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author:("Sun, shuhei S")
1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
14.  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
15.  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
16.  Human Herpesvirus 6 and 7 in Febrile Status Epilepticus: The FEBSTAT study 
Epilepsia  2012;53(9):1481-1488.
In a prospective study of the consequences of prolonged febrile seizures (FEBSTAT), we determined the frequency of Human Herpesvirus (HHV)-6 and HHV-7 infection as a cause of febrile status epilepticus (FSE).
Children ages 1 month to 5 years presenting with FSE were enrolled within 72 hours and received a comprehensive assessment including specimens for HHV-6 and HHV-7. The presence of HHV-6A, HHV-6B or HHV-7 DNA and RNA (amplified across a spliced junction) determined using quantitative polymerase chain reaction (qPCR) at baseline indicated viremia. Antibody titers to HHV-6 and HHV-7 were used in conjunction with the PCR results to distinguish primary infection from reactivated or prior infection
Key findings
Of 199 children evaluated, HHV-6 or HHV-7 status could be determined in 169 (84.9%). HHV-6B viremia at baseline was found in 54 subjects (32.0%), including 38 with primary infection and 16 with reactivated infection. No HHV-6A infections were identified. HHV-7 viremia at baseline was observed in 12 (7.1%) subjects, including 8 with primary infection and 4 with reactivated infection. Two subjects had HHV-6/HHV-7 primary co-infection at baseline. There were no differences in age, characteristics of illness or fever, seizure phenomenology or the proportion of acute EEG or imaging abnormalities in children presenting with FSE with or without HHV infection.
HHV-6B infection is commonly associated with FSE. HHV-7 infection is less frequently associated with FSE. Together, they account for one third of FSE, a condition associated with an increased risk of both hippocampal injury and subsequent temporal lobe epilepsy.
PMCID: PMC3442944  PMID: 22954016
Febrile Seizures; Human Herpesvirus; Status Epilepticus; Mesial Temporal Sclerosis
17.  MRI abnormalities following febrile status epilepticus in children 
Neurology  2012;79(9):871-877.
The FEBSTAT study is a prospective study that seeks to determine the acute and long-term consequences of febrile status epilepticus (FSE) in childhood.
From 2003 to 2010, 199 children age 1 month to 5 years presenting with FSE (>30 minutes) were enrolled in FEBSTAT within 72 hours of the FSE episode. Of these, 191 had imaging with emphasis on the hippocampus. All MRIs were reviewed by 2 neuroradiologists blinded to clinical details. A group of 96 children with first simple FS who were imaged using a similar protocol served as controls.
A total of 22 (11.5%) children had definitely abnormal (n = 17) or equivocal (n = 5) increased T2 signal in the hippocampus following FSE compared with none in the control group (p < 0.0001). Developmental abnormalities of the hippocampus were more common in the FSE group (n = 20, 10.5%) than in controls (n = 2, 2.1%) (p = 0.0097) with hippocampal malrotation being the most common (15 cases and 2 controls). Extrahippocampal imaging abnormalities were present in 15.7% of the FSE group and 15.6% of the controls. However, extrahippocampal imaging abnormalities of the temporal lobe were more common in the FSE group (7.9%) than in controls (1.0%) (p = 0.015).
This prospective study demonstrates that children with FSE are at risk for acute hippocampal injury and that a substantial number also have abnormalities in hippocampal development. Follow-up studies are in progress to determine the long-term outcomes in these children.
PMCID: PMC3425848  PMID: 22843278
18.  The predictive value of childhood blood pressure values for adult elevated blood pressure 
Open journal of pediatrics  2013;3(2):116-126.
Because of the paucity of serial blood pressure data on the same individuals, little is known about the accuracy of elevated blood pressure (BP) in childhood for predicting hypertension (HBP) later in life. The availability of long-term serial BP data from the Fels Longitudinal Study (FLS) presents the opportunity to link HBP in adulthood directly to BP measured decades earlier in the same individuals as children. We analyzed serial data from 965 men and 1114 women in the FLS. We used an autoregressive-moving average (1, 1) [ARMA (1, 1)] longitudinal model to predict adult HBP from childhood values. For 15-year-old boys with SBP 15 mmHg and 30 mmHg above the average SBP of 90 mmHg, the probabilities of having HBP at age 35 are 0.18 and 0.33, respectively. The corresponding probabilities for 15-year-old girls are only 0.04 and 0.08. This striking sex difference in risk of HBP at age 35 between 15-year-old boys and girls indicates that the risk of developing HBP in women is low regardless of their childhood blood pressure at any age from 2 to 17 years. Men are about 4.25 times more likely to have HBP at age 35 than women over a range of SBP of 90 – 140 mmHg at age 15. The ARMA (1, 1) model allows the identification of boys at risk for HBP as adult men.
