Celiac disease serology in patients with different pretest probabilities: Is biopsy avoidable?

Table 1 Demographic, clinical, and histological characteristics of subjects categorized by their pretest probability of having CD and from newly diagnosed CD patients from each subgroup

Characteristic	High pretest	Low pretest	P value
No. of subjects enrolled (F/M)	161 (131/30)	518 (351/167)
Mean age (range), yr	40 (16-80)	46 (16-87)
No. of CD patients (%)	63 (39.1)	17 (3.3)
Body mass index
mean ± SE (kg/m2)	20.6 ± 3.9	25.2 ± 5.0	< 0.0001
Histological characterization of duodenal biopsy samples (Marsh’s modified)[25]
Type 0 (No. of patients)	97	495
Type I	0	5
Type II	1	1
Type IIIa	4	6
Type IIIb	12	4
Type IIIc	47	7	< 0.0001
Newly diagnosed CD patients
No. of patients	63	17
Mean age (range), yr	37 (24-74)	37 (19-72)
Body mass index
mean ± SE (kg/m2)	19.6 ± 3.1	23.6 ± 5.0	< 0.0001
Clinical categorization at diagnosis
No. of patients (%)
Classical CD	52	1	< 0.0001
Atypical CD	11	10	< 0.0010
Silent CD	0	6	< 0.0001

CD: Celiac disease.

Table 2 Statistical performance of individual CD serologic tests for high- and low-risk populations at cut-offs provided by the manufacturer and when the cut-off is set for a 100% PPV

Test	% (95% CI)			(%)
	Sensitivity	Specificity	AU ROC	PPV	NPV
High-risk population
IgA a-tTG
(cut-off 20 U/mL)	95.2 (86.7-99.0)	97.9 (92.8-99.7)	0.997 (0.971-0.998)	96.9	96.8
(cut-off 34 U/mL)	93.6 (84.5-98.2)	100.0 (96.3-100.0)	0.968 (0.928-0.989)	100.0	96.0
IgA a-DGP
(cut-off 20 U/mL)	98.4 (91.4-99.7)	92.7 (85.5-97.1)	0.995 (0.968-0.999)	90.0	98.9
(cut-off 77 U/mL)	87.3 (76.5-94.3)	100.0 (96.3-100.0)	0.995 (0.968-0.999)	100.0	92.5
IgG a-DGP
(cut-off 20 U/mL)	95.2 (86.7-99.0)	100.0 (96.2-100.0)	0.989 (0.958-0.998)	100.0	97.0
(cut-off 20 U/mL)
DGP Dual
(cut-off 20 U/mL)	96.8 (89.0-99.5)	99.0 (94.4-99.8)	0.995 (0.967-0.999)	98.4	97.9
(cut-off 22 U/mL)	96.8 (89.0-99.5)	100.0 (96.3-100.0)	0.984 (0.951-0.997)	100.0	98.0
DGP/tTG Screen
(cut-off 20 U/mL)	100.0 (94.3-100.0)	92.8 (85.8-97.1)	0.999 (0.976-1.000)	90.3	100.0
(cut-off 54 U/mL)	98.4 (91.4-99.7)	100.0 (96.3-100)	0.992 (0.963-0.999)	100.0	99.0
IgA AAA
(cut-off 25 U/mL)	87.3 (76.5-94.3)	94.9 (88.5-98.3)	0.968 (0.927-0.989)	91.9	91.8
(cut-off 64 U/mL)	52.4 (39.4-65.0)	100.0 (96.3-100.0)	0.770 (0.697-0.832)	100.0	76.6
Low-risk population
IgA a-tTG
(cut-off 20 U/mL)	76.5 (50.1-93.0)	97.4 (95.6-98.6)	0.921 (0.894-0.942)	50.0	99.2
(cut-off 139 U/mL)	35.3 (14.3-61.6)	100.0 (98.9-100.0)	0.706 (0.665-0.745)	100.0	97.8
IgA a-DGP
(cut-off 20 U/ mL)	82.3 (56.6-96.0)	96.2 (94.1-97.7)	0.932 (0.907-0.952)	42.4	99.4
(cut-off 313 U/mL)	35.3 (14.3-61.6)	100.0 (99.3-100.0)	0.706 (0.655-0.745)	100.0	97.9
IgG a-DGP
(cut-off 20U/mL)	70.6 (44.1-89.6)	99.0 (97.7-99.7)	0.926 (0.900-0.947)	70.6	99.0
(cut-off 109 U/mL)	29.4 (10.4-55.9)	100.0 (99.3-100.0)	0.676 (0.634-0.717)	100.0	97.7
DGP Dual
(cut-off 20 U/ mL)	76.5 (50.1-93.0)	95.8 (93.7-97.4)	0.963 (0.943-0.978)	38.2	99.2
(cut-off 77 U/mL)	47.1 (23.0-72.1)	100.0 (99.3-100.0)	0.735 (0.695-0.773)	100.0	98.2
DGP/tTG Screen
(cut-off 20 U/mL)	82.3 (56.6-96.0)	88.2 (85.1-90.9)	0.972 (0.954-0.984)	19.2	99.3
(cut-off 128 U/mL)	64.7 (38.4-85.7)	100.0 (98.9-100.0)	0.824 (0.788-0.855)	100.0	97.8
IgA AAA
(cut-off 25 U/mL)	52.9 (27.9-77.0)	91.6 (88.8-93.9)	0.835 (0.800-0.866)	17.6	98.3
(cut-off 106 U/mL)	29.4 (10.4-55.9)	100.0 (99.3-100.0)	0.647 (0.604-0.688)	100.0	97.7

The statistical performance of tests if concentrations are above the cutoff. PPV: Positive predictive value; NPV: Negative predictive value; tTG: Tissue transglutaminase; DGP: Deamidated gliadin peptide; AAA: IgA antiactin antibodies; AU ROC: Area under the ROC curve.

