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

OBJECTIVE: To utilize 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 US 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), glutamic acid decarboxylase (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=909), GADA (n=1076) or IA-2A (n=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=954) and multiple (n=527) autoantibodies could be stratified from 6% to 75% (p<0.0001). The thresholds effectively identified children with 50% or higher 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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Cord-Blood Lipidome in Progression to Islet Autoimmunity and Type 1 Diabetes

Biomolecules ◽

10.3390/biom9010033 ◽

2019 ◽

Vol 9 (1) ◽

pp. 33 ◽

Cited By ~ 10

Author(s):

Santosh Lamichhane ◽

Linda Ahonen ◽

Thomas Sparholt Dyrlund ◽

Alex M. Dickens ◽

Heli Siljander ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cord Blood ◽

Characteristic Curve ◽

Newborn Infants ◽

Study Groups ◽

Islet Autoimmunity ◽

Molecular Profile ◽

Islet Autoantibody ◽

Risk Of Progression

Previous studies suggest that children who progress to type 1 diabetes (T1D) later in life already have an altered serum lipid molecular profile at birth. Here, we compared cord blood lipidome across the three study groups: children who progressed to T1D (PT1D; n = 30), children who developed at least one islet autoantibody but did not progress to T1D during the follow-up (P1Ab; n = 33), and their age-matched controls (CTR; n = 38). We found that phospholipids, specifically sphingomyelins, were lower in T1D progressors when compared to P1Ab and the CTR. Cholesterol esters remained higher in PT1D when compared to other groups. A signature comprising five lipids was predictive of the risk of progression to T1D, with an area under the receiver operating characteristic curve (AUROC) of 0.83. Our findings provide further evidence that the lipidomic profiles of newborn infants who progress to T1D later in life are different from lipidomic profiles in P1Ab and CTR.

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Immunization profiles and progression of islet autoimmunity in children at type 1 diabetes risk

Diabetologie und Stoffwechsel ◽

10.1055/s-0032-1314464 ◽

2012 ◽

Vol 7 (S 01) ◽

Author(s):

R Chmiel ◽

S Krause ◽

A Knopff ◽

C Matzke ◽

D Höfelmann ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Risk ◽

Islet Autoimmunity

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Stratification of Type 1 Diabetes Risk on the Basis of Islet Autoantibody Characteristics

Diabetes ◽

10.2337/diabetes.53.2.384 ◽

2004 ◽

Vol 53 (2) ◽

pp. 384-392 ◽

Cited By ~ 171

Author(s):

P. Achenbach ◽

K. Warncke ◽

J. Reiter ◽

H. E. Naserke ◽

A. J.K. Williams ◽

...

Keyword(s):

Type 1 Diabetes ◽

Diabetes Risk ◽

Islet Autoantibody

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An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

10.2337/figshare.13643756 ◽

2021 ◽

Author(s):

Ezio Bonifacio ◽

Andreas Weiß ◽

Christiane Winkler ◽

Markus Hippich ◽

Marian J. Rewers ◽

...

Keyword(s):

Type 1 Diabetes ◽

Confidence Interval ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Age Related ◽

At Risk Children ◽

Exponential Decline ◽

Design And Methods

Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes. Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

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Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105532 ◽

2018 ◽

Vol 56 (9) ◽

pp. 602-605 ◽

Cited By ~ 4

Author(s):

Andreas Beyerlein ◽

Ezio Bonifacio ◽

Kendra Vehik ◽

Markus Hippich ◽

Christiane Winkler ◽

...

Keyword(s):

Type 1 Diabetes ◽

Risk Score ◽

Genetic Risk ◽

Genetic Factors ◽

Genetic Risk Score ◽

Risk Scores ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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

Diabetes Care ◽

10.2337/dc21-0878 ◽

2021 ◽

pp. dc210878

Author(s):

Kenney Ng ◽

Harry Stavropoulos ◽

Vibha Anand ◽

Riitta Veijola ◽

Jorma Toppari ◽

...

Keyword(s):

Type 1 Diabetes ◽

Islet Autoantibody ◽

Risk Of Progression

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An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood

10.2337/figshare.13643756.v1 ◽

2021 ◽

Author(s):

Ezio Bonifacio ◽

Andreas Weiß ◽

Christiane Winkler ◽

Markus Hippich ◽

Marian J. Rewers ◽

...

Keyword(s):

Type 1 Diabetes ◽

Confidence Interval ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Age Related ◽

At Risk Children ◽

Exponential Decline ◽

Design And Methods

Objective. Islet autoimmunity develops prior to clinical type 1 diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic type 1 diabetes. Research Design and Methods. The Environmental Determinants of Diabetes in the Young study prospectively followed 8,556 genetically at-risk children at 3–6-month intervals from birth for the development of islet autoantibodies and type 1 diabetes. The age-related change in the risk of developing islet autoantibodies was determined using landmark and regression models. Results. The 5-year risk of developing multiple islet autoantibodies was 4.3% (95% confidence interval, 3.8–4.7) at 7.5 months of age and declined to 1.1% (95% confidence interval, 0.8–1.3) at a landmark age of 6.25 years (P<0.0001). Risk decline was slight or absent in single insulin- and GAD-autoantibody phenotypes. The influence of sex, HLA and other susceptibility genes on risk subsided with increasing age and was abrogated by age six years. Highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for type 1 diabetes was achieved by autoantibody screening at 2 years and again at 5–7 years of age. Conclusions. The risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.

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Respiratory Infections in Early Life and the Development of Islet Autoimmunity in Children at Increased Type 1 Diabetes Risk

JAMA Pediatrics ◽

10.1001/jamapediatrics.2013.158 ◽

2013 ◽

Vol 167 (9) ◽

pp. 800 ◽

Cited By ~ 45

Author(s):

Andreas Beyerlein ◽

Fabienne Wehweck ◽

Anette-Gabriele Ziegler ◽

Maren Pflueger

Keyword(s):

Type 1 Diabetes ◽

Early Life ◽

Respiratory Infections ◽

Diabetes Risk ◽

Islet Autoimmunity

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Circulating Metabolites in Progression to Islet Autoimmunity and Type 1 Diabetes

10.1101/496943 ◽

2018 ◽

Cited By ~ 1

Author(s):

Santosh Lamichhane ◽

Esko Kemppainen ◽

Kajetan Trost ◽

Heli Siljander ◽

Heikki Hyoty ◽

...

Keyword(s):

Type 1 Diabetes ◽

Study Groups ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Metabolic Disturbances ◽

Longitudinal Plasma ◽

Sugar Derivatives ◽

Negative Controls

Previous studies suggest that metabolic dysregulation precedes the onset of type 1 diabetes (T1D). However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. Here we analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to T1D (PT1D), who seroconverted to one islet autoantibody (Ab) but not to T1D (P1Ab), and Ab-negative controls (CTR). In early infancy, PT1D associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, as compared to CTR. Methionine remained persistently upregulated in PT1D as compared to CTR and P1Ab. Appearance of islet autoantibodies associated with decreased glutamic and aspartic acids. Our findings suggest that children who progress to T1D have a unique metabolic profile, which is however altered with the onset of islet autoantibodies. Our findings may assist in early prediction of T1D.

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