Assisting the implementation of screening for type 1 diabetes by using artificial intelligence on publicly available data.

The type 1 diabetes community is coalescing around the benefits and advantages of early screening for disease risk. To be accepted by healthcare providers, regulatory authorities and payers, screening programmes need to show that the testing variables allow accurate risk prediction and that individualised risk-informed monitoring plans are established, as well as operational feasibility, cost-effectiveness and acceptance at population level. Artificial intelligence (AI) has the potential to contribute to solving these issues, starting with the identification and stratification of at-risk individuals. ASSET (AI for Sustainable Prevention of Autoimmunity in the Society; www.asset.healthcare ) is a public/private consortium that was established to contribute to research around screening for type 1 diabetes and particularly to how AI can drive the implementation of a precision medicine approach to disease prevention. ASSET will additionally focus on issues pertaining to operational implementation of screening. The authors of this article, researchers and clinicians active in the field of type 1 diabetes, met in an open forum to independently debate key issues around screening for type 1 diabetes and to advise ASSET. The potential use of AI in the analysis of longitudinal data from observational cohort studies to inform the design of improved, more individualised screening programmes was also discussed. A key issue was whether AI would allow the research community and industry to capitalise on large publicly available data repositories to design screening programmes that allow the early detection of individuals at high risk and enable clinical evaluation of preventive therapies. Overall, AI has the potential to revolutionise type 1 diabetes screening, in particular to help identify individuals who are at increased risk of disease and aid in the design of appropriate follow-up plans. We hope that this initiative will stimulate further research on this very timely topic.

Early-childhood body mass index and its association with the COVID-19 pandemic, containment measures and islet autoimmunity in children with increased risk for type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity. METHODS: Between February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk. RESULTS: The COVID-19 pandemic was associated with increased time-varying BMI (ß = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months (ß = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI (ß = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months (ß = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months (ß = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively). CONCLUSIONS/INTERPRETATION: Early-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes.

Clinical care advice for monitoring of islet autoantibody positive individuals with presymptomatic type 1 diabetes.

BACKGROUND/AIM: Type 1 diabetes is an autoimmune disease that involves the development of autoantibodies against pancreatic islet beta-cell antigens, preceding clinical diagnosis by a period of preclinical disease activity. As screening activity to identify autoantibody-positive individuals increases, a rise in presymptomatic type 1 diabetes individuals seeking medical attention is expected. Current guidance on how to monitor these individuals in a safe but minimally invasive way is limited. This article aims to provide clinical guidance for monitoring individuals with presymptomatic type 1 diabetes to reduce the risk of diabetic ketoacidosis (DKA) at diagnosis. METHODS: Expert consensus was obtained from members of the Fr1da, GPPAD, and INNODIA consortia, three European diabetes research groups. The guidance covers both specialist and primary care follow-up strategies. RESULTS: The guidance outlines recommended monitoring approaches based on age, disease stage and clinical setting. Individuals with presymptomatic type 1 diabetes are best followed up in specialist care. For stage 1, biannual assessments of random plasma glucose and HbA1c are suggested for children, while annual assessments are recommended for adolescents and adults. For stage 2, 3-monthly clinic visits with additional home monitoring are advised. The value of repeat OGTT in stage 1 and the use of continuous glucose monitoring in stage 2 are discussed. Primary care is encouraged to monitor individuals who decline specialist care, following the guidance presented. CONCLUSIONS: As type 1 diabetes screening programs become more prevalent, effective monitoring strategies are essential to mitigate the risk of complications such as DKA. This guidance serves as a valuable resource for clinicians, providing practical recommendations tailored to an individual's age and disease stage, both within specialist and primary care settings.

SARS-CoV-2 Infection and Development of Islet Autoimmunity in Early Childhood.

Importance: The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. Objective: To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Design, Setting, and Participants: Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. Exposure: SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. Main Outcomes and Measures: The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Results: Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). Conclusion and relevance: In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.

Immunocyte single cell analysis of vaccine-induced narcolepsy.

