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1.  Human Leukocyte Antigens and Cellular Immune Responses to Anthrax Vaccine Adsorbed 
Infection and Immunity  2013;81(7):2584-2591.
Interindividual variations in vaccine-induced immune responses are in part due to host genetic polymorphisms in the human leukocyte antigen (HLA) and other gene families. This study examined associations between HLA genotypes, haplotypes, and homozygosity and protective antigen (PA)-specific cellular immune responses in healthy subjects following immunization with Anthrax Vaccine Adsorbed (AVA). While limited associations were observed between individual HLA alleles or haplotypes and variable lymphocyte proliferative (LP) responses to AVA, analyses of homozygosity supported the hypothesis of a “heterozygote advantage.” Individuals who were homozygous for any HLA locus demonstrated significantly lower PA-specific LP than subjects who were heterozygous at all eight loci (median stimulation indices [SI], 1.84 versus 2.95, P = 0.009). Similarly, we found that class I (HLA-A) and class II (HLA-DQA1 and HLA-DQB1) homozygosity was significantly associated with an overall decrease in LP compared with heterozygosity at those three loci. Specifically, individuals who were homozygous at these loci had significantly lower PA-specific LP than subjects heterozygous for HLA-A (median SI, 1.48 versus 2.13, P = 0.005), HLA-DQA1 (median SI, 1.75 versus 2.11, P = 0.007), and HLA-DQB1 (median SI, 1.48 versus 2.13, P = 0.002) loci, respectively. Finally, homozygosity at an increasing number (≥4) of HLA loci was significantly correlated with a reduction in LP response (P < 0.001) in a dose-dependent manner. Additional studies are needed to reproduce these findings and determine whether HLA-heterozygous individuals generate stronger cellular immune response to other virulence factors (Bacillus anthracis LF and EF) than HLA-homozygous subjects.
doi:10.1128/IAI.00269-13
PMCID: PMC3697592  PMID: 23649091
2.  The Effect of Parental Mental Health on Proxy reports of Health-related Quality of Life in Children with Sickle Cell Disease 
Pediatric blood & cancer  2010;55(4):10.1002/pbc.22651.
Background
The objectives of this study were to evaluate factors that influence agreement between parent-proxy and child self-report of health-related quality of life (HRQL) in sickle cell disease. We hypothesized that the mental health of the parent, parental HRQL and child characteristics would affect agreement.
Procedure
In a cross-sectional study of children with sickle cell disease, HRQL of the child and the parent’s HRQL and mental health were assessed. The effect of parent and child characteristics on agreement between parent-proxy and child self-report of HRQL were determined.
Results
Rates of agreement between parent-proxy and child self-report of HRQL ranged between 42–49%. Parents with increased symptoms of distress had an increased odds of reporting a worse physical (Odds Ratio (OR) 1.12) and psychosocial HRQL (OR 1.10) compared to the child’s self-report. Severe sickle cell disease was associated with an increased odds of the parent reporting the child’s physical HRQL was worse, (OR 4.68) compared to the child’s self-report.
Conclusions
Greater symptoms of distress in the parent are associated with worse parent-proxy report of the child’s HRQL. Severe sickle cell disease is associated with greater disagreement between parent-proxy and child self-report of HRQL. These findings broaden our understanding of factors that influence proxy-reporting of a child’s HRQL.
doi:10.1002/pbc.22651
PMCID: PMC3835190  PMID: 20589646
sickle cell disease; health-related quality of life; family factors; well being
3.  Racial and Ethnic Disparities in Non-Traumatic Dental Condition Visits to Emergency Departments and Physicians’ Offices in the Wisconsin Medicaid Program 
Background
Non-traumatic dental condition (NTDC) visits frequently occur in emergency departments (EDs) and physicians’ offices (POs), but little is known about whether racial/ethnic disparities exist in Medicaid NTDC visit rates to EDs and POs.
Methods
All Medicaid dental claims in Wisconsin from 2001–2003 were analyzed to examine factors associated with NTDC visits to EDs and POs. Bivariable and multivariable analyses were performed; independent variables examined included race/ethnicity, age, gender, dental health professional shortage area (DHPSA) designation, and Urban Influence Code (UIC) for county of residence.
Results
956,774 NTDC visits made during 1,718,006 person-years were evaluated; 4.3% of visits occurred in EDs/POs. Native Americans, African-Americans, and enrollees of unknown race/ethnicity had the highest unadjusted ED/PO visit rates for NTDCs. African-Americans, Native-Americans, adults, and residence in partial or entire DHPSAs had significantly higher adjusted rates of NTDC visits to EDs. Significantly higher adjusted NTDC visit rates to POs were observed for Native-Americans, adults, and enrollees residing in entire DHPSAs, but African-Americans had a significantly lower adjusted rate.
Conclusions
Native Americans, those residing in entire DHPSAs, and adults have significantly higher risks of NTDC visits to EDs and POs; African-Americans are at increased risk of ED visits but at decreased risk of PO visits for NTDCs.
