Jeffrey P Krischer

University of South Florida, Tampa, Florida, United States

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Publications (291)1857.24 Total impact

  • Diabetes Care 10/2015; 38(10):1964-1974. DOI:10.2337/dc15-1419 · 8.42 Impact Factor
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    ABSTRACT: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of linked multisystem life- and organ-threatening diseases. The Outcome Measures in Rheumatology (OMERACT) vasculitis working group has been at the forefront of outcome development in the field and has achieved OMERACT endorsement of a core set of outcomes for AAV. Patients with AAV report as important some manifestations of disease not routinely collected through physician-completed outcome tools; and they rate common manifestations differently from investigators. The core set includes the domain of patient-reported outcomes (PRO). However, PRO currently used in clinical trials of AAV do not fully characterize patients' perspectives on their burden of disease. The OMERACT vasculitis working group is addressing the unmet needs for PRO in AAV. Current activities of the working group include (1) evaluating the feasibility and construct validity of instruments within the PROMIS (Patient-Reported Outcome Measurement Information System) to record components of the disease experience among patients with AAV; (2) creating a disease-specific PRO measure for AAV; and (3) applying The International Classification of Functioning, Disability and Health to examine the scope of outcome measures used in AAV. The working group has developed a comprehensive research strategy, organized an investigative team, included patient research partners, obtained peer-reviewed funding, and is using a considerable research infrastructure to complete these interrelated projects to develop evidence-based validated outcome instruments that meet the OMERACT filter of truth, discrimination, and feasibility. The OMERACT vasculitis working group is on schedule to achieve its goals of developing validated PRO for use in clinical trials of AAV.
    The Journal of Rheumatology 09/2015; DOI:10.3899/jrheum.141143 · 3.19 Impact Factor
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    ABSTRACT: Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut. We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity. We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders. There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest vs. lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example. These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life. © 2015 American Society for Nutrition.
    American Journal of Clinical Nutrition 07/2015; 102(2). DOI:10.3945/ajcn.115.108159 · 6.77 Impact Factor
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    ABSTRACT: 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. 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. Three centres in the USA (Colorado, Georgia/Florida and Washington) and three in Europe (Finland, Germany and Sweden). Families who finished the first 3 years of TEDDY participation (n 8096). 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. These findings identified specific groups for targeted strategies to encourage completion of food records, thereby reducing potential bias in multidisciplinary collaborative research.
    Public Health Nutrition 06/2015; -1:1-10. DOI:10.1017/S1368980015001883 · 2.68 Impact Factor
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    ABSTRACT: Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.Am J Gastroenterol advance online publication, 26 May 2015; doi:10.1038/ajg.2015.150.
    The American Journal of Gastroenterology 05/2015; 110(6). DOI:10.1038/ajg.2015.150 · 10.76 Impact Factor
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    ABSTRACT: Early childhood environmental exposures, possibly infections, may be responsible for triggering islet autoimmunity and progression to type 1 diabetes (T1D). The Environmental Determinants of Diabetes in the Young (TEDDY) follows children with increased HLA-related genetic risk for future T1D. TEDDY asks parents to prospectively record the child’s infections using a diary book. The present paper shows how these large amounts of partially structured data were reduced into quantitative data-sets and further categorized into system-specific infectious disease episodes. The numbers and frequencies of acute infections and infectious episodes are shown. Study subjects (n = 3463) included children who had attended study visits every three months from age 3 months to 4 years, without missing two or more consecutive visits during the follow-up. Parents recorded illnesses prospectively in a TEDDY Book at home. The data were entered into the study database during study visits using ICD-10 codes by a research nurse. TEDDY investigators grouped ICD-10 codes and fever reports into infectious disease entities and further arranged them into four main categories of infectious episodes: respiratory, gastrointestinal, other, and unknown febrile episodes. Incidence rate of infections was modeled as function of gender, HLA-DQ genetic risk group and study center using the Poisson regression. A total of 113,884 ICD-10 code reports for infectious diseases recorded in the database were reduced to 71,578 infectious episodes, including 74.0% respiratory, 13.1% gastrointestinal, 5.7% other infectious episodes and 7.2% febrile episodes. Respiratory and gastrointestinal infectious episodes were more frequent during winter. Infectious episode rates peaked at 6 months and began declining after 18 months of age. The overall infectious episode rate was 5.2 episodes per person-year and varied significantly by country of residence, sex and HLA genotype. The data reduction and categorization process developed by TEDDY enables analysis of single infectious agents as well as larger arrays of infectious agents or clinical disease entities. The preliminary descriptive analyses of the incidence of infections among TEDDY participants younger than 4 years fits well with general knowledge of infectious disease epidemiology. This protocol can be used as a template in forthcoming time-dependent TEDDY analyses and in other epidemiological studies.
