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

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

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Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes

BMC Pediatrics ◽

10.1186/1471-2431-13-124 ◽

2013 ◽

Vol 13 (1) ◽

Cited By ~ 34

Author(s):

Megan AS Penno ◽

◽

Jennifer J Couper ◽

Maria E Craig ◽

Peter G Colman ◽

...

Keyword(s):

At Risk ◽

Type 1 Diabetes ◽

Cohort Study ◽

Early Life ◽

Islet Autoimmunity ◽

Children At Risk ◽

Environmental Determinants

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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.

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Higher ultraviolet radiation during early life is associated with lower risk of childhood type 1 diabetes among boys

Scientific Reports ◽

10.1038/s41598-021-97469-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kate M. Miller ◽

Prue H. Hart ◽

Robyn M. Lucas ◽

Elizabeth A. Davis ◽

Nicholas H. de Klerk

Keyword(s):

Type 1 Diabetes ◽

Ultraviolet Radiation ◽

Western Australia ◽

Early Life ◽

Case Control ◽

Diabetes Risk ◽

First Year ◽

Lower Type ◽

First Year Of Life

AbstractPopulation-level ecological studies show type 1 diabetes incidence is inversely correlated with ambient ultraviolet radiation (UVR) levels. We conducted a nested case–control study using administrative datasets to test this association at the individual level. Cases (n = 1819) were children born in Western Australia (WA) from 1980–2014, diagnosed with type 1 diabetes at ≤ 16 years. Controls (n = 27,259) were randomly selected from all live births in WA, matched to cases by sex and date of birth. Total ambient erythemal ultraviolet radiation (UVR) doses for each trimester of pregnancy and first year of life were estimated for each individual, using daily NASA satellite data that were date- and geographically-specific. Conditional logistic regression tested the association between UVR dose and case–control status. Type 1 diabetes risk was 42% lower in boys of mothers with third-trimester UVR dose in the highest (compared to the lowest) quartile (p = 0.04). Higher UVR in the first year of life was associated with lower type 1 diabetes risk among boys (p = 0.01). UVR dose was not associated with type 1 diabetes risk in girls. Higher UVR in late pregnancy and early life appear to interact with sex-specific factors to lower type 1 diabetes risk among boys in Western Australia.

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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.

10.2337/figshare.14384324.v3 ◽

2021 ◽

Author(s):

Vibha Anand ◽

Ying Li ◽

Bin Liu ◽

Mohamed Ghalwash ◽

Eileen Koski ◽

...

Keyword(s):

Type 1 Diabetes ◽

Cohort Studies ◽

Prospective Cohort ◽

Diabetes Risk ◽

Islet Autoantibodies ◽

Islet Autoimmunity ◽

Diabetes Incidence ◽

Prospective Cohort Studies ◽

Hla Dr

OBJECTIVE: To combine prospective cohort studies, by including HLA harmonization, and to estimate risk of islet autoimmunity and progression to clinical diabetes. RESEARCH DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US have followed 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years. RESULTS: In the infant-toddler cohort, 1413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two or three autoantibodies at seroconversion: 45% (95% CI 40-52%), 85% (78-90%), and 92% (85-97%), respectively. Among those with single autoantibody, their status two years after seroconversion predicted diabetes risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if retaining single autoantibody, and 82% (80-95%) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single autoantibody. Their 15-year diabetes incidence for higher vs. lower risk genotypes was 40% (28-50%) vs. 12% (5-38%). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies ranging from 20%/year to 6%/year in children developing multi-positivity ≤2 years or >7.4 years, respectively. CONCLUSIONS: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

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