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).

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.

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.

Factors associated with longitudinal food record compliance in a paediatric cohort study.

OBJECTIVE: Non-compliance with food record submission can induce bias in nutritional epidemiological analysis and make it difficult to draw inference from study findings. We examined the impact of demographic, lifestyle and psychosocial factors on such non-compliance during the first 3 years of participation in a multidisciplinary prospective paediatric study. DESIGN: The Environmental Determinants of Diabetes in the Young (TEDDY) study collects a 3 d food record quarterly during the first year of life and semi-annually thereafter. High compliance with food record completion was defined as the participating families submitting one or more days of food record at every scheduled clinic visit. SETTING: Three centres in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden). SUBJECTS: Families who finished the first 3 years of TEDDY participation (n 8096). RESULTS: High compliance was associated with having a single child, older maternal age, higher maternal education and father responding to study questionnaires. Families showing poor compliance were more likely to be living far from the study centres, from ethnic minority groups, living in a crowded household and not attending clinic visits regularly. Postpartum depression, maternal smoking behaviour and mother working outside the home were also independently associated with poor compliance. CONCLUSIONS: These findings identified specific groups for targeted strategies to encourage completion of food records, thereby reducing potential bias in multidisciplinary collaborative research.

Influenza A virus antibodies show no association with pancreatic islet autoantibodies in children genetically predisposed to type 1 diabetes.

AIMS/HYPOTHESIS: Viral infections have long been considered potential triggers of beta cell autoimmunity and type 1 diabetes. Recent studies have suggested that influenza A virus might increase the risk of type 1 diabetes. The present study evaluates this risk association in prospectively observed children at the time when islet autoimmunity starts and autoantibodies are first detected. METHODS: IgG class antibodies to influenza A virus were analysed in 95 case children whose antibody screening test turned permanently positive for two or more islet autoantibodies and from 186 autoantibody-negative and non-diabetic control children who were matched for time of birth, sex, date of sampling and HLA-conferred risk of diabetes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Virus antibodies were measured from the first autoantibody-positive sample using an enzyme immunoassay. None of the children had been vaccinated against influenza A. RESULTS: The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units). A similar result was obtained when case and control children were compared separately in subgroups according to different sex, age and HLA-DQ genotype. However, girls had higher antibody levels than boys among both case and control children (median antibody levels 9.0 vs 2.3 enzyme immunoassay units; p = 0.01). CONCLUSIONS/INTERPRETATION: Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes.

The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study.

AIMS/HYPOTHESIS: Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. METHODS: Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. RESULTS: Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. CONCLUSIONS/INTERPRETATION: Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.

High lipoprotein(a) concentrations are associated with impaired endothelial function in children.

OBJECTIVE: To examine the association between familial high lipoprotein(a), or Lp(a), concentrations and endothelial function in children participating in the Special Turku Coronary Risk Factor Intervention Project study. STUDY DESIGN: Seven-month-old children (n = 1062) with their families were randomized to a risk intervention group or to a control group. The intervention group received individualized dietary counseling to reduce the total cholesterol concentration. Children's Lp(a) and lipid values were measured repeatedly. At age 11 years, children were recruited to an ultrasound study of the flow-mediated dilation (FMD) of the brachial artery. The association between relative peak FMD and Lp(a) concentration was examined in 198 control and 193 intervention group children by linear regression analyses adjusted for sex, total cholesterol concentration, and basal artery diameter. The analyses were made in both the control and intervention groups and in the familial risk children who had a parent with Lp(a) concentration greater than 250 mg/l. RESULTS: Lp(a) concentrations were similar at age 11 years in the intervention and control groups. In all control children, FMD (%) associated inversely with Lp(a) concentration: (ß [%/1000 mg/L] = -3.74, 95% CI [-6.43, -1.45]; P = .007) and in 68 familial risk children (ß = -4.92, 95% CI [-8.18, -1.66]; P = .0037). In the intervention group the associations were lacking (P > .5), and FMD in the children with high Lp(a) concentrations (>500 mg/L, n = 12) had no attenuation (P = .027). CONCLUSIONS: Familial high Lp(a) concentration is associated with attenuated endothelial function. This association may be mitigated by an early lifestyle intervention. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00223600.

First-emerging islet autoantibody and glucose metabolism: search for type 1 diabetes subtypes.

