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author:("Sun, shuhei S")
1.  Hippocampal Malrotation (HIMAL) is Associated with Prolonged Febrile Seizures: Results of the FEBSTAT Study 
AJR. American journal of roentgenology  2015;205(5):1068-1074.
HIMAL (hippocampal malrotation) is characterized by incomplete hippocampal inversion with rounded shape and blurred internal architecture. There is still debate whether or not HIMAL has pathological significance. We present findings from the FEBSTAT study on the frequency and risk factors for HIMAL.
Materials and Methods
FEBSTAT is a prospective multicenter study investigating consequences of febrile status epilepticus (FSE) in childhood. MR imaging studies of 226 FSE subjects were analyzed visually by two board-certified neuroradiologists blinded to clinical details and compared to MR imaging studies of 96 subjects with first simple febrile seizure (FS). Quantitative analysis of hippocampal volume was performed by two independent observers.
HIMAL was present in 20 (8.8%), of FSE cases compared with 2 (2.1%) of controls (odds ratio 4.56; 95% CI=1.05, 19.9). HIMAL was exclusively left-sided in 18 (81.8%), and bilateral in the remaining 4 (18.2%). There was no case of exclusively right-sided HIMAL. HIMAL was more common in boys than in girls (OR 6.1, 95%CI = (1.7, 21.5) On quantitative volumetric MR imaging analysis, the left hippocampal volume in HIMAL cases was smaller than in simple FS controls (p=0.004), and the R/L hippocampal volume ratio was higher in the HIMAL group compared to the simple FS group (p<0.001).
HIMAL is a developmental malformation that predominantly affects the left hippocampus in males, and is more frequently found in children with prolonged FSE than in controls. These data provide further evidence that HIMAL represents a pathological error in brain development rather than a normal variant.
PMCID: PMC4621774  PMID: 26496555
HIMAL; Febrile Seizures; Status Epilepticus; MR Imaging
2.  Small hepatocyte-like progenitor cells may be a Hedgehog signaling pathway-controlled subgroup of liver stem cells 
The present study aimed to investigate the expression levels of components of the Hedgehog signaling pathway (HH) during the proliferation of a liver stem cell subgroup, namely small hepatocyte-like progenitor cells (SHPCs). Retrorsine-treated Fisher 344 rats underwent a partial hepatectomy (PH) to induce the proliferation of SHPCs, after which reverse transcription-polymerase chain reaction (PCR), quantitative PCR, immunohistochemistry and western blot analysis were performed to analyze the expression of various components of the HH in primary SHPCs at different times points post-PH. A number of components of the HH, including Indian hedgehog (IHH), patched (PTCH), smoothened and glioma-associated oncogene (GLI)1, 2 and 3, were continuously expressed and showed dynamic changes in proliferating SHPCs. In addition, the expression levels of IHH, PTCH and GLI1 were significantly different as compared with those of the control group at the same time point, and there were significant differences among the various time points in the experimental group (P<0.01). Furthermore, there was an association between the postoperative day and expression levels of HH components in the retrorsine-treated group. An immunohistochemical analysis demonstrated that PTCH was also expressed at the protein level. In conclusion, the results of the present study suggested that the HH was continuously activated during the proliferation of SHPCs, thus indicating that SHPCs may be a subgroup of stem cells that are regulated by the HH.
PMCID: PMC5038904  PMID: 27703504
Hedgehog signaling pathway; small hepatocyte-like progenitor cells; liver regeneration
3.  A generalized sequential Bonferroni procedure for GWAS in admixed populations incorporating admixture mapping information into association tests 
Human heredity  2015;79(2):80-92.
To develop effective methods for genome wide association studies (GWAS) in admixed populations, such as African Americans.
We show that when testing the null hypothesis that the test single nucleotide polymorphism (SNP) is not in background linkage disequilibrium (LD) with the causal variants, several existing methods cannot control well the family-wise error rate (FWER) in the strong sense in GWAS; the existing methods include association tests adjusting for global ancestry and joint association tests that combine statistics from admixture mapping tests and association tests that correct for local ancestry. Furthermore, we describe a generalized sequential Bonferroni (smooth-GSB) procedure for GWAS that incorporates smoothed weights calculated from admixture mapping tests into association tests that correct for local ancestry. We have applied the smooth-GSB procedure to analyses of GWAS data on American Africans from the Atherosclerosis Risk in Communities (ARIC) Study.
