Carin Andrén Aronsson

The environmental determinants of diabetes in the young (TEDDY) study: Study design

Abstract:  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 7800 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.

Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

BACKGROUND The presence of HLA haplotype DR3-DQ2 or DR4-DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3-DQ2 or DR4-DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3-DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3-DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4-DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3-DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries highlights the importance of studying environmental factors associated with celiac disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

Misreporting of energy: prevalence, characteristics of misreporters and influence on observed risk estimates in the Malmö Diet and Cancer cohort.

The present study investigates the prevalence of misreporting of energy in the Malmö Diet and Cancer cohort, and examines anthropometric, socio-economic and lifestyle characteristics of the misreporters. Further, the influence of excluding misreporters on risk estimates of post-menopausal breast cancer was examined. Information of reported energy intake (EI) was obtained from a modified diet history method. A questionnaire provided information on lifestyle and socio-economic characteristics. Individual physical activity level (PAL) was calculated from self-reported information on physical activity at work, leisure time physical activity and household work, and from estimates of hours of sleeping, self-care and passive time. Energy misreporting was defined as having a ratio of EI to BMR outside the 95 % CI limits of the calculated PAL. Logistic regression analysed the risk of being a low-energy reporter or a high-energy reporter. Almost 18 % of the women and 12 % of the men were classified as low-energy reporters, 2.8 % of the women and 3.5 % of the men were classified as high-energy reporters. In both genders high BMI, large waist circumference, short education and being a blue-collar worker were significantly associated with low-energy reporting. High-energy reporting was significantly associated with low BMI, living alone and current smoking. The results add support to the practice of energy adjustment as a means to reduce the influence of errors in risk assessment.

Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study

IMPORTANCE Probiotics have been hypothesized to affect immunologic responses to environmental exposures by supporting healthy gut microbiota and could therefore theoretically be used to prevent the development of type 1 diabetes mellitus (T1DM)-associated islet autoimmunity. OBJECTIVE To examine the association between supplemental probiotic use during the first year of life and islet autoimmunity among children at increased genetic risk of T1DM. DESIGN, SETTING, AND PARTICIPANTS In this ongoing prospective cohort study that started September 1, 2004, children from 6 clinical centers, 3 in the United States (Colorado, Georgia/Florida, and Washington) and 3 in Europe (Finland, Germany, and Sweden), were followed up for T1DM-related autoantibodies. Blood samples were collected every 3 months between 3 and 48 months of age and every 6 months thereafter to determine persistent islet autoimmunity. Details of infant feeding, including probiotic supplementation and infant formula use, were monitored from birth using questionnaires and diaries. We applied time-to-event analysis to study the association between probiotic use and islet autoimmunity, stratifying by country and adjusting for family history of type 1 diabetes, HLA-DR-DQ genotypes, sex, birth order, mode of delivery, exclusive breastfeeding, birth year, childs antibiotic use, and diarrheal history, as well as maternal age, probiotic use, and smoking. Altogether 8676 infants with an eligible genotype were enrolled in the follow-up study before the age of 4 months. The final sample consisted of 7473 children with the age range of 4 to 10 years (as of October 31, 2014). EXPOSURES Early intake of probiotics. MAIN OUTCOMES AND MEASURES Islet autoimmunity revealed by specific islet autoantibodies. RESULTS Early probiotic supplementation (at the age of 0-27 days) was associated with a decreased risk of islet autoimmunity when compared with probiotic supplementation after 27 days or no probiotic supplementation (hazard ratio [HR], 0.66; 95% CI, 0.46-0.94). The association was accounted for by children with the DR3/4 genotype (HR, 0.40; 95% CI, 0.21-0.74) and was absent among other genotypes (HR, 0.97; 95% CI, 0.62-1.54). CONCLUSIONS AND RELEVANCE Early probiotic supplementation may reduce the risk of islet autoimmunity in children at the highest genetic risk of T1DM. The result needs to be confirmed in further studies before any recommendation of probiotics use is made.

Ability of physical activity measurements to assess health-related risks.