PMCID: PMC3752649  PMID: 23991354
Blood Pressure; Body Mass Index; Systolic Blood Pressure; Diastolic Blood Pressure; Adult; Children
19.  Secular Trends in Body Composition for Children and Young Adults: The Fels Longitudinal Study 
American Journal of Human Biology  2012;24(4):506-514.
To determine secular trends by birth decade in body mass index (BMI), waist circumference/height (W/Ht), percent body fat (PBF), and fat free mass adjusted for height squared (FFM/Ht2) in children and adolescents aged 8–18 years.
Serial data were analyzed from 628 boys and 591girls aged 8 to 18 years who participated in the Fels Longitudinal Study. Subjects were stratified by birth decade from 1960 through 1999. Means and standard deviations were computed for all measurements by birth decade, age and sex. A repeated-measures analysis of variance was used data to ascertain secular trends separately for boys and girls.
Boys and girls born in the 1990s had significantly higher mean BMI, W/Ht and PBF than did children born in previous decades. Mean FFM/Ht2 was significantly smaller in boys born in the 1990s than boys of the same age born in earlier decades. No secular trend was noted in FFM/ Ht2 in girls by decade of birth.
Our analysis of serial data collected over four decades confirms the secular trend in childhood BMI previously observed in successive cross-sectional studies. Our analysis discloses significant positive secular trends in W/Ht and PBF in both boys and girls and a significant negative secular trend in FFM/Ht2 in boys over the last four decades of the 20th century. The secular changes presage increases in the prevalence of conditions associated with childhood and adolescent obesity – such as hypertension, glucose intolerance, and dyslipidemia – that may appear as early as the second decade of life.
PMCID: PMC3372655  PMID: 22410970
Body Composition; Obesity; Secular Trends; Body Mass Index
20.  Serial Childhood Body Mass Index and Associations with Adult Hypertension and Obesity: the Fels Longitudinal Study 
Obesity (Silver Spring, Md.)  2012;20(8):1741-1743.
Previous studies estimated critical periods of childhood body mass index (BMI) growth and linked these events to adult adiposity and cardiovascular health. We expand upon both results to link childhood BMI growth patterns with adult blood pressure. Data from male and female participants in the Fels Longitudinal Study were used to estimate childhood BMI growth curves, from which we isolate ages of childhood BMI divergence based upon adult BMI and blood pressure measurements. Repeated measure analysis of variances models were used to estimate BMI growth curves from ages 2 to 17.5 based on both adult BMI (< 25 kg/m2 or ≥ 25 kg/m2) and adult blood pressure (< 120 mmHg or ≥ 120 mmHg for systolic blood pressure; < 80 mmHg or ≥ 80 mm Hg for diastolic blood pressure). Participants with lower bodyweight throughout childhood had lower systolic and diastolic blood pressures in early adulthood. Any relationships between childhood adiposity and adult bodyweight and blood pressure disappeared by age 60. These results were independent of adult BMI and were observed in both men and women. Increased adult blood pressure has its genesis in part from increased childhood BMI.
PMCID: PMC3383882  PMID: 22402734
Blood Pressure; Overweight; Serial Childhood Measurements; Growth Curves
21.  Double genomic control is not effective to correct for population stratification in meta-analysis for genome-wide association studies 
Frontiers in Genetics  2012;3:300.
Meta-analysis of genome-wide association studies (GWAS) has become a useful tool to identify genetic variants that are associated with complex human diseases. To control spurious associations between genetic variants and disease that are caused by population stratification, double genomic control (GC) correction for population stratification in meta-analysis for GWAS has been implemented in the software METAL and GWAMA and is widely used by investigators. In this research, we conducted extensive simulation studies to evaluate the double GC correction method in meta-analysis and compared the performance of the double GC correction with that of a principal components analysis (PCA) correction method in meta-analysis. Results show that when the data consist of population stratification, using double GC correction method can have inflated type I error rates at a marker with significant allele frequency differentiation in the subpopulations (such as caused by recent strong selection). On the other hand, the PCA correction method can control type I error rates well and has much higher power in meta-analysis compared to the double GC correction method, even though in the situation that the casual marker does not have significant allele frequency difference between the subpopulations. We applied the double GC correction and PCA correction to meta-analysis of GWAS for two real datasets from the Atherosclerosis Risk in Communities (ARIC) project and the Multi-Ethnic Study of Atherosclerosis (MESA) project. The results also suggest that PCA correction is more effective than the double GC correction in meta-analysis.
PMCID: PMC3529452  PMID: 23269928
genome-wide association studies; meta-analysis; double genomic control correction; principal components analysis; population stratification
22.  A confirmatory factor analysis of the metabolic syndrome in adolescents: an examination of sex and racial/ethnic differences 
The metabolic syndrome (MetS) is a cluster of clinical indices that signals increased risk for cardiovascular disease and Type 2 diabetes. The diagnosis of MetS is typically based on cut-off points for various components, e.g. waist circumference and blood pressure. Because current MetS criteria result in racial/ethnic discrepancies, our goal was to use confirmatory factor analysis to delineate differential contributions to MetS by sub-group.