Increased incidence of narcolepsy type 1 (NT1) was observed following Pandemrix®-vaccination, initiated as a preventive measure against the 2009 Influenza pandemic. Here, single cell analysis was conducted to suggest a lower number of CD8+ CD27+ T cells among these patients. These findings provide understanding into the autoimmune pathogenesis of NT1.

The emotional well-being of parents with children at genetic risk for type 1 diabetes before and during participation in the POInT-study.

INTRODUCTION: This study examined the emotional impact that parents experience when confronted with an increased genetic risk of type 1 diabetes (T1D) in their child. Population-based screening of neonates for genetic risk of chronic disease carries the risk of increased emotional burden for parents. METHODS: Information was collected using a well-being questionnaire for parents of infants identified as having an increased risk for T1D in a multinational research study. Parents were asked to complete this questionnaire after they were told their child had an increased risk for T1D (Freder1k-study) and at several time points during an intervention study (POInT-study), where oral insulin was administered daily. RESULTS: Data were collected from 2595 parents of 1371 children across five countries. Panic-related anxiety symptoms were reported by only 4.9% after hearing about their child having an increased risk. Symptoms of depression were limited to 19.4% of the parents at the result-communication visit and declined over time during the intervention study. When thinking about their child's risk for developing T1D (disease-specific anxiety), 47.2% worried, felt nervous and tense. Mothers and parents with a first-degree relative (FDR) with T1D reported more symptoms of depression and disease-specific anxiety (p < 0.001) than fathers and parents without a FDR. CONCLUSION: Overall, symptoms of depression and panic-related anxiety are comparable with the German population. When asked about their child's risk for T1D during the intervention study, some parents reported disease-specific anxiety, which should be kept in mind when considering population-based screening. As certain subgroups are more prone, it will be important to continue psychological screening and, when necessary, to provide support by an experienced, multidisciplinary team.

Vibrotactile sense might improve over time in paediatric subjects with type 1 diabetes-A mid-term follow-up using multifrequency vibrometry.

AIM: Impaired vibrotactile sense, mirroring diabetic peripheral neuropathy, is present among children and adolescents with type 1 diabetes. This study aims to re-examine the vibrotactile sense of paediatric type 1 diabetes subjects in order to evaluate any alterations in the vibrotactile sense over time. METHODS: A VibroSense Meter I device was used to determine the vibrotactile perception thresholds (VPTs) for seven frequencies from the pulp of index and little fingers and for five frequencies from metatarsal heads one and five on the sole of the foot, of 37 children and adolescents with type 1 diabetes, previously examined in a larger cohort. Subjects were followed up after a median time of 30 months. Z-scores of VPTs were calculated using previously collected normative data. RESULTS: Vibrotactile perception thresholds improved over time at low frequencies (especially 16 Hz) on the foot, while not being statistically significant different on the rest of the frequencies, either on hand or foot. VPTs were not correlated with HbA1c. CONCLUSION: A mid-term follow-up of vibrotactile sense in paediatric subjects with type 1 diabetes shows a conceivable normalization of previously impaired vibrotactile sense on some frequencies on the foot, indicating that vibrotactile sense might fluctuate over time.

Month of birth and the risk of developing type 1 diabetes among children in the Swedish national Better Diabetes Diagnosis Study.

AIM: Previous studies have reported an association between month of birth and incidence of type 1 diabetes. Using population-based data, including almost all newly diagnosed children with type 1 diabetes in Sweden, we tested whether month of birth influences the risk of type 1 diabetes. METHODS: For 8761 children diagnosed with type 1 diabetes between May 2005 and December 2016 in the Better Diabetes Diagnosis study, month of birth, sex and age were compared. Human leucocyte antigen (HLA) genotype and autoantibodies at diagnosis were analysed for a subset of the cohort (n = 3647). Comparisons with the general population used data from Statistics Sweden. RESULTS: We found no association between month of birth or season and the incidence of type 1 diabetes in the cohort as a whole. However, boys diagnosed before 5 years were more often born in May (p = 0.004). We found no correlation between month of birth and HLA or antibodies. CONCLUSION: In this large nationwide study, the impact of month of birth on type 1 diabetes diagnosis was weak, except for boys diagnosed before 5 years of age, who were more likely born in May. This may suggest different triggers for different subgroups of patients with type 1 diabetes.

