Systematic Review With Meta-analysis

The Accuracy of Serological Tests to Support the Diagnosis of Coeliac Disease

Athena L. Sheppard; Martha M. C. Elwenspoek; Lauren J. Scott; Victoria Corfield; Hazel Everitt; Peter M. Gillett; Alastair D. Hay; Hayley E. Jones; Susan Mallett; Jessica Watson; Penny F. Whiting

Disclosures

Aliment Pharmacol Ther. 2022;55(5):514-527.

Abstract and Introduction

Abstract

Background: There is growing support for a biopsy avoidant approach to diagnose coeliac disease in both children and adults, using a serological diagnosis instead.

Aims: To assess the diagnostic accuracy of serological tests for coeliac disease in adults and children.

Methods: Seven electronic databases were searched between January 1990 and August 2020. Eligible diagnostic studies evaluated the accuracy of serological tests for coeliac disease against duodenal biopsy. Risk of bias assessment was performed using QUADAS-2. Bivariate random-effects meta-analyses were used to estimate serology sensitivity and specificity at the most commonly reported thresholds.

Results:113 studies (n = 28,338) were included, all in secondary care populations. A subset of studies were included in meta-analyses due to variations in diagnostic thresholds. Summary sensitivity and specificity of immunoglobulin A (IgA) anti-tissue transglutaminase were 90.7% (95% confidence interval: 87.3%, 93.2%) and 87.4% (84.4%, 90.0%) in adults (5 studies) and 97.7% (91.0%, 99.4%) and 70.2% (39.3%, 89.6%) in children (6 studies); and of IgA endomysial antibodies were 88.0% (75.2%, 94.7%) and 99.6% (92.3%, 100%) in adults (5 studies) and 94.5% (88.9%, 97.3%) and 93.8% (85.2%, 97.5%) in children (5 studies).

Conclusions:Anti-tissue transglutaminase sensitivity appears to be sufficient to rule out coeliac disease in children.

Abstract and Introduction
Materials and Methods
Results
Discussion
References

Table 1. Study estimates of test accuracy, stratified by age group and test
Serological test	Studies, n	Participants (coeliac disease), n	Threshold	Sensitivity (range), %	Specificity (range), %
All data
Adults
IgA tTG	27	11 355 (2566)	5–25 U/mL	35.2–100.0	0.0–100.0
IgG tTG	1	65 (14)	10 U/mL	71.4	96.1
IgA EMA	19	7122 (1028)	1:5–1:20	61.3–100.0	87.5–100.0
IgG EMA	1	96 (28)	1:20	39.3	98.5
IgA DGP	3	885 (154)	10–20 U/mL	85.7–98.3	92.2–95.7
IgG DGP	4	1046 (217)	10–20 U/mL	90.0–96.7	99.2–100.0
IgA/IgG DGP	4	1161 (280)	20 U/mL	86.2–98.3	95.9–98.8
IgA/IgG tTG/DGP	3	1849 (173)	20 U/mL	72.2–96.3	80.4–97.4
IgA AAA	2	820 (140)	25 U/mL	80.0, 86.7	92.2, 95.1
Children
IgA tTG	37	7944 (4164)	3–100 U/mL	28.6–100.0	7.9–100.0
IgG tTG	5	599 (278)	3, 7 U/mL	31.0–97.4	70.8–100.0
IgA/IgG tTG	2	742 (282)	6, 45.1 U/mL	94.4, 96.0	85.8, 99.5
IgA EMA	28	4974 (2472)	1:5–1:40	40.0–100.0	29.4–100.0
IgA/IgG EMA	2	173 (131)	1:2.5, 1:5	95.3, 95.7	74.2, 90.9
IgA DGP	1	212 (109)	20 U/mL	85.3	88.3
IgG DGP	3	1135 (669)	10–25 U/mL	77.2–92.0	83.5–94.1
IgA/IgG DGP	6	941 (464)	16–20 U/mL	87.5–100.0	22.2–96.4
IgA/IgG tTG/DGP	4	986 (415)	3–32.7 U/mL	87.5–98.2	61.2–99.5
Mixed or unspecified
IgA tTG	25	4564 (1414)	2–89.5 U/mL	38.1–100.0	9.5–100.0
IgG tTG	2	432 (122)	10, 18.9 U/mL	40.6, 84.6	78.0, 89.0
IgA/IgG tTG	1	254 (26)	7.8 U/mL	92.3	82.9
IgA EMA	15	2884 (843)	1:2.5–1:10	68.0–100.0	38.9–100.0
IgA DGP	2	561 (58)	19.9 U/mL	77.1, 90.0	93.4, 96.6
IgG DGP	2	562 (56)	19.9 U/mL	76.1, 80.0	92.0, 99.2
IgA/IgG DGP	3	480 (48)	NR	70.6–85.7	92.9–98.7
IgA AAA	1	391 (10)	NR	50	91.3

Abbreviations: AAA, anti-actin antibodies; DGP, deamidated gliadin peptide; EMA, endomysial antibodies; IgA, immunoglobulin A; IgG, immunoglobulin G; NR, not reported; tTG, anti-tissue transglutaminase.

