Consensus guidance for monitoring individuals with islet autoantibody-positive pre-stage 3 type 1 diabetes.

Given the proven benefits of screening to reduce diabetic ketoacidosis (DKA) likelihood at the time of stage 3 type 1 diabetes diagnosis, and emerging availability of therapy to delay disease progression, type 1 diabetes screening programmes are being increasingly emphasised. Once broadly implemented, screening initiatives will identify significant numbers of islet autoantibody-positive (IAb+) children and adults who are at risk of (confirmed single IAb+) or living with (multiple IAb+) early-stage (stage 1 and stage 2) type 1 diabetes. These individuals will need monitoring for disease progression; much of this care will happen in non-specialised settings. To inform this monitoring, JDRF in conjunction with international experts and societies developed consensus guidance. Broad advice from this guidance includes the following: (1) partnerships should be fostered between endocrinologists and primary-care providers to care for people who are IAb+; (2) when people who are IAb+ are initially identified there is a need for confirmation using a second sample; (3) single IAb+ individuals are at lower risk of progression than multiple IAb+ individuals; (4) individuals with early-stage type 1 diabetes should have periodic medical monitoring, including regular assessments of glucose levels, regular education about symptoms of diabetes and DKA, and psychosocial support; (5) interested people with stage 2 type 1 diabetes should be offered trial participation or approved therapies; and (6) all health professionals involved in monitoring and care of individuals with type 1 diabetes have a responsibility to provide education. The guidance also emphasises significant unmet needs for further research on early-stage type 1 diabetes to increase the rigour of future recommendations and inform clinical care.

CVOT Summit Report 2023: new cardiovascular, kidney, and metabolic outcomes.

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

Infection episodes and islet autoantibodies in children at increased risk for type 1 diabetes before and during the COVID-19 pandemic.

OBJECTIVES: To determine the impact of the COVID-19 pandemic on the incidence rates of infection and islet autoimmunity in children at risk for type 1 diabetes. METHODS: 1050 children aged 4 to 7 months with an elevated genetic risk for type 1 diabetes were recruited from Germany, Poland, Sweden, Belgium and the UK. Reported infection episodes and islet autoantibody development were monitored until age 40 months from February 2018 to February 2023. RESULTS: The overall infection rate was 311 (95% Confidence Interval [CI], 304-318) per 100 person years. Infection rates differed by age, country, family history of type 1 diabetes, and period relative to the pandemic. Total infection rates were 321 per 100 person-years (95% CI 304-338) in the pre-pandemic period (until February 2020), 160 (95% CI 148-173) per 100 person-years in the first pandemic year (March 2020-February 2021; P < 0.001) and 337 (95% CI 315-363) per 100 person-years in subsequent years. Similar trends were observed for respiratory and gastrointestinal infections. Islet autoantibody incidence rates were 1.6 (95% CI 1.0-2.4) per 100 person-years in the pre-pandemic period, 1.2 (95% CI 0.8-1.9) per 100 person-years in the first pandemic year (P = 0.46), and 3.4 (95% CI 2.3-4.8) per 100 person-years in subsequent years (P = 0.005 vs. pre-pandemic year; P < 0.001 vs. first pandemic year). CONCLUSIONS: The COVID-19 pandemic was associated with significantly altered infection patterns. Islet autoantibody incidence rates increased two-fold when infection rates returned to pre-pandemic levels.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/Objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI. Research Design and Methods: Genetically at-risk children (n = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually. Of these, 495 (9.7%) children developed IA. Mediation analysis for time-varying covariates (BMI z-score) and exposure (energy intake) was conducted. Cox proportional hazard method was used in sensitivity analysis. Results: We found an indirect effect of total energy intake (estimates: indirect effect 0.13 [0.05, 0.21]) and energy from protein (estimates: indirect effect 0.06 [0.02, 0.11]), fat (estimates: indirect effect 0.03 [0.01, 0.05]), and carbohydrates (estimates: indirect effect 0.02 [0.00, 0.04]) (kcal/day) on the development of IA. A direct effect was found for protein, expressed both as kcal/day (estimates: direct effect 1.09 [0.35, 1.56]) and energy percentage (estimates: direct effect 72.8 [3.0, 98.0]) and the development of GAD autoantibodies (GADA). In the sensitivity analysis, energy from protein (kcal/day) was associated with increased risk for GADA, hazard ratio 1.24 (95% CI: 1.09, 1.53), p = 0.042. Conclusions: This study confirms that higher total energy intake is associated with higher BMI, which leads to higher risk of the development of IA. A diet with larger proportion of energy from protein has a direct effect on the development of GADA.