Our simulation studies indicate that the smooth-GSB procedure not only can control the FWER, but also improve statistical power compared with association tests correcting for local ancestry.
The smooth-GSB procedure can result in a better performance than several existing methods for GWAS in admixed populations.
PMCID: PMC4821476  PMID: 26087776
Admixture mapping; GWAS; sequential Bonferroni procedures; admixture LD; background LD
4.  A Randomized Controlled Trial Assessing Growth of Infants Fed a 100% Whey Extensively Hydrolyzed Formula Compared With a Casein-Based Extensively Hydrolyzed Formula 
Global Pediatric Health  2016;3:2333794X16636613.
This study compared the growth of healthy infants fed a hypoallergenic 100% whey-based extensively hydrolyzed formula (EHF) with Bifidobacterium lactis (test) with that of infants fed an extensively hydrolyzed casein formula (control). Formula-fed infants (14 ± 3 days) were randomized to test or control groups until 112 days of age. Anthropometrics were assessed at 14, 28, 56, 84, and 112 days, and daily records were kept for 2 days prior to study visits. Serum albumin and plasma amino acids at 84 days were assessed in a subset. A total of 282 infants were randomized (124 test, 158 control). Significantly more infants dropped out of the control (56%) as compared with the test (41%) group. Mean daily weight gain was significantly higher in the test group compared with the control group (27.95 ± 5.91 vs 25.93 ± 6.12 g/d; P = .027) with the test group reporting significantly fewer stools (2.2 vs 3.6 stools/d; P < .0001). The control group reported significantly more days with >3 loose stools/d and a higher incidence of vomiting as compared with the test group. There were no differences in gas, mood, sleep, or serum albumin. Plasma arginine and valine were significantly lower in the test group, whereas leucine and lysine were higher; all values were within normal limits. Significantly more adverse events attributed to the study formula were reported in the control group. The 100% whey-based hypoallergenic EHF containing Bifidobacterium lactis and medium chain triglycerides supported growth of healthy infants. Future studies on the application of this formula in clinically indicated populations are warranted.
PMCID: PMC4905054  PMID: 27336009
extensively hydrolyzed; infant formula; growth; cow’s milk allergy; whey protein; Bifidobacterium lactis
5.  Multivariate Granger Causality Analysis of Obesity Related Variables 
Obesity is a complex health outcome that is a combination of multiple health indicators. Here we attempt to explore the dependence network among multiple aspects of obesity. Two longitudinal cohort studies across multiple decades have been used. The concept of causality is defined similar to Granger causality among multiple time series, however, modified to accommodate multivariate time series as the nodes of the network. Our analysis reveals relatively central position of physical measurements and blood chemistry measures in the overall network across both genders. Also there are some patterns specific to only male or female population. The geometry of the causality network is expected to help in our strategy to control the increasing trend of obesity rate.
PMCID: PMC4743668  PMID: 26855968
Obesity; Granger causality; Network; Canonical correlation
6.  Assessment of Growth of Infants Fed an Amino Acid-Based Formula 
This study’s primary aim was to compare the growth (daily weight gain) of infants consuming a new (Test) amino acid-based formula (AAF) or a commercially available AAF (Control).
Healthy infants were randomized to Test or Control from 14 to 112 days of age. Anthropometric measurements were taken at 14, 28, 56, 84, and 112 days of age. Tolerance records were completed prior to each visit. Serum albumin and plasma amino acids were ascertained in a subset of infants at 84 days of age.
A total of 119 subjects completed the study per protocol. Mean daily weight gains were 27.26 ± 4.92 g/day for Control and 27.42 ± 6.37 g/day for Test (P = 0.8812). There were no significant differences between groups in formula intake, adverse events, flatulence, spit-up/vomiting, mood, or sleep. Albumin and plasma amino acids were within normal limits for both groups.
Infants fed the new AAF had similar daily weight gains as infants fed a commercially available AAF.