Clinical Implications
Reductions in Medicaid visits to EDs and POs and the associated costs might be achieved by improving dental care access and targeted educational strategies among minorities, DHPSA residents, and adults.
PMCID: PMC3817617  PMID: 19047672
Medicaid; racial/ethnic disparities; non-traumatic dental conditions; emergency department; DHPSAs
4.  25(OH)D3 and Cardiovascular Risk Factors in Female Nonhuman Primates 
Journal of Women's Health  2012;21(9):959-965.
Abstract
Objective
To determine if interindividual differences in plasma concentrations of 25-hydroxyvitamin D3 (25(OH)D3) have pathophysiologic significance, we evaluated a cohort of female monkeys, seeking to identify associations with clinically relevant cardiovascular risk factors, including age, abdominal obesity (waist circumference), and high-density lipoprotein cholesterol (HDL-C).
Methods
One hundred fifty-five female vervet monkeys (Chlorocebus aethiops sabaeus) aged 3–25 years consumed a typical western diet for 7–8 weeks that provided a woman's equivalent of approximately 1000 IU/day of vitamin D3. Measurements of vitamin D3 and HDL-C concentrations, as well as waist circumference, were obtained.
Results
Among young monkeys (aged 3–5 years), compared to older monkeys (aged 16–25 years), the mean plasma 25(OH)D3 concentrations were 82.3±3.2 ng/mL and 58.6±2.9 ng/mL (p<0.0001), respectively. Plasma 25(OH)D3 concentrations had a range of 19.6–142.0 ng/mL (mean±standard error [SE] 66.4±1.7 ng/mL). 25(OH)D3 concentrations were inversely associated with age (p<0.0001) and waist circumference (p=0.016) and were positively correlated with HDL-C (p=0.01). However, when statistically controlling for age, none of these relationships remained significant.
Conclusions
Higher plasma concentrations of 25(OH)D3 were associated with more favorable cardiovascular risk factors, with inverse associations observed between 25(OH)D3 and abdominal obesity, HDL-C, and age. These associations were no longer significant when controlling for age.
doi:10.1089/jwh.2011.3416
PMCID: PMC3482874  PMID: 22876774
5.  Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13 
Arthritis and rheumatism  2012;64(8):2781-2791.
Objective
We have conducted a GWAS in a Caucasian cohort of juvenile idiopathic arthritis (JIA) patients and have previously published findings limited to autoimmune loci shared with other diseases. The goal of this study was to identify novel JIA predisposing loci using genome-wide approaches.
Methods
The Discovery cohort consisted of Caucasian JIA cases (814) and local controls (658) genotyped on the Affymetrix SNP 6.0 Array along with 2400 out-of-study controls. A replication study consisted of 10 SNPs genotyped in 1744 cases and 7010 controls from the US and Europe.
Results
Analysis within the Discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011, OR=1.37, P=1.88×10−6), and 10q21 near the gene JMJD1C [rs6479891, odds ratio (OR) =1.59, P=6.1×10−8; rs12411988, OR=1.57, P=1.16×10−7 and rs10995450, OR = 1.31, P=6.74×10−5]. Meta-analysis continued to provide evidence for association for these 4 SNPs (rs4688011, P=3.6×10−7, rs6479891, P=4.33×10−5; rs12411988, P=2.71×10−5; and rs10995450, 5.39×10−5;). Gene expression data from 68 JIA cases and 23 local controls showed cis eQTL associations for C3orf1 SNP rs4688011 (P=0.024 or P=0.034, depending on probe set) and the JMJD1C SNPs rs6479891 and rs12411988 (P=0.01 and P=0.008, respectively). A variance component liability model estimated that common SNP variation accounts for ~1/3 of JIA susceptibility.
Conclusions
Genetic association results and correlated gene expression findings provide evidence of association at 3q13 and 10q21 for JIA and offer novel genes as plausible candidates in disease pathology.
doi:10.1002/art.34429
PMCID: PMC3366043  PMID: 22354554
6.  A Genome-wide Association Study of Host Genetic Determinants of the Antibody Response to Anthrax Vaccine Adsorbed 
Vaccine  2012;30(32):4778-4784.
Several lines of evidence have supported a host genetic contribution to vaccine response, but genome-wide assessments for specific determinants have been sparse. Here we describe a genome-wide association study (GWAS) of protective antigen-specific antibody (AbPA) responses among 726 European-Americans who received Anthrax Vaccine Adsorbed (AVA) as part of a clinical trial. After quality control, 736,996 SNPs were tested for association with the AbPA response to 3 or 4 AVA vaccinations given over a 6-month period. No SNP achieved the threshold of genome-wide significance (p=5x10−8), but suggestive associations (p<1x10−5) were observed for SNPs in or near the class II region of the major histocompatibility complex (MHC), in the promoter region of SPSB1, and adjacent to MEX3C. Multivariable regression modeling suggested that much of the association signal within the MHC corresponded to previously identified HLA DR-DQ haplotypes involving component HLA-DRB1 alleles of *15:01, *01:01, or *01:02. We estimated the proportion of additive genetic variance explained by common SNP variation for the AbPA response after the 6 month vaccination. This analysis indicated a significant, albeit imprecisely estimated, contribution of variation tagged by common polymorphisms (p=0.032). Future studies will be required to replicate these findings in European Americans and to further elucidate the host genetic factors underlying variable immune response to AVA.
doi:10.1016/j.vaccine.2012.05.032
PMCID: PMC3387748  PMID: 22658931
Anthrax vaccines; Bacillus anthracis; bacterial vaccines; vaccination; Genome-wide association study
7.  Characterization of autosomal copy-number variation in African Americans: the HyperGEN Study 
European Journal of Human Genetics  2011;19(12):1271-1275.
