Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of ce... more Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. 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. 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. Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. Islet autoimmunity and CD autoimmunity...
The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared wit... more The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter randomized controlled trial in the knee. This report was undertaken to investigate 5-year structural and clinical outcomes. The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. Patients were randomized to receive BST-CarGel® treatment or microfracture alone, and followed standardized 12-week rehabilitation. Co-primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling (%) and T2 relaxation times. Secondary endpoints were clinical benefit measured with WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires and safety. General estimating equations were used for longitudinal statistical analysis of repeated measures. Blinded MRI analys...
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or ... more Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression...
Type 1 diabetes (T1D) research has made great strides over the past decade with advances in under... more Type 1 diabetes (T1D) research has made great strides over the past decade with advances in understanding the pathogenesis, natural history, candidate environmental exposures, exposure triggering time, disease prediction, and diagnosis. Major monitoring efforts have provided baseline historical measures, leading to better epidemiological studies incorporating longitudinal biosamples (ie, biobanks), which have allowed for new technologies ('omics') to further expose the etiological agents responsible for the initiation, progression, and eventual clinical onset of T1D. These new frontiers have brought forth high-dimensionality data, which have furthered the evidence of the heterogeneous nature of T1D pathogenesis and allowed for a more mechanistic approach in understanding the etiology of T1D. This review will expand on the most recent advances in the quest for T1D determinants, drawing upon novel research tools that epidemiology, genetics, microbiology, and immunology have provided, linking them to the major hypotheses associated with T1D etiology, and discussing the future frontiers.
Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. T... more Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight, height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk of type 1 diabetes, followed in Finland, Germany, Sweden and US. Growth data collected every third month were used to estimate individual growth curves using mixed models. Cox proportional hazards models were used to evaluate the body size and risk of islet autoimmunity and T1D. In the overall cohort, development of islet autoimmunity (n=575) was related to weight z-scores at 12 months, (HR 1.16 per 1.14 kg in males or per 1.02 kg in females; 95%CI 1.06-1.27, p<0.001, FDR=0.008), but not at 24 or 36 months. A similar relationship was seen between weight z-scores and development of multiple islet autoantibodies (1 year, HR 1.21 95%CI 1.08-1.35, p=0.001, FDR=0.008; 2 years, HR 1.1...
Clinical and epidemiological researchers across all medical special-ties need tools and knowledge... more Clinical and epidemiological researchers across all medical special-ties need tools and knowledge representations to support the classi-fication, aggregation, and analysis of medication data. The National Drug File Reference Terminology (NDF-RT), a named standard for classifying medications, is developed by the US Department of Vet-erans Affairs (VA) as an extension to their National Drug File, which is the master list of drugs prescribed to VA patients, which are adults. NDF-RT is organized as a multi-axial hierarchy with addition-al relations between ingredients, medications, chemical structures, mechanism of action, and therapeutic indications. We describe our experience applying NDF-RT to a dataset of encoded medications that were collected from an international cohort of over 8,000 chil-dren. Our data-driven approach allows us to extract selected NDF-RT sub-classes of a researcher-provided concept of "antibiotics". We believe that a subset of concepts and relationship...
International journal of probiotics & prebiotics, Aug 1, 2012
The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 month... more The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 months old children was investigated. The aim was to determine total lactobacilli and Lactobacillus plantarum (L. plantarum) content (ng/g feces) in 50 infants each from Colorado (648 samples), Finland (624 samples) and Sweden (685 samples) who participated in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. Total lactobacilli content varied markedly between 5 and 16,800 ng/g feces in the three clinical sites within and between individuals especially in infants. L.plantarum also varied markedly intra- and inter-individually from <0.5 - 736 ng/g feces. A higher variability of total lactobacilli was found before 10 months of age than after in the three different clinical sites. Sweden had the lowest total lactobacilli content compared to Colorado and Finland while the L.plantarum content was higher in Sweden. Mail-in stool samples from infants should prove useful in...
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or ... more Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression...