PMCID: PMC4743746  PMID: 26862300
infant formula; amino acid-based formula; growth
7.  Retarded tempo of physiological development in childhood delays the onset of the metabolic syndrome in adulthood 
Annals of nutrition & metabolism  2014;65(0):175-183.
Using serial data from the Fels Longitudinal Study (FLS), we investigate the effects of early and late attainment of the peak height velocity (PHV) in childhood on the timing of the appearance of the metabolic syndrome later in life. We show that if early attainment of PHV engenders greater risks for chronic disease in boys than in girls.
We define those boys and girls in the sex-specific quartiles of the study population that were slowest to attain PHV as having a slow tempo of development, and those in the growth that most rapidly attained PHV as having a rapid tempo of development.
Boys who experienced an early onset of PHV tended to have higher risk for the metabolic syndrome, dyslipidemia, and impaired fasting glucose than those who had late onset of PHV. Girls who had an early onset of PHV tended to develop more abdominal obesity than females who had a late onset of PHV.
PMCID: PMC4309272  PMID: 25413656
8.  First multicenter study on multidrug resistant bacteria carriage in Chinese ICUs 
BMC Infectious Diseases  2015;15:358.
The importance of multidrug-resistant organisms (MDRO) in Chinese hospitals is not clearly delineated. Thus we sought to assess the prevalence of MDRO in Chinese intensive care units (ICUs).
Prospective study of inpatients admitted consecutively to eight ICUs in four Chinese cities in 2009–10. Admission and weekly screenings were performed by using selective media for methicillin resistant Staphylococcus aureus, extended-spectrum beta-lactamase-producing Enterobacteriaceae, Acinetobacter and Pseudomonas aeruginosa. For the two latters, resistance to ceftazidime defined MDRO. Backward logistic regression models were designed to assess factors independently associated with MDRO carriage on admission and MDRO acquisition within ICUs.
686 patients were included, and the MDRO prevalence rate on admission was 30.5 % (32.7 % for ESBL-positive Enterobacteriaceae, 3.2 % for MRSA). Antibiotic treatment prior to ICU admission was independently associated with carriage on admission (OR: 1.4) in multivariate analysis. A total of 104 patients acquired ≥1 MDRO in ICU (overall attack rate: 23.7 %; 14.9 % for ESBL-positive Enterobacteriaceae, and 5.1 % for MRSA). The MDRO attack rate increased from 13.2 % in the first week to 82.1 % for ICU stay > 3 weeks. Duration of antibiotic exposure (OR: 1.16; 1.1–1.2) and prior antibiotic treatment before ICU (OR: 2.1; 1.1–3.3) were associated with MDRO acquisition in multivariate analysis. The MDRO prevalence rate on ICU discharge was 51.2 % and the global prevalence density rate 71 per 1000 hospital-days.
More than one out of two patients was MDRO carrier on ICU discharge in Chinese hospitals. This is the result of the combination of a high MDRO prevalence rate on ICU admission and a high MDRO acquisition rate within ICU.
PMCID: PMC4545921  PMID: 26290050
9.  Emergency Management of Febrile Status Epilepticus: Results of the FEBSTAT study 
Epilepsia  2014;55(3):388-395.
Treatment of seizures varies by region with no standard emergency treatment protocol. Febrile status epilepticus (FSE) is often a child’s first seizure; therefore, families are rarely educated about emergency treatment.
From 2002 to 2010, 199 subjects, age 1 month to 6 years, were recruited as part of a prospective, multicenter study of consequences of FSE. FSE was defined as a febrile seizure or series of seizures lasting >30 minutes. The patients’ charts were reviewed. No standardized treatment protocol was implemented for this observational study.
179 received at least one antiepileptic drug (AED) to terminate FSE and more than one AED was required in 140 patients (70%). Median time from the seizure onset to first AED by EMS or ED was 30 minutes. Mean seizure duration was 81 minutes for subjects given medication prior to ED and 95 minutes for those who did not (p=0.1). Median time from the first dose of AED to end of seizure was 38 minutes. Initial dose of lorazepam or diazepam was suboptimal in 32 of 166 patients (19%). Ninety-five (48%) subjects received respiratory support by EMS or ED. Median seizure duration for respiratory support group was 83 minutes; for non-respiratory support group was 58 minutes (p-value < 0.001). Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration.