    BMC Pediatrics 03/2015; 15(1):24. DOI:10.1186/s12887-015-0333-8 · 1.93 Impact Factor
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    ABSTRACT: We developed a scale to serve as a potential end point for 6-month glycemic progression (PS6M) toward type 1 diabetes (T1D) in autoantibody-positive relatives of individuals with T1D. The PS6M was developed from Diabetes Prevention Trial-Type 1 (DPT-1) data and tested in the TrialNet Pathway to Prevention Study (PTP). It is the difference between 6-month glucose sum values (30-120 min oral glucose tolerance test values) and values predicted for nonprogressors. The PS6M predicted T1D in the PTP (P < 0.001). The area under the receiver operating chacteristic curve was greater (P < 0.001) for the PS6M than for the baseline-to-6-month difference. PS6M values were higher in those with two or more autoantibodies, 30-0 min C-peptide values <2.00 ng/mL, or DPT-1 Risk Scores >7.00 (P < 0.001 for all). The PS6M is an indicator of short-term glycemic progression to T1D that could be a useful tool for assessing preventive treatments and biomarkers. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 03/2015; 38(5). DOI:10.2337/dc14-2787 · 8.42 Impact Factor
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    ABSTRACT: This study investigated the effect of parenteral insulin therapy on endogenous insulin secretion in the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1). In the parenteral insulin arm of DPT-1, subjects without diabetes at high risk of future type 1 diabetes randomized to active treatment received a yearly 4-day intravenous insulin infusion (IV-I) and daily subcutaneous insulin (SC-I). To examine the effects of these insulin therapies on endogenous insulin secretion, C-peptide and glucose concentrations were compared during oral glucose tolerance tests (OGTTs) performed on and off IV-I and SC-I. Forty-six paired OGTTs were performed in 30 subjects from DPT-1 to determine the effect of IV-I. Twenty paired OGTTs were performed in 15 subjects from DPT-1 to determine the effect of SC-I. IV-I suppressed fasting and OGTT-stimulated C-peptide (62% and 40%, respectively), and it significantly lowered fasting glucose (67.4 ± 4.5 mg/dL during IV-I vs. 90.9 ± 1.8 mg/dL off insulin; P < 0.05). By contrast, post-OGTT glucose levels were significantly higher during IV-I: Glucose during IV-I versus off insulin at 120 minutes was 203.9 ± 15.1 vs. 151.8 ± 10.2 mg/dL, respectively (P < 0.05). Of OGTTs, 49% became transiently diabetic (>200 mg/dL at 120 minutes) when receiving IV-I. Fasting glucose was significantly lower when receiving SC-I versus when off insulin (85 ± 3 vs. 94 ± 2 mg/dL, respectively; P < 0.05), but SC-I did not significantly alter fasting or OGTT-stimulated C-peptide compared with being off insulin. These data demonstrate that the IV-I used in the DPT-1 markedly suppressed endogenous insulin secretion, which was frequently associated with postprandial glucose intolerance. SC-I, however, did not. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 02/2015; 38(5). DOI:10.2337/dc14-1825 · 8.42 Impact Factor
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    ABSTRACT: 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. 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. 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. Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.