The association of physical activity to oral glucose tolerance test outcomes in multiple autoantibody positive children: The TEDDY Study.

OBJECTIVE: To examine the association of physical activity (PA), measured by accelerometry, to hemoglobin AIC (HbA1c) and oral glucose tolerance test (OGTT) outcomes in children who were multiple persistent confirmed autoantibody positive for type 1 diabetes (T1D). METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) multinational study followed children from birth. Children ≥3 years of age who were multiple persistent confirmed autoantibody positive were monitored by OGTTs every 6 months. TEDDY children's PA was measured by accelerometry beginning at 5 years of age. We examined the relationship between moderate plus vigorous (mod + vig) PA, HbA1c, and OGTT in 209 multiple autoantibody children who had both OGTT and PA measurements. RESULTS: Mod + vig PA was associated with both glucose and C-peptide measures (fasting, 120-min, and AUC); higher mod + vig PA was associated with a better OGTT response primarily in children with longer duration of multiple autoantibody positivity. Mod + vig PA also interacted with child age; lower mod + vig PA was associated with a greater increase in C-peptide response across age. Mod + vig PA was not related to fasting insulin, HOMA-IR or HbA1c. CONCLUSIONS: The OGTT is the gold standard for diabetes diagnosis and is used to monitor those at high risk for T1D. We found higher levels of mod + vig PA were associated with better OGTT outcomes in children ≥5 years of age who have been multiple autoantibody positive for longer periods of time. Physical activity should be the focus of future efforts to better understand the determinants of disease progression in high-risk children.

HbA1c as a time predictive biomarker for an additional islet autoantibody and type 1 diabetes in seroconverted TEDDY children.

OBJECTIVE: Increased level of glycated hemoglobin (HbA1c) is associated with type 1 diabetes onset that in turn is preceded by one to several autoantibodies against the pancreatic islet beta cell autoantigens; insulin (IA), glutamic acid decarboxylase (GAD), islet antigen-2 (IA-2) and zinc transporter 8 (ZnT8). The risk for type 1 diabetes diagnosis increases by autoantibody number. Biomarkers predicting the development of a second or a subsequent autoantibody and type 1 diabetes are needed to predict disease stages and improve secondary prevention trials. This study aimed to investigate whether HbA1c possibly predicts the progression from first to a subsequent autoantibody or type 1 diabetes in healthy children participating in the Environmental Determinants of Diabetes in the Young (TEDDY) study. RESEARCH DESIGN AND METHODS: A joint model was designed to assess the association of longitudinal HbA1c levels with the development of first (insulin or GAD autoantibodies) to a second, second to third, third to fourth autoantibody or type 1 diabetes in healthy children prospectively followed from birth until 15 years of age. RESULTS: It was found that increased levels of HbA1c were associated with a higher risk of type 1 diabetes (HR 1.82, 95% CI [1.57-2.10], p < 0.001) regardless of first appearing autoantibody, autoantibody number or type. A decrease in HbA1c levels was associated with the development of IA-2A as a second autoantibody following GADA (HR 0.85, 95% CI [0.75, 0.97], p = 0.017) and a fourth autoantibody following GADA, IAA and ZnT8A (HR 0.90, 95% CI [0.82, 0.99], p = 0.036). HbA1c trajectory analyses showed a significant increase of HbA1c over time (p < 0.001) and that the increase is more rapid as the number of autoantibodies increased from one to three (p < 0.001). CONCLUSION: In conclusion, increased HbA1c is a reliable time predictive marker for type 1 diabetes onset. The increased rate of increase of HbA1c from first to third autoantibody and the decrease in HbA1c predicting the development of IA-2A are novel findings proving the link between HbA1c and the appearance of autoantibodies.

Is staff consistency important to parents' satisfaction in a longitudinal study of children at risk for type 1 diabetes: the TEDDY study.

