Objective
To describe obstacles in the implementation of a controlled treatment trial of adolescent anorexia nervosa (AN).
Method
The original aim was to enter 240 participants with AN to one of 4 cells: Behavioral family therapy (BFT) plus fluoxetine; BFT plus placebo; systems family therapy (SFT) plus fluoxetine; SFT plus placebo.
Results
Recruitment was delayed pending a satisfactory resolution concerning participant safety. After 6 months of recruitment it became clear that the medication was associated with poor recruitment leading to a study redesign resulting in a comparison of two types of family therapy with a projected sample size of 160. One site was unable to recruit and was replaced.
Discussion
Problems with the delineation of safety procedures, recruitment, re-design of the study, and replacement of a site, were the main elements resulting in a 1-year delay. Suggestions are made for overcoming such problems in future AN trials.
doi:10.1002/eat.20923
PMCID: PMC3140589
PMID: 21495052
Anorexia nervosa; adolescents; Behavioral Family Therapy; Systems Family Therapy; RIAN trial
Dellava, Jocilyn E. | Trace, Sara E. | Strober, Michael | Thornton, Laura M. | Klump, Kelly L. | Brandt, Harry | Crawford, Steve | Fichter, Manfred M. | Halmi, Katherine A. | Johnson, Craig | Kaplan, Allan S. | Mitchell, James E. | Treasure, Janet | Woodside, D. Blake | Berrettini, Wade H. | Kaye, Walter H. | Bulik, Cynthia M.
This exploratory study assessed whether maternal recall of childhood feeding and eating practices differed across anorexia nervosa (AN) subtypes. Participants were 325 women from the Genetics of Anorexia Nervosa study whose mothers completed a childhood feeding and eating questionnaire. Multinomial logistic regression analyses were used to predict AN subtype from measures related to childhood eating: (a) infant feeding (breastfed, feeding schedule, age of solid food introduction), (b) childhood picky eating (picky eating before age one and between ages one and five), and (c) infant gastrointestinal problems (vomiting and colic). Results revealed no significant differences in retrospective maternal report of childhood feeding and eating practices among AN subtypes.
doi:10.1002/erv.1153
PMCID: PMC3391535
PMID: 21830261
Anorexia Nervosa; Anorexia Nervosa Subtype; Feeding; Maternal Report; Infancy
Background
We assessed the association between sleep apnea, snoring, incident cardiovascular (CV) events and all-cause mortality in the Multi Ethnic Study of Atherosclerosis (MESA) cohort.
Methods
Out of 5338 respondents to a sleep questionnaire administered during the second MESA exam period, 208 had physician-diagnosed sleep apnea (PDSA), 1452 were habitual snorers (HS) and 3678 were neither a habitual snorer nor had PDSA (normal participants). Cox proportional hazard analysis was used to assess the associations adjusting for age, gender, race/ethnicity, smoking, diabetes mellitus, total cholesterol, HDL, triglycerides, BMI, current alcohol use, benzodiazepine use, BP medications and statin use.
Results
Over a 7.5 year average follow-up period, 310 adjudicated CV events including MI, stroke, angina, resuscitated cardiac arrest, stroke death and CVD death and 189 deaths occurred. Compared to HS, PDSA was associated with higher incident CV rates in both univariate and multivariable models [hazard ratio (95%); 1.89(1.22–2.93), p=0.004 and 1.91(1.20 –3.04), p=0.007 respectively]. PDSA was also associated with a higher death rates compared with HS [hazard ratio (95%); 2.13(1.25 – 3.63), p=0.006 and 2.70(1.52– 4.79), p=0.007 respectively]. Compared with normal participants, PDSA had higher incident CV event rates in both univariate and multivariable models [hazard ratio (95%); 2.23[1.39–3.60], p=0.001 and 2.16[1.30–3.58], p=0.003 respectively]. Similarly, PDSA had a higher death rate compared with normal participants in both the univariate and multivariable models [hazard ratio (95%CI); 2.44(1.36 – 4.37), p=0.003 and 2.71(1.45 – 5.08), p=0.002 respectively]. Habitual snorers had similar incident CV event rates and death rates in both univariate and multivariable models compared with normal participants.
Conclusion
PDSA but not habitual snoring was associated with high incident CV events and all-cause mortality in a multi-ethnic population based study of adults free of clinical CV disease at baseline.
doi:10.1016/j.atherosclerosis.2011.08.021
PMCID: PMC3255297
PMID: 22078131
Obstructive sleep apnea; habitual snorers; cardiovascular events; mortality; population
Bell, Robert C. | Rogith, Deevakar | Johnson, Craig W. | Badea, Cristian T. | Athreya, Khannan K. | Espinosa, Gabriela | Clark, Darin | Ghafoori, A. Paiman | Li, Yifan | Kirsch, David G. | Annapragada, Ananth | Ghaghada, Ketankumar
Proposed is a method for statistical analysis for a small sample size, repeated measure experiment with nesting factors. In the original experiment the Student t-test was used for analysis. Using the same data, we modeled the experiment into two groups of mice with benign and malignant primary lung tumors. 4 tumor nodules were selected from each mouse (N= 36). The dependent variables are the volume, diameter, and signal attenuation measured using computed tomography (CT). The measurements are made before injecting the contrast and at 0, 72, and 168 hours after injection. The contrast agent enhances tumor nodule volume and volume differences between benign and malignant tumor nodules measured across time (p < 0.05). The signal attenuation measured across time differentiates between benign and malignant groups (p < 0.05). There is significant correlation between rate of change of volume and diameter of tumor. The advantages of this statistical method are discussed.
