Journal
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Volume 95, Issue 7, Pages 3360-3367Publisher
ENDOCRINE SOC
DOI: 10.1210/jc.2010-0293
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Funding
- National Institutes of Health (NIH), National Heart, Lung and Blood Institute [R01 HL61753, R01 HL079611]
- Diabetes Endocrinology Research Center [P30 DK57516]
- NIH [M01 RR000051]
- National Institute of Diabetes and Digestive and Kidney Diseases [DK 63829, 63861, 63821, 63865, 63863, 63836, 63790]
- National Institute of Allergy and Infectious Diseases
- National Institute of Child Health and Human Development
- National Institute of Environmental Health Sciences
- Juvenile Diabetes Research Foundation
- Centers for Disease Control and Prevention
- Kompetenznetz Diabetes mellitus (Competence Network for Diabetes mellitus)
- Federal Ministry of Education and Research in Germany [FKZ 01GI0805-07]
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Background/Rationale: Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies. Methods: Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using S-35-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays. Results: The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001). Conclusion: Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements. (J Clin Endocrinol Metab 95: 3360-3367, 2010)
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