Adherence to oral glucose tolerance testing in children in stage 1 of type 1 diabetes: The TEDDY study.

OBJECTIVE: To examine adherence to the oral glucose tolerance test (OGTT) in multiple islet autoantibody children in stage 1 of developing type 1 diabetes (T1D). METHODS: Children are followed from birth in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Completion of an OGTT is recommended every 6 months in children ≥3 years of age who are multiple islet autoantibody positive. Factors associated with adherence to the OGTT protocol were examined. RESULTS: The average subject level adherence with the OGTT protocol was 62% although there were large differences across countries; Finnish participants and older children from Sweden were more adherent than participants from the United States and Germany. Factors associated with nonadherence included having a first-degree relative with T1D, using a local laboratory rather than a TEDDY center for the OGTT, and maternal underestimation of the child's risk for T1D. Children were more adherent to the OGTT if their mothers: were more satisfied with TEDDY participation, reported monitoring the child for T1D by checking blood glucose levels at home, and viewed participating in TEDDY as the primary way they were monitoring the child for T1D. CONCLUSIONS: In a study of children in stage 1 of T1D, adherence to an OGTT protocol was suboptimal despite extensive efforts to communicate the child's high risk to parents. These findings provide important guidance for development of strategies to improve methods for detecting progression or the development of T1D in high-risk pediatric populations.

Celiac disease can be predicted by high levels of tissue transglutaminase antibodies in children and adolescents with type 1 diabetes.

OBJECTIVES: Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were ≥ 10 times the upper limit of normal (10× ULN) predicted CD in T1D. METHODS: Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhüber classification. RESULTS: All of the 60 children with anti-tTG ≥10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. CONCLUSIONS: As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.

Screening for autoantibody targets in post-vaccination narcolepsy using proteome arrays.

Narcolepsy type 1 (NT1) is a chronic sleep disorder caused by a specific loss of hypocretin-producing neurons. The incidence of NT1 increased in Sweden, Finland and Norway following Pandemrix®-vaccination, initiated to prevent the 2009 influenza pandemic. The pathogenesis of NT1 is poorly understood, and causal links to vaccination are yet to be clarified. The strong association with Human leukocyte antigen (HLA) DQB1*06:02 suggests an autoimmune pathogenesis, but proposed autoantigens remain controversial. We used a two-step approach to identify autoantigens in patients that acquired NT1 after Pandemrix®-vaccination. Using arrays of more than 9000 full-length human proteins, we screened the sera of 10 patients and 24 healthy subjects for autoantibodies. Identified candidate antigens were expressed in vitro to enable validation studies with radiobinding assays (RBA). The validation cohort included NT1 patients (n = 39), their first-degree relatives (FDR) (n = 66), population controls (n = 188), and disease controls representing multiple sclerosis (n = 100) and FDR to type 1 diabetes patients (n = 41). Reactivity towards previously suggested NT1 autoantigen candidates including Tribbles homolog 2, Prostaglandin D2 receptor, Hypocretin receptor 2 and α-MSH/proopiomelanocortin was not replicated in the protein array screen. By comparing case to control signals, three novel candidate autoantigens were identified in the protein array screen; LOC401464, PARP3 and FAM63B. However, the RBA did not confirm elevated reactivity towards either of these proteins. In summary, three putative autoantigens in NT1 were identified by protein array screening. Autoantibodies against these candidates could not be verified with independent methods. Further studies are warranted to identify hypothetical autoantigens related to the pathogenesis of Pandemrix®-induced NT1.

Parental anxiety after 5 years of participation in a longitudinal study of children at high risk of type 1 diabetes.