PMCID: PMC3540499
PMID: 23304269
Bloss, Cinnamon S | Berrettini, Wade | Bergen, Andrew W | Magistretti, Pierre | Duvvuri, Vikas | Strober, Michael | Brandt, Harry | Crawford, Steve | Crow, Scott | Fichter, Manfred M | Halmi, Katherine A | Johnson, Craig | Kaplan, Allan S | Keel, Pamela | Klump, Kelly L | Mitchell, James | Treasure, Janet | Woodside, D Blake | Marzola, Enrica | Schork, Nicholas J | Kaye, Walter H
Follow-up studies of eating disorders (EDs) suggest outcomes ranging from recovery to chronic illness or death, but predictors of outcome have not been consistently identified. We tested 5151 single-nucleotide polymorphisms (SNPs) in approximately 350 candidate genes for association with recovery from ED in 1878 women. Initial analyses focused on a strictly defined discovery cohort of women who were over age 25 years, carried a lifetime diagnosis of an ED, and for whom data were available regarding the presence (n=361 ongoing symptoms in the past year, ie, ‘ill') or absence (n=115 no symptoms in the past year, ie, ‘recovered') of ED symptoms. An intronic SNP (rs17536211) in GABRG1 showed the strongest statistical evidence of association (p=4.63 × 10−6, false discovery rate (FDR)=0.021, odds ratio (OR)=0.46). We replicated these findings in a more liberally defined cohort of women age 25 years or younger (n=464 ill, n=107 recovered; p=0.0336, OR=0.68; combined sample p=4.57 × 10−6, FDR=0.0049, OR=0.55). Enrichment analyses revealed that GABA (γ-aminobutyric acid) SNPs were over-represented among SNPs associated at p<0.05 in both the discovery (Z=3.64, p=0.0003) and combined cohorts (Z=2.07, p=0.0388). In follow-up phenomic association analyses with a third independent cohort (n=154 ED cases, n=677 controls), rs17536211 was associated with trait anxiety (p=0.049), suggesting a possible mechanism through which this variant may influence ED outcome. These findings could provide new insights into the development of more effective interventions for the most treatment-resistant patients.
doi:10.1038/npp.2011.108
PMCID: PMC3176559
PMID: 21750581
GABA; anorexia nervosa; recovery from eating disorders; genetic association; single nucleotide polymorphisms; eating/metabolic disorders; GABA; eating/metabolic disorders; neurogenetics; biological psychiatry; genetic association; anorexia nervosa; recovery from eating disorders; single-nucleotide polymorphisms; phenomic association
Background
Common carotid artery intima-media thickness (IMT), a measure of subclinical cardiovascular disease, changes during the cardiac cycle. The magnitude of this effect and its implications have not been well studied.
Methods and Results
Far-wall IMT measurements of the right common carotid artery were measured at end diastole and peak systole in 5633 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA). Multivariable regression models were generated with end-diastolic IMT, peak-systolic IMT, and change in IMT during the cardiac cycle as dependent variables and traditional cardiovascular risk factors as independent variables. The average age of our population was 61.9 (45 to 84) years. Average change in carotid IMT during the cardiac cycle was 0.041 mm (95% confidence interval: 0.039 to 0.042 mm), with a mean IMT of 0.68 mm. End-diastolic IMT and peak-systolic IMT were similarly associated with risk factors. In a fully adjusted model, change in carotid IMT during the cardiac cycle was associated with ethnicity and pulse pressure (P=0.001) and not age, sex, or other risk factors. Chinese and Hispanics had less of a change in IMT than did non-Hispanic whites. With peak-systolic IMT reference values used as normative data, 31.3% more individuals were classified as being in the upper quartile of IMT and at high risk for cardiovascular disease than would be expected when IMT is measured at end diastole.
Conclusions
Measurable differences in IMT are seen during the cardiac cycle. This affects the interpretation of IMT measurements used for cardiovascular risk assessment, given published normative data with IMT measured at peak systole.
Clinical Trial Registration
URL: www.ClinicalTrials.gov. Unique identifier: NCT00063440. (J Am Heart Assoc. 2012;1:e001420 doi: 10.1161/JAHA.112.001420.)
doi:10.1161/JAHA.112.001420
PMCID: PMC3487346
PMID: 23130162
atherosclerosis; blood pressure; carotid arteries; diastole; epidemiology; risk factors; systole; ultrasonics
Hixson, James E. | Shimmin, Lawrence C. | Montasser, May E. | Kim, Do-Kyun | Zhong, Yu | Ibaguen, Heladio | Follis, Jack | Malcom, Gray | Strong, Jack | Howard, Tim | Langefeld, Carl | Liu, Yongmei | Rotter, Jerome I. | Johnson, Craig | Herrington, David
OBJECTIVE
We investigated the influence of genetic variants (rare and common) in the gene encoding periostin (POSTN) on atherosclerosis as measured in arterial specimens from the “Pathobiological Determinants of Atherosclerosis in Youth” study (PDAY).