FSE rarely stops spontaneously, is fairly resistant to medications and even with treatment persists for a significant period of time. The total seizure duration is composed of two separate factors; the time from seizure onset to AED initiation, and the time from first AED to seizure termination. Earlier onset of treatment results in shorter total seizure duration. A standard pre-hospital treatment protocol should be used nationwide and education of EMS responders is necessary.
PMCID: PMC3959260  PMID: 24502379
Seizure; Pediatric; Pre-hospital
10.  Hippocampal Sclerosis After Febrile Status Epilepticus: The FEBSTAT Study 
Annals of neurology  2014;75(2):178-185.
Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS.
FEBSTAT and two affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute MRIs and follow-up MRIs were obtained at approximately 1 year later in the majority. Visual interpretation by two neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intra-hippocampal distribution of T2 signal, and apparent diffusion coefficients.
Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRIs obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRIs had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially and reduced hippocampal growth.
Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after one year. Furthermore, impaired growth of normal appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.
PMCID: PMC3980500  PMID: 24318290
11.  Associations between Childhood Body Size, Composition, Blood Pressure and Adult Cardiac Structure: The Fels Longitudinal Study 
PLoS ONE  2014;9(9):e106333.
To determine whether childhood body size, composition and blood pressure are associated with adult cardiac structure by estimating childhood “age of divergence.”
385 female and 312 male participants in the Fels Longitudinal Study had echocardiographic measurements of left ventricular mass, relative wall thickness, and interventricular septal thickness. Also available were anthropometric measurements of body mass index, waist circumference, percentage body fat, fat free mass, total body fat, and systolic and diastolic blood pressures, taken in both childhood and adulthood. The age of divergence is estimated as the lowest age at which childhood measurements are significantly different between patients with low and high measurements of adult cardiac structure.
Childhood body mass index is significantly associated with adult left ventricular mass (indexed by height) in men and women (ages of divergence: 7.5 years and 11.5 years, respectively), and with adult interventricular septal thickness in boys (age of divergence: 9 years). Childhood waist circumference indexed by height is associated with left ventricular mass (indexed by height) in boys (age of divergence: 8 years). Cardiac structure was in general not associated with childhood body composition and blood pressure.
Though results are affected by adult body size, composition and blood pressure, some aspects of adult cardiac structure may have their genesis in childhood body size.
PMCID: PMC4156369  PMID: 25191997
12.  Comparing Height-Adjusted Waist Circumference Indices: The Fels Longitudinal Study 
While researchers are increasingly recognizing the importance of adjusting waist circumference (WC) for height, no standard has yet been established. In this study we contrast three standard methods for indexing WC by height (using height, root-height and height-squared) via comparisons with age-specific optimal indices.
Study Design and Setting
Measurements from 722 male and 746 female Caucasian participants in the Fels Longitudinal Study were used. The three standard waist-circumference indices (as well as an optimal index) were determined for ages 2 through 18, and for every decade thereafter to 70 years of age. Pearson correlations were used to assess the suitability of all indices.
The three standard indices remain correlated with the original WC measures, though each was associated with height at some ages. Waist-to-height ratio is suitable for some childhood ages (boys: 5 - 9, 13 - 16; girls: 4 - 7, 9, 11 - 14) but not for adult ages; Root-height works well mostly for older teenage children and adults but not in early childhood and adolescence; Height-squared is nowhere suitable. In both men and women, the optimal indexing factor ranged between root-height and height-squared in childhood, and is close to root-height in adulthood.
No one index is most suitable, as WC indexed by root-height is suitable for use with measurements from teenage children and adults, while waist-to-height ratio is generally suitable for use in children. WC indexed by height-squared is nowhere suitable.
PMCID: PMC4079075  PMID: 24999447
Obesity; Adiposity; Stature; Indexing
13.  Genetic Architecture of Knee Radiographic Joint Space in Healthy Young Adults 
Human biology  2008;80(1):1-9.