Table 2. Summary estimates of sensitivity, specificity and likelihood ratios, restricted to the most commonly reported threshold only
Serological test	Studies, n	Participants (coeliac disease), n	Threshold	Sensitivity (95% CI), %	Specificity (95% CI), %	Positive likelihood ratio (95% CI)	Inverse negative likelihood ratio (95% CI)
Most common threshold
Adults
IgA tTG	5	4310 (454)	15 U/mL	90.7 (87.3, 93.2)	87.4 (84.4, 90.0)	7.2 (5.8, 9.1)	9.4 (6.8, 12.8)
IgA EMA	5	927 (446)	1:05	88.0 (75.2, 94.7)	99.6 (92.3, 100.0)	340.7 (12.2, 9539.8)	7.6 (3.9, 14.7)
IgA DGP^†	2	820 (140)	20 U/mL	96.4 (91.7, 98.5)	95.4 (93.6, 96.8)	21.2 (15.0, 29.9)	26.7 (11.3, 63.2)
IgG DGP^†	3	981 (203)	20 U/mL	93.6 (88.6, 96.5)	99.4 (98.5, 99.7)	145.7 (60.8, 349.4)	15.6 (8.6, 28.3)
IgA/IgG DGP	4	1161 (280)	20 U/mL	91.5 (84.7, 95.4)	96.7 (95.3, 97.7)	27.7 (19.0, 40.5)	11.4 (6.2, 20.9)
IgA/IgG tTG/DGP^†	2	851 (155)	20 U/mL	93.5 (88.4, 96.5)	86.3 (79.7, 91.0)	6.8 (4.5, 10.3)	13.4 (7.3, 24.5)
IgA AAA^†	2	820 (140)	25 U/mL	82.9 (75.7, 88.2)	92.5 (90.3, 94.3)	11.0 (8.4, 14.5)	5.4 (3.7, 7.8)
Children
IgA tTG	6	2232 (1051)	20 U/mL	97.7 (91.0, 99.4)	70.2 (39.3, 89.6)	3.3 (1.3, 8.0)	30.4 (8.5, 108.7)
IgA EMA	5	1257 (685)	1:10	94.5 (88.9, 97.3)	93.8 (85.2, 97.5)	11.2 (3.3, 37.4)	14.8 (7.7, 28.2)
IgA/IgG DGP	5	533 (276)	20 U/mL	96.4 (91.7, 98.5)	77.4 (44.0, 93.7)	4.3 (1.4, 13.1)	21.5 (10.7, 43.4)
IgA/IgG tTG/DGP^†	2	244 (133)	20 U/mL	95.6 (83.9, 98.9)	62.2 (52.8, 70.7)	2.5 (2.0, 3.2)	14.3 (3.6, 57.0)

Abbreviations: AAA, anti-actin antibodies; CI, confidence interval; DGP, deamidated gliadin peptide; EMA, endomysial antibodies; IgA, immunoglobulin A; IgG, immunoglobulin G; tTG, anti-tissue transglutaminase.
^†Univariate fixed-effect meta-analysis.

Table 3. Study estimates of sensitivity and specificity limited to specific subgroups, stratified by age group and test
Serological test	Studies, n	Participants (coeliac disease), n	Threshold	Sensitivity (range), %	Specificity (range), %
Symptomatic patients only
Adults
IgA tTG	7	4244 (325)	5–20 U/mL	64.3–100.0	88.2–98.1
IgA EMA	8	3786 (327)	1:5–1:20	61.3–100.0	98.1–100.0
Children
IgA tTG	8	1126 (615)	4–20 U/mL	40.0–100.0	7.9–100.0
IgA EMA	8	1327 (753)	1:5–1:20	40.0–97.6	42.9–100.0
All patients underwent biopsy
Adults
IgA tTG	26	11 183 (2444)	5–25 U/mL	64.3–100.0	0.0–100.0
IgA EMA	18	7010 (1021)	1:5–1:20	61.3–100.0	87.5–100.0
Children
IgA tTG	31	5824 (3330)	3–100 U/mL	28.6–100.0	23.5–100.0
IgA EMA	22	3685 (2015)	1:5–1:40	45.8–100.0	29.4–100.0
Low risk of bias
Adults
IgA tTG	5	1577 (426)	5–20 U/mL	76.0–100.0	87.5–98.3
IgA EMA	2	268 (103)	1:5, 1:20	61.3, 89.3	100.0, 100.0
Children
IgA tTG	4	1319 (823)	20–21 U/mL	94.8–100.0	23.5–98.7
IgA EMA	1	873 (528)	1:10	95.3	94.2

Abbreviations: EMA, endomysial antibodies; IgA, immunoglobulin A; tTG, anti-tissue transglutaminase.