METHODS AND RESULTS
A comprehensive survey of common POSTN variants (87 SNPs) in PDAY subjects (n=2,527) identified numerous SNPs associated with raised lesions in abdominal aorta, and with fatty streaks in thoracic aorta. These SNPs belonged to a small number of correlation bins that spanned the entire locus. To examine effects of rare variants, we resequenced POSTN functional regions in PDAY cases with raised lesions (n=291) and controls with no raised lesions (n=294). However, we found no significant associations with case-control status for carriers of POSTN rare variants using the Weighted Sum Method for rare variant analysis.
CONCLUSION
We identified common variants in POSTN that are associated with arterial lesions in young persons from the PDAY study. This finding strongly supports a role for periostin in atherogenesis, as suggested by recent proteomics analysis that found abundant expression of periostin in atherosclerotic lesions. Genetic variation may influence atherosclerosis via periostin’s known involvement in multiple relevant pathways including angiogenesis, vascular remodeling, and stimulation of migration and differentiation of vascular smooth muscle cells.
doi:10.1161/ATVBAHA.111.224352
PMCID: PMC3116984
PMID: 21474826
Reyes-Rodríguez, Mae Lynn | Von Holle, Ann | Ulman, T. Frances | Thornton, Laura M. | Klump, Kelly L. | Brandt, Harry | Crawford, Steve | Fichter, Manfred M. | Halmi, Katherine A. | Huber, Thomas | Johnson, Craig | Jones, Ian | Kaplan, Allan S. | Mitchell, James E. | Strober, Michael | Treasure, Janet | Woodside, D. Blake | Berrettini, Wade H. | Kaye, Walter H. | Bulik, Cynthia M.
Objective
Comorbidity among eating disorders, traumatic events, and post traumatic stress disorder (PTSD) has been reported in several studies. The main objectives of this study were to describe the nature of traumatic events experienced and to explore the relation between PTSD and anorexia nervosa (AN) in a sample of women.
Methods
Eight hundred twenty-four participants from the National Institutes of Health funded Genetics of Anorexia Nervosa Collaborative Study were assessed for eating disorders, PTSD, and personality characteristics.
Results
From a final sample of 753 women with AN, 13.7% (n=103) met DSM-IV criteria for PTSD. The sample mean age was 29.5 years (SD=11.1). In pairwise comparisons across AN subtypes, the odds of having a PTSD diagnosis were significantly lower in individuals with restricting AN (RAN) than individuals with purging AN without binge eating (PAN) (OR=0.49, 95% CI=0.30, 0.80). The majority of participants with PTSD reported the first traumatic event before the onset of AN (64.1%, n=66). The most common traumatic events reported by those with a PTSD diagnosis were sexual related traumas during childhood (40.8%) and during adulthood (35.0%).
Conclusions
AN and PTSD do co-occur and traumatic events tend to occur prior to the onset of AN. Clinically, these results underscore the importance of assessing trauma history and PTSD in individuals with AN and raise the question of whether specific modifications or augmentations to standard treatment for AN should be considered in a subgroup to address PTSD-related psychopathology.
doi:10.1097/PSY.0b013e31822232bb
PMCID: PMC3132652
PMID: 21715295
PTSD; anorexia nervosa; trauma; prevalence; comorbid; epigenetic
Porcine reproductive and respiratory syndrome virus (PRRSV) is an arterivirus that emerged in the late 1980s in both Europe and North America as the causative agent of porcine reproductive and respiratory syndrome (PRRS), now the most important disease of swine worldwide. Despite extensive characterization of PRRSV proteins by direct analysis and comparison with other arteriviruses, determinants of virulence, pathogenesis and protective immune recognition remain poorly understood. Thus, we hypothesized that additional ORFs are present in the PRRSV genome that may contribute to its biological properties, and so we screened highly purified virions of strain VR2332, the prototype type 2 PRRSV, for evidence of novel polypeptides. A 51 aa polypeptide was discovered that is encoded by an alternative ORF of the subgenomic mRNA encoding the major envelope glycoprotein, GP5, and which is incorporated into virions. The protein, referred to as ORF5a protein, is expressed in infected cells, and pigs infected with PRRSV express anti-ORF5a protein antibodies. A similar ORF is present as an alternative reading frame in all PRRSV subgenomic RNA5 genes and in all other arteriviruses, suggesting that this ORF5a protein plays a significant role in arterivirology. Its discovery also provides a new potential target for immunological and pharmacological intervention in PRRS.
doi:10.1099/vir.0.030213-0
PMCID: PMC3139420
PMID: 21307222
Root, Tammy L. | Szatkiewicz, Jin P. | Jonassaint, Charles R. | Thornton, Laura M. | Pinheiro, Andrea Poyastro | Strober, Michael | Bloss, Cinnamon | Berrettini, Wade | Schork, Nicholas J. | Kaye, Walter H. | Bergen, Andrew W. | Magistretti, Pierre | Brandt, Harry | Crawford, Steve | Crow, Scott | Fichter, Manfred M. | Goldman, David | Halmi, Katherine A. | Johnson, Craig | Kaplan, Allan S. | Keel, Pamela K. | Klump, Kelly L. | La Via, Maria | Mitchell, James E. | Rotondo, Alessandro | Treasure, Janet | Woodside, D. Blake | Bulik, Cynthia M.