    Diabetologia 02/2015; 58(5). DOI:10.1007/s00125-015-3514-y · 6.67 Impact Factor
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    ABSTRACT: While it is known that there is progression to diabetes in <10 years in 70% of children with two or more islet autoantibodies, predictors of the progression to diabetes are only partially defined. The Environmental Determinants of Diabetes in the Young (TEDDY) study has observed 8,503 children who were at increased genetic risk for autoimmune diabetes. Insulin autoantibodies (IAAs), GAD65 autoantibodies (GADAs), and insulinoma-associated protein 2 autoantibodies (IA-2As) were measured every 3 months until 4 years of age and every 6 months thereafter; if results were positive, the autoantibodies were measured every 3 months. Life table analysis revealed that the cumulative incidence of diabetes by 5 years since the appearance of the first autoantibody differed significantly by the number of positive autoantibodies (47%, 36%, and 11%, respectively, in those with three autoantibodies, two autoantibodies, and one autoantibody, P < 0.001). In time-varying survival models adjusted for first-degree relative status, number of autoantibodies, age at first persistent confirmed autoantibodies, and HLA genotypes, higher mean IAA and IA-2A levels were associated with an increased risk of type 1 diabetes in children who were persistently autoantibody positive (IAAs: hazard ratio [HR] 8.1 [95% CI 4.6-14.2]; IA-2A: HR 7.4 [95% CI 4.3-12.6]; P < 0.0001]. The mean GADA level did not significantly affect the risk of diabetes. In the TEDDY study, children who have progressed to diabetes usually expressed two or more autoantibodies. Higher IAA and IA-2A levels, but not GADA levels, increased the risk of diabetes in those children who were persistently autoantibody positive. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 02/2015; 38(5). DOI:10.2337/dc14-2426 · 8.42 Impact Factor
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    ABSTRACT: Role of the funding source: Funding from the NIH was used for support of the participating clinical centers and the coordinating center. The funding source did not participate in the collection or the analysis of the data. BACKGROUND. The β cell killing that characterizes type 1 diabetes (T1D) is thought to begin years before patients present clinically with metabolic decompensation; however, this primary pathologic process of the disease has not been measured. METHODS. Here, we measured β cell death with an assay that detects β cell-derived unmethylated insulin (INS) DNA. Using this assay, we performed an observational study of 50 participants from 2 cohorts at risk for developing T1D from the TrialNet Pathway to Prevention study and of 4 subjects who received islet autotransplants. RESULTS. In at-risk subjects, those who progressed to T1D had average levels of unmethylated INS DNA that were elevated modestly compared with those of healthy control subjects. In at-risk individuals that progressed to T1D, the observed increases in unmethylated INS DNA were associated with decreases in insulin secretion, indicating that the changes in unmethylated INS DNA are indicative of β cell killing. Subjects at high risk for T1D had levels of unmethylated INS DNA that were higher than those of healthy controls and higher than the levels of unmethylated INS DNA in the at-risk progressor and at-risk nonprogressor groups followed for 4 years. Evaluation of insulin secretory kinetics also distinguished high-risk subjects who progressed to overt disease from those who did not. CONCLUSION. We conclude that a blood test that measures unmethylated INS DNA serves as a marker of active β cell killing as the result of T1D-associated autoimmunity. Together, the data support the concept that β cell killing occurs sporadically during the years prior to diagnosis of T1D and is more intense in the peridiagnosis period. TRIAL REGISTRATION. Clinical NCT00097292. FUNDING. Funding was from the NIH, the Juvenile Diabetes Research Foundation, and the American Diabetes Association.
