The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361,588 newborns, of which it is anticipated that 17,804 will be eligible for enrollment with just over 7,800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.

Aims/hypothesis: The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight. Methods: HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW). Results: Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08-1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]= 0.72 [0.56-0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors. Conclusions/interpretation: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

Objective-The Environmental Determinants of Diabetes in the Young (TEDDY) study seeks to identify environmental triggers of autoimmunity and type 1 diabetes (T1DM) in children at increased HLA-conferred genetic risk for this disease. This study's objective was to identify predictors of early withdrawal from TEDDY among families with no immediate family history of T1DM.Method-Logistic multiple regression was used to discriminate 2994 (83%) families currently active in the TEDDY study for ≥ 1 year from 763 (17%) who withdrew in the first year. Data collected on the screening form at the time of the child's birth and from interview and questionnaire data obtained at the baby's first study visit (at ≤ 4.5 months of age) were used.Results-Significant and independent predictors of early withdrawal included country of residence, young maternal age, no father participation and female gender of the study participant. Mothers of children who withdrew were more likely to report smoking during pregnancy, abstaining from alcohol, and reducing their work hours or not working at all during pregnancy. Mothers who withdrew were also more likely to underestimate their child's risk for T1DM and fail to respond to multiple items on the enrollment questionnaires or interview. Among mothers with accurate risk perceptions, those experiencing high anxiety about their child's risk were more likely to be early withdrawals. Study demands on TEDDY families are considerable and include blood draws, stool sample collections, diet records, interviews, and questionnaires. The participating infants are examined every three months until four years of age and every six months thereafter. Since TEDDY participation is both time-consuming and expensive for the families, the investigators and the funders, any loss of these valuable participants diminishes the power of the study to meet its objectivesIn this report, we describe family characteristics identified at study inception that predicted study withdrawal among general population families during the first year of the TEDDY study. This information may guide future efforts to retain families in studies like TEDDY and should prove useful in the design of future natural history epidemiological studies with pediatric populations. MethodsThe TEDDY study TEDDY is a natural history study that seeks to identify the environmental triggers of autoimmunity and T1DM onset in genetically at-risk children identified at three centers in the United States (Colorado, Washington, and Georgia/Florida) and three centers in Europe (Finland, Germany, and Sweden). Infants from the general population, as well as infants who have first degree relatives (FDR) with T1DM, are screened for genetic risk at birth using HLA genotyping. Parents with infants at increased genetic risk for T1DM are invited to participate in TEDDY. Parents are fully informed of the child's increased genetic risk and the protocol requirements of the TEDDY study, including the requirement that eligible infants must join TEDDY before the infant...

The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility of identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skåne), which is examining a total of about 10,000 pregnancies expected every year in the Skåne (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes.

Objective The TEDDY Study is an international, multi-center prospective study designed to identify the environmental triggers of type 1 diabetes (T1D) in genetically at-risk children. This report investigates ethnic minority (EM) differences in patterns of enrollment and retention in the US centers. Methods As of June 2009, 267,739 newborns had been screened at birth for high risk T1D genotypes. Data collected at the time of screening, enrollment and at the baseline visit were used. Descriptive and multiple-logistic regression analyses assessed differences between EM groups regarding exclusion, enrollment and early withdrawal. Results Of the 10,975 eligible subjects, 6,912 (67%) were invited to participate. EM subjects were more likely to be excluded because of an inability to contact. Of those invited 3,265 (47%) enrolled by the age of 4.5 months. Adjusted analyses showed that except for those classified as other EM, the odds of enrolling were similar across groups. EM subjects had elevated early withdrawal rates. Adjusted models demonstrated that this was significantly more likely among Hispanic subjects. Conclusion Understanding patterns associated with EM participation in research extends our ability to make more accurate inferences and permits assessment of strategies that promote inclusion of EM to better address health disparities.