This analysis is a follow-up to an earlier investigation of 182 genes selected as likely candidate genetic variations conferring susceptibility to anorexia nervosa (AN). As those initial case-control results revealed no statistically significant differences in single nucleotide polymorphisms, herein we investigate alternative phenotypes associated with AN. In 1762 females using regression analyses we examined: (1) lowest illness-related attained body mass index; (2) age at menarche; (3) drive for thinness; (4) body dissatisfaction; (5) trait anxiety; (6) concern over mistakes; and (7) the anticipatory worry and pessimism vs. uninhibited optimism subscale of the harm avoidance scale. After controlling for multiple comparisons, no statistically significant results emerged. Although results must be viewed in the context of limitations of statistical power, the approach illustrates a means of potentially identifying genetic variants conferring susceptibility to AN because less complex phenotypes associated with AN are more proximal to the genotype and may be influenced by fewer genes.
doi:10.1002/erv.1138
PMCID: PMC3261131
PMID: 21780254
covariates; eating disorders; association studies; personality; genetic
Ventetuolo, Corey E. | Ouyang, Pamela | Bluemke, David A. | Tandri, Harikrishna | Barr, R. Graham | Bagiella, Emilia | Cappola, Anne R. | Bristow, Michael R. | Johnson, Craig | Kronmal, Richard A. | Kizer, Jorge R. | Lima, Joao A. C. | Kawut, Steven M.
Rationale: Sex hormones have effects on the left ventricle, but hormonal influences on the right ventricle (RV) are unknown.
Objectives: We hypothesized that sex hormones would be associated with RV morphology in a large cohort free of cardiovascular disease.
Methods: Sex hormones were measured by immunoassay and RV ejection fraction (RVEF), stroke volume (RVSV), mass, end-diastolic volume, and end-systolic volume (RVESV) were measured by cardiac magnetic resonance imaging in 1,957 men and 1,738 postmenopausal women. The relationship between each hormone and RV parameter was assessed by multivariate linear regression.
Measurements and Main Results: Higher estradiol levels were associated with higher RVEF (β per 1 ln[nmol/L], 0.88; 95% confidence interval [CI], 0.32 to 1.43; P = 0.002) and lower RVESV (β per 1 ln[nmol/L], −0.87; 95% CI, −1.67 to −0.08; P = 0.03) in women using hormone therapy. In men, higher bioavailable testosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.97; 95% CI, 0.20 to 3.73; P = 0.03) and greater RV mass and volumes (P ≤ 0.01). Higher dehydroepiandrosterone levels were associated with higher RVSV (β per 1 ln[nmol/L], 1.37; 95% CI, 0.15 to 2.59; P = 0.03) and greater RV mass (β per 1 ln[nmol/L], 0.25; 95% CI, 0.00 to 0.49; P = 0.05) and volumes (P ≤ 0.001) in women.
Conclusions: Higher estradiol levels were associated with better RV systolic function in women using hormone therapy. Higher levels of androgens were associated with greater RV mass and volumes in both sexes.
doi:10.1164/rccm.201007-1027OC
PMCID: PMC3081282
PMID: 20889903
sex; sex hormones; right ventricle
Kawel, Nadine | Nacif, Marcelo | Arai, Andrew E | Gomes, Antoinette S | Hundley, William | Johnson, Craig | Prince, Martin R | Stacey, Brandon | Lima, Joao A | Bluemke, David A
doi:10.1186/1532-429X-14-S1-O86
PMCID: PMC3304787
Background
Prenatal tobacco exposure is a risk factor for the development of externalizing behaviors and is associated with several adverse health outcomes. Because pregnancy smoking is a complex behavior with both daily fluctuations and changes over the course of pregnancy, quantifying tobacco exposure is a significant challenge. To better measure the degree of tobacco exposure, costly biological specimens and repeated self-report measures of smoking typically are collected throughout pregnancy. With such designs, there are multiple, and substantially correlated, indices that can be integrated via new statistical methods to identify patterns of prenatal exposure.
Method
A multiple-imputation-based fuzzy clustering technique was designed to characterize topography of prenatal exposure. This method leveraged all repeatedly measured maternal smoking variables in our sample data, including (a) cigarette brand; (b) Fagerstrom nicotine dependence item scores; (c) self-reported smoking; and (d) cotinine level in maternal urine and infant meconium samples. Identified exposure groups then were confirmed using a suite of clustering validation indices based on multiple imputed datasets. The classifications were validated against irritable reactivity in the first month of life and birth weight of 361 neonates (Male_n = 185; Female_n = 176; Gestational Age_Mean = 39 weeks).
