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Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy.
Gastroenterology 2017; 153(2):410-419.e17G

Abstract

BACKGROUND & AIMS

A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures.

METHODS

We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease.

RESULTS

Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays.

CONCLUSIONS

In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854.

Authors+Show Affiliations

Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University and University Hospital, Leipzig, Germany.Clinical Trial Centre, University of Leipzig, Leipzig, Germany.Children's Hospital of the Clinical Centre Sankt Georg Leipzig, Leipzig, Germany.Alder Hey Children's National Health Service Foundation Trust, Liverpool, United Kingdom.Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; Department of Pediatrics, University of Oxford, Oxford, United Kingdom.University Children's Hospital, Technical University Dresden, Dresden, Germany.German Clinic for Diagnostics, Helios Children's Hospital, Wiesbaden, Germany.Children's Hospital Prinzessin Margaret, Darmstadt, Germany.University Children's Hospital Leipzig, Germany.Children's Hospital, Justus Liebig University Giessen, Germany.University Children's Hospital Graz, Austria.Department of Pediatrics, Helios Hospital, Plauen, Germany.Medical School, Hannover, Germany.University Children's Hospital Halle, Halle, Germany.Department of Pediatrics, University of Oxford, Oxford, United Kingdom.Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Medical Faculty of the University and University Hospital, Leipzig, Germany. Electronic address: mothes@medizin.uni-leipzig.de.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Validation Studies
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28461188

Citation

Wolf, Johannes, et al. "Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy." Gastroenterology, vol. 153, no. 2, 2017, pp. 410-419.e17.
Wolf J, Petroff D, Richter T, et al. Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy. Gastroenterology. 2017;153(2):410-419.e17.
Wolf, J., Petroff, D., Richter, T., Auth, M. K. H., Uhlig, H. H., Laass, M. W., ... Mothes, T. (2017). Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy. Gastroenterology, 153(2), pp. 410-419.e17. doi:10.1053/j.gastro.2017.04.023.
Wolf J, et al. Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy. Gastroenterology. 2017;153(2):410-419.e17. PubMed PMID: 28461188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Validation of Antibody-Based Strategies for Diagnosis of Pediatric Celiac Disease Without Biopsy. AU - Wolf,Johannes, AU - Petroff,David, AU - Richter,Thomas, AU - Auth,Marcus K H, AU - Uhlig,Holm H, AU - Laass,Martin W, AU - Lauenstein,Peter, AU - Krahl,Andreas, AU - Händel,Norman, AU - de Laffolie,Jan, AU - Hauer,Almuthe C, AU - Kehler,Thomas, AU - Flemming,Gunter, AU - Schmidt,Frank, AU - Rodrigues,Astor, AU - Hasenclever,Dirk, AU - Mothes,Thomas, Y1 - 2017/04/28/ PY - 2016/12/07/received PY - 2017/03/31/revised PY - 2017/04/19/accepted PY - 2017/5/4/pubmed PY - 2017/9/1/medline PY - 2017/5/3/entrez KW - AbCD Study KW - ELISA KW - Endoscopy KW - Gluten SP - 410 EP - 419.e17 JF - Gastroenterology JO - Gastroenterology VL - 153 IS - 2 N2 - BACKGROUND & AIMS: A diagnosis of celiac disease is made based on clinical, genetic, serologic, and duodenal morphology features. Recent pediatric guidelines, based largely on retrospective data, propose omitting biopsy analysis for patients with concentrations of IgA against tissue transglutaminase (IgA-TTG) >10-fold the upper limit of normal (ULN) and if further criteria are met. A retrospective study concluded that measurements of IgA-TTG and total IgA, or IgA-TTG and IgG against deamidated gliadin (IgG-DGL) could identify patients with and without celiac disease. Patients were assigned to categories of no celiac disease, celiac disease, or biopsy required, based entirely on antibody assays. We aimed to validate the positive and negative predictive values (PPV and NPV) of these diagnostic procedures. METHODS: We performed a prospective study of 898 children undergoing duodenal biopsy analysis to confirm or rule out celiac disease at 13 centers in Europe. We compared findings from serologic analysis with findings from biopsy analyses, follow-up data, and diagnoses made by the pediatric gastroenterologists (celiac disease, no celiac disease, or no final diagnosis). Assays to measure IgA-TTG, IgG-DGL, and endomysium antibodies were performed by blinded researchers, and tissue sections were analyzed by local and blinded reference pathologists. We validated 2 procedures for diagnosis: total-IgA and IgA-TTG (the TTG-IgA procedure), as well as IgG-DGL with IgA-TTG (TTG-DGL procedure). Patients were assigned to categories of no celiac disease if all assays found antibody concentrations <1-fold the ULN, or celiac disease if at least 1 assay measured antibody concentrations >10-fold the ULN. All other cases were considered to require biopsy analysis. ULN values were calculated using the cutoff levels suggested by the test kit manufacturers. HLA typing was performed for 449 participants. We used models that considered how specificity values change with prevalence to extrapolate the PPV and NPV to populations with lower prevalence of celiac disease. RESULTS: Of the participants, 592 were found to have celiac disease, 345 were found not to have celiac disease, and 24 had no final diagnosis. The TTG-IgA procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.934; the TTG-DGL procedure identified patients with celiac disease with a PPV of 0.988 and an NPV of 0.958. Based on our extrapolation model, we estimated that the PPV and NPV would remain >0.95 even at a disease prevalence as low as 4%. Tests for endomysium antibodies and HLA type did not increase the PPV of samples with levels of IgA-TTG ≥10-fold the ULN. Notably, 4.2% of pathologists disagreed in their analyses of duodenal morphology-a rate comparable to the error rate for serologic assays. CONCLUSIONS: In a prospective study, we validated the TTG-IgA procedure and the TTG-DGL procedure in identification of pediatric patients with or without celiac disease, without biopsy. German Clinical Trials Registry no.: DRKS00003854. SN - 1528-0012 UR - https://www.unboundmedicine.com/medline/citation/28461188/Validation_of_Antibody_Based_Strategies_for_Diagnosis_of_Pediatric_Celiac_Disease_Without_Biopsy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(17)35532-4 DB - PRIME DP - Unbound Medicine ER -