African Americans are a genetically diverse population with a high burden of many, common heritable diseases. However, our understanding of genetic variation in African Americans is substandard because of a lack of published population-based genetic studies. We report the distribution of copy-number variation (CNV) in African Americans collected as part of the Hypertension Genetic Epidemiology Network (HyperGEN) using the Affymetrix 6.0 array and the CNV calling algorithms Birdsuite and PennCNV. We present population estimates of CNV from 446 unrelated African-American subjects randomly selected from the 451 families collected within HyperGEN. Although the majority of CNVs discovered were individually rare, we found the frequency of CNVs to be collectively high. We identified a total of 11 070 CNVs greater than 10 kb passing quality control criteria that were called by both algorithms – leading to an average of 24.8 CNVs per person covering 2214 kb (median). We identified 1541 unique copy-number variable regions, 309 of which did not overlap with the Database of Genomic Variants. These results provide further insight into the distribution of CNV in African Americans.
doi:10.1038/ejhg.2011.115
PMCID: PMC3230358  PMID: 21673747
DNA copy-number variation; African American; calling algorithm; Birdsuite; PennCNV; HyperGEN
8.  Can Rodent Longevity Studies be Both Short and Powerful? 
Many rodent experiments have assessed effects of diets, drugs, genes, and other factors on life span. A challenge with such experiments is their long duration, typically over 3.5 years given rodent life spans, thus requiring significant time costs until answers are obtained. We collected longevity data from 15 rodent studies and artificially truncated them at 2 years to assess the extent to which one will obtain the same answer regarding mortality effects. When truncated, the point estimates were not significantly different in any study, implying that in most cases, truncated studies yield similar estimates. The median ratio of variances of coefficients for truncated to full-length studies was 3.4, implying that truncated studies with roughly 3.4 times as many rodents will often have equivalent or greater power. Cost calculations suggest that shorter studies will be more expensive but perhaps not so much to not be worth the reduced time.
doi:10.1093/gerona/glq190
PMCID: PMC3041472  PMID: 21051569
Longevity; Rodent studies; Proportional hazards; Survival analysis; Sample size
9.  The Role of HLA DR-DQ Haplotypes in Variable Antibody Responses to Anthrax Vaccine Adsorbed 
Genes and immunity  2011;12(6):457-465.
Host genetic variation, particularly within the human leukocyte antigen (HLA) loci, reportedly mediates heterogeneity in immune response to certain vaccines; however, no large study of genetic determinants of anthrax vaccine response has been described. We searched for associations between the IgG antibody to protective antigen (AbPA) response to Anthrax Vaccine Adsorbed (AVA) in humans and polymorphisms at HLA class I (HLA-A, -B, and -C) and class II (HLA-DRB1, -DQA1, -DQB1, -DPB1) loci. The study included 794 European-Americans and 200 African-Americans participating in a 43-month, double-blind, placebo-controlled, clinical trial of AVA (clinicaltrials.gov identifier NCT00119067). Among European-Americans, genes from tightly linked HLA-DRB1-DQA1-DQB1 haplotypes displayed significant overall associations with longitudinal variation in AbPA levels at 4, 8, 26, and 30 weeks from baseline in response to vaccination with 3 or 4 doses of AVA (global p=6.53×10−4). In particular, carriage of the DRB1-DQA1-DQB1 haplotypes *1501-*0102-*0602 (p=1.17×10−5), *0101-*0101-*0501 (p=0.009), and *0102-*0101-*0501 (p=0.006) was associated with significantlylower AbPA levels. In carriers of two copies of these haplotypes, lower AbPA levels persisted following subsequent vaccinations. No significant associations were observed amongst African-Americans or for any HLA class I allele/haplotype. Further studies will be required to replicate these findings and to explore the role of host genetic variation outside of the HLA region.
doi:10.1038/gene.2011.15
PMCID: PMC3165112  PMID: 21368772
Anthrax vaccines; Bacillus anthracis; Bacterial vaccines; Vaccination; HLA Antigens
10.  Six Degrees of Epistasis: Statistical Network Models for GWAS 
Frontiers in Genetics  2012;2:109.
