Predicting Later Study Withdrawal in Participants Active in a Longitudinal Birth Cohort Study for 1 Year: The TEDDY Study.

OBJECTIVE: To identify predictors of later study withdrawal among participants active in The Environmental Determinants of Diabetes in the Young (TEDDY) for 1 year. METHODS: Multiple logistic regression was used to discriminate 3,042 children active in TEDDY for the first 3 years from 432 children who withdrew in Years 2 or 3. Predictor variables were tested in blocks-demographic, maternal lifestyle behaviors, stress and child illness, maternal reactions to child's increased diabetes risk, in-study behaviors-and a final best model developed. RESULTS: Few demographic factors predicted study withdrawal. Maternal lifestyle behaviors, accuracy of the mother's risk perception, and in-study behaviors were more important. Frequent child illnesses were associated with greater study retention. CONCLUSIONS: Demographic measures are insufficient predictors of later study withdrawal among those active in a study for at least 1 year; behavioral/psychological factors offer improved prediction and guidance for the development of retention strategies.

Maternal anxiety about a child's diabetes risk in the TEDDY study: the potential role of life stress, postpartum depression, and risk perception.

OBJECTIVE: To understand the association between life stress, postpartum depression (PD), maternal perception of her child's risk for type 1 diabetes (T1D) and a mother's anxiety about her child's T1D risk in mothers of genetically at risk children in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: A short form of the state component (SAI) of the State-Trait Anxiety Inventory, negative life events (LE), the Edinburgh Postnatal Depression Scale (EPDS), and one question about the child's risk of developing T1D risk perceptions (RP) were given to mothers at the 6-month TEDDY clinic visit. The relationship between the four measures was modeled using multiple regressions. RESULTS: Controlling for sociodemographic factors, significant country differences in SAI, LE, EPDS, and RP emerged. LE - particularly interpersonal LE - had a strong association to maternal anxiety about the baby's risk of diabetes. Both evidence of PD and accurate risk perceptions (RPs) about the child's T1D risk were associated with increased maternal anxiety about the child's T1D risk. CONCLUSION: Heightened maternal anxiety in response to the news that a child is at increased risk for T1D is common. Mothers who have experienced recent negative LE, who experience PD and who accurately understand their child's risk may be particularly vulnerable to high levels of anxiety. The findings reported here need to be confirmed in future prospective studies.

Virus infections among young children--the first year of the INDIS study.

The frequencies of early childhood infections were studied in healthy children with increased genetic risk for type 1 diabetes participating in the ongoing prospective high intensive infection follow-up Study, INDIS, started in 2009 in Turku, Finland. Here the results obtained from 160 stool to 160 nasal swab specimens collected in parallel at times of infectious symptoms in 2009-2010 from 45 children at the age of 24 months or younger are reported. The specimens were analyzed for enteric (human enterovirus, norovirus, rotavirus, sapovirus, astrovirus) and respiratory RNA viruses (human enterovirus and rhinovirus) common in early childhood, respectively, using highly validated virus-specific real-time PCR methods. According to the results 96% of the children had at least one virus infection during the study period and one or several viral agents were detected in 76% of sample sets. The most prevalent viral agents were human rhinovirus, enterovirus, parechovirus, and norovirus (genotype GII) with positive specimens 57.5%, 28.8%, 19.4%, and 6.9%, respectively. Other intestinal viruses were found in less than 2% of stool specimens. Single infections covered 40.0% of the specimens while multiple infections with two or more infectious agents were detected in 36.3% of specimens and altogether 11 combinations of viruses were included in the mixed infections. Although human enterovirus is known to be a frequent finding in stool specimens, especially during early childhood, it was found in this study more frequently in nasal swab specimens. Whether this is true, more general, in countries with the high hygiene level remains to be shown.

Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.

IMPORTANCE: Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain. OBJECTIVE: To determine the rate of progression to diabetes after islet autoantibody seroconversion. DESIGN, SETTING, AND PARTICIPANTS: Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012. MAIN OUTCOMES AND MEASURES: The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies. RESULTS: Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]). CONCLUSIONS AND RELEVANCE: The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.

The Environmental Determinants of Diabetes in the Young (TEDDY) study: predictors of early study withdrawal among participants with no family history of type 1 diabetes.