    Journal of Clinical Investigation 02/2015; 125(3). DOI:10.1172/JCI78142 · 13.22 Impact Factor
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    ABSTRACT: The goal of this study was to determine whether age at introduction to gluten was associated with risk for celiac disease (CD) in genetically predisposed children. TEDDY (The Environmental Determinants of Diabetes in the Young) is a prospective birth cohort study. Newborn infants (N = 6436) screened for high-risk HLA-genotypes for CD were followed up in Finland, Germany, Sweden, and the United States. Information about infant feeding was collected at clinical visits every third month. The first outcome was persistent positive for tissue transglutaminase autoantibodies (tTGA), the marker for CD. The second outcome was CD, defined as either a diagnosis based on intestinal biopsy results or on persistently high levels of tTGA. Swedish children were introduced to gluten earlier (median: 21.7 weeks) compared with children from Finland (median: 26.1 weeks), Germany, and the United States (both median: 30.4 weeks) (P < .0001). During a median follow-up of 5.0 years (range: 1.7-8.8 years), 773 (12%) children developed tTGA and 307 (5%) developed CD. Swedish children were at increased risk for tTGA (hazard ratio: 1.74 [95% CI: 1.47-2.06]) and CD (hazard ratio: 1.76 [95% CI: 1.34-2.24]) compared with US children, respectively (P < .0001).Gluten introduction before 17 weeks or later than 26 weeks was not associated with increased risk for tTGA or CD, adjusted for country, HLA, gender, and family history of CD, neither in the overall analysis nor on a country-level comparison. In TEDDY, the time to first introduction to gluten introduction was not an independent risk factor for developing CD. Copyright © 2015 by the American Academy of Pediatrics.
    Pediatrics 01/2015; 135(2). DOI:10.1542/peds.2014-1787 · 5.47 Impact Factor
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    ABSTRACT: Abstract We recently developed new electrochemiluminescence (ECL) insulin autoantibody (IAA) and glutamic acid decarboxylase 65 autoantibody (GADA) assays that discriminate high-affinity, high-risk diabetes-specific autoantibodies from low-affinity, low-risk islet autoantibodies (iAbs) detected by radioassay (RAD). Here, we report a further validation of the ECL-IAA and -GADA assays in 3,484 TrialNet study participants. The ECL assay and RAD were congruent in those with prediabetes and in subjects with multiple autoantibodies, but only 24% (P<0.0001) of single RAD-IAA-positive and 46% (P<0.0001) of single RAD-GADA-positive were confirmed by the ECL-IAA and -GADA assays, respectively. During a follow-up (mean, 2.4 years), 51% of RAD-IAA-positive and 63% of RAD-GADA-positive subjects not confirmed by ECL became iAb negative, compared with only 17% of RAD-IAA-positive (P<0.0001) and 15% of RAD-GADA-positive (P<0.0001) subjects confirmed by ECL assays. Among subjects with multiple iAbs, diabetes-free survival was significantly shorter if IAA or GADA was positive by ECL and negative by RAD than if IAA or GADA was negative by ECL and positive by RAD (P<0.019 and P<0.0001, respectively). Both positive and negative predictive values in terms of progression to type 1 diabetes mellitus were superior for ECL-IAA and ECL-GADA, compared with RADs. The prevalence of the high-risk human leukocyte antigen-DR3/4, DQB1*0302 genotype was significantly higher in subjects with RAD-IAA or RAD-GADA confirmed by ECL. In conclusion, both ECL-IAA and -GADA are more disease-specific and better able to predict the risk of progression to type 1 diabetes mellitus than the current standard RADs.
    Diabetes Technology &amp Therapeutics 01/2015; 17(2). DOI:10.1089/dia.2014.0186 · 2.11 Impact Factor
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    ABSTRACT: We assessed whether type 1 diabetes (T1D) can be diagnosed earlier using a new approach based on prediction and natural history in autoantibody-positive individuals. Diabetes Prevention Trial-Type 1 (DPT-1) and TrialNet Natural History Study (TNNHS) participants were studied. A metabolic index, the T1D Diagnostic Index60 (Index60), was developed from 2-h oral glucose tolerance tests (OGTTs) using the log fasting C-peptide, 60-min C-peptide, and 60-min glucose. OGTTs with Index60 ≥2.00 and 2-h glucose <200 mg/dL (Ind60+Only) were compared with Index60 <2.00 and 2-h glucose ≥200 mg/dL (2hglu+Only) OGTTs as criteria for T1D. Individuals were assessed for C-peptide loss from the first Ind60+Only OGTT to diagnosis. Areas under receiver operating characteristic curves were significantly higher for Index60 than for the 2-h glucose (P < 0.001 for both DPT-1 and the TNNHS). As a diagnostic criterion, sensitivity was higher for Ind60+Only than for 2hglu+Only (0.44 vs. 0.15 in DPT-1; 0.26 vs. 0.17 in the TNNHS) OGTTs. Specificity was somewhat higher for 2hglu+Only OGTTs in DPT-1 (0.97 vs. 0.91) but equivalent in the TNNHS (0.98 for both). Positive and negative predictive values were higher for Ind60+Only OGTTs in both studies. Postchallenge C-peptide levels declined significantly at each OGTT time point from the first Ind60+Only OGTT to the time of standard diagnosis (range -22 to -34% in DPT-1 and -14 to -27% in the TNNHS). C-peptide and glucose patterns differed markedly between Ind60+Only and 2hglu+Only OGTTs. An approach based on prediction and natural history appears to have utility for diagnosing T1D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 12/2014; 38(2). DOI:10.2337/dc14-1813 · 8.42 Impact Factor