There is growing evidence that much more of the genome than previously thought is required to explain the heritability of complex phenotypes. Recent studies have demonstrated that numerous common variants from across the genome explain portions of genetic variability, spawning various avenues of research directed at explaining the remaining heritability. This polygenic structure is also the motivation for the growing application of pathway and gene set enrichment techniques, which have yielded promising results. These findings suggest that the coordination of genes in pathways that are known to occur at the gene regulatory level also can be detected at the population level. Although genes in these networks interact in complex ways, most population studies have focused on the additive contribution of common variants and the potential of rare variants to explain additional variation. In this brief review, we discuss the potential to explain additional genetic variation through the agglomeration of multiple gene–gene interactions as well as main effects of common variants in terms of a network paradigm. Just as is the case for single-locus contributions, we expect each gene–gene interaction edge in the network to have a small effect, but these effects may be reinforced through hubs and other connectivity structures in the network. We discuss some of the opportunities and challenges of network methods for analyzing genome-wide association studies (GWAS) such as the study of hubs and motifs, and integrating other types of variation and environmental interactions. Such network approaches may unveil hidden variation in GWAS, improve understanding of mechanisms of disease, and possibly fit into a network paradigm of evolutionary genetics.
doi:10.3389/fgene.2011.00109
PMCID: PMC3261632  PMID: 22303403
epistasis network; genetic association interaction network; missing heritability
11.  Using the Edmonton obesity staging system to predict mortality in a population-representative cohort of people with overweight and obesity 
Background:
Anthropometric-based classification schemes for excess adiposity do not include direct assessment of obesity-related comorbidity and functional status and thus have limited clinical utility. We examined the ability of the Edmonton obesity staging system, a 5-point ordinal classification system that considers comorbidity and functional status, in predicting mortality in a nationally representative US sample.
Methods:
We analyzed data from the National Health and Human Nutrition Examination Surveys (NHANES) III (1988–1994) and the NHANES 1999–2004, with mortality follow-up through to the end of 2006. Adults (age ≥ 20 yr) with overweight or obesity who had been randomized to the morning session at the mobile examination centre were scored according to the Edmonton obesity staging system. We examined the relationship between staging system scores and mortality, and Cox proportional hazards models were adjusted for the presence of the metabolic syndrome or hypertriglyceridemic waist.
Results:
Over 75% of the cohort with overweight or obesity were given scores of 1 or 2. Scores of 4 could not be reliably assigned because specific data elements were lacking. Survival curves clearly diverged when stratified by scores of 0–3, but not when stratified by obesity class alone. Within the data from the NHANES 1988–1994, scores of 2 (hazard ratio [HR] 1.57; 95% confidence interval [CI] 1.16 to 2.13) and 3 (HR 2.69; 95% CI 1.98 to 3.67) were associated with increased mortality compared with scores of 0 or 1, even after adjustment for body mass index and the metabolic syndrome. We found similar results after adjusting for hypertriglyceridemic waist (i.e., waist circumference ≥ 90 cm and a triglyceride level ≥ 2 mmol/L for men; the corresponding values for women were ≥ 85 cm and ≥ 1.5 mmol/L), as well as in a cohort eligible for bariatric surgery.
Interpretation:
The Edmonton obesity staging system independently predicted increased mortality even after adjustment for contemporary methods of classifying adiposity. The Edmonton obesity staging system may offer improved clinical utility in assessing obesity-related risk and prioritizing treatment.
doi:10.1503/cmaj.110387
PMCID: PMC3185097  PMID: 21844111
12.  Use of self-reported height and weight biases the body mass index-mortality association 
Background
Many large-scale epidemiologic data sources used to evaluate the body mass index (BMI: kg/m2) mortality association have relied on BMI derived from self-reported height and weight. Although measured BMI (BMIM) and self-reported BMI (BMISR) correlate highly, self-reports are systematically biased.
Objective
To rigorously examine how self-reporting bias influences the association between BMI and mortality rate.
Subjects
Samples representing the US non-institutionalized civilian population.
Design and Methods
National Health and Nutrition Examination Survey data (NHANES II: 1976-80; NHANES III: 1988-94) contain BMIM and BMISR. We applied Cox regression to estimate mortality hazard ratios (HRs) for BMIM and BMISR categories, respectively, and compared results. We similarly analyzed subgroups of ostensibly healthy never-smokers.
Results
Misclassification by BMISR among the underweight and obesity ranged from 30–40% despite high correlations between BMIM and BMISR (r>0.9). The reporting bias was moderately correlated with BMIM (r>0.35), but not BMISR (r<0.15). Analyses using BMISR failed to detect six of eight significant mortality HRs detected by BMIM. Significantly biased HRs were detected in the NHANES II full dataset (χ2 = 12.49; p = 0.01) and healthy subgroup (χ2 = 9.93; p = 0.04), but not in the NHANES III full dataset (χ2 = 5.63; p = 0.23) or healthy subgroup (χ2 = 1.52; p = 0.82).