OBJECTIVE: The Environmental Determinants of Diabetes in the Young (TEDDY) study seeks to identify environmental triggers of autoimmunity and type 1 diabetes mellitus (T1DM) in children at increased human-leukocyte-antigen conferred genetic risk for this disease. The objective of this study 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 yr from 763 (17%) families 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. CONCLUSIONS: Identifying families at high risk for study withdrawal at the time of enrollment allows for targeting these families with individually tailored plans to help maintain their participation in the study.

Early suppression of immune response pathways characterizes children with prediabetes in genome-wide gene expression profiling.

Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic beta cells in the islets of Langerhans. Although defects in various T cell subsets have been linked to the disease pathogenesis, mechanisms initiating or enhancing the autoimmunity in prediabetes remain poorly understood. To unravel genes and molecular pathways affected by the diabetes-associated autoimmunity, we investigated transcriptomic profiles of prospective whole-blood samples from children who have developed T1D-associated autoantibodies and eventually clinical T1D. Gene-level investigation of the data showed systematic differential expression of 520 probesets. A network-based analysis revealed then a highly significant down-regulated network of genes involved in antigen presentation as well as T-cell receptor and insulin signaling. Finally, detection of dynamic changes in the affected pathways at the early or late phases of autoimmunity showed down-regulation of several novel T1D-associated pathways as well as known key components of immune response. The longitudinal genome-wide data generated in the present study allows the detection of dynamic changes relevant to the disease that may be completely missed in conventional cross-sectional studies or in genome-wide association studies. Taken together, our analysis showed systemic high-level repression of immune response pathways associated with T1D autoimmunity.

Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial.

BACKGROUND: In mouse models of diabetes, prophylactic administration of insulin reduced incidence of the disease. We investigated whether administration of nasal insulin decreased the incidence of type 1 diabetes, in children with HLA genotypes and autoantibodies increasing the risk of the disease. METHODS: At three university hospitals in Turku, Oulu, and Tampere (Finland), we analysed cord blood samples of 116 720 consecutively born infants, and 3430 of their siblings, for the HLA-DQB1 susceptibility alleles for type 1 diabetes. 17 397 infants and 1613 siblings had increased genetic risk, of whom 11 225 and 1574, respectively, consented to screening of diabetes-associated autoantibodies at every 3-12 months. In a double-blind trial, we randomly assigned 224 infants and 40 siblings positive for two or more autoantibodies, in consecutive samples, to receive short-acting human insulin (1 unit/kg; n=115 and n=22) or placebo (n=109 and n=18) once a day intranasally. We used a restricted randomisation, stratified by site, with permuted blocks of size two. Primary endpoint was diagnosis of diabetes. Analysis was by intention to treat. The study was terminated early because insulin had no beneficial effect. This study is registered with ClinicalTrials.gov, number NCT00223613. FINDINGS: Median duration of the intervention was 1.8 years (range 0-9.7). Diabetes was diagnosed in 49 index children randomised to receive insulin, and in 47 randomised to placebo (hazard ratio [HR] 1.14; 95% CI 0.73-1.77). 42 and 38 of these children, respectively, continued treatment until diagnosis, with yearly rates of diabetes onset of 16.8% (95% CI 11.7-21.9) and 15.3% (10.5-20.2). Seven siblings were diagnosed with diabetes in the insulin group, versus six in the placebo group (HR 1.93; 0.56-6.77). In all randomised children, diabetes was diagnosed in 56 in the insulin group, and 53 in the placebo group (HR 0.98; 0.67-1.43, p=0.91). INTERPRETATION: In children with HLA-conferred susceptibility to diabetes, administration of nasal insulin, started soon after detection of autoantibodies, could not be shown to prevent or delay type 1 diabetes.

Role of insulin autoantibody affinity as a predictive marker for type 1 diabetes in young children with HLA-conferred disease susceptibility.

