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1.  Corticosteroid Treatment and Growth Patterns in Ambulatory Males with Duchenne Muscular Dystrophy 
The Journal of pediatrics  2016;173:207-213.e3.
Objectives
To evaluate growth patterns of ambulatory males with Duchenne muscular dystrophy (DMD) treated with corticosteroids compared with ambulatory, steroid-naïlve males with DMD and age-matched unaffected general-population males and to test associations between growth and steroid treatment patterns among treated males.
Study design
Using data from the Muscular Dystrophy Surveillance, Tracking, and Research Network, we identified a total of 1768 height, 2246 weight, and 1755 body mass index (BMI) measurements between age 2 and 12 years for 324 ambulatory males who were treated with corticosteroids for at least 6 months. Growth curve comparisons and linear mixed-effects modeling, adjusted for race/ethnicity and birth year, were used to evaluate growth and steroid treatment patterns (age at initiation, dosing interval, duration, cumulative dose).
Results
Growth curves for ambulatory males treated with corticosteroids showed significantly shorter stature, heavier weight, and greater BMI compared with ambulatory, steroid-naïlve males with DMD and general-population US males. Adjusted linear mixed-effects models for ambulatory males treated with corticosteroids showed that earlier initiation, daily dosing, longer duration, and greater dosages predicted shorter stature with prednisone. Longer duration and greater dosages predicted shorter stature for deflazacort. Daily prednisone dosing predicted lighter weight, but longer duration, and greater dosages predicted heavier weight. Early initiation, less than daily dosing, longer duration, and greater doses predicted greater BMIs. Deflazacort predicted shorter stature, but lighter weight, compared with prednisone.
Conclusion
Prolonged steroid use is significantly associated with short stature and heavier weight. Growth alterations associated with steroid treatment should be considered when making treatment decisions for males with DMD.
doi:10.1016/j.jpeds.2016.02.067
PMCID: PMC5100357  PMID: 27039228
2.  Timing of Solid Food Introduction is Associated with Urinary F2-Isoprostane Concentrations in Childhood 
Pediatric research  2015;78(4):451-456.
BACKGROUND
Timing of solid food introduction in infancy has been associated with several chronic diseases. To explore potential mechanisms, we investigated the relationship between timing of solid food introduction and F2-isoprostanes – a marker of oxidative stress.
METHODS
Urinary F2-isoprostanes were assessed in 336 healthy children
RESULTS
Later solid food introduction was associated with lower F2-isoprostane concentrations in childhood (on average, 0.10 ng/mg per month of age at introduction) (estimate: −0.10, 95% CI: −0.18, −0.02, P-value=0.02). Moreover, childhood F2-isoprostane concentrations were, on average, 0.24 ng/mg lower in individuals breastfed at solid food introduction (estimate: −0.24, 95% CI: −0.47, −0.01, P-value=0.04) compared with those who were not. Associations remained significant after limiting analyses to F2-isoprostanes after age 2 years.
CONCLUSION
Our results suggest a long-term protective effect of later solid food introduction and breastfeeding at solid food introduction against increased F2-isoprostane concentrations throughout childhood.
doi:10.1038/pr.2015.116
PMCID: PMC4589419  PMID: 26083762
Diabetologia  2015;58(9):2027-2034.
Aims/hypothesis
Dietary sugar intake may increase insulin production, stress the beta cells and increase the risk for islet autoimmunity (IA) and subsequent type 1 diabetes.
Methods
Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased genetic risk for type 1 diabetes for the development of IA (autoantibodies to insulin, GAD or protein tyrosine phosphatase-like protein [IA2] twice or more in succession) and progression to type 1 diabetes. Information on intake of fructose, sucrose, total sugars, sugar-sweetened beverages, beverages with non-nutritive sweetener and juice was collected prospectively throughout childhood via food frequency questionnaires (FFQs). We examined diet records for 1,893 children (mean age at last follow-up 10.2 years); 142 developed IA and 42 progressed to type 1 diabetes. HLA genotype was dichotomised as high risk (HLA-DR3/4,DQB1*0302) or not. All Cox regression models were adjusted for total energy, FFQ type, type 1 diabetes family history, HLA genotype and ethnicity.