Advances in experimental medicine and biology, 2010
Patient registries are essential tools for public health surveillance and research inquiry, and a... more Patient registries are essential tools for public health surveillance and research inquiry, and are a particularly important resource for understanding rare diseases. Registries provide consistent data for defined populations and can support the study of the distribution and determinants of various diseases. One advantage of registries is the ability to observe caseload and population characteristics over time, which might facilitate the evaluation of disease incidence, disease etiology, planning, operation and evaluation of services, evaluation of treatment patterns, and diagnostic classification. Any registry program must collect high quality data to be useful for its stated purpose. Registries can be developed for many different needs, and caution should be taken in interpreting registry data, which has inherent biases. We describe the methodological issues, limitations, and ideal features of registries to support various rare disease purposes. The future impact of registries on ...
To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, a... more To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, and metabolic markers and synthesize these patterns for risk prediction. RuleFit is used to identify the risk-predictive baseline profile patterns of demographic, immunologic, and metabolic markers, using 356 subjects who were randomized into the control arm of the prospective Diabetes Prevention Trial-Type 1 (DPT-1) study. A novel latent trait model is developed to synthesize these baseline profile patterns for disease risk prediction. The primary outcome was Type 1 Diabetes (T1D) onset. We identified ten baseline profile patterns that were significantly predictive to the disease onset. Using these ten baseline profile patterns, a risk prediction model was built based on the latent trait model, which produced superior prediction performance over existing risk score models for T1D. Our results demonstrated that the underlying disease progression process of T1D can be detected through some...
Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of ce... more Evidence is lacking regarding the consequences of antibiotic use in early life and the risk of certain autoimmune diseases. 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. 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. Parental reports of the most common antibiotics (cephalosporins, penicillins, and macrolides) used between age 3 months and age 4 years were recorded prospectively. Islet autoimmunity and CD autoimmunity...
The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared wit... more The efficacy and safety of BST-CarGel®, a chitosan scaffold for cartilage repair was compared with microfracture alone at 1 year during a multicenter randomized controlled trial in the knee. This report was undertaken to investigate 5-year structural and clinical outcomes. The international randomized controlled trial enrolled 80 patients, aged 18 to 55 years, with grade III or IV focal lesions on the femoral condyles. Patients were randomized to receive BST-CarGel® treatment or microfracture alone, and followed standardized 12-week rehabilitation. Co-primary endpoints of repair tissue quantity and quality were evaluated by 3-dimensional MRI quantification of the degree of lesion filling (%) and T2 relaxation times. Secondary endpoints were clinical benefit measured with WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaires and safety. General estimating equations were used for longitudinal statistical analysis of repeated measures. Blinded MRI analys...
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or ... more Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression...
Type 1 diabetes (T1D) research has made great strides over the past decade with advances in under... more Type 1 diabetes (T1D) research has made great strides over the past decade with advances in understanding the pathogenesis, natural history, candidate environmental exposures, exposure triggering time, disease prediction, and diagnosis. Major monitoring efforts have provided baseline historical measures, leading to better epidemiological studies incorporating longitudinal biosamples (ie, biobanks), which have allowed for new technologies (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;omics&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;) to further expose the etiological agents responsible for the initiation, progression, and eventual clinical onset of T1D. These new frontiers have brought forth high-dimensionality data, which have furthered the evidence of the heterogeneous nature of T1D pathogenesis and allowed for a more mechanistic approach in understanding the etiology of T1D. This review will expand on the most recent advances in the quest for T1D determinants, drawing upon novel research tools that epidemiology, genetics, microbiology, and immunology have provided, linking them to the major hypotheses associated with T1D etiology, and discussing the future frontiers.
Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. T... more Increased growth in early childhood has been suggested to increase the risk of type 1 diabetes. This study explored the relationship between weight, height and development of persistent islet autoimmunity and progression to type 1 diabetes during the first 4 years of life in 7,468 children at genetic risk of type 1 diabetes, followed in Finland, Germany, Sweden and US. Growth data collected every third month were used to estimate individual growth curves using mixed models. Cox proportional hazards models were used to evaluate the body size and risk of islet autoimmunity and T1D. In the overall cohort, development of islet autoimmunity (n=575) was related to weight z-scores at 12 months, (HR 1.16 per 1.14 kg in males or per 1.02 kg in females; 95%CI 1.06-1.27, p<0.001, FDR=0.008), but not at 24 or 36 months. A similar relationship was seen between weight z-scores and development of multiple islet autoantibodies (1 year, HR 1.21 95%CI 1.08-1.35, p=0.001, FDR=0.008; 2 years, HR 1.1...