Evidence of a significant genetic component to the age-related degenerative joint disease osteoarthritis has been established, but the nature of genetic influences on normal joint morphology in healthy individuals remains unclear. Following up on our previous findings on the influence of body habitus on phenotypic variation in knee joint space [Duren et al., Human Biology 78:353–364 (2006)], the objective of the current study was to estimate the heritability of radiographic joint space in the knees of healthy young adults from a community-based sample of families. A sample of 253 subjects (mean age = 18.02 years) from 87 randomly ascertained nuclear and extended families was examined. Joint width (JW) and minimum joint space in the medial (MJS) and lateral (LJS) knee compartments were measured. A maximum-likelihood variance components method was used to estimate the heritability of MJS, LJS, and JW. Covariate effects of age, sex, age-by-sex interactions, stature, weight, and BMI were simultaneously estimated. Genetic correlation analyses were then conducted to examine relationships between trait pairs. MJS, LJS, and JW were each significantly heritable (p < 0.001), with heritabilities of 0.52, 0.53, and 0.63, respectively. The genetic correlation between MJS and LJS was not significantly different from 1. Genetic correlations between each joint space measure and JW were not significantly different from 0. This study demonstrates a significant genetic component to radiographic knee joint space during young adulthood in healthy subjects. This suggests that there are specific but as yet unidentified genes that influence the morphology of healthy articular cartilage, the target tissue of osteoarthritis. Genetic correlation analyses indicate complete pleiotropy between MJS and LJS but genetic independence of joint space and JW.
PMCID: PMC3988673  PMID: 18505041
14.  Additive Utility of Family History and Waist Circumference to Body Mass Index in Childhood for Predicting Metabolic Syndrome in Adulthood 
The Journal of pediatrics  2009;155(3):S6.e9-S6.13.
To determine whether waist circumference (WC) and family history of disease increase the predictive utility of body mass index (BMI) for adult metabolic syndrome (MetS).
Study design
A subsample of 161 men and women from the Fels Longitudinal Study with childhood and adulthood measures were analyzed. Using logistic regression, childhood BMI categories (50th, 75th, and 85th percentiles), WC categories (75th and 90th percentiles), and family history of type 2 diabetes mellitus or cardiovascular disease were modeled separately and in combinations to predict adult MetS. Predicted probabilities and c-statistics were compared across models.
The addition of family history to BMI improved the predicted probability of adult MetS from 29% to 52% (Δc-statistic = 0.13). The combination of WC and BMI was more predictive than BMI alone but did not outperform the combination of family history and BMI. In 3 of the 4 models with a combination of family history, WC, and BMI, the predicted probability of adult MetS did not exceed that from the combination of family history and BMI.
Family history of type 2 diabetes or cardiovascular disease is a useful addition to BMI in childhood to predict the future risk of adult MetS.
PMCID: PMC3988675  PMID: 19732567
15.  Patterns of Change in Cardiometabolic Risk Factors Associated with the Metabolic Syndrome among Children and Adolescents: The Fels Longitudinal Study 
The Journal of pediatrics  2009;155(3):S5.e9-S5.16.
To examine the patterns of change in cardiometabolic risk factors associated with the metabolic syndrome in children and adolescents between the ages of 8 to 19 years.
Study Design
Data of children and adolescents who participated in the Fels Longitudinal Study were analyzed. Body mass index, waist circumference, fasting insulin, fasting glucose, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and diastolic blood pressure were assessed annually with a standardized protocol.
The proportion of participants having at least 1 change between states of high and normal risk ranged from of 11.0% for body mass index to 30.4% for triglycerides. Youth in the high-risk category at baseline had a higher proportion having changed their status for all risk factors (all P < .05) except waist circumference compared with those in the normal-risk category. There were significant time effects for all risk factors (all P < .01) except fasting glucose and triglyceride levels in metric scores, but insignificant time effects for all risk factors in Z-scores in growth curve analyses.
The cardiometabolic risk factors associated with the MetS were relatively stable among white children and adolescents in the normal risk category. Changes in status were common if the risk factor was elevated.
PMCID: PMC3988693  PMID: 19732564
16.  Childhood Obesity Predicts Adult Metabolic Syndrome: The Fels Longitudinal Study 
The Journal of pediatrics  2007;152(2):191-200.
To determine the age of significant divergence in body mass index (BMI) and waist circumference in adults with and without the metabolic syndrome, and to provide age- and sex-specific childhood values that predict adult metabolic syndrome.
