This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Barker, J. M. Articles by Rewers, M. Search for Related Content PubMed PubMed Citation Articles by Barker, J. M. Articles by Rewers, M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Diabetes Type 1

Prediction of Autoantibody Positivity and Progression to Type 1 Diabetes: Diabetes Autoimmunity Study in the Young (DAISY)

Barbara Davis Center for Childhood Diabetes (J.M.B., L.Y., D.M., G.S.E., M.R.) and Department of Preventive Medicine and Biometrics (K.J.B., J.M.N.), University of Colorado Health Sciences Center, Denver, Colorado 80262; and Department of Human Genetics (H.A.E.), Roche Molecular Systems, Inc., Alameda, California 94501

Address all correspondence and requests for reprints to: Jennifer M. Barker, M.D., 4200 East 9th Avenue, Box B-140, Denver, Colorado 80262. E-mail: jennifer.barker{at}uchsc.edu.

Diabetes Autoimmunity Study in the Young (DAISY) has followed 1972 children for islet autoimmunity and diabetes: 837 first-degree relatives of persons with type 1 diabetes and 1135 general population newborns identified through human leukocyte antigen (HLA) screening. During follow-up of 4.06 yr (range, 0.17–9 yr), serial determination of autoantibodies to glutamic acid decarboxylase, protein tyrosine phosphatase IA2, and insulin has generated approximately 20,000 results. Among 162 children with at least one positive autoantibody, in 31% the test was false positive (autoantibodies were negative twice on blinded duplicate aliquots), in 31% it was transiently positive (confirmed on blinded duplicate aliquots but negative on follow-up), and in 36% it was persistently positive. Using proportional hazards modeling, the HLA-DR3/4 DQ8 genotype, another positive autoantibody at the first positive visit, and level of autoantibody were predictive of persistent positivity. Only HLA-DR3/4 DQ8 genotype was predictive of progression to diabetes in proportional hazards modeling. This prospective study reveals that cross-sectional determination of islet autoantibodies in a population with relatively low previous probability of autoimmunity identifies as "positive" a large number of individuals who are either false or transiently positive. Predictive value of autoantibodies increases with blinded duplicate and independent sample retesting and incorporation of the level of autoantibody in the predictive algorithm.

This work was supported by National Institutes of Health Grants DK 32083, DK 32493, DK 57516, AI 39213, AI 50864, and S-M01-RR00051. J.M.B. was supported by a fellowship grant from the Juvenile Diabetes Research Foundation (13-2002-444).

Abbreviations: GAA, Antibodies to glutamic acid decarboxylase; HLA, human leukocyte antigen; IA-2AA, antibodies to protein tyrosine phosphatase IA2; IAA, antibodies to insulin; ICA, islet cell autoantibodies; PPV, positive predictive value; T1DM, type 1 diabetes mellitus.

This article has been cited by other articles:

				G. S. COOPER Unraveling the Etiology of Systemic Autoimmune Diseases: Peering into the Preclinical Phase of Disease J Rheumatol, September 1, 2009; 36(9): 1853 - 1855. [Full Text] [PDF]

				P. Concannon, S. S. Rich, and G. T. Nepom Genetics of Type 1A Diabetes N. Engl. J. Med., April 16, 2009; 360(16): 1646 - 1654. [Full Text] [PDF]

				K. L. Mehers and K. M. Gillespie The genetic basis for type 1 diabetes Br. Med. Bull., December 1, 2008; 88(1): 115 - 129. [Abstract] [Full Text] [PDF]

				J. M. Barker, T. M. Triolo, T. A. Aly, E. E. Baschal, S. R. Babu, A. Kretowski, M. J. Rewers, and G. S. Eisenbarth Two Single Nucleotide Polymorphisms Identify the Highest-Risk Diabetes HLA Genotype: Potential for Rapid Screening Diabetes, November 1, 2008; 57(11): 3152 - 3155. [Abstract] [Full Text] [PDF]

				M. M. Lamb, X. Yin, K. Barriga, M. R. Hoffman, A. E. Baron, G. S. Eisenbarth, M. Rewers, and J. M. Norris Dietary Glycemic Index, Development of Islet Autoimmunity, and Subsequent Progression to Type 1 Diabetes in Young Children J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3936 - 3942. [Abstract] [Full Text] [PDF]