Table 3 Statistical performance of combinations of two tests in the high- and low-risk populations at the cut-off provided by the manufacturer

Test	% (95% CI)			(%)
	Sensitivity	Specificity	AU ROC	PPV	NPV
High-risk
IgA a-DGP + IgA a-tTG	93.6 (84.5-98.2)	99.0 (94.4-99.8)	0.963 (0.921-0.986)	98.4	95.9
IgG a-DGP + IgA a-tTG	90.5 (80.4-96.4)	100.0 (96.3-100)	0.952 (0.907-0.980)	100.0	94.0
DGP Dual + IgA a-tTG	92.0 (82.4-97.3)	100.0 (96.3-100)	0.960 (0.917-0.985)	100.0	95.0
DGP/tTG Screen + IgA a-tTG	95.2 (86.7-99.0)	100.0 (96.3-100.0)	0.976 (0.939-0.994)	100.0	96.9
IgA a-DGP + DGP/tTG Screen	98.4 (91.4-99.7)	96.9 (91.3-99.3)	0.977 (0.940-0.994)	95.4	99.0
IgG a-DGP + IgA a-DGP	95.2 (86.7-99.0)	100.0 (96.3-100.0)	0.976 (0.939-0.994)	100.0	97.0
IgA a-DGP + DGP Dual	96.8 (89.0-99.5)	100.0 (96.3-100.0)	0.984 (0.951-0.997)	100.0	98.0
IgG a-DGP + DGP Dual	95.2 (86.7-99.0)	100.0 (96.3-100.0)	0.976 (0.939-0.994)	100.0	97.0
IgG a-DGP + DGP/tTG Screen	95.2 (86.7-99.0)	100.0 (96.3-100.0)	0.976 (0.939-0.994)	100.0	97.0
DGP Dual + DGP/tTG Screen	96.8 (89.0-99.5)	100.0 (96.3-100.0)	0.984 (0.951-0.997)	100.0	98.0
Low-risk
IgA a-DGP + IgA a-tTG	72.2 (46.5-90.2)	99.8 (98.9-100.0)	0.860 (0.827-0.889)	92.9	99.0
IgG a-DGP + IgA a-tTG	66.7 (41.0-86.6)	100.0 (99.3-100.0)	0.833 (0.798-0.864)	100.0	98.8
DGP Dual + IgA a-tTG	72.2 (46.5-90.2)	99.8 (99.3-100.0)	0.861 (0.828-0.890)	92.8	99.0
DGP/tTG Screen + IgA a-tTG	72.2 (46.5-90.2)	98.8 (97.4-99.6)	0.855 (0.822-0.884)	68.4	99.0
IgA a-DGP + DGP/tTG Screen	82.3 (56.6-96.0)	99.0 (97.7-99.7)	0.907 (0.878-0.930)	73.6	99.4
IgG a-DGP + IgA a-DGP	70.6 (44.1-89.6)	100.0 (99.3-100.0)	0.853 (0.819-0.882)	100.0	99.0
IgA a-DGP + DGP Dual	76.5 (50.1-93.0)	99.6 (98.6-99.9)	0.880 (0.849-0.907)	86.6	99.2
IgG a-DGP + DGP Dual	70.6 (44.1-89.6)	99.0 (97.7-99.7)	0.848 (0.814-0.878)	70.5	99.0
IgG a-DGP + DGP/tTG Screen	70.6 (44.1-89.6)	99.4 (98.3-99.9)	0.850 (0.816-0.880)	80.0	99.0
DGP Dual + DGP/tTG Screen	76.5 (89.0-99.5)	99.0 (96.3-100.0)	0.877 (0.846-0.904)	72.2	99.2

The statistical performance of the 10 combinations assessed is reported, considering a result to be positive if both tests of the combination have concentrations above the cutoff.

Table 4 Performance of individual assays in both risk populations in the theoretical analysis aiming to avoid duodenal biopsy when serology is negative

Individual serology tests	High-risk		Low-risk
	Biopsy avoided (%)	Missed CD cases (n)	Biopsy avoided (%)	Missed CD cases (n)
IgA a-tTG	61.5	3	95.4	4
IgA a-DGP	57.1	1	93.6	3
IgG a-DGP	62.7	3	96.7	5
DGP Dual	61.5	2	96.0	4
DGP/tTG Screen	56.5	0	91.3	3
AAA	62.7	8	90.3	8

Table 5 Performance of combinations of two assays in both risk populations exploring the potential avoidance of duodenal biopsy if the procedure is only performed in +/- cases

Combination of two tests	High risk		Low risk
	Biopsy avoided (%)	Missed CD cases (n)	Biopsy avoided (%)	Missed CD cases (n)
IgA a-tTG + IgA a-DGP	93.2	0	96.7	4
IgA a-tTG + IgG a-DGP	95.6	0	94.4	3
IgA a-tTG + DGP Dual	95.0	0	96.1	4
IgA-tTG + DGP/tTG Screen	92.0	0	94.4	3
IgA aDGP + DGP/tTG Screen	95.0	2	92.1	3
IgG a-DGP + IgA a-DGP	94.4	1	95.0	3
IgA a-DGP + DGP Dual	94.4	1	95.2	3
IgG a-DGP + DGP Dual	98.7	2	99.0	4
IgG a-DGP + DGP/tTG Screen	93.8	0	93.6	3
DGP Dual + DGP/tTG Screen	93.8	0	93.8	5