Study design
Part 1 of this study is a retrospective cohort study of 92 men and 59 women (mean age, 51 years) who had metabolic syndrome and 154 randomly selected adults matched for age and sex who did not have the syndrome. Part 2 is a study of predictive accuracy in a validation sample of 743 participants.
The first appearance of differences between adults with and without metabolic syndrome occurred at ages 8 and 13 for BMI and 6 and 13 for waist circumference in boys and girls, respectively. Odds ratios (ORs) for the metabolic syndrome at 30 years and older ranged from 1.4 to 1.9 across age groups in boys and from 0.8 to 2.8 across age groups in girls if BMI exceeded criterion values in childhood. The corresponding ORs for waist circumference ranged from 2.5 to 31.4 in boys and 1.7 to 2.5 in girls. These ORs increased with the number of examinations.
Children with BMI and waist circumference values exceeding the established criterion values are at increased risk for the adult metabolic syndrome.
PMCID: PMC3988700  PMID: 18206688
17.  Risk Factors for Febrile Status Epilepticus: A Case-Control Study 
The Journal of pediatrics  2013;163(4):1147-51.e1.
To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS).
Study design
Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression.
Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant.
Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE.
PMCID: PMC3989363  PMID: 23809042
18.  A Rapid Association Test Procedure Robust under Different Genetic Models Accounting for Population Stratification 
Human heredity  2013;75(1):23-33.
For genome-wide association studies (GWAS) in case-control data with stratification, a commonly used association test is the generalized Armitage (GA) trend test implemented in the software EIGENSTRAT. The GA trend test uses principal component analysis to correct for population stratification. It usually assumes an additive disease model and can have high power when the underlying disease model is additive or multiplicative, but may have relatively low power when the underlying disease model is recessive or dominant. The purpose of this paper is to provide a test procedure for GWAS with increased power over the GA trend test under the recessive and dominant models while maintaining the power of the GA trend test under the additive and multiplicative models.
We extend a Hardy-Weinberg disequilibrium (HWD) trend test for a homogeneous population to account for population stratification, and then propose a robust association test procedure for GWAS that incorporates information from the extended HWD trend test into the GA trend test.
Results and Conclusions
Our simulation studies and application of our method to a GWAS data set indicate that our proposed method can achieve the purpose described above.
PMCID: PMC3786013  PMID: 23571404
generalized sequential Bonferroni procedure; genome-wide association studies; Hardy-Weinberg trend test; robust test; recessive model
19.  Pubertal pathways and the relationship to anthropometric changes in childhood: The Fels longitudinal study 
Open journal of pediatrics  2012;2(2):10.4236/ojped.2012.22020.
To examine the relationship of the initial manifestation of pubertal development in children to anthropometric measurements recorded during the early childhood and adolescence.
The Fels Longitudinal study is an observational study of growth and development of healthy white children. A total of 109 boys and 75 girls with serial self-assessments of Tanner stages of genital/breast and pubic hair developments provided data for a longitudinal analysis with a linear mixed model.
About 11.0% of boys and 22.7% of girls witnessed the appearance of pubic hair (adrenarche) prior to the onset of genital/breast growth (gonadarche/thelarche) and about 13.7% of boys and 22.7% of girls experienced the onset of gonadarche/thelarche prior to adrenarche. The remaining 75.3% of boys and 54.7% of girls were concordant for adrenarche and gonadarche/thelarche. During the first two years of life, boys and girls with earlier gonadarche and thelarche than adrenarche were found to have more rapid weight gain than those with earlier adrenarche than gonadarche/thelarche. During early childhood from age 2 – 7 years, those girls with early thelarche had higher body mass index (BMI) and waist circumference to height ratio (waist/height) than those with early adrenarche. In children of ages 8 – 20, girls with early gonadarche had higher BMI z-scores than those with early adrenarche.
Girls with early thelarche and later adrenarche, have more rapid mean weight gain during the first two years of life, higher BMI and waist/height during early childhood, and higher BMI z-scores during adolescence. Boys with early gonadarche and later adrenarche experienced more rapid weight gain during the first two years of life than boys with early adrenarche and later gonadarche. In other words, girls with early thelarche are more likely to be triggered by early accumulation of fat mass than those with early adrenarche.