BACKGROUND: Participants' study satisfaction is important for both compliance with study protocols and retention, but research on parent study satisfaction is rare. This study sought to identify factors associated with parent study satisfaction in The Environmental Determinants of Diabetes in the Young (TEDDY) study, a longitudinal, multinational (US, Finland, Germany, Sweden) study of children at risk for type 1 diabetes. The role of staff consistency to parent study satisfaction was a particular focus. METHODS: Parent study satisfaction was measured by questionnaire at child-age 15 months (5579 mothers, 4942 fathers) and child-age four years (4010 mothers, 3411 fathers). Multiple linear regression analyses were used to identify sociodemographic factors, parental characteristics, and study variables associated with parent study satisfaction at both time points. RESULTS: Parent study satisfaction was highest in Sweden and the US, compared to Finland. Parents who had an accurate perception of their child's type 1 diabetes risk and those who believed they can do something to prevent type 1 diabetes were more satisfied. More educated parents and those with higher depression scores had lower study satisfaction scores. After adjusting for these factors, greater study staff change frequency was associated with lower study satisfaction in European parents (mothers at child-age 15 months: - 0.30,95% Cl - 0.36, - 0.24, p < 0.001; mothers at child-age four years: -0.41, 95% Cl - 0.53, - 0.29, p < 0.001; fathers at child-age 15 months: -0.28, 95% Cl - 0.34, - 0.21, p < 0.001; fathers at child-age four years: -0.35, 95% Cl - 0.48, - 0.21, p < 0.001). Staff consistency was not associated with parent study satisfaction in the US. However, the number of staff changes was markedly higher in the US compared to Europe. CONCLUSIONS: Sociodemographic factors, parental characteristics, and study-related variables were all related to parent study satisfaction. Those that are potentially modifiable are of particular interest as possible targets of future efforts to improve parent study satisfaction. Three such factors were identified: parent accuracy about the child's type 1 diabetes risk, parent beliefs that something can be done to reduce the child's risk, and study staff consistency. However, staff consistency was important only for European parents. TRIAL REGISTRATION: NCT00279318 .

Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident ß-cell autoantibodies.

ß-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing ß-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first ß-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3-4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing ß-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing ß-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged ≥2 years. Gestational infections were not associated with the first appearing ß-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45-0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing ß-cell autoantibody in early life.

Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden.

Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA), or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radio binding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA, and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615), and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (P = 0.007) and GADA (P < 0.001), but not with IA-2A (P = 0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (P = 0.002) and GADA (P < 0.001), but not of IA-2A (P = 0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer. In conclusion, LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild. J. Med. Virol. 89:24-31, 2017. © 2016 Wiley Periodicals, Inc.

Building and validating a prediction model for paediatric type 1 diabetes risk using next generation targeted sequencing of class II HLA genes.

AIM: It is of interest to predict possible lifetime risk of type 1 diabetes (T1D) in young children for recruiting high-risk subjects into longitudinal studies of effective prevention strategies. METHODS: Utilizing a case-control study in Sweden, we applied a recently developed next generation targeted sequencing technology to genotype class II genes and applied an object-oriented regression to build and validate a prediction model for T1D. RESULTS: In the training set, estimated risk scores were significantly different between patients and controls (P = 8.12 × 10-92 ), and the area under the curve (AUC) from the receiver operating characteristic (ROC) analysis was 0.917. Using the validation data set, we validated the result with AUC of 0.886. Combining both training and validation data resulted in a predictive model with AUC of 0.903. Further, we performed a "biological validation" by correlating risk scores with 6 islet autoantibodies, and found that the risk score was significantly correlated with IA-2A (Z-score = 3.628, P < 0.001). When applying this prediction model to the Swedish population, where the lifetime T1D risk ranges from 0.5% to 2%, we anticipate identifying approximately 20 000 high-risk subjects after testing all newborns, and this calculation would identify approximately 80% of all patients expected to develop T1D in their lifetime. CONCLUSION: Through both empirical and biological validation, we have established a prediction model for estimating lifetime T1D risk, using class II HLA. This prediction model should prove useful for future investigations to identify high-risk subjects for prevention research in high-risk populations.

Residual beta-cell function in diabetes children followed and diagnosed in the TEDDY study compared to community controls.

OBJECTIVE: To explore whether children diagnosed with type 1 diabetes during islet autoantibody surveillance through The Environmental Determinants of Diabetes in the Young (TEDDY) study retain greater islet function than children diagnosed through the community. METHODS: TEDDY children identified at birth with high-risk human leukocyte antigen and followed every 3 months until diabetes diagnosis were compared to age-matched children diagnosed with diabetes in the community. Both participated in long-term follow up after diagnosis. Hemoglobin A1c (HbA1c) and mixed meal tolerance test were performed within 1 month of diabetes onset, then at 3, 6, and 12 months, and biannually thereafter. RESULTS: Comparison of 43 TEDDY and 43 paired control children showed that TEDDY children often had no symptoms (58%) at diagnosis and none had diabetic ketoacidosis (DKA) compared with 98% with diabetes symptoms and 14% DKA in the controls (P < 0.001 and P = 0.03, respectively). At diagnosis, mean HbA1c was lower in TEDDY (6.8%, 51 mmol/mol) than control (10.5%, 91 mmol/mol) children (P < 0.0001). TEDDY children had significantly higher area under the curve and peak C-peptide values than the community controls throughout the first year postdiagnosis. Total insulin dose and insulin dose-adjusted A1c were lower throughout the first year postdiagnosis for TEDDY compared with control children. CONCLUSIONS: Higher C-peptide levels in TEDDY vs community-diagnosed children persist for at least 12 months following diabetes onset and appear to represent a shift in the disease process of about 6 months. Symptom-free diagnosis, reduction of DKA, and the potential for immune intervention with increased baseline C-peptide may portend additional long-term benefits of early diagnosis.