				D. M. Waid, G. M. Vaitaitis, N. D. Pennock, and D. H. Wagner Jr Disruption of the homeostatic balance between autoaggressive (CD4+CD40+) and regulatory (CD4+CD25+FoxP3+) T cells promotes diabetes J. Leukoc. Biol., August 1, 2008; 84(2): 431 - 439. [Abstract] [Full Text] [PDF]

				A. K. Steck and G. S. Eisenbarth Genetic Similarities Between Latent Autoimmune Diabetes and Type 1 and Type 2 Diabetes Diabetes, May 1, 2008; 57(5): 1160 - 1162. [Full Text] [PDF]

				T. A. Aly, E. E. Baschal, M. M. Jahromi, M. S. Fernando, S. R. Babu, T. E. Fingerlin, A. Kretowski, H. A. Erlich, P. R. Fain, M. J. Rewers, et al. Analysis of Single Nucleotide Polymorphisms Identifies Major Type 1A Diabetes Locus Telomeric of the Major Histocompatibility Complex Diabetes, March 1, 2008; 57(3): 770 - 776. [Abstract] [Full Text] [PDF]

				E. E. Baschal, T. A. Aly, S. R. Babu, M. S. Fernando, L. Yu, D. Miao, K. J. Barriga, J. M. Norris, J. A. Noble, H. A. Erlich, et al. HLA-DPB1*0402 Protects Against Type 1A Diabetes Autoimmunity in the Highest Risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY Population Diabetes, September 1, 2007; 56(9): 2405 - 2409. [Abstract] [Full Text] [PDF]

				R. F. Green Summary of Workgroup Meeting on Use of Family History Information in Pediatric Primary Care and Public Health Pediatrics, September 1, 2007; 120(SUPPLEMENT_2): S87 - S100. [Abstract] [Full Text] [PDF]

				T. A. Aly, A. Ide, M. M. Jahromi, J. M. Barker, M. S. Fernando, S. R. Babu, L. Yu, D. Miao, H. A. Erlich, P. R. Fain, et al. Extreme genetic risk for type 1A diabetes PNAS, September 19, 2006; 103(38): 14074 - 14079. [Abstract] [Full Text] [PDF]

				C. A. Deeg, D. Pompetzki, A. J. Raith, S. M. Hauck, B. Amann, S. Suppmann, T. W. F. Goebel, U. Olazabal, H. Gerhards, S. Reese, et al. Identification and Functional Validation of Novel Autoantigens in Equine Uveitis Mol. Cell. Proteomics, August 1, 2006; 5(8): 1462 - 1470. [Abstract] [Full Text] [PDF]

				R. D. G. Leslie, R. Williams, and P. Pozzilli Type 1 Diabetes and Latent Autoimmune Diabetes in Adults: One End of the Rainbow J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1654 - 1659. [Abstract] [Full Text] [PDF]

				D. Larizza, V. Calcaterra, M. Martinetti, R. Negrini, A. De Silvestri, M. Cisternino, A. M. Iannone, and E. Solcia Helicobacter pylori Infection and Autoimmune Thyroid Disease in Young Patients: The Disadvantage of Carrying the Human Leukocyte Antigen-DRB1*0301 Allele J. Clin. Endocrinol. Metab., January 1, 2006; 91(1): 176 - 179. [Abstract] [Full Text] [PDF]

				P. Achenbach, E. Bonifacio, K. Koczwara, and A.-G. Ziegler Natural History of Type 1 Diabetes Diabetes, December 1, 2005; 54(suppl_2): S25 - S31. [Abstract] [Full Text] [PDF]

				C. Pihoker, L. K. Gilliam, C. S. Hampe, and A. Lernmark Autoantibodies in Diabetes Diabetes, December 1, 2005; 54(suppl_2): S52 - S61. [Abstract] [Full Text] [PDF]

				E. J. Woodward and J. W. Thomas Multiple Germline {kappa} Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice J. Immunol., July 15, 2005; 175(2): 1073 - 1079. [Abstract] [Full Text] [PDF]