BACKGROUND: Insulin autoantibodies (IAA) are early markers of prediabetic autoimmunity. As transient and fluctuating IAA positivity are common among young children, distinguishing non-progressive IAA from destruction-related IAA is essential when preventive measures are considered. We tested whether children progressing rapidly to type 1 diabetes (progressors) are characterized by a higher prediabetic IAA affinity than IAA-positive children remaining unaffected or progressing more slowly to diabetes (non-progressors), and whether IAA affinity increases towards diagnosis. METHODS: Finnish children with HLA-conferred diabetes susceptibility were observed from birth for diabetes-associated autoantibodies and progression to overt type 1 diabetes. IAA levels and affinities of the first IAA-positive prediabetic samples and samples obtained closest to the diagnosis in 64 progressors were compared with corresponding values in 64 matched IAA-positive non-progressors. RESULTS: The median age at diagnosis was 3.9 years in progressors and the median follow-up time 7.6 years among unaffected subjects. In the first samples the median IAA affinity was 1.4 x 10(10) L/mol in both groups (p = 0.33), while at the second sampling it was 1.1 x 10(10) L/mol in progressors and 1.2 x 10(10) L/mol in unaffected subjects (p = 0.46). No changes in affinity levels were observed (p = 0.33 and p = 0.84, respectively). IAA titers increased towards diagnosis among progressors (from a median of 13.6 to 20.1 relative units; p = 0.02). CONCLUSIONS: Among young IAA-positive children with HLA-conferred disease susceptibility IAA affinity failed to distinguish rapid progressors from slowly or non-progressing subjects. In relation to IAA affinity, no maturation of the humoral immune response was observed over time from seroconversion to diagnosis.

Time-resolved fluorescence imaging of islet cell autoantibodies.

Time-resolved fluorescence of lanthanide chelates has been widely used in bioanalytical assays. Long fluorescence time, large Stokes shift, and minute fading out of the fluorescence over years are major advantages of the lanthanides over the conventional fluorescent dyes. We have now applied time-resolved fluorescence imaging (TRFI) also for measurement of type 1 diabetes mellitus (T1DM)-related islet cell autoantibodies (ICA). Retaining the accuracy of conventional ICA, TRFI has over 10 times better signal-to-noise ratio than the conventional fluorochromes. The technology allows objective determination of fluorescence intensity with the camera and computer software, and serial dilutions for obtaining the antibody titer in autoantibody-positive samples are unnecessary. We now describe the TRFI as a method and its application for measurement of ICA.

Parental reactions to information about increased genetic risk of type 1 diabetes mellitus in infants.

OBJECTIVE: To assess the anxiety, emotions, thoughts, and coping behaviors of parents 1 week after they receive the results of screening of their infant's genetic risk of type 1 diabetes mellitus. DESIGN: Survey. SETTING: The population-based Type 1 Diabetes Prediction and Prevention project conducted in Turku. PARTICIPANTS: Parents of 443 consecutive high-risk infants and 506 next-born low-risk infants. INTERVENTIONS: An infant's genetic risk of type 1 diabetes mellitus was measured from cord blood. High-risk information was delivered by telephone and low-risk information by mail 4 weeks later. MAIN OUTCOME MEASURES: Anxiety measured using the state anxiety scale of the State-Trait Anxiety Inventory, and feelings, thoughts, and coping behaviors extracted from the questionnaire. RESULTS: One week after obtaining the results, 67% of mothers and 63% of fathers of high-risk children and 58% of mothers and 54% of fathers of low-risk children had returned the questionnaire. Anxiety levels of parents of high-risk infants were similar to those of parents of low-risk infants (P = .86). More than 90% of the parents thought that it was good to know about the risk. Fifty-five percent of mothers and 37% of fathers of high-risk infants expressed modest worry. Increased anxiety was connected with other stressful life events, catastrophizing thoughts of diabetes mellitus risk, and emotion-focused or avoiding coping attitudes. CONCLUSIONS: Learning about their infant's genetic diabetes mellitus risk induces only mild anxiety in most parents. Identifying the few parents with stronger anxiety helps focus intensified counseling.

The effects of type 1 diabetes and its long-term complications on physical and mental health status.

OBJECTIVE: To analyse how type 1 diabetes mellitus (DM) and the symptoms of its chronic long-term complications correlate with health status domains in the adult population in Finland. METHODS: A representative sample of patients with type 1 DM was selected randomly from the Finnish drug reimbursement registry. Participants reported symptoms, diagnoses and treatments indicating the presence and time of appearance of long-term complications, and completed the RAND 36 questionnaire. A principal component analysis was performed to compress the eight RAND 36 dimensions into composite domains of health status. The results were validated with split-sample analysis. Regression analyses were used to estimate the effects of age, sex, symptoms of long-term complications and comorbidities on the component T-scores. RESULTS: Of the 752 (70.8%) responders, 592 fulfilled the criteria of type 1 DM. Of these, 82.6% fully completed the RAND 36 questionnaire. Principal component analysis of our data supports the theory of the 2-factor model of health, as physical and mental health domains were reflected unambiguously by different RAND 36 dimensions. The regression results show that the symptoms of long-term complications correlate more strongly with the physical than the mental domain of health status. CONCLUSION: Type 1 DM, and especially the symptoms of its long-term complications, correlate mainly with the physical domain of health, although the mental domain is also affected. The prevalence of long-term complications with type 1 DM is sufficiently high within the Finnish population to substantially influence the health status of people with type 1 DM.