PMCID: PMC3846359  PMID: 24307981
Adrenarche; Gonadarche; Children Obesity; Body Mass Index (BMI); BMI z-Score
20.  Cerebrospinal Fluid Findings in Children with Fever-Associated Status Epilepticus; Results of the Febrile Status Epilepticus (FEBSTAT) Study 
The Journal of pediatrics  2012;161(6):1169-1171.e1.
This prospective multicenter study of 200 patients with fever-associated status epilepticus (FSE) patients of whom 136 had nontraumatic lumbar punctures confirms that FSE rarely causes cerebrospinal fluid (CSF) pleocytosis. CSF glucose and protein were unremarkable. Temperature, age, seizure focality, and seizure duration did not affect results. CSF pleocytosis should not be attributed to FSE.
PMCID: PMC3504634  PMID: 22985722
21.  Acute EEG findings in children with febrile status epilepticus 
Neurology  2012;79(22):2180-2186.
The FEBSTAT (Consequences of Prolonged Febrile Seizures) study is prospectively addressing the relationships among serial EEG, MRI, and clinical follow-up in a cohort of children followed from the time of presentation with febrile status epilepticus (FSE).
We recruited 199 children with FSE within 72 hours of presentation. Children underwent a detailed history, physical examination, MRI, and EEG within 72 hours. All EEGs were read by 2 teams and then conferenced. Associations with abnormal EEG were determined using logistic regression. Interrater reliability was assessed using the κ statistic.
Of the 199 EEGs, 90 (45.2%) were abnormal with the most common abnormality being focal slowing (n = 47) or attenuation (n = 25); these were maximal over the temporal areas in almost all cases. Epileptiform abnormalities were present in 13 EEGs (6.5%). In adjusted analysis, the odds of focal slowing were significantly increased by focal FSE (odds ratio [OR] = 5.08) and hippocampal T2 signal abnormality (OR = 3.50) and significantly decreased with high peak temperature (OR = 0.18). Focal EEG attenuation was also associated with hippocampal T2 signal abnormality (OR = 3.3).
Focal EEG slowing or attenuation are present in EEGs obtained within 72 hours of FSE in a substantial proportion of children and are highly associated with MRI evidence of acute hippocampal injury. These findings may be a sensitive and readily obtainable marker of acute injury associated with FSE.
PMCID: PMC3570819  PMID: 23136262
22.  Predictive Ability of Childhood Metabolic Components for Adult Metabolic Syndrome and Type 2 Diabetes 
The Journal of pediatrics  2009;155(3):S6.e1-S6.e7.
To estimate sensitivity, specificity, and positive and negative predictive values of components of the metabolic syndrome (MetS) during childhood for MetS and type 2 diabetes (T2D) in adulthood.
Study design
Data from 3 major studies—the Fels Longitudinal Study, the Muscatine Study, and the Princeton Follow-up Study—were combined to examine how thresholds of metabolic components during childhood determine adult MetS and T2D. Available metabolic components examined in the 1789 subjects included high-density lipoprotein, triglyceride levels, glucose, and percentiles for body mass index, waist circumference, triglycerides, and systolic and diastolic blood pressures. Sensitivity, specificity, and positive and negative predictive values for a refined set of component threshold values were examined individually and in combination.
Sensitivity and positive predictive values remained low for adult MetS and T2D for individual components. However, specificity and negative predictive values were fairly high for MetS and exceptionally so for T2D. In combination, having 1 or more of the components showed the highest sensitivity over any individual component and high negative predictive value. Overall, specificity and negative predictive values remained high whether considering individual or combined components for T2D.
Sensitivity and positive predictive values on the basis of childhood measures remained relatively low, but specificity and negative predictive values were consistently higher, especially for T2D. This indicates that these components, when examined during childhood, may provide a useful screening approach to identifying children not at risk so that further attention can be focused on those who may be in need of future intervention.
PMCID: PMC3777811  PMID: 19732565
24.  Stability of the Factor Structure of the Metabolic Syndrome across Pubertal Development: Confirmatory Factor Analyses of Three Alternative Models 
The Journal of pediatrics  2009;155(3):S5.e1-S5.e8.
