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1.  A benchmark comparison of deterministic and probabilistic methods for defining manual review datasets in duplicate records reconciliation 
Clinical databases require accurate entity resolution (ER). One approach is to use algorithms that assign questionable cases to manual review. Few studies have compared the performance of common algorithms for such a task. Furthermore, previous work has been limited by a lack of objective methods for setting algorithm parameters. We compared the performance of common ER algorithms: using algorithmic optimization, rather than manual parameter tuning, and on two-threshold classification (match/manual review/non-match) as well as single-threshold (match/non-match).
We manually reviewed 20 000 randomly selected, potential duplicate record-pairs to identify matches (10 000 training set, 10 000 test set). We evaluated the probabilistic expectation maximization, simple deterministic and fuzzy inference engine (FIE) algorithms. We used particle swarm to optimize algorithm parameters for a single and for two thresholds. We ran 10 iterations of optimization using the training set and report averaged performance against the test set.
The overall estimated duplicate rate was 6%. FIE and simple deterministic algorithms allowed a lower manual review set compared to the probabilistic method (FIE 1.9%, simple deterministic 2.5%, probabilistic 3.6%; p<0.001). For a single threshold, the simple deterministic algorithm performed better than the probabilistic method (positive predictive value 0.956 vs 0.887, sensitivity 0.985 vs 0.887, p<0.001). ER with FIE classifies 98.1% of record-pairs correctly (1/10 000 error rate), assigning the remainder to manual review.
Optimized deterministic algorithms outperform the probabilistic method. There is a strong case for considering optimized deterministic methods for ER.
PMCID: PMC3912727  PMID: 23703827
Medical Records Systems, Computerized [L01.700.508.300.695]; Medical Record Linkage [N04.452.859.564.550]
2.  Primary Amenorrhea in Anorexia Nervosa: Impact on Characteristic Masculine and Feminine Traits 
Animal studies indicate gonadal hormones at puberty have an effect on the development of masculine and feminine traits. However, it is unknown whether similar processes occur in humans. We examined whether women with anorexia nervosa (AN), who often experience primary amenorrhea, exhibit attenuated feminization in their psychological characteristics in adulthood due to the decrease/absence of gonadal hormones at puberty. Women with AN were compared on a number of psychological characteristics using General Linear Models based on the presence/absence of primary amenorrhea. Although women with primary amenorrhea exhibited lower anxiety scores than those without primary amenorrhea, in general, results did not provide evidence of attenuated feminization in women with AN with primary amenorrhea. Future research should utilize novel techniques and direct hormone measurement to explore the effects of pubertal gonadal hormones on masculine and feminine traits.
PMCID: PMC4266542  PMID: 24123541
Organizational effects; sex differences; amenorrhea; pubertal timing; anorexia nervosa
3.  Purifying selection in Porcine reproductive and respiratory syndrome virus ORF5a protein influences variation in envelope glycoprotein 5 glycosylation 
Porcine Reproductive and Respiratory Syndrome Virus ORF5a protein is encoded in an alternate open reading frame upstream of the major envelope glycoprotein (GP5) in subgenomic mRNA5. Bioinformatic analysis of 3,466 Type 2 PRRSV sequences showed that the two proteins have co-evolved through a fine balance of purifying codon usage to maintain a conserved RQ-rich motif in ORF5a protein, while eliciting a variable N-linked glycosylation motif in the alternative GP5 reading frame. Conservation of the ORF5a protein RQ-motif also explains an anomalous uracil desert in GP5 hypervariable glycosylation region. The N-terminus of the mature GP5 protein was confirmed to start with amino acid 32, the hypervariable region of the ectodomain. Since GP5 glycosylation variability is assumed to result from immunological selection against neutralizing antibodies, these findings show that an alternative possibility unrelated to immunological selection not only exists, but provides a foundation for investigating previously unsuspected aspects of PRRSV biology. Understanding functional consequences of subtle nucleotide sequence modifications in the region responsible for critical function in ORF5a protein and GP5 glycosylation is essential for rational design of new vaccines against PRRS.
PMCID: PMC3875317  PMID: 24084290
natural selection; evolution; PRRSV
4.  Factors Associated With Recovery from Anorexia Nervosa 
Journal of psychiatric research  2013;47(7):972-979.
Previous studies of prognostic factors of anorexia nervosa (AN) course and recovery have followed clinical populations after treatment discharge. This retrospective study examined the association between prognostic factors—eating disorder features, personality traits, and psychiatric comorbidity—and likelihood of recovery in a large sample of women with AN participating in a multi-site genetic study. The study included 680 women with AN. Recovery was defined as the offset of AN symptoms if the participant experienced at least one year without any eating disorder symptoms of low weight, dieting, binge eating, and inappropriate compensatory behaviors. Participants completed a structured interview about eating disorders features, psychiatric comorbidity, and self-report measures of personality. Survival analysis was applied to model time to recovery from AN. Cox regression models were used to fit associations between predictors and the probability of recovery. In the final model, likelihood of recovery was significantly predicted by the following prognostic factors: vomiting, impulsivity, and trait anxiety. Self-induced vomiting and greater trait anxiety were negative prognostic factors and predicted lower likelihood of recovery. Greater impulsivity was a positive prognostic factor and predicted greater likelihood of recovery. There was a significant interaction between impulsivity and time; the association between impulsivity and likelihood of recovery decreased as duration of AN increased. The anxiolytic function of some AN behaviors may impede recovery for individuals with greater trait anxiety.