Results
In children with IA, progression to type 1 diabetes was significantly associated with intake of total sugars (HR 1.75, 95% CI 1.07–2.85). Progression to type 1 diabetes was also associated with increased intake of sugar-sweetened beverages in those with the high-risk HLA genotype (HR 1.84, 95% CI 1.25–2.71), but not in children without it (interaction p value = 0.02). No sugar variables were associated with IA risk.
Conclusions/interpretation
Sugar intake may exacerbate the later stage of type 1 diabetes development; sugar-sweetened beverages may be especially detrimental to children with the highest genetic risk of developing type 1 diabetes.
doi:10.1007/s00125-015-3657-x
PMCID: PMC4529377  PMID: 26048237
Childhood diet; Islet autoimmunity; Sugars; Sugar-sweetened beverage; Type 1 diabetes
Background
Acute bacterial meningitis (ABM) remains a significant cause of pediatric illness and death in low and middle income countries (LMICs). Identifying severity risk factors and predictive scores may guide interventions to reduce poor outcomes.
Methods
Data from a prospective surveillance study for ABM in children aged 0-59 months admitted to 3 referral hospitals in Guatemala City from 2000-2007 was analyzed. ABM was defined as positive cerebrospinal fluid (CSF) culture; positive latex agglutination; or CSF WBC > 100 cells/mL. Univariate and multivariate analyses of risk factors at hospital admission that predicted major morbidity or death during hospitalization were performed, along with validation of the predictive Herson-Todd (HTS).
Results
Of 809 children with ABM episodes, 221 (27.3%) survived with major morbidity, and 192 (23.7%) died. Among 383 children with non-missing data, the most significant multivariate predictors for death or major morbidity were seizure (OR 101.5, p<0.001), CSF glucose < 20 mg/dL (OR 5.3, p = 0.0004), symptom duration > 3 days (OR 3.7, p=0.003), and coma (OR 6.3, p=0.004). Of 221 children with a HTS score > 5, 204 (92%) died or suffered major morbidity (OR 10.3, p<0.0001).
Conclusion
ABM is a cause of considerable morbidity and mortality in Guatemala. Several clinical risk factors and the composite Herson-Todd Score predicted death or major morbidity. These predictors could help clinicians in LMIC guide medical care for ABM, and could contribute to the public health impact assessment in preventing meningitis with vaccines.
doi:10.1097/INF.0000000000000720
PMCID: PMC4467373  PMID: 26069947
meningitis; predictive score; Guatemala; risk factor; outcome
Pediatric diabetes  2014;16(1):31-38.
Background
Cow's milk intake has been inconsistently associated with islet autoimmunity (IA) and type 1 diabetes (T1D) development. Genetic and environmental factors may modify the effect of cow's milk on IA and T1D risk.
Methods
The Diabetes Autoimmunity Study in the Young (DAISY) follows children at increased T1D risk for IA (presence of autoantibodies to insulin, GAD65 or IA-2 twice in succession) and T1D development. We examined 1,835 DAISY children with data on cow's milk intake: 143 developed IA, 40 subsequently developed T1D. Cow's milk protein and lactose intake were calculated from prospectively collected parent- and self-reported food frequency questionnaires (FFQ). High risk HLA-DR genotype: HLA-DR3/4,DQB1*0302; low/moderate risk: all other genotypes. We examined interactions between cow's milk intake, age at cow's milk introduction, and HLA-DR genotype in IA and T1D development. Interaction models contained the base terms (e.g., cow's milk protein and HLA-DR genotype) and an interaction term (cow's milk protein*HLA-DR genotype).
Results
In survival models adjusted for total calories, FFQ type, T1D family history, and ethnicity, greater cow's milk protein intake was associated with increased IA risk in children with low/moderate risk HLA-DR genotypes (Hazard Ratio (HR): 1.41, 95% Confidence Interval (CI): 1.08–1.84), but not in children with high risk HLA-DR genotypes. Cow's milk protein intake was associated with progression to T1D (HR: 1.59, CI: 1.13–2.25) in children with IA.
Conclusions
Greater cow's milk intake may increase risk of IA and progression to T1D. Early in the T1D disease process, cow's milk intake may be more influential in children with low/moderate genetic T1D risk.
doi:10.1111/pedi.12115
PMCID: PMC4104257  PMID: 24444005
cow's milk protein; childhood diet; HLA-DR genotype; Islet Autoimmunity
BioMed Research International  2015;2015:708289.