AIM: Parents of children participating in screening studies may experience increased levels of anxiety. The aim of this study was to assess parental anxiety levels after 5 years of participation in the Diabetes Prediction in Skåne study. Associations between parental anxiety about their child developing type 1 diabetes and clinical, demographic, and immunological factors were analyzed. METHOD: Mothers and fathers of participating 5-year-old children answered a questionnaire regarding parental anxiety associated with their child's increased risk of type 1 diabetes. Anxiety levels were assessed using the State Anxiety Inventory scale. Data were analyzed using logistic and multinomial regression. RESULTS: Parents of 2088 5-year-old children participated. Both parents answered the questionnaire for 91.2% (n = 1904) of children. In 67.1% of families, neither parent reported being anxious that their child had an increased risk of developing type 1 diabetes. Anxiety was higher in mothers of children positive for autoantibodies (OR 2.21 95% CI 1.41, 3.48, P < .001) and those perceiving their child had a higher risk for type 1 diabetes (2.01; 1.29, 3.13, P = .002). Frequency of worry was associated with parental anxiety (mothers 5.33; 3.48, 8.17, P < .001, fathers 5.27; 3.51, 7.92, P < .001). Having a family member with type 1 diabetes and having lower education level were also associated with increased anxiety. CONCLUSIONS: Diabetes in the family, the child's autoantibody status, education level, frequency of worry and risk perception where associated with higher parental anxiety. These findings add to our understanding of the impact of screening for type 1 diabetes in children on parental anxiety.

Effect of screening for type 1 diabetes on early metabolic control: the DiPiS study.

AIMS/HYPOTHESIS: It has been shown that children previously enrolled in follow-up studies have better glycaemic control during the early period after diabetes diagnosis. The aim of this study was to analyse glycaemic control over a longer period, past the period of partial remission, after diagnosis in children followed before diagnosis in the Swedish Diabetes Prediction in Skåne (DiPiS) study compared with children of equal age not enrolled in pre-diabetes follow-up, receiving equivalent diabetes care. METHODS: HbA1c from diagnosis and for the following 5 years, as well as differences in insulin dosage, BMI, pump use, partial remission according to insulin dose-adjusted HbA1c and baseline demographics were compared between children who were enrolled in follow-up and had received information on diabetes risk (n = 51) and children not enrolled in follow-up (n = 78). RESULTS: The group followed before diagnosis had a higher proportion of first-degree relatives (FDRs) with diabetes (28% vs 5.6%; p = 0.001) and a higher proportion of participants with mothers born in Sweden (100% vs 89%; p = 0.02). No significant differences in total daily insulin dose, pump use or other baseline sociodemographic factors were detected between the groups. Median HbA1c at diagnosis and at 1, 2, 3, 4 and 5 years after diabetes diagnosis was significantly lower in children followed before diagnosis (all p < 0.05), and was not related to FDR status. CONCLUSIONS/INTERPRETATION: Compared with controls not previously enrolled in follow-up, our study shows that children enrolled in longitudinal follow-up before the diagnosis of diabetes have better glycaemic control, measured by HbA1c, up to 5 years after diagnosis and during the initial period of partial remission. Improved glycaemic control in the initial years of living with type 1 diabetes could affect long-term outcome and complications and might also improve study enrolment in future longitudinal studies.

Correction to: Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study.

The authors regret that the SNP in SH2B3 was incorrectly referred to as rs3184505 instead of rs3184504 on both mentions in this paper (Methods section and Table 1).

Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children.

AIMS/HYPOTHESIS: During the A/H1N1 2009 (A/California/04/2009) pandemic, mass vaccination with a squalene-containing vaccine, Pandemrix®, was performed in Sweden and Finland. The vaccination was found to cause narcolepsy in children and young adults with the HLA-DQ 6.2 haplotype. The aim of this study was to investigate if exposure to Pandemrix® similarly increased the risk of islet autoimmunity or type 1 diabetes. METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, children are followed prospectively for the development of islet autoimmunity and type 1 diabetes. In October 2009, when the mass vaccination began, 3401 children at risk for islet autoimmunity and type 1 diabetes were followed in Sweden and Finland. Vaccinations were recorded and autoantibodies against insulin, GAD65 and insulinoma-associated protein 2 were ascertained quarterly before the age of 4 years and semi-annually thereafter. RESULTS: By 5 August 2010, 2413 of the 3401 (71%) children observed as at risk for an islet autoantibody or type 1 diabetes on 1 October 2009 had been vaccinated with Pandemrix®. By 31 July 2016, 232 children had at least one islet autoantibody before 10 years of age, 148 had multiple islet autoantibodies and 96 had developed type 1 diabetes. The risk of islet autoimmunity was not increased among vaccinated children. The HR (95% CI) for the appearance of at least one islet autoantibody was 0.75 (0.55, 1.03), at least two autoantibodies was 0.85 (0.57, 1.26) and type 1 diabetes was 0.67 (0.42, 1.07). In Finland, but not in Sweden, vaccinated children had a lower risk of islet autoimmunity (0.47 [0.29, 0.75]), multiple autoantibodies (0.50 [0.28, 0.90]) and type 1 diabetes (0.38 [0.20, 0.72]) compared with those who did not receive Pandemrix®. The analyses were adjusted for confounding factors. CONCLUSIONS/INTERPRETATION: Children with an increased genetic risk for type 1 diabetes who received the Pandemrix® vaccine during the A/H1N1 2009 pandemic had no increased risk of islet autoimmunity, multiple islet autoantibodies or type 1 diabetes. In Finland, the vaccine was associated with a reduced risk of islet autoimmunity and type 1 diabetes.