Objective: Subtypes in type 1 diabetes pathogenesis have been implicated based on the first-appearing autoantibody (primary autoantibody). We set out to describe the glucose metabolism in preclinical diabetes in relation to the primary autoantibody in children with HLA-conferred disease susceptibility. Design and methods: Dysglycemic markers are defined as a 10% increase in HbA1c in a 3-12 months interval or HbA1c ≥5.9% (41 mmol/mol) in two consecutive samples, impaired fasting glucose or impaired glucose tolerance, or a random plasma glucose value ≥7.8 mmol/L. A primary autoantibody could be detected in 295 children who later developed at least 1 additional biochemical autoantibody. These children were divided into three groups: insulin autoantibody (IAA) multiple (n = 143), GAD antibody (GADA) multiple (n = 126) and islet antigen 2 antibody (IA-2A) multiple (n = 26). Another 229 children seroconverted to positivity only for a single biochemical autoantibody and were grouped as IAA only (n = 87), GADA only (n = 114) and IA-2A only (n = 28). Results: No consistent differences were observed in selected autoantibody groups during the preclinical period. At diagnosis, children with IAA only showed the highest HbA1c (P < 0.001 between groups) and the highest random plasma glucose (P = 0.005 between groups). Children with IA-2A only progressed to type 1 diabetes as frequently as those with IA-2A multiple (46% vs 54%, P = 0.297) whereas those with IAA only or GADA only progressed less often than children with IAA multiple or GADA multiple (22% vs 62% (P < 0.001) and 7% vs 43% (P < 0.001)), respectively. Conclusions: The phenotype of preclinical diabetes defined by the primary autoantibody is not associated with any discernible differences in glucose metabolism before the clinical disease manifestation.

First Infant Formula Type and Risk of Islet Autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) Study.

OBJECTIVE: Studies on the introduction of infant formulas and its effect on the risk of islet autoimmunity and type 1 diabetes (T1D) have yielded inconsistent results. We investigated whether the introduction of formula based on hydrolyzed cow's milk as the first formula is associated with reduced islet autoimmunity risk in a large prospective cohort. RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively monitors 8,676 children at increased genetic risk for T1D. Autoantibodies to insulin, GAD65, and IA2 were measured regularly to define islet autoimmunity. Information on formula feeding was collected by questionnaires at 3 months of age. RESULTS: In survival analyses, after adjustment for family history with T1D, HLA genotype, sex, country, delivery mode, breast-feeding ≥3 months, and seasonality of birth, we observed no significant association with islet autoimmunity in infants who received extensively hydrolyzed compared with nonhydrolyzed cow's milk-based formula as the first formula during the first 3 months (adjusted hazard ratio 1.38 [95% CI 0.95; 2.01]), and a significantly increased risk for extensively hydrolyzed formula introduced during the first 7 days (adjusted hazard ratio 1.57 [1.04; 2.38]). Using a partially hydrolyzed or other formula as the first formula, or no formula, was not associated with islet autoimmunity risk. CONCLUSIONS: These results add to the existing evidence that islet autoimmunity risk is not reduced, and may be increased, by using hydrolyzed compared with nonhydrolyzed cow's milk-based infant formula as the first formula in infants at increased genetic risk for T1D.

Association Between Early-Life Antibiotic Use and the Risk of Islet or Celiac Disease Autoimmunity.

Importance: Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. Objective: To test the association between early-life antibiotic use and islet or celiac disease (CD) autoimmunity in genetically at-risk children prospectively followed up for type 1 diabetes (T1D) or CD. Design, Setting, and Participants: HLA-genotyped newborns from Finland, Germany, Sweden, and the United States were enrolled in the prospective birth cohort of The Environmental Determinants of Diabetes in the Young (TEDDY) study between November 20, 2004, and July 8, 2010. The dates of analysis were November 20, 2004, to August 31, 2014. Individuals from the general population and those having a first-degree relative with T1D were enrolled if they had 1 of 9 HLA genotypes associated with a risk for T1D. Exposures: Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. Main Outcomes and Measures: Islet autoimmunity and CD autoimmunity were defined as being positive for islet or tissue transglutaminase autoantibodies at 2 consecutive clinic visits at least 3 months apart. Hazard ratios and 95% CIs calculated from Cox proportional hazards regression models were used to assess the relationship between antibiotic use in early life before seroconversion and the development of autoimmunity. Results: Participants were 8495 children (49.0% female) and 6558 children (48.7% female) enrolled in the TEDDY study who were tested for islet and tissue transglutaminase autoantibodies, respectively. Exposure to and frequency of use of any antibiotic assessed in this study in early life or before seroconversion did not influence the risk of developing islet autoimmunity or CD autoimmunity. Cumulative use of any antibiotic during the first 4 years of life was not associated with the appearance of any autoantibody (hazard ratio [HR], 0.98; 95% CI, 0.95-1.01), multiple islet autoantibodies (HR, 0.99; 95% CI, 0.95-1.03), or the transglutaminase autoantibody (HR, 1.00; 95% CI, 0.98-1.02). Conclusions and Relevance: The use of the most prescribed antibiotics during the first 4 years of life, regardless of geographic region, was not associated with the development of autoimmunity for T1D or CD. These results suggest that a risk of islet or tissue transglutaminase autoimmunity need not influence the recommendations for clinical use of antibiotics in young children at risk for T1D or CD.