Results
This proposed approach identified three exposure groups, non-exposed, lighter-tobacco-exposed, and heavier-tobacco-exposed based on high-dimensional attributes. Unlike cutoff score derived groups, these groupings reflect complex smoking behavior and individual variation of nicotine metabolism across pregnancy. The identified groups predicted differences in birth weight and in the pattern of change in neonatal irritable reactivity, as well as resulted in increased predictive power. Multiple-imputation based fuzzy clustering appears to be a useful method to categorize patterns of exposure and their impact on outcomes.
doi:10.1016/j.ntt.2010.08.003
PMCID: PMC3052936
PMID: 21256430
Prenatal tobacco exposure; fuzzy clustering; multiple imputation; exposure pattern; irritable reactivity
Smoking during pregnancy is a persistent public health problem that has been linked to later adverse outcomes. The neonatal period, the first month of life, carries substantial developmental change in regulatory skills, and is the period when tobacco metabolites are cleared physiologically. Studies to date mostly have used cross-sectional designs that limit characterizing potential impacts of prenatal tobacco exposure on the development of key self-regulatory processes and cannot disentangle short-term withdrawal effects from residual exposure-related impacts. In this study, pregnant participants (N = 304) were recruited prospectively during pregnancy and smoking was measured at multiple time points, using both self report and biochemical measures. Neonatal attention, irritable reactivity, and stress dysregulation were examined longitudinally at three time points during the first month of life, and physical growth indices were measured at birth. Tobacco-exposed infants showed significantly poorer attention skills after birth, and the magnitude of the difference between exposed and non-exposed groups attenuated across the neonatal period. In contrast, exposure-related differences in irritable reactivity were not evident and stable across the first month of life, but differed only marginally at 4-weeks of age. Third trimester smoking was associated with pervasive, deleterious, dose-response impacts on physical growth measured at birth, whereas nearly all smoking indicators throughout pregnancy predicted level and growth rates of early attention. The observed neonatal pattern is consistent with the neurobiology of tobacco on the developing nervous system and fits with developmental vulnerabilities observed later in life.
doi:10.1037/a0020724
PMCID: PMC3057676
PMID: 21038943
Prenatal Tobacco Exposure; Self-Regulation; Longitudinal Modeling
Jonassaint, Charles R. | Szatkiewicz, Jin Peng | Bulik, Cynthia M. | Thornton, Laura M. | Bloss, Cinnamon | Berrettini, Wade | Kaye, Walter H. | Bergen, Andrew W. | Magistretti, Pierre | Strober, Michael | Keel, Pamela K. | Brandt, Harry | Crawford, Steve | Crow, Scott | Fichter, Manfred M. | Goldman, David | Halmi, Katherine A. | Johnson, Craig | Kaplan, Allan S. | Klump, Kelly L. | La Via, Maria | Mitchell, James | Rotondo, Alessandro | Treasure, Janet | Woodside, D. Blake
Extensive population-based genome-wide association studies have identified an association between the FTO gene and BMI; however, the mechanism of action is still unknown. To determine whether FTO may influence weight regulation through psychological and behavioral factors, seven single nucleotide polymorphisms (SNPs) of the FTO gene were genotyped in 1085 individuals with anorexia nervosa (AN) and 677 healthy weight controls from the international Price Foundation Genetic Studies of Eating Disorders. Each SNP was tested in association with eating disorder phenotypes and measures that have previously been associated with eating behavior pathology: trait anxiety, harm-avoidance, novelty seeking, impulsivity, obsessionality, compulsivity, and concern over mistakes. After appropriate correction for multiple comparisons, no significant associations between individual FTO gene SNPs and eating disorder phenotypes or related eating behavior pathology were identified in cases or controls. Thus, this study found no evidence that FTO gene variants associated with weight regulation in the general population are associated with eating disorder phenotypes in AN participants or matched controls.
doi:10.1002/ajmg.b.31182
PMCID: PMC3249222
PMID: 21438147
Introduction:
Despite efforts to control for confounding variables using stringent sampling plans, selection bias typically exists in observational studies, resulting in unbalanced comparison groups. Ignoring selection bias can result in unreliable or misleading estimates of the causal effect.
Methods:
Generalized boosted models were used to estimate propensity scores from 42 confounding variables for a sample of 361 neonates. Using emergent neonatal attention and orientation skills as an example developmental outcome, we examined the impact of tobacco exposure with and without accounting for selection bias. Weight at birth, an outcome related to tobacco exposure, also was used to examine the functionality of the propensity score approach.
Results:
Without inclusion of propensity scores, tobacco-exposed neonates did not differ from their nonexposed peers in attention skills over the first month or in weight at birth. When the propensity score was included as a covariate, exposed infants had marginally lower attention and a slower linear change rate at 4 weeks, with greater quadratic deceleration over the first month. Similarly, exposure-related differences in birth weight emerged when propensity scores were included as a covariate.
Conclusions:
The propensity score method captured the selection bias intrinsic to this observational study of prenatal tobacco exposure. Selection bias obscured the deleterious impact of tobacco exposure on the development of neonatal attention. The illustrated analytic strategy offers an example to better characterize the impact of prenatal tobacco exposure on important developmental outcomes by directly modeling and statistically accounting for the selection bias from the sampling process.