Conclusions
BMISR should not be treated as interchangeable with BMIM in BMI-mortality analyses. Bias and inconsistency introduced by using BMISR in place of BMIM in BMI-mortality estimation and hypothesis tests may account for important discrepancies in published findings.
doi:10.1038/ijo.2010.148
PMCID: PMC3040787  PMID: 20680015
self-reported BMI; measured BMI; self-reporting bias; obesity; mortality; NHANES
13.  Increased Children's Access to Fluoride Varnish Treatment by Involving Medical Care Providers: Effect of a Medicaid Policy Change 
Health Services Research  2009;44(4):1144-1156.
Background
In 2004, the State of Wisconsin introduced a change to their Medicaid Policy allowing medical care providers to be reimbursed for fluoride varnish treatment provided to Medicaid enrolled children.
Objective
To determine the extent by which a state-level policy change impacted access to fluoride varnish treatment (FVT) for Medicaid enrolled children.
Data Source
The Electronic Data Systems of Medicaid Evaluation and Decision Support database for Wisconsin from 2002 to 2006.
Study Design
We analyzed Wisconsin Medicaid claims for FVT for children between the ages of 1 and 6 years, comparing rates in the prepolicy period (2002–2003) to the period (2004–2006) following the policy change.
Principal Findings
Medicaid claims for FVT in 2002–2003 totaled 3,631. Following the policy change, claims for FVT increased to 28,303, with 38.0 percent submitted by medical care providers. FVT rates increased for children of both sexes and all ages, rising from 1.4 per 1,000 person-years of enrollment in 2002–2003 to 6.6 per 1,000 person-years in 2004–2006. Overall, 48.6 percent of the increase in FVT was attributable to medical care providers. The largest increase was seen in children 1–2 years of age, among whom medical care providers were responsible for 83.5 percent of the increase.
Conclusions
A state-level Medicaid policy change was followed by both a significant involvement of medical care providers and an overall increase in FVT. Children between the ages of 1 and 2 years appear to benefit the most from the involvement of medical care providers.
doi:10.1111/j.1475-6773.2009.00975.x
PMCID: PMC2739021  PMID: 19453390
Medicaid-enrolled children; oral health disparities; fluoride varnish treatment; medical care providers; policy change
14.  Capitalizing on admixture in genome-wide association studies: a two-stage testing procedure and application to height in African-Americans 
Frontiers in genetics  2011;2:00011.
As genome-wide association studies expand beyond populations of European ancestry, the role of admixture will become increasingly important in the continued discovery and fine-mapping of variation influencing complex traits. Although admixture is commonly viewed as a confounding influence in association studies, approaches such as admixture mapping have demonstrated its ability to highlight disease susceptibility regions of the genome. In this study, we illustrate a powerful two-stage testing strategy designed to uncover trait-associated single nucleotide polymorphisms in the presence of ancestral allele frequency differentiation. In the first stage, we conduct an association scan by using predicted genotypic values based on regional admixture estimates. We then select a subset of promising markers for inclusion in a second-stage analysis, where association is tested between the observed genotype and the phenotype conditional on the predicted genotype. We prove that, under the null hypothesis, the test statistics used in each stage are orthogonal and asymptotically independent. Using simulated data designed to mimic African-American populations in the case of a quantitative trait, we show that our two-stage procedure maintains appropriate control of the family wise error rate and has higher power under realistic effect sizes than the one-stage testing procedure in which all markers are tested for association simultaneously with control of admixture. We apply the proposed procedure to a study of height in 201 African-Americans genotyped at 108 ancestry informative markers. The two-stage procedure identified two statistically significant markers rs1985080 (PTHB1/BBS9) and rs952718 (ABCA12). PTHB1/BBS9 is downregulated by parathyroid hormone in osteoblastic cells and is thought to be involved in parathyroid hormone action in bones and may play a role in height. ABCA12 is a member of the superfamily of ATP-binding cassette transporters and its potential involvement in height is unclear.
doi:10.3389/fgene.2011.00011
PMCID: PMC3132882  PMID: 21754915
two-stage; structured association testing; admixture mapping; regional admixture estimate; genome-wide association studies
15.  Provision of Fluoride Varnish Treatment by Medical and Dental Care Providers: Variation by Race/Ethnicity and Levels of Urban Influence 
Background
In 2004, Wisconsin Medicaid policy changed to allow medical care providers to be reimbursed for fluoride varnish treatment (FVT) to children’s teeth to improve access and utilization. To date, no study has been published on whether geographic and racial/ethnic variation in the provision of FVT in response to this policy change exists.
Objective
To examine the association of rates of FVT for children enrolled in Wisconsin Medicaid with race/ethnicity, Urban Influence Codes (UIC), and Dental Health Professional Shortage Area (DHPSA) designation based on county of residence.
Methods
A retrospective, pre-post design was used based on FVT claims for children in the Wisconsin Medicaid program from 2002 to 2006. Poisson Regression Models were used to evaluate the association of rates of FVT claims with race/ethnicity, UIC, and DHPSA designation.
Results
The rate of FVT claims varied by resident county-type according to UIC and DHPSA designation, age, and race/ethnicity. Post policy, the largest increases were observed for Native Americans residing in none DHPSA counties, enrollees living in rural counties and for Hispanics living in partial and entire DHPSA counties. African-Americans residing in partial DHPSA and metropolitan counties displayed the lowest rates of FVT claims.