Safety and efficacy of autoantigen-specific therapy with 2 doses of alum-formulated glutamate decarboxylase in children with multiple islet autoantibodies and risk for type 1 diabetes: A randomized clinical trial.

OBJECTIVE: Treatments have failed to delay or stop the autoimmune process, preceding onset of type 1 diabetes. We investigated if autoantigen-specific treatment with alum-formulated glutamate decarboxylase (GAD-Alum) was safe and affected progression to type 1 diabetes in children with islet autoimmunity. METHODS: In an investigator-initiated, double-blind, placebo-controlled clinical trial, non-diabetic children aged 4 to 17.9 years with autoantibodies to glutamate decarboxylase (GADA) and at least one of insulinoma-associated protein 2, insulin or zinc-transporter 8, were randomized, stratified by 2 or ≥3 islet autoantibodies, to 2 injections of 20 µg GAD-Alum or placebo, 30 days apart. Main outcome was safety, investigated by adverse events, hematology, chemistry, thyroid and celiac autoimmunity and titers of islet autoantibodies, and efficacy, investigated by cumulative incidence of diabetes onset over 5-year follow-up. Secondary variables: change in first-phase insulin release (FPIR) after intravenous glucose tolerance tests, fasting, 120 minutes and Area under the curve (AUC) C-peptide and p-glucose after oral glucose tolerance tests and HbA1c. RESULTS: Fifty children (median age: 5.2) were assigned 1:1 to GAD-Alum or placebo, all receiving full treatment and included in the analyses. GAD-Alum did not affect any safety parameter, while GADA titers increased (P = .001). Time to clinical diagnosis was not affected by treatment (hazard ratio, HR = 0.77, P = .574) in the full population or in the separate stratum groups. Treatment did not affect any of the secondary variables. CONCLUSIONS: GAD-Alum as a subcutaneous prime and boost injection was safe in prediabetic young children but did not affect progression to type 1 diabetes. The safety of GAD-Alum should prove useful in future prevention studies.

Family adjustment to diabetes diagnosis in children: Can participation in a study on type 1 diabetes genetic risk be helpful?

BACKGROUND: Diagnosis of type 1 diabetes often causes a negative psychological impact on families. We examined whether parents and children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study differ in their psychological adjustment to diabetes diagnosis compared to children diagnosed with diabetes in the community. METHODS: TEDDY follows 8676 children at genetic risk for type 1 diabetes from birth. Fifty-four TEDDY children diagnosed with diabetes and 54 age-matched community control children diagnosed with diabetes were enrolled. Participants were aged 3 to 10 years and study visits occurred at 3, 6, and 12 months postdiagnosis. Psychological measures included an adapted diabetes-specific State Anxiety Inventory, the Pediatric Quality of Life Inventory-Diabetes Module, and the Pediatric Inventory for Parents, which measures frequency and difficulty of parenting stress. RESULTS: A generalized estimating equation analysis based on a difference score between TEDDY children and community controls found no significant differences between TEDDY parents and community controls on parent diabetes-specific anxiety (P = .30). However, TEDDY children exhibited better diabetes-specific quality of life (P = .03) and TEDDY parents reported lower frequency (P = .004) and difficulty (P = .008) of parenting stress compared to community controls. CONCLUSIONS: Children diagnosed with at-risk for type 1 diabetes who have previously enrolled in research monitoring have improved diabetes quality of life and lower parenting stress postdiagnosis compared to children diagnosed in the community. Families in follow-up studies may be more prepared if their child is diagnosed with diabetes.

Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study.

AIMS/HYPOTHESIS: Respiratory infections and onset of islet autoimmunity are reported to correlate positively in two small prospective studies. The Environmental Determinants of Diabetes in the Young (TEDDY) study is the largest prospective international cohort study on the environmental determinants of type 1 diabetes that regularly monitors both clinical infections and islet autoantibodies. The aim was to confirm the influence of reported respiratory infections and to further characterise the temporal relationship with autoantibody seroconversion. METHODS: During the years 2004-2009, 8676 newborn babies with HLA genotypes conferring an increased risk of type 1 diabetes were enrolled at 3 months of age to participate in a 15 year follow-up. In the present study, the association between parent-reported respiratory infections and islet autoantibodies at 3 month intervals up to 4 years of age was evaluated in 7869 children. Time-dependent proportional hazard models were used to assess how the timing of respiratory infections related to persistent confirmed islet autoimmunity, defined as autoantibody positivity against insulin, GAD and/or insulinoma antigen-2, concordant at two reference laboratories on two or more consecutive visits. RESULTS: In total, 87,327 parent-reported respiratory infectious episodes were recorded while the children were under study surveillance for islet autoimmunity, and 454 children seroconverted. The number of respiratory infections occurring in a 9 month period was associated with the subsequent risk of autoimmunity (p < 0.001). For each 1/year rate increase in infections, the hazard of islet autoimmunity increased by 5.6% (95% CI 2.5%, 8.8%). The risk association was linked primarily to infections occurring in the winter (HR 1.42 [95% CI 1.16, 1.74]; p < 0.001). The types of respiratory infection independently associated with autoimmunity were common cold, influenza-like illness, sinusitis, and laryngitis/tracheitis, with HRs (95% CI) of 1.38 (1.11, 1.71), 2.37 (1.35, 4.15), 2.63 (1.22, 5.67) and 1.76 (1.04, 2.98), respectively. CONCLUSIONS/INTERPRETATION: Recent respiratory infections in young children correlate with an increased risk of islet autoimmunity in the TEDDY study. Further studies to identify the potential causative viruses with pathogen-specific assays should focus especially on the 9 month time window leading to autoantibody seroconversion.

Analgesic antipyretic use among young children in the TEDDY study: no association with islet autoimmunity.

BACKGROUND: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. METHODS: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. RESULTS: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). CONCLUSIONS: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.

A Swedish approach to the prevention of type 1 diabetes.

BACKGROUND: The autoimmune destruction of beta cells, resulting in clinical type 1 diabetes, may start early in life and last for several months or years. During this period of time, we have an opportunity to try to prevent or delay further beta-cell destruction and clinical onset of type 1 diabetes. OBJECTIVES: Ongoing prediction and prevention studies in Skåne, Sweden are described. METHODS: During September 2000 to August 2004, 35 000 children were screened at birth for genetic type 1 diabetes risk in the Diabetes Prediction in Skåne Study (DiPiS). In August 2004, the screening continued within the Enviromnental Determinants of Diabetes in the Young study (TEDDY). In the clinical trial Diabetes Prevention - Immune Tolerance (DiAPREV-IT), children with multiple islet autoimmunity have been included to investigate if immune tolerance with Alum-formulated GAD65 may prevent further beta-cell loss. RESULTS: In DiPiS and TEDDY, a large number of children are followed in order to find the factors that trigger the autoimmune process leading to type 1 diabetes. Children followed in the studies develop diabetes at an early stage of disease, with few symptoms and a low frequency of diabetes ketoacidosis. DiAPREV-IT is still blinded and results will be available in December 2016. CONCLUSION: Large prospective studies will be needed to understand the complex process leading to type 1 diabetes. Secondary prevention may be possible in children with islet autoimmunity, but the studies are complicated by the variability of glucose metabolism and beta-cell loss.