Maternal smoking during pregnancy and offspring type 1 diabetes mellitus risk: accounting for HLA haplotype.

The main objective of this study was to investigate the risk of type 1 diabetes mellitus (T1D) in children exposed to tobacco smoking in utero, also taking genetic predisposition as expressed by HLA haplotype into account. In Skåne, the southernmost county of Sweden, all children born 1999-2005 who developed T1D were registered, resulting in 344 cases. For each child with T1D, three control children, matched for HLA haplotype and birthyear, were selected. Information on prenatal smoking exposure was retrieved from a regional birth register. Conditional logistic regressions were used to evaluate T1D risk following prenatal smoking exposure. In these data, maternal smoking in early pregnancy was associated with a higher risk of her child developing T1D [odds ratio (OR) 2.83; 95% confidence interval (CI) 1.67-4.80 for 1-9 cigarettes/day, and OR 3.91; 95% CI 1.22-12.51 for >9 cigarettes/day]. Results remained through all adjustments and sensitivity analyses. When genetic predisposition in terms of HLA haplotype was taken into account, we found that children exposed to smoking during fetal life were at higher risk of developing T1D in childhood.

Maternal exposure to air pollution and type 1 diabetes--Accounting for genetic factors.

BACKGROUND: Genetic and non-genetic factors probably act together to initiate and accelerate development of type 1 diabetes [T1D]. One suggested risk factor contributing to development of T1D is air pollution. OBJECTIVE: The aim of the study was to investigate whether maternal exposure during pregnancy to air pollution, measured as nitrogen oxides [NOx] and ozone, in a low-dose exposure area was associated with the child developing T1D. METHOD: In Scania (Skåne), the most southern county in Sweden, 84,039 infants were born during the period 1999-2005. By the end of April 2013, 324 of those children had been diagnosed with T1D. For each of those T1D children three control children were randomly selected and matched for HLA genotype and birth year. Individually modelled exposure data at residence during pregnancy were assessed for nitrogen oxides [NOx], traffic density and ozone. RESULTS: Ozone as well as NOx exposures were associated with T1D. When the highest exposure group was compared to the lowest group an odds ratios of 1.62 (95% confidence interval [CI] 0.99-2.65) was observed for ozone in the second trimester and 1.58 (95% CI 1.06-2.35) for NOx in the third trimester. CONCLUSION: This study indicates that living in an area with elevated levels of air pollution during pregnancy may be a risk factor for offspring T1D.

A method for reporting and classifying acute infectious diseases in a prospective study of young children: TEDDY.

BACKGROUND: Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child's infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown. METHODS: Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression. RESULTS: A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype. CONCLUSIONS: The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies.

Autoimmunity against INS-IGF2 protein expressed in human pancreatic islets.

Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.

Development of a clinical calculator to aid the identification of MODY in pediatric patients at the time of diabetes diagnosis.

Maturity Onset Diabetes of the Young (MODY) is a young-onset, monogenic form of diabetes without needing insulin treatment. Diagnostic testing is expensive. To aid decisions on who to test, we aimed to develop a MODY probability calculator for paediatric cases at the time of diabetes diagnosis, when the existing "MODY calculator" cannot be used. Firth logistic regression models were developed on data from 3541 paediatric patients from the Swedish 'Better Diabetes Diagnosis' (BDD) population study (n = 46 (1.3%) MODY (HNF1A, HNF4A, GCK)). Model performance was compared to using islet autoantibody testing. HbA1c, parent with diabetes, and absence of polyuria were significant independent predictors of MODY. The model showed excellent discrimination (c-statistic = 0.963) and calibrated well (Brier score = 0.01). MODY probability > 1.3% (ie. above background prevalence) had similar performance to being negative for all 3 antibodies (positive predictive value (PPV) = 10% v 11% respectively i.e. ~ 1 in 10 positive test rate). Probability > 1.3% and negative for 3 islet autoantibodies narrowed down to 4% of the cohort, and detected 96% of MODY cases (PPV = 31%). This MODY calculator for paediatric patients at time of diabetes diagnosis will help target genetic testing to those most likely to benefit, to get the right diagnosis.