TEDDY--The Environmental Determinants of Diabetes in the Young: an observational clinical trial.

The aim of the TEDDY study is to identify infectious agents, dietary factors, or other environmental agents, including psychosocial factors, which may either trigger islet autoimmunity, type 1 diabetes mellitus (T1DM), or both. The study has two end points: (a) appearance of islet autoantibodies and (b) clinical diagnosis of T1DM. Six clinical centers screen newborns for high-risk HLA genotypes. As of December 2005 a total of 54,470 newborns have been screened. High-risk HLA genotypes among 53,560 general population (GP) infants were 2576 (4.8%) and among 910 newborns with a first-degree relative (FDR) were 194 (21%). A total of 1061 children have been enrolled. The initial enrollment results demonstrate the feasibility of this complex and demanding a prospective study.

Recognition of familial dyslipidemias in 5-year-old children using the lipid phenotypes of parents. The STRIP project.

Adult dyslipidemias may reveal familial and, therefore, offspring dyslipidemias. We evaluated the prevalences of the adult-offspring dyslipidemias in 441 general population families composed of both parents and one 5-year-old child. Family members were classified using the 90th or 10th percentiles for hypercholesterolemia (IIA), hypertriglyceridemia (IV), combined hyperlipidemia (IIB), and low high density lipoprotein cholesterol concentration without hyperlipidemia (hypoHDL). In familial combined hyperlipidemia (FCHL), the IIB-phenotype was in one generation and one of the three hyperlipidemias in the other generation. Finally, the parental dyslipidemia phenotypes and elevated lipids (>80th percentile) that reveal offspring dyslipidemia were selected by stepwise logistic regression. Either the IIA-, IV- or hypoHDL phenotype was found in both generations in 2.8, 2.0 and 1.4% of the families, respectively. FCHL was seen in 1.8% of the families, which confirms the earlier views. The predictive values of the elevated parental cholesterol, type IV or hypoHDL parents to find type IIA, IV and hypoHDL children were low for systematic screening: 16, 13 and 15%, respectively. However, 44% of the children of IIB parents expressed hyperlipidemia (odds ratio 4.7, P=0.006). The IIB phenotype of the parent is a good predictor of the child's hyperlipidemia, and when encountered, it indicates that the lipids of the child should be studied. This would be as important as selective screening of familial hypercholesterolemia.

From genetic risk awareness to overt type 1 diabetes: parental stress in a placebo-controlled prevention trial.

OBJECTIVE: To evaluate the psychological burden of parents facing increasing risk of type 1 diabetes in their children. RESEARCH DESIGN AND METHODS: In the population-based Type 1 Diabetes Prediction and Prevention (DIPP) Study, newborn infants with HLA-DQB1-conferred diabetes risk were enrolled in sequential analyses of diabetes-associated autoantibodies. Those persistently positive for at least two autoantibodies were recruited to a randomized double-blinded intervention trial. The experience of stress in parents of 664 children was measured using Parenting Stress Index self-report inventory. RESULTS: While diagnosis of diabetes increased parental stress, the appearance of autoantibodies or participation in the intervention trial did not. Mothers had higher stress levels than fathers. Single parenthood and chronically ill family members increased parental stress. CONCLUSIONS: Parental stress was not increased by notification of autoantibody positivity or by participation in an intervention trial. Other demanding family conditions contributed to the experience of stress.