doi:10.1093/ntr/ntq170
PMCID: PMC2991623
PMID: 21030468
N'Diaye, Amidou | Chen, Gary K. | Palmer, Cameron D. | Ge, Bing | Tayo, Bamidele | Mathias, Rasika A. | Ding, Jingzhong | Nalls, Michael A. | Adeyemo, Adebowale | Adoue, Véronique | Ambrosone, Christine B. | Atwood, Larry | Bandera, Elisa V. | Becker, Lewis C. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Boerwinkle, Eric | Britton, Angela | Casey, Graham | Chanock, Stephen J. | Demerath, Ellen | Deming, Sandra L. | Diver, W. Ryan | Fox, Caroline | Harris, Tamara B. | Hernandez, Dena G. | Hu, Jennifer J. | Ingles, Sue A. | John, Esther M. | Johnson, Craig | Keating, Brendan | Kittles, Rick A. | Kolonel, Laurence N. | Kritchevsky, Stephen B. | Le Marchand, Loic | Lohman, Kurt | Liu, Jiankang | Millikan, Robert C. | Murphy, Adam | Musani, Solomon | Neslund-Dudas, Christine | North, Kari E. | Nyante, Sarah | Ogunniyi, Adesola | Ostrander, Elaine A. | Papanicolaou, George | Patel, Sanjay | Pettaway, Curtis A. | Press, Michael F. | Redline, Susan | Rodriguez-Gil, Jorge L. | Rotimi, Charles | Rybicki, Benjamin A. | Salako, Babatunde | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Stram, Alex H. | Stram, Daniel O. | Strom, Sara S. | Suktitipat, Bhoom | Thun, Michael J. | Witte, John S. | Yanek, Lisa R. | Ziegler, Regina G. | Zheng, Wei | Zhu, Xiaofeng | Zmuda, Joseph M. | Zonderman, Alan B. | Evans, Michele K. | Liu, Yongmei | Becker, Diane M. | Cooper, Richard S. | Pastinen, Tomi | Henderson, Brian E. | Hirschhorn, Joel N. | Lettre, Guillaume | Haiman, Christopher A.
PLoS Genetics
2011;7(11):10.1371/annotation/58c67154-3f10-4155-9085-dcd6e3689008.
doi:10.1371/annotation/58c67154-3f10-4155-9085-dcd6e3689008
PMCID: PMC3227698
N'Diaye, Amidou | Chen, Gary K. | Palmer, Cameron D. | Ge, Bing | Tayo, Bamidele | Mathias, Rasika A. | Ding, Jingzhong | Nalls, Michael A. | Adeyemo, Adebowale | Adoue, Véronique | Ambrosone, Christine B. | Atwood, Larry | Bandera, Elisa V. | Becker, Lewis C. | Berndt, Sonja I. | Bernstein, Leslie | Blot, William J. | Boerwinkle, Eric | Britton, Angela | Casey, Graham | Chanock, Stephen J. | Demerath, Ellen | Deming, Sandra L. | Diver, W. Ryan | Fox, Caroline | Harris, Tamara B. | Hernandez, Dena G. | Hu, Jennifer J. | Ingles, Sue A. | John, Esther M. | Johnson, Craig | Keating, Brendan | Kittles, Rick A. | Kolonel, Laurence N. | Kritchevsky, Stephen B. | Le Marchand, Loic | Lohman, Kurt | Liu, Jiankang | Millikan, Robert C. | Murphy, Adam | Musani, Solomon | Neslund-Dudas, Christine | North, Kari E. | Nyante, Sarah | Ogunniyi, Adesola | Ostrander, Elaine A. | Papanicolaou, George | Patel, Sanjay | Pettaway, Curtis A. | Press, Michael F. | Redline, Susan | Rodriguez-Gil, Jorge L. | Rotimi, Charles | Rybicki, Benjamin A. | Salako, Babatunde | Schreiner, Pamela J. | Signorello, Lisa B. | Singleton, Andrew B. | Stanford, Janet L. | Stram, Alex H. | Stram, Daniel O. | Strom, Sara S. | Suktitipat, Bhoom | Thun, Michael J. | Witte, John S. | Yanek, Lisa R. | Ziegler, Regina G. | Zheng, Wei | Zhu, Xiaofeng | Zmuda, Joseph M. | Zonderman, Alan B. | Evans, Michele K. | Liu, Yongmei | Becker, Diane M. | Cooper, Richard S. | Pastinen, Tomi | Henderson, Brian E. | Hirschhorn, Joel N. | Lettre, Guillaume | Haiman, Christopher A. | Visscher, Peter M.
Adult height is a classic polygenic trait of high heritability (h2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits.
Author Summary
Adult height is an ideal phenotype to improve our understanding of the genetic architecture of complex diseases and traits: it is easily measured and usually available in large cohorts, relatively stable, and mostly influenced by genetics (narrow-sense heritability of height h2∼0.8). Genome-wide association (GWA) studies in individuals of European ancestry have identified >180 single nucleotide polymorphisms (SNPs) associated with height. In the current study, we continued to use height as a model polygenic trait and explored the genetic influence in populations of African ancestry through a meta-analysis of GWA height results from 20,809 individuals of African descent. We identified two novel height loci not previously found in Europeans. We also replicated the European height signals, suggesting that many of the genetic variants that are associated with height are shared between individuals of European and African descent. Finally, in fine-mapping the European height loci in African-ancestry individuals, we found SNPs more likely to be associated with the expression of nearby genes than the SNPs originally found in Europeans. Thus, our results support the utility of performing genetic studies in non-European populations to gain insights into complex human diseases and traits.
doi:10.1371/journal.pgen.1002298
PMCID: PMC3188544
PMID: 21998595
Maxwell, Millie | Thornton, Laura M. | Root, Tammy L. | Pinheiro, Andrea Poyastro | Strober, Michael | Brandt, Harry | Crawford, Steve | Crow, Scott | Fichter, Manfred M. | Halmi, Katherine A. | Johnson, Craig | Kaplan, Allan S. | Keel, Pamela | Klump, Kelly L. | LaVia, Maria | Mitchell, James E. | Plotnicov, Kathy | Rotondo, Alessandro | Woodside, D. Blake | Berrettini, Wade H. | Kaye, Walter H. | Bulik, Cynthia M.