Clinical and epidemiological researchers across all medical special-ties need tools and knowledge... more Clinical and epidemiological researchers across all medical special-ties need tools and knowledge representations to support the classi-fication, aggregation, and analysis of medication data. The National Drug File Reference Terminology (NDF-RT), a named standard for classifying medications, is developed by the US Department of Vet-erans Affairs (VA) as an extension to their National Drug File, which is the master list of drugs prescribed to VA patients, which are adults. NDF-RT is organized as a multi-axial hierarchy with addition-al relations between ingredients, medications, chemical structures, mechanism of action, and therapeutic indications. We describe our experience applying NDF-RT to a dataset of encoded medications that were collected from an international cohort of over 8,000 chil-dren. Our data-driven approach allows us to extract selected NDF-RT sub-classes of a researcher-provided concept of "antibiotics". We believe that a subset of concepts and relationship...
International journal of probiotics & prebiotics, Aug 1, 2012
The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 month... more The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 months old children was investigated. The aim was to determine total lactobacilli and Lactobacillus plantarum (L. plantarum) content (ng/g feces) in 50 infants each from Colorado (648 samples), Finland (624 samples) and Sweden (685 samples) who participated in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. Total lactobacilli content varied markedly between 5 and 16,800 ng/g feces in the three clinical sites within and between individuals especially in infants. L.plantarum also varied markedly intra- and inter-individually from <0.5 - 736 ng/g feces. A higher variability of total lactobacilli was found before 10 months of age than after in the three different clinical sites. Sweden had the lowest total lactobacilli content compared to Colorado and Finland while the L.plantarum content was higher in Sweden. Mail-in stool samples from infants should prove useful in...
Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or ... more Body size is postulated to modulate type 1 diabetes as either a trigger of islet autoimmunity or an accelerator to clinical onset after seroconversion. As overweight and obesity continue to rise among children, the aim of this study was to determine whether human leukocyte antigen DQ (HLA-DQ) genotypes may be related to body size among children genetically at risk for type 1 diabetes. Repeated measures of weight and height were collected from 5969 children 2-4 years of age enrolled in The Environmental Determinants of Diabetes in the Young prospective study. Overweight and obesity was determined by the International Obesity Task Force cutoff values that correspond to body mass index (BMI) of 25 and 30 kg m(-)(2) at age 18. The average BMI was comparable across specific HLA genotypes at every age point. The proportion of overweight was not different by HL A, but percent obesity varied by age with a decreasing trend among DQ2/8 carriers (P for trend=0.0315). A multivariable regression...
Advances in experimental medicine and biology, 2010
Patient registries are essential tools for public health surveillance and research inquiry, and a... more Patient registries are essential tools for public health surveillance and research inquiry, and are a particularly important resource for understanding rare diseases. Registries provide consistent data for defined populations and can support the study of the distribution and determinants of various diseases. One advantage of registries is the ability to observe caseload and population characteristics over time, which might facilitate the evaluation of disease incidence, disease etiology, planning, operation and evaluation of services, evaluation of treatment patterns, and diagnostic classification. Any registry program must collect high quality data to be useful for its stated purpose. Registries can be developed for many different needs, and caution should be taken in interpreting registry data, which has inherent biases. We describe the methodological issues, limitations, and ideal features of registries to support various rare disease purposes. The future impact of registries on ...
To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, a... more To identify the risk-predictive baseline profile patterns of demographic, genetic, immunologic, and metabolic markers and synthesize these patterns for risk prediction. RuleFit is used to identify the risk-predictive baseline profile patterns of demographic, immunologic, and metabolic markers, using 356 subjects who were randomized into the control arm of the prospective Diabetes Prevention Trial-Type 1 (DPT-1) study. A novel latent trait model is developed to synthesize these baseline profile patterns for disease risk prediction. The primary outcome was Type 1 Diabetes (T1D) onset. We identified ten baseline profile patterns that were significantly predictive to the disease onset. Using these ten baseline profile patterns, a risk prediction model was built based on the latent trait model, which produced superior prediction performance over existing risk score models for T1D. Our results demonstrated that the underlying disease progression process of T1D can be detected through some...
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