To test the fit and stability of 3 alternative models of the metabolic syndrome’s factor structure across 3 developmental stages.
Study design
With data from the Fels Longitudinal Study, confirmatory factor analyses tested 3 alternative models of the factor structure underlying relationships among 8 metabolic syndrome-associated risks. Models tested were a 1-factor model (A), a 4-factor model (B), and a second-order latent factor model (C). Developmental stages assessed were prepuberty (ages 8–10), puberty (ages 11–15), and postpuberty (ages 16–20).
Convergence was achieved for all developmental stages for model A, but the fit was poor throughout (root mean square error of approximation > 0.1). Standardized factor loadings for waist circumference and body mass index were much stronger than those for fasting insulin at all 3 time points. Although prepuberty and postpuberty models converged for models B and C, each model had problems with Heywood cases. The puberty model did not converge for either model B or C.
The hypothetical structures commonly used to support the metabolic syndrome concept do not provide adequate fit in a pediatric sample and may be variable by maturation stage. A components-based approach to cardiovascular risk reduction, with emphasis on obesity prevention and control, may be a more appropriate clinical strategy for children and youth than a syndromic approach.
PMCID: PMC3763727  PMID: 19732562
25.  Design and Phenomenology of the FEBSTAT Study 
Epilepsia  2012;53(9):1471-1480.
Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent hipppocampal sclerosis (HS) and temporal lobe epilepsy. The FEBSTAT study was designed to prospectively examine the association between prolonged febrile seizures and development of HS and associated temporal lobe epilepsy, one of the most controversial issues in epilepsy. We report on the baseline phenomenology of the final cohorts as well as detailed aims and methodology.
The “Consequences of Prolonged Febrile Seizures in Childhood” (FEBSTAT) study is a prospective, multicenter study. Enrolled are children, aged 1 month to 6 years, presenting with a febrile seizure lasting 30 minutes or more based upon ambulance, emergency department, and hospital records, and parental interview. At baseline, procedures included an MRI and EEG done within 72 hours of FSE, and a detailed history and neurological examination. Baseline development and behavior are assessed at one month. The baseline assessment is repeated, with age- appropriate developmental testing at one and five years after enrollment as well as at the development of epilepsy and one year after that. Telephone calls every three months document further seizures. Two other groups of children are included: a ‘control’ group consisting of children with a first febrile seizure ascertained at Columbia University and with almost identical baseline and one year follow-up examinations and a pilot cohort of FSE from Duke University.
Key findings
The FEBSTAT cohort consists of 199 children with a median age at baseline of 16.0 months (Interquartile range (IQR)=12.0–24.0) and a median duration of FSE of 70.0 minutes (IQR=47.0–110.0). Seizures were continuous in 57.3% and behaviorally intermittent (without recovery in between) in 31.2%; most were partial (4;2.0%) or secondary generalized (65.8%), and almost all (98.0%) culminated in a generalized tonic clonic seizure. Of the 199 children, 86.4% had normal development and 20% had prior febrile seizures. In one third of cases, FSE was unrecognized in the emergency department.
The Duke existing cohort consists of 23 children with a median age of FSE onset of 18.0 months (IQR 14.0–28.0) and median duration of FSE of 90.0 minutes (IQR 50.0–170.0).
The Columbia control cohort consists of 159 children with a first febrile seizure who received almost the same work-up as the FEBSTAT cohort at baseline and at one-year. They were followed by telephone every 4 months for a median of 42 months. Among the control cohort, 64.2% had a first simple FS, 26.4% had a first complex FS that was not FSE, and 9.4% had FSE. Among the 15 with FSE, the median age at onset was 14.0 months (IQR 12.0–20.0) and the median duration of FSE was 43.0 minutes (IQR 35.0–75.0).
The FEBSTAT study presents an opportunity to prospectively study the relationship between FSE and acute hippocampal damage, the development of MTS, epilepsy (particularly TLE), and impaired hippocampal function in a large cohort. It is hoped that this study may illuminate a major mystery in clinical epilepsy today, and permit the development of interventions designed to prevent the sequelae of FSE.
PMCID: PMC3436982  PMID: 22742587
Febrile Seizures; Status Epilepticus; Epidemiology; Children

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