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

CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study

10.2337/figshare.17049941 ◽

2021 ◽

Author(s):

Andrea K Steck ◽

Fran Dong ◽

Cristy Geno Rasmussen ◽

Kimberly Bautista ◽

Flor Sepulveda ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Area Under The Curve ◽

Glycemic Variability ◽

Receiver Operating Curve ◽

Clinical Diabetes ◽

Islet Autoantibody ◽

Sensor Glucose ◽

Risk Of Progression

Objective: Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish CGM metrics that could predict imminent progression to diabetes. Methods: In the Autoimmunity Screening for Kids study, 91 children persistently islet autoantibody positive (median age 11.5 y, 48% non-Hispanic White, 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range:0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range:0.4-29 months. Results: Compared to non-progressors, progressors had significantly higher average sensor glucose (119 vs 105 mg/dL) and increased glycemic variability: SD 27 vs 16, CV 21 vs 15, MODD 24 vs 16 and MAGE 43 vs 26. Progressors spent 21% of <a>time above 140 mg/dl </a>(TA140) and 8% above 160 mg/dl, compared to 3% and 1%, respectively, for non-progressors. <a>In survival analyses, the risk of progression to diabetes in one year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. </a><a>Performance of prediction by receiver operating curve analyses showed area under the curve of >0.89 for both individual and combined CGM metric models</a>. Conclusions<a>: </a><a>TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year</a> in autoantibody positive children. CGM should be included in the ongoing monitoring of high-risk children<a></a><a> a</a>nd could be used as potential entry criteria for prevention trials.

Download Full-text

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

10.2337/figshare.16826560.v1 ◽

2021 ◽

Author(s):

Kenney Ng ◽

Harry Stavropoulos ◽

Vibha Anand ◽

Riitta Veijola ◽

Jorma Toppari ◽

...

Keyword(s):

Type 1 Diabetes ◽

Familial Risk ◽

Multivariable Analysis ◽

Diabetes Risk ◽

Islet Autoimmunity ◽

Acid Decarboxylase ◽

Islet Autoantibody ◽

Surveillance Strategy ◽

Risk Of Progression

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.

Download Full-text

CGM Metrics Predict Imminent Progression to Type 1 Diabetes: Autoimmunity Screening for Kids (ASK) Study

10.2337/figshare.17049941.v1 ◽

2021 ◽

Author(s):

Andrea K Steck ◽

Fran Dong ◽

Cristy Geno Rasmussen ◽

Kimberly Bautista ◽

Flor Sepulveda ◽

...

Keyword(s):

Type 1 Diabetes ◽

High Risk ◽

Area Under The Curve ◽

Glycemic Variability ◽

Receiver Operating Curve ◽

Clinical Diabetes ◽

Islet Autoantibody ◽

Sensor Glucose ◽

Risk Of Progression

Objective: Children identified with stage 1 type 1 diabetes are at high risk for progressing to stage 3 (clinical) diabetes and require accurate monitoring. Our aim was to establish CGM metrics that could predict imminent progression to diabetes. Methods: In the Autoimmunity Screening for Kids study, 91 children persistently islet autoantibody positive (median age 11.5 y, 48% non-Hispanic White, 57% female) with a baseline CGM were followed for development of diabetes for a median of 6 (range:0.2-34) months. Of these, 16 (18%) progressed to clinical diabetes in a median of 4.5 (range:0.4-29 months. Results: Compared to non-progressors, progressors had significantly higher average sensor glucose (119 vs 105 mg/dL) and increased glycemic variability: SD 27 vs 16, CV 21 vs 15, MODD 24 vs 16 and MAGE 43 vs 26. Progressors spent 21% of <a>time above 140 mg/dl </a>(TA140) and 8% above 160 mg/dl, compared to 3% and 1%, respectively, for non-progressors. <a>In survival analyses, the risk of progression to diabetes in one year was 80% in those with TA140 >10%; in contrast, it was only 5% in the other participants. </a><a>Performance of prediction by receiver operating curve analyses showed area under the curve of >0.89 for both individual and combined CGM metric models</a>. Conclusions<a>: </a><a>TA140 >10% is associated with a high risk of progression to clinical diabetes within the next year</a> in autoantibody positive children. CGM should be included in the ongoing monitoring of high-risk children<a></a><a> a</a>nd could be used as potential entry criteria for prevention trials.