Objective
We investigated sociodemographic characteristics in women with and without lifetime eating disorders.
Method
Participants were from a multi-site international study of eating disorders (N = 2096). Education level, relationship status, and reproductive status were examined across eating disorder subtypes and compared with a healthy control group.
Results
Overall, women with eating disorders were less educated than controls, and duration of illness and age of onset were associated with educational attainment. Menstrual status was associated with both relationship and reproductive status, but eating disorder subtypes did not differ significantly from each other or from healthy controls on these dimensions.
Conclusion
Differences in educational attainment, relationships, and reproduction do exist in individuals with eating disorders and are differentially associated with various eating disorder symptoms and characteristics. These data could assist with educating patients and family members about long-term consequences of eating disorders.
doi:10.1002/eat.20804
PMCID: PMC2888627
PMID: 20143323
Children; relationship; education; anorexia nervosa; bulimia nervosa; amenorrhea
The impact of cardiovascular risk factors on the left ventricle is well known but their impact on right ventricle has not been studied using advanced imaging techniques. The purpose of this study was to determine the relation between cardiovascular risk factors and right ventricular (RV) structure and function and its interaction with the left ventricle. Cardiac magnetic resonance images were analyzed in 4204 participants free of clinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression models were used to study the cross sectional association between individual RV parameters and risk factors. All RV parameters except ejection fraction decreased with age (p<0.0001). RV mass was positively associated with systolic blood pressure (+0.4g, p<0.0001) and high density lipoprotein (HDL) cholesterol (+0.2g, p<0.0001); inversely with diastolic blood pressure (−0.3g, p<0.0001) and total cholesterol (−0.2g, p<0.01). RV end diastolic volume was positively associated with systolic blood pressure (+1.6ml, p<0.01) and HDL cholesterol (+1.8ml, p<0.0001); and inversely with diastolic blood pressure (−2.2 ml, p<0.0001), total cholesterol (−1.4ml, p<0.0001), current smoking (−2.7ml, p<0.05) and diabetes mellitus (−3.1ml, p<0.01). RV ejection fraction was positively related with systolic blood pressure (+1.0%, p<0.0001), HDL cholesterol (+0.4%, p<0.0001) and inversely with diastolic blood pressure (−0.7%, p<0.0001). In conclusion, the mass and volumes of the right ventricle decrease with age. Cardiovascular risk factors, especially blood pressure and HDL cholesterol are associated with subclinical changes in RV mass and volumes.
doi:10.1016/j.amjcard.2010.02.022
PMCID: PMC2901248
PMID: 20609657
Huang, Chiang-Ching | Liu, Kiang | Pope, Richard M. | Du, Pan | Lin, Simon | Rajamannan, Nalini M. | Huang, Qi-Quan | Jafari, Nadereh | Burke, Gregory L. | Post, Wendy | E.Watson, Karol | Johnson, Craig | Daviglus, Martha L. | Lloyd-Jones, Donald M. | Ahuja, Sunil K.
Background
Atherosclerosis is the leading cause of cardiovascular disease (CVD). Traditional risk factors can be used to identify individuals at high risk for developing CVD and are generally associated with the extent of atherosclerosis; however, substantial numbers of individuals at low or intermediate risk still develop atherosclerosis.
Results
A case-control study was performed using microarray gene expression profiling of peripheral blood from 119 healthy women in the Multi-Ethnic Study of Atherosclerosis cohort aged 50 or above. All participants had low (<10%) to intermediate (10% to 20%) predicted Framingham risk; cases (N = 48) had coronary artery calcium (CAC) score >100 and carotid intima-media thickness (IMT) >1.0 mm, whereas controls (N = 71) had CAC<10 and IMT <0.65 mm. We identified two major expression profiles significantly associated with significant atherosclerosis (odds ratio 4.85; P<0.001); among those with Framingham risk score <10%, the odds ratio was 5.30 (P<0.001). Ontology analysis of the gene signature reveals activation of a major innate immune pathway, toll-like receptors and IL-1R signaling, in individuals with significant atherosclerosis.
Conclusion
Gene expression profiles of peripheral blood may be a useful tool to identify individuals with significant burden of atherosclerosis, even among those with low predicted risk by clinical factors. Furthermore, our data suggest an intimate connection between atherosclerosis and the innate immune system and inflammation via TLR signaling in lower risk individuals.
doi:10.1371/journal.pone.0021067
PMCID: PMC3116882
PMID: 21698167
Background
Our objective was to analyze subjective explanations for unsuccessful weight loss among bariatric surgery candidates.
Methods
This was a retrospective analysis of 909 bariatric surgery candidates (78.2% female, average body mass index [BMI] 47.3) at a university center from 2001 to April 2007 who answered an open-ended question about why they were unable to lose weight. We generated a coding scheme for answers to the question and established inter-rater reliability of the coding process. Associations with demographic parameters and initial BMI were tested.