Conclusions
Overall access and utilization of fluoride varnish treatment increased, but substantial racial/ethnic and geographic variation in the provision of FVT for children enrolled in Wisconsin Medicaid was observed. Future policies should incorporate measures that will specifically address the racial and geographic variations identified in this study.
doi:10.1111/j.1752-7325.2010.00168.x
PMCID: PMC2967666  PMID: 20459463
Fluoride varnish treatment; Children; Ethnic groups; Health services accessibility
16.  Vaso-occlusive Painful Events in Sickle Cell Disease: Impact on Child Well-Being 
Pediatric blood & cancer  2010;54(1):92-97.
Background
This study describes how painful events affect the health related quality of life (HRQL) of children with sickle cell disease (SCD) and determines the responsiveness of a generic HRQL measure in SCD. Our hypotheses were twofold: 1) HRQL is significantly impaired at presentation to the emergency department for a painful event and 2) PedsQL 4.0 Acute Version Generic Core Scales is responsive to change in the evolution of a painful event.
Procedure
This prospective cohort study included 57 children with SCD. HRQL was measured with the Acute Version of the PedsQL 4.0 Generic Core Scales, completed by child (self-report) and caregiver (proxy-report) at presentation and seven days post-discharge. Independent comparisons of HRQL scores were made between children in the study cohort and a published reference sample of children with SCD in baseline health (historical SCD controls).
Results
Median PedsQL scores at presentation were significantly lower than historical SCD controls in all domains for child self-report and all domains except social and school functioning in parent-proxy. Clinically and statistically significant changes in HRQL between presentation and post-discharge resulted in similar HRQL scores at seven days post-discharge to historical SCD controls.
Conclusions
The PedsQL is responsive to change; thus a useful tool to measure the impact of interventions in future SCD clinical trials. Painful events significantly diminish all domains of HRQL and this improves seven days post-discharge.
doi:10.1002/pbc.22222
PMCID: PMC3114448  PMID: 19653296
sickle cell disease; painful events; health related quality of life; child well-being; patient reported outcomes
17.  A method to assess linkage disequilibrium between CNVs and SNPs inside copy number variable regions 
Frontiers in genetics  2011;2(17):00017.
Since the discovery of the ubiquitous contribution of copy number variation to genetic variability, researchers have commonly used metrics such as r2 to quantify linkage disequilibrium (LD) between copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). However, these reports have been restricted to SNPs outside copy number variable regions (CNVR) as current methods have not been adapted to account for SNPs displaying variable copy number. We show that traditional LD metrics inappropriately quantify SNP/CNV covariance when SNPs lie within CNVR. We derive a new method for measuring LD that solves this issue, and defaults to traditional metrics otherwise. Finally, we present a procedure to estimate CNV–SNP allele frequencies from unphased CNV–SNP genotypes. Our method allows researchers to include all SNPs in SNP/CNV LD measurements, regardless of copy number.
doi:10.3389/fgene.2011.00017
PMCID: PMC3109359  PMID: 21660233
copy number variation; linkage disequilibrium; CNV–SNP haplotype
18.  Beyond Missing Heritability: Prediction of Complex Traits 
PLoS Genetics  2011;7(4):e1002051.
Despite rapid advances in genomic technology, our ability to account for phenotypic variation using genetic information remains limited for many traits. This has unfortunately resulted in limited application of genetic data towards preventive and personalized medicine, one of the primary impetuses of genome-wide association studies. Recently, a large proportion of the “missing heritability” for human height was statistically explained by modeling thousands of single nucleotide polymorphisms concurrently. However, it is currently unclear how gains in explained genetic variance will translate to the prediction of yet-to-be observed phenotypes. Using data from the Framingham Heart Study, we explore the genomic prediction of human height in training and validation samples while varying the statistical approach used, the number of SNPs included in the model, the validation scheme, and the number of subjects used to train the model. In our training datasets, we are able to explain a large proportion of the variation in height (h2 up to 0.83, R2 up to 0.96). However, the proportion of variance accounted for in validation samples is much smaller (ranging from 0.15 to 0.36 depending on the degree of familial information used in the training dataset). While such R2 values vastly exceed what has been previously reported using a reduced number of pre-selected markers (<0.10), given the heritability of the trait (∼0.80), substantial room for improvement remains.
