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; Toppari, Jorma; Maziarz, Marlena; Lundgren, Markus; Waugh, Kathy; Frohnert, Brigitte I.; Martin, Frank B.; Hagopian, William; Achenbach, Peter

doi:10.2337/dc21-0878

Cited by 12 publications

(13 citation statements)

References 37 publications

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“…The case children in this set included 54 children who developed IAA as the first appearing islet autoantibody (26% girls) and 57 children who developed GADA as the first‐appearing autoantibody (40.3% girls), representing the two main endotypes of T1D (IAA‐first or GADA‐first endotypes). Individuals testing positive for multiple autoantibodies are highly likely to progress to T1D 32–35 …”

Section: Methodsmentioning

confidence: 99%

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HLA‐DQ‐conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine

Sioofy‐Khojine

Lehtonen

Nurminen

et al. 2023

Journal of Medical Virology

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This study investigated whether children with HLA-DQ-conferred risk for type 1 diabetes (T1D) have an altered immune response to the widely-used enterovirus vaccine, namely poliovirus vaccine, and whether initiation of autoimmunity to pancreatic islets modulates this response. Neutralizing antibodies induced by the inactivated poliovirus vaccine against poliovirus type 1 (Salk) were analysed as a marker of protective immunity at the age of 18 months in a prospective birth cohort. No differences were observed in antibody titers between children with and without genetic risk for T1D (odds ratio[OR] = 0.90 [0.83, 1.06], p = 0.30). In the presence of the genetic risk, no difference was observed between children with and without islet autoimmunity (OR = 1.00 [0.78, 1.28], p = 1.00). This did not change when only children with the autoimmunity before 18 months of age were included in the analyses (OR = 1.00 [0.85, 1.18], p = 1.00). No effect was observed when groups were stratified based on autoantigen specificity of the first-appearing autoantibody (IAA or GADA). The children in each comparison group were matched for sex,

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Section: Methodsmentioning

confidence: 99%

“…Individuals testing positive for multiple autoantibodies are highly likely to progress to T1D. [32][33][34][35] The age at seroconversion in the two endotypes was, as…”

Section: Hla Risk-matched Seriesmentioning

confidence: 99%

HLA‐DQ‐conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine

Sioofy‐Khojine

Lehtonen

Nurminen

et al. 2023

Journal of Medical Virology

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“…We and others have shown the value of IA-2A, HbA 1c and intermediate OGTT time points in stratifying risk in islet autoantibody-positive individuals who are genetically at risk for type 1 diabetes [23][24][25][26][27][28][29][30][31][32][33]. Some have developed scores that can stratify risk in relatives with either stage 1 or stage 2 type 1 diabetes [31][32][33].…”

Section: Discussionmentioning

confidence: 99%

Progression likelihood score identifies substages of presymptomatic type 1 diabetes in childhood public health screening

Weiß

Zapardiel‐Gonzalo²,

Voß³

et al. 2022

Diabetologia

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Aims/hypothesis The aim of this study was to develop strategies that identify children from the general population who have late-stage presymptomatic type 1 diabetes and may, therefore, benefit from immune intervention. Methods We tested children from Bavaria, Germany, aged 1.75–10 years, enrolled in the Fr1da public health screening programme for islet autoantibodies (n=154,462). OGTT and HbA1c were assessed in children with multiple islet autoantibodies for diagnosis of presymptomatic stage 1 (normoglycaemia) or stage 2 (dysglycaemia) type 1 diabetes. Cox proportional hazards and penalised logistic regression of autoantibody, genetic, metabolic and demographic information were used to develop a progression likelihood score to identify children with stage 1 type 1 diabetes who progressed to stage 3 (clinical) type 1 diabetes within 2 years. Results Of 447 children with multiple islet autoantibodies, 364 (81.4%) were staged. Undiagnosed stage 3 type 1 diabetes, presymptomatic stage 2, and stage 1 type 1 diabetes were detected in 41 (0.027% of screened children), 30 (0.019%) and 293 (0.19%) children, respectively. The 2 year risk for progression to stage 3 type 1 diabetes was 48% (95% CI 34, 58) in children with stage 2 type 1 diabetes (annualised risk, 28%). HbA1c, islet antigen-2 autoantibody positivity and titre, and the 90 min OGTT value were predictors of progression in children with stage 1 type 1 diabetes. The derived progression likelihood score identified substages corresponding to ≤90th centile (stage 1a, n=258) and >90th centile (stage 1b, n=29; 0.019%) of stage 1 children with a 4.1% (95% CI 1.4, 6.7) and 46% (95% CI 21, 63) 2 year risk of progressing to stage 3 type 1 diabetes, respectively. Conclusions/interpretation Public health screening for islet autoantibodies found 0.027% of children to have undiagnosed clinical type 1 diabetes and 0.038% to have undiagnosed presymptomatic type 1 diabetes. Of the latter group, our novel likelihood ratio score predicted approximately 50% risk of developing clinical diabetes within 2 years. Graphical abstract

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“…The methods used by each study to measure IAA, GADA and IA-2A have been previously described [ 18 ]. Autoantibody levels for IAA, GADA, and IA-2A from the individual T1DI constituent studies were converted to multiples of the upper limit of normal (mULN) to facilitate comparisons, and were combined for analysis as previously described [ 17 ]. All mULN values, regardless of whether they were above or below the autoantibody positivity threshold, were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous work [ 17 ], we harmonised IAb levels from our large, prospective Type 1 Diabetes Intelligence (T1DI) study cohort [ 18 ], identified the IAb type-specific titre thresholds (measured at the time of confirmed positivity) that maximised discrimination of 5-year type 1 diabetes risk, and used the thresholds to risk-stratify children in various age groups via survival analysis. This prior work demonstrated that IAb levels were useful in predicting type 1 diabetes onset, and motivated us to perform a more comprehensive assessment of the utility of measurement of IAb levels.…”

Section: Introductionmentioning

confidence: 99%

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children

Ng¹,

Anand²,

Stavropoulos³

et al. 2022

Diabetologia

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Aims/hypothesis The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children. Methods Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap. Results A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up. Conclusions/interpretation Consideration of quantitative patterns of IAb levels improved the predictive power for type 1 diabetes in IAb-positive children beyond qualitative IAb positivity status. Graphical abstract

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

Cited by 12 publications

References 37 publications

HLA‐DQ‐conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine

HLA‐DQ‐conferred risk for type 1 diabetes does not alter neutralizing antibody response to a widely used enterovirus vaccine, the poliovirus vaccine

Progression likelihood score identifies substages of presymptomatic type 1 diabetes in childhood public health screening

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children

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