The aim of this study is to evaluate if two different physical activity (PA) questionnaires have similar ability to rank individuals, and to examine associations with cardiovascular-metabolic risk factors, compared to an objective measure. In a random sample (n=369, age: 65±6 years) from the population-based ‘Malmö Diet and Cancer’ (MDC) cohort, PA was measured by a leisure-time comprehensive questionnaire (MDC-score), a simple leisure-time questionnaire and by accelerometer-monitoring (CSA). Moderate correlations were observed between MDC-score and CSA in men and women (r=0.35 and 0.24, respectively). In men, both questionnaires and CSA were inversely associated with waist circumference, insulin resistance and metabolic syndrome. In women, the MDC-score was positively associated with high-density lipoprotein-cholesterol, and the simple questionnaire inversely associated with anthropometric indexes, but no association was seen between PA estimates and cardiovascular components. We conclude that both PA questionnaires distinguish health risks associated with anthropometric-metabolic risk factors, particularly in men.

Effects of Gluten Intake on Risk of Celiac Disease: A Case-Control Study on a Swedish Birth Cohort

BACKGROUND & AIMS Early nutrition may affect the risk of celiac disease. We investigated whether amount of gluten in diet until 2 years of age increases risk for celiac disease. METHODS We performed a 1-to-3 nested case-control study of 146 cases, resulting in 436 case-control pairs matched for sex, birth year, and HLA genotype generated from Swedish children at genetic risk for celiac disease. Newborns were annually screened for tissue transglutaminase autoantibodies (tTGA). If tested tTGA positive, time point of seroconversion was determined from frozen serum samples taken every 3 months. Celiac disease was confirmed by intestinal biopsies. Gluten intake was calculated from 3-day food records collected at ages 9, 12, 18 and 24 months. Odds ratios (OR) were calculated through conditional logistic regression. RESULTS Breastfeeding duration (median, 32 wk) and age at first introduction to gluten (median, 22 wk) did not differ between cases and tTGA-negative controls. At the visit before tTGA seroconversion, cases reported a larger intake of gluten than controls (OR, 1.28; 95% confidence interval [CI], 1.13-1.46; P = .0002). More cases than controls were found in the upper third tertile (ie, >5.0 g/d) before they tested positive for tTGA seroconversion than controls (OR, 2.65; 95% CI, 1.70-4.13; P < .0001). This finding was similar in children homozygous for DR3-DQ2 (OR, 3.19; 95% CI, 1.61-6.30; P = .001), heterozygous for DR3-DQ2 (OR, 2.24; 95% CI, 1.08-4.62; P = .030), and for children not carrying DR3-DQ2 (OR, 2.43; 95% CI, 0.90-6.54; P = .079). CONCLUSIONS The amount of gluten consumed until 2 years of age increases the risk of celiac disease at least 2-fold in genetically susceptible children. These findings may be taken into account for future infant feeding recommendations.

Clinical Features of Celiac Disease: A Prospective Birth Cohort

OBJECTIVES: To investigate clinical features of celiac disease (CD) and their association with risk factors for CD in a genetic risk birth cohort. METHODS: Children from 6 clinical centers in 4 countries positive for HLA-DR3-DQ2 or DR4-DQ8 were annually screened for tissue transglutaminase antibodies (tTGA) and assessed for symptoms by questionnaires. Associations of symptoms with anthropometrics, known risk factors for CD, tTGA levels, and mucosal lesions in those biopsied were examined. RESULTS: Of 6706 screened children, 914 developed persistent positive tTGA, 406 underwent biopsies, and 340 had CD. Compared with age-matched tTGA-negative children, those with persistent tTGA were more likely to have symptoms at 2 (34% vs 19%, P < .001) and 3 years of age (28% vs 19%, P = .009) but not at 4 years (27% vs 21%, NS). Z-scores for height, weight, and BMI did not differ between groups. In children with persistent tTGA, having ≥1 symptom was associated with family history of CD (odds ratio = 2.59, 95% confidence interval, 1.21–5.57) but not with age, gender, or HLA-DR3-DQ2 homozygosity. At seroconversion, tTGA levels were higher in symptomatic than asymptomatic children (P < .001), in those from CD families (P < .001), and in US participants (P < .001) but not associated with age, gender, or HLA genotype. tTGA levels correlated with severity of mucosal lesions both in symptomatic (r = 0.53, P < .001) and asymptomatic children (r = 0.22, P = .01). CONCLUSIONS: A majority of children detected with persistent tTGA in screenings are asymptomatic and have normal growth by age 4 years. tTGA levels correlate more strongly with severity of mucosal lesions in symptomatic as compared with asymptomatic children.