Author Summary
While previous genome-wide association studies have implicated numerous loci associated with complex traits, such loci typically account for a very small proportion of phenotypic variation. However, a recent study using height as a model trait has illustrated that common single nucleotide polymorphisms can explain a large amount of genetic variance when evaluated through whole-genome statistical models. However, it is unclear to what extent higher proportions of explained variance will translate into improved predictive accuracy in future populations. Here we evaluate the predictive ability of whole-genome models for human height while varying the modeling approach, the size of the training population, the validation design, and the number of SNPs. Our results suggest that whole-genome prediction models can yield higher accuracy than what is commonly attained by models based on a few selected SNPs; yet, given the heritability of the trait in question, there exists room for improving prediction accuracy. While gains in predictive accuracy are likely to be small based on more expansive genotyping, our results indicate that more substantial benefits are likely to be gained through larger training populations, as well through the inclusion of related individuals.
doi:10.1371/journal.pgen.1002051
PMCID: PMC3084207  PMID: 21552331
19.  A Method to Assess Linkage Disequilibrium between CNVs and SNPs Inside Copy Number Variable Regions 
Since the discovery of the ubiquitous contribution of copy number variation to genetic variability, researchers have commonly used metrics such as r2 to quantify linkage disequilibrium (LD) between copy number variants (CNVs) and single nucleotide polymorphisms (SNPs). However, these reports have been restricted to SNPs outside copy number variable regions (CNVR) as current methods have not been adapted to account for SNPs displaying variable copy number. We show that traditional LD metrics inappropriately quantify SNP/CNV covariance when SNPs lie within CNVR. We derive a new method for measuring LD that solves this issue, and defaults to traditional metrics otherwise. Finally, we present a procedure to estimate CNV–SNP allele frequencies from unphased CNV–SNP genotypes. Our method allows researchers to include all SNPs in SNP/CNV LD measurements, regardless of copy number.
doi:10.3389/fgene.2011.00017
PMCID: PMC3109359  PMID: 21660233
copy number variation; linkage disequilibrium; CNV–SNP haplotype
20.  A Genome-wide Association Study of Carotid Atherosclerosis in HIV-infected Men 
AIDS (London, England)  2010;24(4):583-592.
Background
The role of host genetics in the development of subclinical atherosclerosis in the context of HIV infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.
Methods
The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.
Results
Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the Ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (p-value<1.61×10−7). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.
Conclusions
These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.
doi:10.1097/QAD.0b013e3283353c9e
PMCID: PMC3072760  PMID: 20009918
HIV; HAART; atherosclerosis; GWAS; intima-media thickness
21.  THE DISTRIBUTION AND HYPOTHESIS TESTING OF EIGENVALUES FROM THE CANONICAL ANALYSIS OF THE GAMMA MATRIX OF QUADRATIC AND CORRELATIONAL SELECTION GRADIENTS 
Canonical analysis measures nonlinear selection on latent axes from a rotation of the gamma matrix (γ) of quadratic and correlation selection gradients. Here we document that the conventional method of testing eigenvalues (double regression) under the null hypothesis of no nonlinear selection is incorrect. Through simulation we demonstrate that under the null the expectation of some eigenvalues from canonical analysis will be nonzero, which leads to unacceptably high type 1 error rates. Using a two trait example, we prove that the expectations for both eigenvalues depend on the sampling variability of the estimates in γ. An appropriate test is to slightly modify the double regression method by calculating permutation p-values for the ordered eigenvalues, which maintains correct type 1 error rates. Using simulated data of nonlinear selection on male guppy ornamentation, we show that the statistical power to detect curvature with canonical analysis is higher compared to relying on the estimates from γ alone. We provide a simple R script for permutation testing of the eigenvalues in order to distinguish curvature in the selection surface induced by nonlinear selection from curvature induced by random processes.
doi:10.1111/j.1558-5646.2009.00874.x
PMCID: PMC2857515  PMID: 19863584
Nonlinear Selection; Phenotypic Selection; Selection Surface; Fitness Surface; Stabilizing Selection
22.  Capitalizing on Admixture in Genome-Wide Association Studies: A Two-Stage Testing Procedure and Application to Height in African-Americans 
As genome-wide association studies expand beyond populations of European ancestry, the role of admixture will become increasingly important in the continued discovery and fine-mapping of variation influencing complex traits. Although admixture is commonly viewed as a confounding influence in association studies, approaches such as admixture mapping have demonstrated its ability to highlight disease susceptibility regions of the genome. In this study, we illustrate a powerful two-stage testing strategy designed to uncover trait-associated single nucleotide polymorphisms in the presence of ancestral allele frequency differentiation. In the first stage, we conduct an association scan by using predicted genotypic values based on regional admixture estimates. We then select a subset of promising markers for inclusion in a second-stage analysis, where association is tested between the observed genotype and the phenotype conditional on the predicted genotype. We prove that, under the null hypothesis, the test statistics used in each stage are orthogonal and asymptotically independent. Using simulated data designed to mimic African-American populations in the case of a quantitative trait, we show that our two-stage procedure maintains appropriate control of the family wise error rate and has higher power under realistic effect sizes than the one-stage testing procedure in which all markers are tested for association simultaneously with control of admixture. We apply the proposed procedure to a study of height in 201 African-Americans genotyped at 108 ancestry informative markers. The two-stage procedure identified two statistically significant markers rs1985080 (PTHB1/BBS9) and rs952718 (ABCA12). PTHB1/BBS9 is downregulated by parathyroid hormone in osteoblastic cells and is thought to be involved in parathyroid hormone action in bones and may play a role in height. ABCA12 is a member of the superfamily of ATP binding cassette transporters and its potential involvement in height is unclear.
doi:10.3389/fgene.2011.00011
PMCID: PMC3132882  PMID: 21754915
two-stage; structured association testing; admixture mapping; regional admixture estimate; genome-wide association studies
23.  Prediction of Survival with Alternative Modeling Techniques Using Pseudo Values 
PLoS ONE  2014;9(6):e100234.