Results
The most common categories of answers were nonspecific explanations related to diet (25.3%), physical activity (21.0%), or motivation (19.7%), followed by diet-related motivation (12.7%) and medical conditions or medications affecting physical activity (12.7%). Categories related to time, financial cost, social support, physical environment, and knowledge occurred in less than 4% each. Men were more likely than women to cite a medical condition or medication affecting physical activity (19.2% vs 10.8%, P=0.002, odds ratio [OR]=1.96, 95% confidence interval [CI]=1.28–2.99) but less likely to cite diet-related motivation (7.1% vs 14.2%, P=0.008, OR=0.46, 95% CI=0.26–0.82).
Conclusions
Our findings suggest that addressing diet, physical activity, and motivation in a comprehensive approach would meet the stated needs of obese patients. Raising patient awareness of under-recognized barriers to weight loss, such as the physical environment and lack of social support, should also be considered. Lastly, anticipating gender-specific attributions may facilitate tailoring of interventions.
doi:10.1007/s11695-008-9573-0
PMCID: PMC3063089
PMID: 18542846
Morbid obesity; Bariatric surgery; Barriers
BACKGROUND
Obstructive sleep apnea is underdiagnosed. We conducted a pilot randomized controlled trial of an online intervention to promote obstructive sleep apnea screening among members of an Internet weight-loss community.
METHODS
Members of an Internet weight-loss community who have never been diagnosed with obstructive sleep apnea or discussed the condition with their healthcare provider were randomized to intervention (online risk assessment +feedback) or control. The primary outcome was discussing obstructive sleep apnea with a healthcare provider at 12 weeks.
RESULTS
Of 4700 members who were sent e-mail study announcements, 168 (97% were female, age 39.5 years [standard deviation 11.7], body mass index 30.3 [standard deviation 7.8]) were randomized to intervention (n = 84) or control (n = 84). Of 82 intervention subjects who completed the risk assessment, 50 (61%) were low risk and 32 (39%) were high risk for obstructive sleep apnea. Intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider within 12 weeks (11% [9/84] vs 2% [2/84]; P = .02; relative risk = 4.50; 95% confidence interval, 1.002–20.21). The number needed to treat was 12. High-risk intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider (19% [6/32] vs 2% [2/84]; P = .004; relative risk = 7.88; 95% confidence interval, 1.68–37.02). One high-risk intervention subject started treatment for obstructive sleep apnea.
CONCLUSION
An online screening intervention is feasible and likely effective in encouraging members of an Internet weight-loss community to discuss obstructive sleep apnea with their healthcare provider.
doi:10.1016/j.amjmed.2009.03.031
PMCID: PMC3063127
PMID: 19786163
Internet; Obesity; Obstructive sleep apnea; Screening
Ice-core samples from Upper Fremont Glacier (UFG), Wyoming, were used as proxy records for the chemical composition of atmospheric deposition. Results of analysis of the ice-core samples for stable isotopes of nitrogen (δ15N, ) and sulfur (δ34S, ), as well as and deposition rates from the late-1940s thru the early-1990s, were used to enhance and extend existing National Atmospheric Deposition Program/National Trends Network (NADP/NTN) data in western Wyoming. The most enriched δ34S value in the UFG ice-core samples coincided with snow deposited during the 1980 eruption of Mt. St. Helens, Washington. The remaining δ34S values were similar to the isotopic composition of coal from southern Wyoming. The δ15N values in ice-core samples representing a similar period of snow deposition were negative, ranging from -5.9 to -3.2 ‰ and all fall within the δ15N values expected from vehicle emissions. Ice-core nitrate and sulfate deposition data reflect the sharply increasing U.S. emissions data from 1950 to the mid-1970s.
doi:10.1186/1467-4866-12-4
PMCID: PMC3060858
PMID: 21385368
Root, Tammy | Pinheiro, Andréa Poyastro | Thornton, Laura | Strober, Michael | Fernandez-Aranda, Fernando | Brandt, Harry | Crawford, Steve | Fichter, Manfred M. | Halmi, Katherine A. | Johnson, Craig | Kaplan, Allan S. | Klump, Kelly L. | La Via, Maria | Mitchell, James | Woodside, D. Blake | Rotondo, Alessandro | Berrettini, Wade H. | Kaye, Walter H. | Bulik, Cynthia M.
Objective
We examined prevalence of substance use disorders (SUD) in women with: (1) anorexia nervosa (AN) restricting type (RAN); (2) AN with purging only (PAN); (3) AN with binge eating only (BAN); and (4) lifetime AN and bulimia nervosa (ANBN). Secondary analyses examined SUD related to lifetime purging behavior and lifetime binge eating.
Method
Participants (N = 731) were drawn from the International Price Foundation Genetic Studies.
Results
The prevalence of SUD differed across AN subtypes, with more in the ANBN group reporting SUD than those in the RAN and PAN groups. Individuals who purged were more likely to report substance use than those who did not purge. Prevalence of SUD differed across lifetime binge eating status.
Conclusion
SUD are common in AN and are associated with bulimic symptomatology. Results underscore the heterogeneity in AN, highlighting the importance of screening for SUD across AN subtypes.
doi:10.1002/eat.20670
PMCID: PMC2807480
PMID: 19260043
eating disorders; anorexia nervosa; bulimia nervosa; drug use; alcohol related disorders; cannabis