Type 1 diabetes (T1D), a chronic autoimmune disease, is often preceded by a preclinical phase of islet autoimmunity (IA) where the insulin-producing beta cells of the pancreas are destroyed and circulating autoantibodies can be detected. The goal of this study was to demonstrate methods for identifying exposures that differentially influence the disease process at certain ages by assessing age-related heterogeneity. The Diabetes Autoimmunity Study in the Young (DAISY) has followed 2,547 children at increased genetic risk for T1D from birth since 1993 in Denver, Colorado, 188 of whom developed IA. Using the DAISY population, we evaluated putative determinants of IA, including non-Hispanic white (NHW) ethnicity, maternal age at birth, and erythrocyte membrane n-3 fatty acid (FA) levels, for age-related heterogeneity. A supremum test, weighted Schoenfeld residuals, and restricted cubic splines were used to assess nonproportional hazards, that is, an age-related association of the exposure with IA risk. NHW ethnicity, maternal age, and erythrocyte membrane n-3 FA levels demonstrated a significant age-related association with IA risk. Assessing heterogeneity in disease etiology enables researchers to identify associations that may lead to better understanding of complex chronic diseases.
doi:10.1155/2015/708289
PMCID: PMC4389824  PMID: 25883970
JAMA pediatrics  2013;167(9):808-815.
IMPORTANCE
The incidence of type 1 diabetes mellitus (T1DM) is increasing worldwide, with the most rapid increase among children younger than 5 years of age.
OBJECTIVE
To examine the associations between perinatal and infant exposures, especially early infant diet, and the development of T1DM.
DESIGN
The Diabetes Autoimmunity Study in the Young (DAISY) is a longitudinal, observational study.
SETTING
Newborn screening for human leukocyte antigen (HLA) was done at St. Joseph’s Hospital in Denver, Colorado. First-degree relatives of individuals with T1DM were recruited from the Denver metropolitan area.
PARTICIPANTS
A total of 1835 children at increased genetic risk for T1DM followed up from birth with complete prospective assessment of infant diet. Fifty-three children developed T1DM.
EXPOSURES
Early (<4 months of age) and late (≥6 months of age) first exposure to solid foods compared with first exposures at 4 to 5 months of age (referent).
MAIN OUTCOME AND MEASURE
Risk for T1DM diagnosed by a physician.
RESULTS
Both early and late first exposure to any solid food predicted development of T1DM (hazard ratio [HR], 1.91; 95% CI, 1.04–3.51, and HR, 3.02; 95% CI, 1.26–7.24, respectively), adjusting for the HLA-DR genotype, first-degree relative with T1DM, maternal education, and delivery type. Specifically, early exposure to fruit and late exposure to rice/oat predicted T1DM (HR, 2.23; 95% CI, 1.14–4.39, and HR, 2.88; 95% CI, 1.36–6.11, respectively), while breastfeeding at the time of introduction to wheat/barley conferred protection (HR, 0.47; 95% CI, 0.26–0.86). Complicated vaginal delivery was also a predictor of T1DM (HR, 1.93; 95% CI, 1.03–3.61).
CONCLUSIONS AND RELEVANCE
These results suggest the safest age to introduce solid foods in children at increased genetic risk for T1DM is between 4 and 5 months of age. Breastfeeding while introducing new foods may reduce T1DM risk.
doi:10.1001/jamapediatrics.2013.317
PMCID: PMC4038357  PMID: 23836309
Previously, we examined 20 non-HLA SNPs for association with islet autoimmunity (IA) and/or progression to type 1 diabetes (T1D). Our objective was to investigate fourteen additional non-HLA T1D candidate SNPs for stage- and age-related heterogeneity in the etiology of T1D. Of 1634 non-Hispanic white DAISY children genotyped, 132 developed IA (positive for GAD, insulin, or IA-2 autoantibodies at two or more consecutive visits); 50 IA positive children progressed to T1D. Cox regression was used to analyze risk of IA and progression to T1D in IA positive children. Restricted cubic splines were used to model SNPs when there was evidence that risk was not constant with age. C1QTNF6 (rs229541) predicted increased IA risk (HR: 1.57, CI: 1.20–2.05) but not progression to T1D (HR: 1.13, CI: 0.75–1.71). SNP (rs10517086) appears to exhibit an age-related effect on risk of IA, with increased risk before age 2 years (age 2 HR: 1.67, CI: 1.08–2.56) but not older ages (age 4 HR: 0.84, CI: 0.43–1.62). C1QTNF6 (rs229541), SNP (rs10517086), and UBASH3A (rs3788013) were associated with development of T1D. This prospective investigation of non-HLA T1D candidate loci shows that some SNPs may exhibit stage- and age-related heterogeneity in the etiology of T1D.
