3	76.8 (73.5-79.9)	95.6	70.3 (68.5-72.1)	99.4	2.63 (1.39-4.97)	98.8	0.34 (0.22-0.52)	88.4	8.88 (7.23-10.91)	0.0	< 0.001
Prevalence CRC ≥ 2.5%	4	69.3 (66.3-72.1)	97.1	79.4 (78.2-80.6)	99.6	3.33 (1.67-6.66)	99.1	0.38 (0.27-0.54)	91.1	9.72 (7.46-12.66)	55.4	< 0.001
OC-Sensor, ≥ 20 µg Hb/g faeces
All studies	5	62.9 (60.1-65.7)	97.8	85.1 (84.2-86.0)	99.6	4.34 (2.16-8.73)	99.0	0.45 (0.32-0.62)	95.3	10.62 (8.24-13.67)	57.4	< 0.001
100% Symptomatic	3	75.1 (71.7-78.3)	96.1	72.4 (70.7-74.1)	99.5	2.85 (1.43-5.65)	98.8	0.35 (0.23-0.55)	90.4	9.19 (7.47-11.32)	1.8	< 0.001
Prevalence CRC ≥ 2.5%	4	67.5 (64.5-70.4)	97.3	81.2 (80.0-82.3)	99.6	3.66 (1.74-7.71)	99.1	0.40 (0.29-0.55)	91.7	10.19 (7.49-13.86)	66.5	< 0.001
Significant colonic lesion
OC-Sensor, LoD µg Hb/g faeces
All studies	3	91.7 (89.5-93.6)	0.0	36.9 (35.0-39.0)	94.2	1.45 (1.32-1.59)	80.4	0.24 (0.19-0.30)	0.0	6.01 (4.57-7.92)	0.0	< 0.001
OC-Sensor, ≥ 10 µg Hb/g faeces
All studies	4	78.6 (75.6-81.4)	91.5	69.8 (67.9-71.6)	99.2	3.75 (2.08-6.76)	98.3	0.34 (0.27-0.42)	59.6	11.72 (6.41-21.45)	82.8	< 0.001
100% Symptomatic4	3	80.4 (77.4-83.2)	89.6	67.0 (65.0-68.9)	99.2	2.54 (1.45-4.46)	98.5	0.31 (0.26-0.37)	23.7	8.56 (6.18-11.86)	49.8	< 0.001

¹Values are expressed as percentages and its 95% confidence interval;

²Values are expressed as percentages;

³Values are expressed as absolute numbers and its 95% confidence interval;

⁴The studies that comprise the 100% symptomatic subgroup also have CRC prevalence ≥ 2.5%; P^a: Significance of the threshold effect using the Spearman rank correlation (P < 0.01 is considered statistically significant). I²: Inconsistency index; LoD: Limit of detection; LR: Likelihood ratio; OR: Odds ratio; CRC: Colorectal cancer.

Table 7 Diagnostic accuracy parameters for advanced neoplasia detection based on quantitative faecal immunochemical test for haemoglobin threshold concentration and brand

Brand	Threshold(µg/g faeces)	Author, year	Sensitivity1	Specificity1
Mixed cohorts
OC-Sensor®	5	Ou, 2013[21]	56.8 (39.5-72.9)	88.7 (85.7-91.2)
OC-Sensor®	25	Rozen, 2010[17]	27.5 (20.3-34.7)	96.7 (95.8-97.6)
OC-Sensor®	25	Terhaar sive Droste, 2010[32]	48.3 (42.6-53.9)	94.3 (93.2-95.3)
OC-Sensor®	30	Rozen, 2010[17]	26.8 (19.9-34.7)	97.3 (96.5-98.1)
OC-Sensor®	30	Terhaar sive Droste, 2010[32]	46.0 (40.4-51.7)	95.1 (94.1-96.1)
OC-Sensor®	40	Rozen, 2010[17]	26.2 (19.1-33.2)	97.8 (97.0-98.5)
OC-Sensor®	40	Terhaar sive Droste, 2010[32]	43.2 (37.6-48.9)	95.8 (94.8-96.7)
HM-JACKarc®	LoD	Auge, 2016[22]	96.6 (82.8-93.4)	10.6 (6.9-15.9)
HM-JACKarc®	10	Auge, 2016[22]	34.5 (19.9-52.7)	87.2 (81.6-91.3)
HM-JACKarc®	20	Auge, 2016[22]	31.0 (17.3-49.2)	92.8 (88.0-95.7)
HM-JACKarc®	30	Auge, 2016[22]	31.0 (17.3-49.2)	93.3 (88.7-96.1)
HM-JACKarc®	40	Auge, 2016[22]	27.6 (14.7-45.7)	93.9 (89.4-96.6)
FOB Gold®	10	Auge, 2018[30]	45.7 (33.7-58.1)	84.7 (80.8-88.0)
FOB Gold®	20	Auge, 2018[30]	37.1 (26.1-49.6)	87.9 (84.2-90.8)
FOB Gold®	30	Auge, 2018[30]	35.7 (24.6-48.1)	90.3 (87.0-93.1)
FOB Gold®	40	Auge, 2018[30]	32.9 (22.4-45.2)	91.1 (87.8-93.6)
FOB Gold®	50	Auge, 2018[30]	31.4 (20.9-43.6)	92.3 (89.3-94.7)
FOB Gold®	60	Auge, 2018[30]	30.0 (19.9-42.3)	92.3 (89.2-94.6)
100% symptomatic
HM-JACK®	20	Parente, 2012[24]	35.6 (27.9-44.1)	94.5 (89.7-97.2)

¹Values are expressed as percentages and its 95% confidence interval.

Table 8 Diagnostic accuracy parameters for significant colonic lesion detection based on quantitative faecal immunochemical test for haemoglobin threshold concentration and brand

Brand	Threshold(µg/g faeces)	Author, year	Sensitivity1	Specificity1
Significant colonic lesion (100% symptomatic)
OC-Sensor®	15	Cubiella (DC), 2014[29]	76.2 (72.0-80.0)	74.4 (71.7-76.9)
OC-Sensor®	15	Cubiella (VC), 2017[31]	89.5 (84.1-93.6)	40.6 (36.4-44.9)
OC-Sensor®	20	Cubiella (DC), 2014[29]	74.7 (70.5-78.6)	76.1 (73.5-78.6)
OC-Sensor®	20	Cubiella (VC), 2017[31]	87.8 (82.2-92.2)	42.1 (37.9-46.5)
HM-JACKarc®	10	Godber, 2016[27]	68.9 (53.2-81.4)	80.2 (76.1-83.7)
HM-JACKarc®	15	Godber, 2016[27]	66.7 (50.9-79.6)	83.1 (79.2-86.5)
HM-JACKarc®	20	Godber, 2016[27]	64.4 (48.7-77.7)	85.7 (81.9-88.7)
HM-JACKarc®	25	Godber, 2016[27]	64.4 (48.7-77.7)	87.5 (83.9-90.3)
HM-JACKarc®	30	Godber, 2016[27]	64.4 (48.7-77.7)	88.6 (85.2-91.4)
HM-JACKarc®	35	Godber, 2016[27]	64.4 (48.7-77.7)	89.2 (85.9-92.0)
HM-JACKarc®	40	Godber, 2016[27]	64.4 (48.7-77.7)	90.0 (86.7-92.5)

¹Values are expressed as percentages and their 95% confidence interval. DC: Derivation cohort; VC: Validation cohort.