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    ABSTRACT: Gut microbiome dysbiosis is associated with numerous diseases, including type 1 diabetes. This pilot study determines how geographical location affects the microbiome of infants at high risk for type 1 diabetes in a population of homogenous HLA class II genotypes. High-throughput 16S rRNA sequencing was performed on stool samples collected from 90 high-risk, nonautoimmune infants participating in The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S., Germany, Sweden, and Finland. Study site-specific patterns of gut colonization share characteristics across continents. Finland and Colorado have a significantly lower bacterial diversity, while Sweden and Washington state are dominated by Bifidobacterium in early life. Bacterial community diversity over time is significantly different by geographical location. The microbiome of high-risk infants is associated with geographical location. Future studies aiming to identify the microbiome disease phenotype need to carefully consider the geographical origin of subjects. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 12/2014; 38(2). DOI:10.2337/dc14-0850 · 8.42 Impact Factor
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    ABSTRACT: Rationale: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. Objectives: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. Methods and Measurements: 118 participants <19 years old with PCD were evaluated prospectively at 6 centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. Main Results: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone, n=54) and ODA plus inner dynein arm (IDA) defects (ODA+IDA; n=18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n=40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; p=0.003). Median BMI was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; p=0.003). For all 118 subjects, median number of lobes with bronchiectasis was 3 and alveolar consolidation was 2. However, the 5-11 year old IDA/CA/MTD group had more lobes of bronchiectasis (median= 5, p=0.0008) and consolidation (median=3, p=0.0001) compared to the ODA groups (median=3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. Conclusions: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.
    American Journal of Respiratory and Critical Care Medicine 12/2014; 191(3). DOI:10.1164/rccm.201409-1672OC · 13.00 Impact Factor
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    ABSTRACT: Background Vincristine causes known side effects of peripheral sensory, motor, autonomic and cranial neuropathies. No preventive interventions are known.ProcedureWe performed a randomized, placebo-controlled, double-blind trial of oral glutamic acid as a preventive agent in pediatric patients with cancer who would be receiving vincristine therapy for at least 9 consecutive weeks (Stratum 1 = Wilms tumor and rhabdomyosarcoma) or 4 consecutive weeks in conjunction with steroids (Stratum 2 = Acute lymphoblastic leukemia and non-Hodgkin lymphoma). At designated time points, a scored neurologic exam using the Modified Balis Pediatric Scale of Peripheral Neuropathies was performed to document neurologic toxicity.ResultsBetween 2007 and 2012, 250 patients were enrolled (Stratum 1 = 50, Stratum 2 = 200). The glutamic acid treated group did not have a significantly lower percentage of neurotoxicity compared to placebo treated group either overall or within stratum or age subgroups. The only subgroup which was suggestive of treatment effect was for age. Patients 13 years or older showed a larger benefit in favor of glutamic acid (P = 0.055) compared to patients less than 13 years (P = 1.00). Constipation was the most frequently reported (14%) Grade II or higher neurotoxicity.Conclusion Vincristine-associated neurotoxicity in pediatric oncology remains a frequent complication of chemotherapy for multiple diagnoses with an approximate 30% of patients affected. Glutamic acid is not effective for prevention in pre-adolescents. There is a suggestion of benefit in patients 13 years or older, but the study was not designed to provide adequate power to test the treatment effect within this age group alone. Pediatr Blood Cancer 2014;9999:1–7. © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2014; 62(6). DOI:10.1002/pbc.25384 · 2.39 Impact Factor