doi:10.1155/2013/417657
PMCID: PMC3866813  PMID: 24367383
Public Health Reports  2012;127(2):202-207.
SYNOPSIS
Objectives
In October 2008, pulmonary tuberculosis (TB) was diagnosed in a driver who had transported 762 passengers in the District of Columbia metropolitan area during his infectious period. A passenger contact investigation was conducted by the six public health jurisdictions because of concern that some passengers might be infected with HIV or have other medical conditions that put them at increased risk for developing TB disease if infected.
Methods
Authorities evaluated 92 of 100 passengers with at least 90 minutes of cumulative exposure. Passengers with fewer than 90 minutes of cumulative exposure were evaluated if they had contacted the health department after exposure and had a medical condition that increased their risk of TB. A tuberculin skin test (TST) result of at least 5 millimeters induration was considered positive.
Results
Of 153 passengers who completed TST evaluation, 11 (7%) had positive TST results. TST results were not associated with exposure time or high-risk medical conditions. No TB cases were identified in the passengers.
Conclusions
The investigation yielded insufficient evidence that Mycobacterium tuberculosis transmission to passengers had occurred. TB-control programs should consider transportation-related passenger contact investigations low priority unless exposure is repetitive or single-trip exposure is long.
PMCID: PMC3268805  PMID: 22379220
PLoS ONE  2013;8(2):e57936.
Background
Infant dietary exposures have been linked to type 1 diabetes (T1D) development. IgG4 antibody responses to food antigens are associated with food intolerances but have not been explored prospectively in the period preceding T1D.
Methods
Using a case-cohort design, IgG4 antibodies to ß-lactoglobulin, gluten, and ovalbumin were measured in plasma collected annually from 260 DAISY participants. Of those, 77 developed islet autoimmunity (IA), defined as positive for either insulin, GAD65 or IA-2 autoantibodies on two consecutive visits, and 22 developed T1D.
Results
In mixed model analysis adjusting for HLA-DR status, T1D family history, age and ethnicity, higher ß-lactoglobulin IgG4 concentrations were associated with shorter breastfeeding duration (beta = −0.03, 95% Confidence Interval: −0.05, −0.006) and earlier first cow’s milk exposure (beta = −0.04, 95% Confidence Interval: −0.08, 0.00). Higher gluten IgG4 was associated with older age at gluten introduction (beta = 0.06, 95% Confidence Interval: 0.00, 0.13). In proportional hazards analysis adjusting for HLA-DR status, T1D family history and ethnicity, IgG4 against individual or multiple dietary antigens throughout childhood were not associated with IA. In addition, mean antigen-specific IgG4 concentrations in infancy (age <2 years) were not associated with risk of IA nor progression to T1D. Higher ovalbumin IgG4 at first IA positive visit was marginally associated with progression to T1D (Hazard Ratio: 1.39, 95% Confidence Interval: 1.00, 1.92).
Conclusion
We found no association between the IgG4 response to β-lactoglobulin, gluten, and the development of either IA or T1D. The association between higher ovalbumin and progression to T1D in children with IA should be explored in other populations.
doi:10.1371/journal.pone.0057936
PMCID: PMC3585253  PMID: 23469110
Background/Aims
Childhood obesity tracks into adulthood, and may increase diabetes and cardiovascular disease risk in adulthood. Prospective analyses may better define the pathways between early life factors and greater childhood body mass index (BMI), a measure of obesity.
