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Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children

Ng, Kenney ; Stavropoulos, Harry ; Anand, Vibha ; Veijola, Riitta LU ; Toppari, Jorma ; Maziarz, Marlena LU ; Lundgren, Markus LU ; Waugh, Kathy ; Frohnert, Brigitte I. and Martin, Frank , et al. (2022) In Diabetes Care 45(1). p.160-168
Abstract

OBJECTIVE To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n 5 909), GADA (n 5 1,076), and IA-2A (n 5 714), when stratified by quartiles of titer,... (More)

OBJECTIVE To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n 5 909), GADA (n 5 1,076), and IA-2A (n 5 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n 5 954) and multiple (n 5 527) autoantibodies could be stratified from 6 to 75% (P < 0.0001). The thresholds effectively identified children with a ‡50% 5-year risk when considering age-specific autoantibody screening (57–65% positive predictive value and 56–74% sensitivity for ages 1–5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. CONCLUSIONS This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.

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type
Contribution to journal
publication status
published
subject
in
Diabetes Care
volume
45
issue
1
pages
160 - 168
publisher
American Diabetes Association
external identifiers
  • scopus:85122816872
  • pmid:34758977
ISSN
0149-5992
DOI
10.2337/dc21-0878
language
English
LU publication?
yes
additional info
Funding Information: This work was supported by funding fromJDRF (IBM: 1-RSC-2017-368-I-X, 1-IND-2019-717-I-X; DAISY: 1-SRA-2019-722-I-X, 1-RSC-2017-517-I-X, 5-ECR-2017-388-A-N; DiPiS: 1-SRA-2019-720-I-X, 1-RSC-2017-526-I-X; DIPP: 1-RSC-2018-555-I-X, 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B; and DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) as well as National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DAISY: DK032493, DK032083, DK104351, and DK116073; DiPiS: DK26190) and the Centers for Disease Control and Prevention (DEW-IT: UR6/CCU017247). The DIPP study was also funded by European Union (grant BMH4-CT98-3314), Novo Nordisk Foundation, Academy of Finland (Decision No. 292538 and Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114), Special Research Funds for University Hospitals in Finland, Diabetes Research Foundation, Finland, and Sigrid Juselius Foundation, Finland. The BABYDIAB study was funded by the German Federal Ministry of Education and Research to the German Center for Diabetes Research. The DiPiS study was funded by Swedish Research Council (grant no. 14064), Swedish Childhood Diabetes Foundation, Swedish Diabetes Association, Nordisk Insulin Fund, Sk?ne University Hospital Fund, Lions Club International, district 101-S, The Royal Physiographic Society, Sk?ne County Council Foundation for Research and Development, as well as Lund University Diabetes Centre Industrial Research Centre/EXODIAB funding from the Swedish Foundation for Strategic Research (DNR IRC15-0067) and the Stiftelsen f?or Strategisk Forskning (DNR 2009-1039). Additional funding for DEW-IT was provided by the Hussman Foundation and by the Washington State Life Science Discovery Fund. Funding Information: Acknowledgments. The authors thank the participants of the DAISY, DiPiS, DIPP, DEW-IT, and BABYDIAB studies. Funding. This work was supported by funding fromJDRF (IBM: 1-RSC-2017-368-I-X, 1-IND-2019-717-I-X; DAISY: 1-SRA-2019-722-I-X, 1-RSC-2017-517-I-X, 5-ECR-2017-388-A-N; DiPiS: 1-SRA-2019-720-I-X, 1-RSC-2017-526-I-X; DIPP: 1-RSC-2018-555-I-X, 1-SRA-2016-342-M-R, 1-SRA-2019-732-M-B; and DEW-IT: 1-SRA-2019-719-I-X, 1-RSC-2017-516-I-X) as well as National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases (DAISY: DK032493, DK032083, DK104351, and DK116073; DiPiS: DK26190) and the Centers for Disease Control and Prevention (DEW-IT: UR6/CCU017247). The DIPP study was also funded by European Union (grant BMH4-CT98-3314), Novo Nordisk Foundation, Academy of Finland (Decision No. 292538 and Centre of Excellence in Molecular Systems Immunology and Physiology Research 2012-2017, Decision No. 250114), Special Research Funds for University Hospitals in Finland, Diabetes Research Foundation, Finland, and Sigrid Juselius Foundation, Finland. The BABYDIAB study was funded by the German Federal Ministry of Education and Research to the German Center for Diabetes Research. The DiPiS study was funded by Swedish Research Council (grant no. 14064), Swedish Childhood Diabetes Foundation, Swedish Diabetes Association, Nordisk Insulin Fund, Skåne University Hospital Fund, Lions Club International, district 101-S, The Royal Physiographic Society, Skåne County Council Foundation for Research and Development, as well as Lund University Diabetes Centre Industrial Research Centre/EXODIAB funding from the Swedish Foundation for Strategic Research (DNR IRC15-0067) and the Stiftelsen fo€r Strategisk For-skning (DNR 2009-1039). Additional funding for DEW-IT was provided by the Hussman Foundation and by the Washington State Life Science Discovery Fund. Duality of Interest. K.N., H.S., and V.A. are employed by IBM Research. No other potential conflicts of interest relevant to this article were reported. Publisher Copyright: © 2021 by the American Diabetes Association.
id
d74671fe-5ced-4f6d-8d17-a88d640e2a6c
date added to LUP
2022-02-20 11:09:59
date last changed
2024-06-07 15:23:56
@article{d74671fe-5ced-4f6d-8d17-a88d640e2a6c,
  abstract     = {{<p>OBJECTIVE To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children. RESEARCH DESIGN AND METHODS Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses. RESULTS Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA (n 5 909), GADA (n 5 1,076), and IA-2A (n 5 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single (n 5 954) and multiple (n 5 527) autoantibodies could be stratified from 6 to 75% (P &lt; 0.0001). The thresholds effectively identified children with a ‡50% 5-year risk when considering age-specific autoantibody screening (57–65% positive predictive value and 56–74% sensitivity for ages 1–5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy. CONCLUSIONS This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.</p>}},
  author       = {{Ng, Kenney and Stavropoulos, Harry and Anand, Vibha and Veijola, Riitta and Toppari, Jorma and Maziarz, Marlena and Lundgren, Markus and Waugh, Kathy and Frohnert, Brigitte I. and Martin, Frank and Hagopian, William and Achenbach, Peter}},
  issn         = {{0149-5992}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{160--168}},
  publisher    = {{American Diabetes Association}},
  series       = {{Diabetes Care}},
  title        = {{Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children}},
  url          = {{http://dx.doi.org/10.2337/dc21-0878}},
  doi          = {{10.2337/dc21-0878}},
  volume       = {{45}},
  year         = {{2022}},
}