Data-Driven Phenotyping of Presymptomatic Type 1 Diabetes Using Longitudinal Autoantibody Profiles

Overview

Journal Diabetes Care

Specialty Endocrinology

Date 2024 Jun 11

PMID 38861550

Authors

Mohamed Ghalwash

Vibha Anand

Kenney Ng

Jessica L Dunne

Olivia Lou

Markus Lundgren

William A Hagopian

Marian Rewers

Anette-G Ziegler

Riitta Veijola

Affiliations

Soon will be listed here.

Abstract

Objective: To characterize distinct islet autoantibody profiles preceding stage 3 type 1 diabetes.

Research Design And Methods: The T1DI (Type 1 Diabetes Intelligence) study combined data from 1,845 genetically susceptible prospectively observed children who were positive for at least one islet autoantibody: insulin autoantibody (IAA), GAD antibody (GADA), or islet antigen 2 antibody (IA-2A). Using a novel similarity algorithm that considers an individual's temporal autoantibody profile, age at autoantibody appearance, and variation in the positivity of autoantibody types, we performed an unsupervised hierarchical clustering analysis. Progression rates to diabetes were analyzed via survival analysis.

Results: We identified five main clusters of individuals with distinct autoantibody profiles characterized by seroconversion age and sequence of appearance of the three autoantibodies. The highest 5-year risk from first positive autoantibody to type 1 diabetes (69.9%; 95% CI 60.0-79.2) was observed in children who first developed IAA in early life (median age 1.6 years) followed by GADA (1.9 years) and then IA-2A (2.1 years). Their 10-year risk was 89.9% (95% CI 81.9-95.4). A high 5-year risk was also found in children with persistent IAA and GADA (39.1%) and children with persistent GADA and IA-2A (30.9%). A lower 5-year risk (10.5%) was observed in children with a late appearance of persistent GADA (6.1 years). The lowest 5-year diabetes risk (1.6%) was associated with positivity for a single, often reverting, autoantibody.

Conclusions: The novel clustering algorithm identified children with distinct islet autoantibody profiles and progression rates to diabetes. These results are useful for prediction, selection of individuals for prevention trials, and studies investigating various pathways to type 1 diabetes.

References

Ziegler A, Rewers M, Simell O, Simell T, Lempainen J, Steck A . Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013; 309(23):2473-9. PMC: 4878912. DOI: 10.1001/jama.2013.6285. View

Wion E, Brantley M, Stevens J, Gallinger S, Peng H, Glass M . Population-wide infant screening for HLA-based type 1 diabetes risk via dried blood spots from the public health infrastructure. Ann N Y Acad Sci. 2003; 1005:400-3. DOI: 10.1196/annals.1288.067. View

Ilonen J, Hammais A, Laine A, Lempainen J, Vaarala O, Veijola R . Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes. 2013; 62(10):3636-40. PMC: 3781470. DOI: 10.2337/db13-0300. View

Senbabaoglu Y, Michailidis G, Li J . Critical limitations of consensus clustering in class discovery. Sci Rep. 2014; 4:6207. PMC: 4145288. DOI: 10.1038/srep06207. View

Kukko M, Kimpimaki T, Korhonen S, Kupila A, Simell S, Veijola R . Dynamics of diabetes-associated autoantibodies in young children with human leukocyte antigen-conferred risk of type 1 diabetes recruited from the general population. J Clin Endocrinol Metab. 2005; 90(5):2712-7. DOI: 10.1210/jc.2004-1371. View

Endesfelder D, Hagen M, Winkler C, Haupt F, Zillmer S, Knopff A . A novel approach for the analysis of longitudinal profiles reveals delayed progression to type 1 diabetes in a subgroup of multiple-islet-autoantibody-positive children. Diabetologia. 2016; 59(10):2172-80. DOI: 10.1007/s00125-016-4050-0. View

Giannopoulou E, Winkler C, Chmiel R, Matzke C, Scholz M, Beyerlein A . Islet autoantibody phenotypes and incidence in children at increased risk for type 1 diabetes. Diabetologia. 2015; 58(10):2317-23. DOI: 10.1007/s00125-015-3672-y. View

Beyerlein A, Bonifacio E, Vehik K, Hippich M, Winkler C, Frohnert B . Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study. J Med Genet. 2018; 56(9):602-605. PMC: 6690814. DOI: 10.1136/jmedgenet-2018-105532. View

Hummel M, Bonifacio E, Schmid S, Walter M, Knopff A, Ziegler A . Brief communication: early appearance of islet autoantibodies predicts childhood type 1 diabetes in offspring of diabetic parents. Ann Intern Med. 2004; 140(11):882-6. DOI: 10.7326/0003-4819-140-11-200406010-00009. View

10.

Insel R, Dunne J, Atkinson M, Chiang J, Dabelea D, Gottlieb P . Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015; 38(10):1964-74. PMC: 5321245. DOI: 10.2337/dc15-1419. View

11.

Bingley P, Wherrett D, Shultz A, Rafkin L, Atkinson M, Greenbaum C . Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use in Type 1 Diabetes. Diabetes Care. 2018; 41(4):653-661. PMC: 5860837. DOI: 10.2337/dc17-0806. View

12.

Endesfelder D, Zu Castell W, Bonifacio E, Rewers M, Hagopian W, She J . Time-Resolved Autoantibody Profiling Facilitates Stratification of Preclinical Type 1 Diabetes in Children. Diabetes. 2018; 68(1):119-130. PMC: 6302536. DOI: 10.2337/db18-0594. View

13.

Anand V, Li Y, Liu B, Ghalwash M, Koski E, Ng K . Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S. Diabetes Care. 2021; . PMC: 8929180. DOI: 10.2337/dc20-1836. View

14.

Bauer W, Veijola R, Lempainen J, Kiviniemi M, Harkonen T, Toppari J . Age at Seroconversion, HLA Genotype, and Specificity of Autoantibodies in Progression of Islet Autoimmunity in Childhood. J Clin Endocrinol Metab. 2019; 104(10):4521-4530. DOI: 10.1210/jc.2019-00421. View

15.

Vehik K, Lynch K, Schatz D, Akolkar B, Hagopian W, Rewers M . Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study. Diabetes Care. 2016; 39(9):1535-42. PMC: 5001144. DOI: 10.2337/dc16-0181. View

16.

Jacobsen L, Larsson H, Tamura R, Vehik K, Clasen J, Sosenko J . Predicting progression to type 1 diabetes from ages 3 to 6 in islet autoantibody positive TEDDY children. Pediatr Diabetes. 2019; 20(3):263-270. PMC: 6456374. DOI: 10.1111/pedi.12812. View

17.

Kohler M, Beyerlein A, Vehik K, Greven S, Umlauf N, Lernmark A . Joint modeling of longitudinal autoantibody patterns and progression to type 1 diabetes: results from the TEDDY study. Acta Diabetol. 2017; 54(11):1009-1017. PMC: 5645259. DOI: 10.1007/s00592-017-1033-7. View

18.

Rewers M, Bugawan T, Norris J, Blair A, Beaty B, Hoffman M . Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY). Diabetologia. 1996; 39(7):807-12. DOI: 10.1007/s001250050514. View

19.

Elding Larsson H . A Swedish approach to the prevention of type 1 diabetes. Pediatr Diabetes. 2016; 17 Suppl 22:73-7. PMC: 5556697. DOI: 10.1111/pedi.12325. View

20.

Parikka V, Nanto-Salonen K, Saarinen M, Simell T, Ilonen J, Hyoty H . Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk. Diabetologia. 2012; 55(7):1926-36. DOI: 10.1007/s00125-012-2523-3. View