Participant Experiences in the Environmental Determinants of Diabetes in the Young Study: Common Reasons for Withdrawing.

BACKGROUND: To characterize participant reasons for withdrawing from a diabetes focused longitudinal clinical observational trial (TEDDY) during the first three study years. METHODS: 8677 children were recruited into the TEDDY study. At participant withdrawal staff recorded any reason parents provided for withdrawal. Reasons were categorized into (1) family characteristics and (2) protocol reasons. Families who informed staff of their withdrawal were classified as active withdrawals (AW); families without a final contact were considered passive withdrawals (PW). RESULTS: Withdrawal was highest during the first study year (n = 1220). Most families were AW (n = 1549; 73.4%). PW was more common in the United States (n = 1001; 37.8%) and among young mothers (p = 0.001). The most frequent protocol characteristic was blood draw (55%) and the most common family reason was not having enough time (66%). The blood draw was more common among female participants; being too busy was more common among males. Both reasons were associated with study satisfaction. CONCLUSIONS: Results suggest that, for families of children genetically at risk for diabetes, procedures that can be painful/frightening should be used with caution. Study procedures must also be considered for the demands placed on participants. Study satisfaction should be regularly assessed as an indicator of risk for withdrawal.

Reduced ß-cell function in early preclinical type 1 diabetes.

OBJECTIVE: We aimed to characterize insulin responses to i.v. glucose during the preclinical period of type 1 diabetes starting from the emergence of islet autoimmunity. DESIGN AND METHODS: A large population-based cohort of children with HLA-conferred susceptibility to type 1 diabetes was observed from birth. During regular follow-up visits islet autoantibodies were analysed. We compared markers of glucose metabolism in sequential intravenous glucose tolerance tests between 210 children who were positive for multiple (≥2) islet autoantibodies and progressed to type 1 diabetes (progressors) and 192 children testing positive for classical islet-cell antibodies only and remained healthy (non-progressors). RESULTS: In the progressors, the first phase insulin response (FPIR) was decreased as early as 4-6 years before the diagnosis when compared to the non-progressors (P=0.001). The difference in FPIR between the progressors and non-progressors was significant (P<0.001) in all age groups, increasing with age (at 2 years: difference 50% (95% CI 28-75%) and at 10 years: difference 172% (95% CI 128-224%)). The area under the 10-min insulin curve showed a similar difference between the groups (P<0.001; at 2 years: difference 36% (95% CI 17-58%) and at 10 years: difference 186% (95% CI 143-237%)). Insulin sensitivity did not differ between the groups. CONCLUSIONS: FPIR is decreased several years before the diagnosis of type 1 diabetes, implying an intrinsic defect in ß-cell mass and/or function.

Genetic risk determines the emergence of diabetes-associated autoantibodies in young children.

Timing of onset of autoimmunity is a prerequisite for unmasking triggers and pathogenesis of type 1 diabetes. We followed 4,590 consecutive newborns with 8 or 3% HLA-DQB1 conferred risk for type 1 diabetes at 3-, 6-, or 12-month intervals up to 5.5 years of age. Islet cell autoantibodies (ICAs) and, in the 137 children with ICAs, insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and IA-2 protein autoantibodies (IA-2As) were measured. Children with high genetic risk developed ICAs more often than those with moderate risk (log-rank P = 0.0015); 85 and 91% remained ICA negative by 5 years of age, respectively. The time of appearance of biochemical autoantibodies was then compared with the appearance of ICAs. IAAs and GADAs emerged usually before ICAs (means -1.8 and -1.5 months, respectively) and IA-2As after ICAs (mean 2.0 months). Ninety-five percent of all IAAs, GADAs, and IA-2As seroconversions occurred in a cluster (-12 to 8 months) around the ICA seroconversion. We conclude that diabetes-associated autoantibodies emerged in children with predisposing HLA-DQB1 alleles after 3 months of age at a constant tempo, determined by the genetic risk level, usually in the order of IAA, GADA, ICA, and IA-2A. Seroconversion to multiple autoantibody positivity usually occurred tightly clustered in time.