Childhood screening for type 1 diabetes comparing automated multiplex Antibody Detection by Agglutination-PCR (ADAP) with single plex islet autoantibody radiobinding assays.

BACKGROUND: Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity. METHODS: IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ2-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented. FINDINGS: The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC. INTERPRETATION: ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes. FUNDING: Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.

Factors assessed in the first year of a longitudinal study predict subsequent study visit compliance: the TEDDY study.

BACKGROUND: Compliance with a study protocol is central to meeting its research goals. In longitudinal research studies, data loss due to missed visits limit statistical power and introduce bias. The Environmental Determinants of Diabetes in the Young (TEDDY) study is a longitudinal multinational (US, Finland, Germany, and Sweden) investigation of children at risk for type 1 diabetes (T1D) that seeks to identify the environmental triggers of islet autoimmunity and T1D. The purpose of the current study was to identify sociodemographic variables and maternal characteristics assessed in the first year of TEDDY that were associated with study visit compliance in the subsequent 3 years. METHODS: Sociodemographic variables, maternal life-style behaviors, post-partum depression, maternal reactions to the child's T1D risk, and study-related variables were collected at child-age 6 months and 15 months. Multiple linear regression was used to examine the association of these variables to study visit compliance in the subsequent 3 years. RESULTS: Study visit compliance was highest in Sweden (p > 0.001), in children who were their mother's first child (p > 0.001), and whose mothers were older (p > 0.001) and more satisfied with the TEDDY study (p > 0.001). Father participation was also associated with better study visit compliance (p > 0.001). In contrast, children whose mothers smoked (p > 0.001), suffered from post-partum depression (p = 0.034), and were more anxious about their child's T1D risk (p = 0.002), completed fewer visits. Father's study satisfaction was also associated with study visit compliance (p = 0.029); however, it was not significant in models that included maternal study satisfaction. CONCLUSIONS: Sociodemographic variables, maternal characteristics-including study satisfaction-and fathers' participation in the first year of a longitudinal study were associated with subsequent study visit compliance in a sample of children genetically at-risk for T1D followed for 4 years. This information can inform future strategies designed to improve study visit compliance in longitudinal pediatric studies. TRIAL REGISTRATION: NCT00279318, 06/09/2004.

Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA.

BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone. METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24). RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046). CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.

Multiplex agglutination-PCR (ADAP) autoantibody assays compared to radiobinding autoantibodies in type 1 diabetes and celiac disease.

Multiplex Antibody-Detection by Agglutination-PCR (ADAP) assay was compared to singleplex standard radiobinding assays (RBA) to detect autoantibodies against insulin (IAA), GAD65 (GADA), islet antigen-2 (IA-2A), ZnT8 (ZnT8A) and tissue transglutaminase (TGA). Serum samples from 273 (114F/158M), 15-73 years of age healthy controls and 227 (109F/118M) newly diagnosed type 1 diabetes children, 1-11 years of age, were analyzed in both assay systems.The original WHO standard 97/550 and in-house reference standards for RBA were compared to ADAP. The ADAP and RBA generated parallel reference standards in all assays except TGA. Lower detection limits were observed in the ADAP assay for GADA,IAA and ZnT8A, markedly for TGA, but not for IA-2A. The Receiver Operating Characteristics (ROC) curve AUC analyses for pairwise comparison of ADAP with RBA showed no difference for GADA (n.s.), ADAP greater AUC for IAA (p = 0.005), RBA greater AUC for IA-2A (p = 0.0004) and ZnT8A (p < 0.0001) while ADAP TGA had a greater AUC compared to both RBA TGA-IgG (p < 0.0001) and TGA-IgA (p < 0.0001). These data suggest that the ADAP and RBA assays are comparable with equal performance for GADA, better ADAP performance for IAA while the RBA showed better performance in both IA-2A and ZnT8A associated with greater heterogeneity in autoantibody levels. The simultaneous analysis of 5 different autoantibodies by ADAP in sample volume reduced to only 4 µL and at an increased lower detection limit in all assays except IA-2A makes the ADAP automated autoantibody assay a distinct advantage for high throughput screening.