Use of dietary supplements in pregnant women in relation to sociodemographic factors - a report from The Environmental Determinants of Diabetes in the Young (TEDDY) study

OBJECTIVES The aim of the present study was to examine the prevalence and associated factors of dietary supplement use, particularly supplements containing vitamin D and fatty acids, in pregnant women enrolled in a multi-national study. DESIGN The Environmental Determinants of Diabetes in the Young (TEDDY) study is a prospective longitudinal cohort study. Maternal dietary supplement use was self-reported through questionnaires at month 3 to 4 postpartum. SETTING Six clinical research centres; three in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Sweden, Finland and Germany). SUBJECTS Mothers (n 7326) to infants screened for high-risk HLA-DQ genotypes of type 1 diabetes. RESULTS Ninety-two per cent of the 7326 women used one or more types of supplement during pregnancy. Vitamin D supplements were taken by 65% of the women, with the highest proportion of users in the USA (80.5 %). Overall, 16% of the women reported taking fatty acid supplements and a growing trend was seen in all countries between 2004 and 2010 (P,0.0001). The use was more common in Germany (32 %) and the USA (24 %) compared with Finland (8.5%) and Sweden (7.0 %). Being pregnant with the first child was a strong predictor for any supplement use in all countries. Low maternal age (<25 years), higher education, BMI<=25.0 kg/m2 and smoking during pregnancy were factors associated with supplement use in some but not all countries. CONCLUSIONS The majority of the women used dietary supplements during pregnancy. The use was associated with sociodemographic and behavioural factors, such as parity, maternal age, education, BMI and maternal smoking.

Age at first introduction to complementary foods is associated with sociodemographic factors in children with increased genetic risk of developing type 1 diabetes.

Infants age at introduction to certain complementary foods (CF) has in previous studies been associated with islet autoimmunity, which is an early marker for type 1 diabetes (T1D). Various maternal sociodemographic factors have been found to be associated with early introduction to CF. The aims of this study were to describe early infant feeding and identify sociodemographic factors associated with early introduction to CF in a multinational cohort of infants with an increased genetic risk for T1D. The Environmental Determinants of Diabetes in the Young study is a prospective longitudinal birth cohort study. Infants (N = 6404) screened for T1D high risk human leucocyte antigen-DQ genotypes (DR3/4, DR4/4, DR4/8, DR3/3, DR4/4, DR4/1, DR4/13, DR4/9 and DR3/9) were followed for 2 years at six clinical research centres: three in the United States (Colorado, Georgia/Florida, Washington) and three in Europe (Sweden, Finland, Germany). Age at first introduction to any food was reported at clinical visits every third month from the age of 3 months. Maternal sociodemographic data were self-reported through questionnaires. Age at first introduction to CF was primarily associated with country of residence. Root vegetables and fruits were usually the first CF introduced in Finland and Sweden and cereals were usually the first CF introduced in the United States. Between 15% and 20% of the infants were introduced to solid foods before the age of 4 months. Young maternal age (<25 years), low educational level (<12 years) and smoking during pregnancy were significant predictors of early introduction to CF in this cohort. Infants with a relative with T1D were more likely to be introduced to CF later.

Infant feeding patterns in families with a diabetes history – observations from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study

OBJECTIVE To assess the association between diabetes family history and infant feeding patterns. DESIGN Data on breast-feeding duration and age at first introduction of cows milk and gluten-containing cereals were collected in 3-month intervals during the first 24 months of life. SETTING Data from the multicentre TEDDY (The Environmental Determinants of Diabetes in the Young) study, including centres in the USA, Sweden, Finland and Germany. SUBJECTS A total of 7026 children, including children with a mother with type 1 diabetes (T1D; n 292), gestational diabetes mellitus (GDM; n 404) or without diabetes but with a father and/or sibling with T1D (n 464) and children without diabetes family history (n 5866). RESULTS While exclusive breast-feeding ended earlier and cows milk was introduced earlier in offspring of mothers with T1D and GDM, offspring of non-diabetic mothers but a father and/or sibling with T1D were exclusively breast-fed longer and introduced to cows milk later compared with infants without diabetes family history. The association between maternal diabetes and shorter exclusive breast-feeding duration was attenuated after adjusting for clinical variables (delivery mode, gestational age, Apgar score and birth weight). Country-specific analyses revealed differences in these associations, with Sweden showing the strongest and Finland showing no association between maternal diabetes and breast-feeding duration. CONCLUSIONS Family history of diabetes is associated with infant feeding patterns; however, the associations clearly differ by country, indicating that cultural differences are important determinants of infant feeding behaviour. These findings need to be considered when developing strategies to improve feeding patterns in infants with a diabetes family history.