Serum proteomes distinguish children developing type 1 diabetes in a cohort with HLA-conferred susceptibility.

We determined longitudinal serum proteomics profiles from children with HLA-conferred diabetes susceptibility to identify changes that could be detected before seroconversion and positivity for disease-associated autoantibodies. Comparisons were made between children who seroconverted and progressed to type 1 diabetes (progressors) and those who remained autoantibody negative, matched by age, sex, sample periodicity, and risk group. The samples represented the prediabetic period and ranged from the age of 3 months to 12 years. After immunoaffinity depletion of the most abundant serum proteins, isobaric tags for relative and absolute quantification were used for sample labeling. Quantitative proteomic profiles were then measured for 13 case-control pairs by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, a label-free LC-MS/MS approach was used to analyze depleted sera from six case-control pairs. Importantly, differences in abundance of a set of proteins were consistently detected before the appearance of autoantibodies in the progressors. Based on top-scoring pairs analysis, classification of such progressors was observed with a high success rate. Overall, the data provide a reference of temporal changes in the serum proteome in healthy children and children progressing to type 1 diabetes, including new protein candidates, the levels of which change before clinical diagnosis.

A simulation model for estimating direct costs of type 1 diabetes prevention.

BACKGROUND: The ongoing Type 1 Diabetes Prediction and Prevention Project in Finland (DIPP) is based on screening of genetic type 1 diabetes mellitus susceptibility, subsequent autoantibody follow-up and experimental preventive treatment with nasal insulin. OBJECTIVE: To analyse direct costs of type 1 diabetes prevention therapy with nasal insulin as it is now being studied in the DIPP project, and as it might be used as a part of routine healthcare in Finland. DATA AND METHODS: For the purposes of cost analysis, two different diabetes prevention models were constructed. The research-oriented model followed accurately the DIPP protocol and the practice-oriented model was based on the estimates of a panel of experts on how the prevention would be conducted as a part of the routine healthcare in Finland. To take into account the uncertainty and variability attached to the use of resources, a Monte Carlo simulation model was utilised. The costs of the two models comprising 500 iterations each were simulated using the Monte Carlo model. STUDY PERSPECTIVE: This study was performed from the healthcare provider's viewpoint. RESULTS: The total direct costs per person of the research-oriented model were 2102 and 1676 euros (EUR) in the first and second year and those of the practice-oriented model EUR827 and EUR675, respectively (EUR1 approximately dollars US1.1; 2002 values). Subsequently, the costs rose only as a result of the increased use of insulin as the children grew older. After the 15th year, when the age structure of the population in the study had stabilised, the annual direct costs per person were EUR1798 (research-oriented model) and EUR797 (practice-oriented model). CONCLUSIONS: The costs of prevention with nasal insulin are low when compared with estimates of the annual healthcare costs of type 1 diabetes. This study suggests, with some critical assumptions (in particular, that nasal insulin is effective in the prevention of type I diabetes), that a 2 to 3-year delay in the disease onset may make prevention according to the practice-oriented model cost saving.

Factors associated with maternal-reported actions to prevent type 1 diabetes in the first year of the TEDDY study.

OBJECTIVE: Mothers of children at risk for type 1 diabetes report engaging in preventive behaviors. The purpose of this study is to further document these actions in an international, longitudinal sample and examine variables that predict whether mothers engage in these behaviors. RESEARCH DESIGN AND METHODS: This study examined an international sample (from Finland, Germany, Sweden, and the U.S.) from the naturalistic, longitudinal The Environmental Determinants of Diabetes in the Young (TEDDY) study, which tracked children genetically at risk for type 1 diabetes from birth to age 15 years. Mothers of 7,613 infants aged 6 months and 6,503 infants aged 15 months completed questionnaires assessing psychosocial factors and actions intended to prevent diabetes. RESULTS: Many mothers (29.9% at 6 months and 42.8% at 15 months) reported engaging in a behavior intended to prevent type 1 diabetes, with the largest percentages (20.9-29.2%) reporting making changes to their child's diet (e.g., reducing the consumption of sweets and carbohydrates). Factors related to engaging in preventive behaviors include older maternal age; higher maternal education; minority status; having only one child; having a first-degree relative with type 1 diabetes; being from a country other than Sweden; having an accurate perception of the child's increased risk for developing diabetes; having postpartum depression, maternal anxiety, and worry about the risk of diabetes; and believing that diabetes can be prevented. CONCLUSIONS: The findings of this study suggest that many mothers engage in actions to prevent diabetes and highlight the importance of tracking these behaviors to ensure the validity of naturalistic observational studies.