Research Design and Methods
Using 1999–2010 data from the National Health and Nutrition Examination Survey (NHANES), we performed a confirmatory factor analysis of a single MetS factor that allowed differential loadings across sex and race/ethnicity, resulting in a continuous MetS risk score that is sex and race/ethnicity-specific.
Loadings to the MetS score differed by racial/ethnic and gender subgroup with respect to triglycerides and HDL-cholesterol. ROC-curve analysis revealed high area-under-the-curve concordance with MetS by traditional criteria (0.96), and with elevations in MetS-associated risk markers, including high-sensitivity C-reactive protein (0.71), uric acid (0.75) and fasting insulin (0.82). Using a cut off for this score derived from ROC-curve analysis, the MetS risk score exhibited increased sensitivity for predicting elevations in ≥2 of these risk markers as compared with traditional pediatric MetS criteria.
The equations from this sex- and race/ethnicity-specific analysis provide a clinically-accessible and interpretable continuous measure of MetS that can be used to identify children at higher risk for developing adult diseases related to MetS, who could then be targeted for intervention. These equations also provide a powerful new outcome for use in childhood obesity and MetS research.
PMCID: PMC3489601  PMID: 23062212
Metabolic syndrome; Factor analysis, Statistical; Insulin resistance; Pediatrics; Adolescents; Epidemiology; Clinical studies; Obesity; Risk factors
23.  Phased implementation of electronic health records through an office of clinical transformation 
Evidence suggests that when carefully implemented, health information technologies (HIT) have a positive impact on behavior, as well as operational, process, and clinical outcomes. Recent economic stimulus initiatives have prompted unprecedented federal investment in HIT. Despite strong interest from the healthcare delivery community to achieve ‘meaningful use’ of HIT within a relatively short time frame, few best-practice implementation methodologies have been described. Herein we outline HIT implementation strategies at an academic health center with an office of clinical transformation. Seven percent of the medical center's information technology budget was dedicated to the Office of Clinical Transformation, and successful conversion of 1491 physicians to electronic-based documentation was accomplished. This paper outlines the process re-design, end-user adoption, and practice transformation strategies that resulted in a 99.7% adoption rate within 6 months of the introduction of digital documentation.
PMCID: PMC3168317  PMID: 21659444
Computerized patient records; computers; computer literacy; medical informatics; computerized physician order entry systems
Several studies have shown that causes of adult hypertension arise in childhood, and obesity may be a potential cause or at least a mitigating factor in this development. Body mass index is a well studied obesity metric, yet other potential adiposity measures such as percent body fat and waist circumference have been somewhat less considered. The purpose of this study is to determine associations between these alternative serial childhood adiposity measures and adulthood blood pressure.
Measurements from participants in the Fels Longitudinal Study were used to summarize childhood adiposity, represented by childhood measurements of percent body fat and height-adjusted waist circumference. These subjects also provided systolic and diastolic blood pressure as adults. Childhood adiposity levels were categorized as high or low as compared to the respective upper quartile, and associations with adult blood pressure were measured using Poisson regression to estimate the number of expected occurrences of elevated adiposity during childhood. Adult lifestyle covariates and adiposity were accounted for using multiple linear regression.
Summary indices of the childhood adiposity measures were significantly associated with both adult blood pressure metrics in men and women, though some of these associations were altered or reduced in the presence of adult lifestyle characteristics and adult adiposity measures.
Childhood measures of percent body fat and height-adjusted waist circumference have an effect on adult blood pressure, though the effect can be mitigated by adult lifestyles.
PMCID: PMC2968707  PMID: 20865760
blood pressure; percent body fat; waist circumference; Fels Longitudinal Study
25.  Prolonged Juvenile States and Delay of Cardiovascular and Metabolic Risk Factors 
The Journal of pediatrics  2009;155(3):S7.e1-S7.e6.
To ascertain the influence of such a prolonged juvenile state on delaying the onset of the metabolic syndrome, cardiovascular disease (CVD), and type 2 diabetes mellitus (T2DM) later in life.
Study design
We define prolongation of a juvenile state as a retarded tempo of growth, determined by the timing of peak height velocity in each subject and relate the retarded tempo of growth to metabolic syndrome, cardiovascular disease (CVD), and type 2 diabetes mellitus (T2DM) later in life using serial data of 237 study participants (119 men and 118 women) participants enrolled in the Fels Longitudinal study.
Children who matured early tended to have greater BMI, waist circumference, percent of body fat and were more likely to have adverse cardiovascular risk profiles than children who matured late. The differences in these risk factors between early and late maturers were significant for percent body fat, fasting plasma triglycerides, and fasting plasma insulin.
The analyses disclosed a clear separation between early and late maturers in the appearance of these risk factors in young adulthood.
PMCID: PMC2797823  PMID: 19732568

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