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    ABSTRACT: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p<0.05), whereof four were significant after adjustment for multiple testing (p<0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 11/2014; 64(5). DOI:10.2337/db14-1497 · 8.10 Impact Factor
  • Ping Xu · Xiang Liu · David Hadley · Shuai Huang · Jeffrey Krischer · Craig Beam
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    ABSTRACT: Background: In modeling a N by m data matrix, i.e. N samples on a m dimensional space, the issue arises when m is bigger than N. The sample size cannot be increased, especially in medical research, due to the limited number of diseased subjects. Feature selection is often used to select a subset of relevant m variables, often lower than N, for use in model construction. Method: A multiple step bootstrap method is proposed to quantify relevance of candidate predictors with the outcome based on their areas under the Receiver Operating Characteristic curve (ROCAUCs) from bootstrap resamples and then select only significant variables, which meet pre-specified criteria, as a feature selection process. Results: Extensive simulation was conducted using thousands of predictor variables and 5 levels of prediction ability between the true predictor and the outcome. The results from the simulation data indicate that the mean of ROCAUCs from bootstrap samples is close to the true ROCAUC. Even with only 30 cases and 30 controls, 25 out of 25 listed predictor variables provide the correct level of classification ability by using mean of bootstrapped ROCAUCs. The proposed bootstrapped ROCAUCs method outperforms the single ROCAUC. The standard error of mean of bootstrapped ROCAUCs was 20% to 50% smaller than the standard error of the single ROCAUC estimate from the original sample. An illustrative example is presented to apply the proposed methodology to identify the gene expressions that could predict clinical survival in breast cancer patients, using the Van’t Veer study’s breast cancer data. Conclusion: We conclude that the bootstrapped ROCAUCs methodology is intuitive and attractive for use in feature selection problems when the goals of the study are to identify important predictors and to provide insight regarding the discriminative or predictive ability of individual predictor variables. Such goals are common among microarray studies and new biomarker discovery.
    Journal of Proteomics & Bioinformatics 10/2014; S9. DOI:10.4172/jpb.S9-006
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    ABSTRACT: 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 analyzing probiotics in childhood.
    International Journal of Probiotics and Prebiotics 08/2014; 7(3-4):135.

Publication Stats

9k Citations
1,857.24 Total Impact Points


  • 1996–2015
    • University of South Florida
      • • Pediatrics Epidemiology Center
      • • Department of Pediatrics
      • • Department of Computer Science & Engineering
      • • Moffitt Cancer Center
      • • Department of Family Medicine
      Tampa, Florida, United States
  • 2011
    • University of Cincinnati
      Cincinnati, Ohio, United States
    • University of Alabama at Birmingham
      • Department of Pediatrics
      Birmingham, Alabama, United States
  • 2008–2010
    • Cincinnati Children's Hospital Medical Center
      • Division of Pulmonary Biology
      Cincinnati, OH, United States
  • 2002–2008
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 1995–2007
    • Moffitt Cancer Center
      Tampa, Florida, United States
    • University at Buffalo, The State University of New York
      • School of Medicine and Biomedical Sciences
      Buffalo, NY, United States
  • 2006
    • Columbia University
      New York, New York, United States
  • 2001–2003
    • Cornell University
      • Department of Pediatrics
      Итак, New York, United States
    • University of Washington Seattle
      • Department of Medicine
      Seattle, WA, United States
  • 2000
    • University of Southern California
      Los Angeles, California, United States
  • 1994
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 1993
    • McGill University
      Montréal, Quebec, Canada
  • 1983–1993
    • University of Florida
      • Department of Pediatrics
      Gainesville, Florida, United States
  • 1992
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
  • 1991
    • Baylor College of Medicine
      • Department of Pediatrics
      Houston, Texas, United States
    • Emory University
      Atlanta, Georgia, United States
  • 1984–1991
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1986
    • Pediatric Oncology Group of Ontario
      Toronto, Ontario, Canada