Background
The use of alternative modeling techniques for predicting patient survival is complicated by the fact that some alternative techniques cannot readily deal with censoring, which is essential for analyzing survival data. In the current study, we aimed to demonstrate that pseudo values enable statistically appropriate analyses of survival outcomes when used in seven alternative modeling techniques.
Methods
In this case study, we analyzed survival of 1282 Dutch patients with newly diagnosed Head and Neck Squamous Cell Carcinoma (HNSCC) with conventional Kaplan-Meier and Cox regression analysis. We subsequently calculated pseudo values to reflect the individual survival patterns. We used these pseudo values to compare recursive partitioning (RPART), neural nets (NNET), logistic regression (LR) general linear models (GLM) and three variants of support vector machines (SVM) with respect to dichotomous 60-month survival, and continuous pseudo values at 60 months or estimated survival time. We used the area under the ROC curve (AUC) and the root of the mean squared error (RMSE) to compare the performance of these models using bootstrap validation.
Results
Of a total of 1282 patients, 986 patients died during a median follow-up of 66 months (60-month survival: 52% [95% CI: 50%−55%]). The LR model had the highest optimism corrected AUC (0.791) to predict 60-month survival, followed by the SVM model with a linear kernel (AUC 0.787). The GLM model had the smallest optimism corrected RMSE when continuous pseudo values were considered for 60-month survival or the estimated survival time followed by SVM models with a linear kernel. The estimated importance of predictors varied substantially by the specific aspect of survival studied and modeling technique used.
Conclusions
The use of pseudo values makes it readily possible to apply alternative modeling techniques to survival problems, to compare their performance and to search further for promising alternative modeling techniques to analyze survival time.
doi:10.1371/journal.pone.0100234
PMCID: PMC4065009  PMID: 24950066
24.  PREVALENCE OF THE FEMALE ATHLETE TRIAD IN HIGH SCHOOL ATHLETES AND SEDENTARY STUDENTS 
Objective
To determine the prevalence of the female athlete triad (low energy availability, menstrual dysfunction and low bone mineral density) in high school varsity athletes in a variety of sports compared with sedentary students/controls.
Design
Prospective study.
Setting
Academic medical center in the Midwest.
Participants
Eighty varsity athletes and eighty sedentary students/controls volunteered for this study.
Intervention
Subjects completed questionnaires, had their blood drawn and underwent bone mineral density testing.
Main Outcome Measures
Each participant completed screening questionnaires assessing eating behavior, menstrual status and physical activity. Each subject completed a 3-day food diary. Serum hormonal, TSH and prolactin levels were determined. Bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA).
Results
Low energy availability was present in similar numbers of athletes (36%) and sedentary/control subjects (39%; p=0.74). Athletes suffered more menstrual abnormalities (54%) compared with sedentary students/controls (21%) (p=<0.001). DXA revealed that 16% of the athletes and 30% of the sedentary/controls had low BMD (p=0.03). Risk factors for reduced BMD include sedentary control student, low BMI and increased caffeine consumption.
Conclusions
A substantial number of high school athletes (78%) and a surprising number of sedentary students (65%) suffer from one or more components of the triad. Given the high prevalence of triad characteristics in both groups, education in the formative elementary school years has the potential to prevent several of the components in both groups, therefore, improving health and averting long-term complications.
doi:10.1097/JSM.0b013e3181b8c136
PMCID: PMC2848387  PMID: 19741317
female athletes; energy deficit; reduced bone mineral density; amenorrhea
25.  Impact of family income and sickle cell disease on the health-related quality of life of children 
Purpose
The objective of this study was to determine the impact of family income and sickle cell disease on the health-related quality of life (HRQL) of children.
Methods
This was a cross-sectional study of children with and without sickle cell disease. Participants completed the PedsQL™ generic core scales parent-proxy or child self-report questionnaire during a routine clinic visit. HRQL was the primary outcome measured. Family income and sickle cell disease were the primary independent variables of interest.
Results
A total of 104 children with sickle cell disease and 74 without disease participated in the study. After adjusting for family income, patient age, and the presence of co-morbidities, children with severe sickle cell disease had increased odds of worse overall HRQL (parent-proxy HRQL report odds ratio [OR] 4.0) and physical HRQL (parent-proxy report OR 5.67, child self-report OR 3.33) compared to children without sickle cell disease.
Conclusions
Children with sickle cell disease have significantly impaired HRQL, even after considering the potential detrimental effect of family income on HRQL. Targeted interventions to improve these children’s HRQL are warranted.
doi:10.1007/s11136-008-9412-8
PMCID: PMC2840660  PMID: 18989755
Sickle cell disease; Health-related quality of life; Socioeconomic factors; Children; Family income

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