Methods
The Diabetes Autoimmunity Study in the Young (DAISY) prospectively follows children from birth that are at increased genetic risk for type 1 diabetes. We examined longitudinal data for 1,178 DAISY subjects (mean age at last follow-up: 6.59 years (range: 2.0–11.5 years). Birth size and diabetes exposure in utero were collected in the enrollment interview. Infant diet information was collected via interviews throughout infancy. Infant weight gain and childhood BMI were measured at clinic visits.
Results
Female gender, diabetes exposure in utero, larger size for gestational age, shorter breastfeeding duration, and more rapid infant weight gain predicted higher childhood BMI. Formal mediation analysis suggests the effect of shorter breastfeeding duration on childhood BMI may be mediated by more rapid infant weight gain. Also, the effect of diabetes exposure in utero on childhood BMI may be mediated by larger size for gestational age.
Conclusion
We identified strong interrelationships between early life factors and childhood BMI. Understanding these pathways may aid childhood obesity prevention efforts.
doi:10.1159/000261899
PMCID: PMC2855270  PMID: 19940472
Breastfeeding duration; Infant weight gain; Diabetes exposure in utero; Birth size; Mediator
Background
To compare the diagnostic accuracy of two continuous screening tests, a common approach is to test the difference between the areas under the receiver operating characteristic (ROC) curves. After study participants are screened with both screening tests, the disease status is determined as accurately as possible, either by an invasive, sensitive and specific secondary test, or by a less invasive, but less sensitive approach. For most participants, disease status is approximated through the less sensitive approach. The invasive test must be limited to the fraction of the participants whose results on either or both screening tests exceed a threshold of suspicion, or who develop signs and symptoms of the disease after the initial screening tests.
The limitations of this study design lead to a bias in the ROC curves we call paired screening trial bias. This bias reflects the synergistic effects of inappropriate reference standard bias, differential verification bias, and partial verification bias. The absence of a gold reference standard leads to inappropriate reference standard bias. When different reference standards are used to ascertain disease status, it creates differential verification bias. When only suspicious screening test scores trigger a sensitive and specific secondary test, the result is a form of partial verification bias.
Methods
For paired screening tests with bivariate normally distributed scores, we give formulae and programs to quantify the effect of paired screening trial bias on a paired comparison of area under the curves. We fix the prevalence of disease, and the chance a diseased subject manifests signs and symptoms. We derive the formulas for true sensitivity and specificity, and those for the sensitivity and specificity observed by the study investigator.
Results
The observed area under the ROC curves is quite different from the true area under the ROC curves. The typical direction of the bias is a strong inflation in sensitivity, paired with a concomitant slight deflation of specificity.
Conclusion
In paired trials of screening tests, when area under the ROC curve is used as the metric, bias may lead researchers to make the wrong decision as to which screening test is better.
doi:10.1186/1471-2288-9-4
PMCID: PMC2657218  PMID: 19154609
Academic radiology  2007;14(6):670-676.
Rationale and Objectives
To compare the cancer detection rate and ROC area under the curve of full-field digital mammography, screen-film mammography, and a combined technique that allowed diagnosis if a finding was suspicious on film, on digital, or both.
Materials and Methods
We used the data originally analyzed in Lewin et al. (2002). In that trial, 6,736 paired full-field and digital mammograms were performed in 4,489 women. We used parametric and nonparametric tests to compare the area under the curve for ROC scores of film-screen only, digital mammography only, and the combined test. We used McNemar’s test for paired proportions to compare the cancer detection rates.
Results
With the parametric test, neither the difference in AUC between the film and combined, nor the difference between the digital and combined ROC curves was significant at the Bonferroni-corrected 0.025 alpha level (film vs. combined difference = 0.0563, p = 0.0712; digital vs. combined difference = 0.0894, p = 0.0455). The nonparametric test showed that there was a significant difference between both film and combined (difference = 0.073, p = 0.008) and digital vs. combined ROC curves (difference = 0.1164, p = 0.0008). The continuity corrected McNemar’s test showed a significant increase in the proportion of cancers detected by the combined modality over film (chi squared = 7.111, df = 1, p=0.0077), and over digital (chi squared = 12.071, df =1, p = 0.0005).
Conclusion
Using two mammograms, one film and one digital, significantly increases the detection of breast cancer.
doi:10.1016/j.acra.2007.02.011
PMCID: PMC1975808  PMID: 17502256
Digital mammography; film mammography; combined test; ROC area under the curve analysis

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