Table 4. Study estimates of sensitivity and specificity, restricted to comparative studies only
Serological test	Studies, n	Participants (coeliac disease), n	Threshold	Sensitivity (range), %	Relative sensitivity (range), %	Specificity (range), %	Relative specificity (range), %
Comparative data
Adults
IgA tTG vs IgA EMA	14	6575 (881)
IgA tTG			5–25 U/mL	64.3–100.0		81.3–99.1
IgA EMA			1:05	61.3–100.0	0.81–1.22	87.5–100.0	1.00–1.17
IgA tTG vs IgA DGP	3	885 (154)
IgA tTG			10–20 U/mL	64.3–95.0		88.2–97.5
IgA DGP			10–20 U/mL	85.7–98.3	1.04–1.33	92.2–95.7	0.96–1.04
IgA tTG vs IgG DGP	4	1046 (217)
IgA tTG			10–20 U/mL	64.3–95.2		88.2–98.0
IgG DGP			10–20 U/mL	90.0–96.7	0.99–1.44	99.2–100.0	1.02–1.13
IgA tTG vs IgA/IgG DGP	4	1161 (280)
IgA tTG			5–20 U/mL	76.0–95.0		94.8–99.0
IgA/IgG DGP			20 U/mL	86.2–98.3	1.01–1.14	95.9–98.8	0.99–1.01
Children
IgA tTG vs IgA EMA	16	3021 (1746)
IgA tTG			5.5–21 U/mL	28.6–99.0		23.5–100.0
IgA EMA			1:5–1:10	50.0–100.0	0.91–2.25	29.4–100.0	0.76–1.25

Abbreviations: DGP, deamidated gliadin peptide; EMA, endomysial antibodies; IgA, immunoglobulin A; IgG, immunoglobulin G; tTG, anti-tissue transglutaminase.

Authors and Disclosures

Athena L. Sheppard^1,2, Martha M. C. Elwenspoek^1,2, Lauren J. Scott^1,2, Victoria Corfield², Hazel Everitt³, Peter M. Gillett⁴, Alastair D. Hay², Hayley E. Jones², Susan Mallett⁵, Jessica Watson² and Penny F. Whiting²

¹The National Institute for Health Research Applied Research Collaboration West (NIHR ARC West) at University Hospitals Bristol NHS Foundation Trust, Bristol, UK
²Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
³Primary Care Research Centre, Faculty of Medicine, University of Southampton, Southampton, UK
⁴Paediatric Gastroenterology Department, Royal Hospital for Children and Young People, Edinburgh, UK
⁵Centre for Medical Imaging, University College London, London, UK

Correspondence
Athena L. Sheppard, Swansea University Medical School, Swansea University, Swansea, UK. Email: 2138248@swansea.ac.uk

Author contributions
Conceptualisation: ALS, MMCE, LJS, VC, HE, PMG, HEJ, JW, PFW. Data curation: ALS, MMCE, LJS, VC. Formal analysis: ALS, MMCE, LJS, HE, PMG, ADH, HEJ, SM, JW, PFW. Funding acquisition: PFW. Investigation: ALS, MMCE, LJS, HE, PMG, ADH, HEJ, SM, JW, PFW. Methodology: ALS, MMCE, LJS, HE, PMG, ADH, HEJ, SM, JW, PFW. Project administration: ALS. Resources: ALS. Software: ALS. Supervision: PFW. Validation: ALS, MMCE, LJS, HE, PMG, ADH, HEJ, SM, JW, PFW. Visualisation: ALS, MMCE, LJS, HE, PMG, ADH, HEJ, SM, JW, PFW. Writing—original draft: ALS. Writing—review and editing: ALS, MMCE, LJS, VC, HE, PMG, ADH, HEJ, SM, JW, PFW. All authors approved the final version of the manuscript.

Declaration of funding interests
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment Programme (grant number NIHR129020). Athena L. Sheppard (Systematic Review Fellowship, grant number NIHR-RM-SR-2017-08-012) was funded by the NIHR for this research project. This research was supported by the NIHR Applied Research Collaboration West (NIHR ARC West) at University Hospital Bristol NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Declaration of personal interests
Athena L. Sheppard has received research funding from the National Institute for Health Research.
The authors wish to thank Alison Richards, Research Associate, and Sarah Dawson, Senior Research Associate in Information Retrieval, at NIHR ARC West at University Hospitals Bristol NHS Foundation Trust, and Population Health Sciences, Bristol Medical School, University of Bristol, UK, for performing the searches.