Download Full-text

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.

Download Full-text

High-affinity ZnT8 autoantibodies by electrochemiluminescence assay improve risk prediction for type 1 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab575 ◽

2021 ◽

Author(s):

Xiaofan Jia ◽

Ling He ◽

Dongmei Miao ◽

Kathleen Waugh ◽

Cristy Geno Rasmussen ◽

...

Keyword(s):

Type 1 Diabetes ◽

Binding Assay ◽

Islet Autoantibody ◽

Newly Diagnosed ◽

High Affinity ◽

Diabetic Children ◽

Risk Of Progression ◽

High Prediction ◽

Znt8 Autoantibodies

Abstract Background The risk of progression to type 1 diabetes (T1D) in subjects positive only for ZnT8 autoantibody (ZnT8A) is currently not known. Methods We developed an electrochemiluminescence (ECL) assay to detect high-affinity ZnT8A and validated it in three populations: 302 patients newly diagnosed with T1D, 135 non-diabetic children positive for ZnT8A by standard radio-binding assay (RBA) among 23400 children screened by the Autoimmunity Screening for Kids (ASK), and 123 non-diabetic children multiple autoantibody positive or single ZnT8A positive by RBA participating in the Diabetes Autoimmunity Study in the Young (DAISY). Results In 302 patients with T1D at diagnosis, the positivity for ZnT8A was 62% in both RBA and ECL. Among ASK 135 participants positive for RBA-ZnT8A, 64 were detected ZnT8A as the only islet autoantibody. Of these 64, only 9 were confirmed by ECL-ZnT8A, found to be of high affinity with increased T1D risk. Overall positive predictive value of ECL-ZnT8A for T1D risk was 87.1%, significantly higher than that of RBA-ZnT8A (53.5%, P<0.0001). In DAISY, 11/2547 children who had no positivity previously detected for other islet autoantibodies were identified as single ZnT8A by RBA; of these, three were confirmed positive by ECL-ZnT8A and all three progressed to clinical T1D. Conclusions Large proportion of ZnT8A by RBA are single ZnT8A with low T1D risk while ZnT8A by ECL were of high-affinity and high prediction for T1D development.

Download Full-text

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

10.2337/figshare.16826560 ◽

2021 ◽

Author(s):

Kenney Ng ◽

Harry Stavropoulos ◽

Vibha Anand ◽

Riitta Veijola ◽

Jorma Toppari ◽

...

Keyword(s):

Type 1 Diabetes ◽

Familial Risk ◽

Multivariable Analysis ◽

Diabetes Risk ◽

Islet Autoimmunity ◽

Acid Decarboxylase ◽

Islet Autoantibody ◽

Surveillance Strategy ◽

Risk Of Progression

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.

Download Full-text

1116-P: Macronutrient Intake and Risk of Progression to Type 1 Diabetes in TrialNet

Diabetes ◽

10.2337/db21-1116-p ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 1116-P

Author(s):

ERIKA L. LUNDGRIN ◽

ANURADHA VISWANATHAN ◽

SUZANNE B. JOHNSON ◽

JILL M. NORRIS ◽

HEBA M. ISMAIL ◽

...

Keyword(s):

Type 1 Diabetes ◽

Macronutrient Intake ◽

Risk Of Progression

Download Full-text

243-OR: Integrating Genetic Risk Score and Islet Autoantibody Characteristics in the Predictive Model for Type 1 Diabetes in the TrialNet Study

Diabetes ◽

10.2337/db21-243-or ◽

2021 ◽

Vol 70 (Supplement 1) ◽

pp. 243-OR

Author(s):

LAURIC A. FERRAT ◽

ANDREA STECK ◽

HEMANG M. PARIKH ◽

LU YOU ◽

SUNA ONENGUT-GUMUSCU ◽

...

Keyword(s):

Type 1 Diabetes ◽

Predictive Model ◽

Risk Score ◽

Genetic Risk ◽

Genetic Risk Score ◽

Islet Autoantibody

Download Full-text

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

Download Full-text

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.

Download Full-text