Coxsackievirus B1 is associated with induction of ß-cell autoimmunity that portends type 1 diabetes.

The rapidly increasing incidence of type 1 diabetes implies that environmental factors are involved in the pathogenesis. Enteroviruses are among the suspected environmental triggers of the disease, and the interest in exploring the possibilities to develop vaccines against these viruses has increased. Our objective was to identify enterovirus serotypes that could be involved in the initiation of the disease process by screening neutralizing antibodies against 41 different enterovirus types in a unique longitudinal sample series from a large prospective birth-cohort study. The study participants comprised 183 case children testing persistently positive for at least two diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. Coxsackievirus B1 was associated with an increased risk of ß-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and was attenuated by the presence of maternal antibodies against the virus. Two other coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern, suggesting immunological cross-protection against coxsackievirus B1. These results support previous observations suggesting that the group B coxsackieviruses are associated with the risk of type 1 diabetes. The clustering of the risk and protective viruses to this narrow phylogenetic lineage supports the biological plausibility of this phenomenon.

Innate immune activity is detected prior to seroconversion in children with HLA-conferred type 1 diabetes susceptibility.

The insult leading to autoantibody development in children who will progress to develop type 1 diabetes (T1D) has remained elusive. To investigate the genes and molecular pathways in the pathogenesis of this disease, we performed genome-wide transcriptomics analysis on a unique series of prospective whole-blood RNA samples from at-risk children collected in the Finnish Type 1 Diabetes Prediction and Prevention study. We studied 28 autoantibody-positive children, out of which 22 progressed to clinical disease. Collectively, the samples covered the time span from before the development of autoantibodies (seroconversion) through the diagnosis of diabetes. Healthy control subjects matched for date and place of birth, sex, and HLA-DQB1 susceptibility were selected for each case. Additionally, we genotyped the study subjects with Immunochip to identify potential genetic variants associated with the observed transcriptional signatures. Genes and pathways related to innate immunity functions, such as the type 1 interferon (IFN) response, were active, and IFN response factors were identified as central mediators of the IFN-related transcriptional changes. Importantly, this signature was detected already before the T1D-associated autoantibodies were detected. Together, these data provide a unique resource for new hypotheses explaining T1D biology.

Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes.

The incidence of the autoimmune disease, type 1 diabetes (T1D), has increased dramatically over the last half century in many developed countries and is particularly high in Finland and other Nordic countries. Along with genetic predisposition, environmental factors are thought to play a critical role in this increase. As with other autoimmune diseases, the gut microbiome is thought to play a potential role in controlling progression to T1D in children with high genetic risk, but we know little about how the gut microbiome develops in children with high genetic risk for T1D. In this study, the early development of the gut microbiomes of 76 children at high genetic risk for T1D was determined using high-throughput 16S rRNA gene sequencing. Stool samples from children born in the same hospital in Turku, Finland were collected at monthly intervals beginning at 4-6 months after birth until 2.2 years of age. Of those 76 children, 29 seroconverted to T1D-related autoimmunity (cases) including 22 who later developed T1D, the remaining 47 subjects remained healthy (controls). While several significant compositional differences in low abundant species prior to seroconversion were found, one highly abundant group composed of two closely related species, Bacteroides dorei and Bacteroides vulgatus, was significantly higher in cases compared to controls prior to seroconversion. Metagenomic sequencing of samples high in the abundance of the B. dorei/vulgatus group before seroconversion, as well as longer 16S rRNA sequencing identified this group as Bacteroides dorei. The abundance of B. dorei peaked at 7.6 months in cases, over 8 months prior to the appearance of the first islet autoantibody, suggesting that early changes in the microbiome may be useful for predicting T1D autoimmunity in genetically susceptible infants. The cause of increased B. dorei abundance in cases is not known but its timing appears to coincide with the introduction of solid food.