PMCID: PMC3682792  PMID: 23535032
Eating disorders; anorexia nervosa; recovery; prognostic factors; personality; comorbidity
5.  Age and sex affect protein metabolism at protein intakes that span the range of adequacy: comparison of leucine kinetics and nitrogen balance data☆ 
The Journal of nutritional biochemistry  2012;24(4):10.1016/j.jnutbio.2012.03.021.
Research suggests that changes in leucine oxidation (leuox) with feeding may reflect adult protein requirements. We evaluated this possibility by assessing the effects of age, sex, and different protein intakes on whole-body leucine kinetics and nitrogen balance. Thirty-four young (n = 18, 22–46 years) and old (n= 16, 63–81 years) men and women completed three 18-day trials with protein intakes of 0.50, 0.75 and 1.00 g protein·kg body weight−1·d−1. Fasting and fed-state leucine kinetics were quantified on day 12 of each trial using a primed, constant infusion of L-[1-13C]leucine. Protein requirement was estimated using classical nitrogen balance measurements and calculations. Leucine kinetics parameters were influenced by age and sex across all protein intakes. With feeding, leuox increased more in old vs. young adults. Independent of age, fasting and fed-state leuox were lower, and net leucine balance (fasting+fed-state) was higher in women vs. men. Among all subjects and protein intakes, nitrogen balance was correlated with fed-state leuox (r=0.39), fed-state leucine balance (r=0.60), net leucine balance (r=0.49) and the change in leuox from the fasting to fed state (r=0.49) (P<.05 for all results). At the highest protein intake, the change in leuox with feeding was inversely correlated with protein requirement (r=−0.39). These findings indicate that leucine kinetics, especially leuox, reflect nitrogen balance-based estimates of the need for dietary protein and generally support the view that protein requirement is comparable between young and old adults.
PMCID: PMC3885868  PMID: 22841544
Dietary protein; Protein adequacy; Protein metabolism
6.  Temporal Sequence of Comorbid Alcohol Use Disorder and Anorexia Nervosa 
Addictive behaviors  2012;38(3):1704-1709.
Women with eating disorders have a significantly higher prevalence of substance use disorders than the general population. The goal of the current study was to assess the temporal pattern of comorbid anorexia nervosa (AN) and alcohol use disorder (AUD) and the impact this ordering has on symptomatology and associated features. Women were placed into one of three groups based on the presence or absence of comorbid AUD and the order of AN and AUD onset in those with both disorders: (1) AN Only, (2) AN First, and (3) AUD First. The groups were compared on psychological symptoms and personality characteristics often associated with AN, AUD, or both using general linear models. Twenty-one percent of women (n = 161) with AN reported a history of AUD with 115 reporting AN onset first and 35 reporting AUD onset first. Women with binge-eating and/or purging type AN were significantly more likely to have AUD. In general, differences were found only between women with AN Only and women with AN and AUD regardless of order of emergence. Women with AN and AUD had higher impulsivity scores and higher prevalence of depression and borderline personality disorder than women with AN Only. Women with AN First scored higher on traits commonly associated with AN, whereas women with comorbid AN and AUD displayed elevations in traits more commonly associated with AUD. Results do not indicate a distinct pattern of symptomatology in comorbid AN and AUD based on the temporal sequence of the disorders.
PMCID: PMC3558554  PMID: 23254222
anorexia nervosa; alcohol use disorder; comorbidity; age of onset
7.  Nutrient Ingestion, Protein Intake, and Sex, but Not Age, Affect the Albumin Synthesis Rate in Humans123 
The Journal of nutrition  2007;137(7):1734-1740.
The aim of this study was to assess the effects of nutrient ingestion, dietary protein intake, age, and sex on the fractional synthesis rate (FSR) of albumin. Thirty-six healthy free-living individuals (8 females and 10 males aged 21–43 y and 9 females and 9 males aged 63–79 y) completed three 18-d periods of controlled feeding with protein intakes of 125% (P125, 1.00 g protein · kg−1 · d−1), 94% (P94, 0.75 g protein · kg−1 · d−1), and 63% (P63, 0.50 g protein · kg−1 · d−1) of the recommended dietary allowance. On d 12 of each trial, postabsorptive (PA) serum albumin concentration was determined and PA and postprandial (PP) albumin FSR were estimated from the rate of L-[1-13C] leucine incorporation into plasma albumin during an 8-h infusion. There were no age-related differences in PA and PP albumin FSR. Albumin FSR was higher PP than PA (P < 0.0001), and the increase in albumin FSR from PA to PP was smaller as dietary protein intake decreased from P125 to P94 and P63 (P < 0.05). Independent of protein intake, males had a higher albumin FSR (P < 0.05) and a greater increase in albumin FSR with feeding (P < 0.05). There was no age or dietary protein effect on serum albumin concentrations, but males had higher albumin concentrations than females (P < 0.0001). These results show that older persons are responsive to nutrient ingestion and dietary protein-related changes in albumin FSR. The greater albumin synthesis rate in males might contribute to a higher albumin concentration set point.
PMCID: PMC3885871  PMID: 17585023
8.  Predictors of Accessing Substance Abuse Services Among Individuals With Mental Disorders Released From Correctional Custody 
Journal of dual diagnosis  2012;9(1):11-22.
In the context of an increasing correctional population and corresponding rates of mental illness and substance abuse among this population, this study focuses on describing the predictors of substance abuse service utilization for ex-inmates with dual disorders. Our aim is to assess the likelihood and characteristics of ex-inmates with mental disorders who access substance abuse treatment services within two years of correctional release.
Using merged administrative data on all ex-inmates with open mental health cases released from Massachusetts Department of Corrections and two County Houses of Corrections from 2007 to 2009 (N=2,280) and substance abuse treatment outcome data through 2011, we analyze the influence of demographics, behavioral and mental disorders, and criminal justice variables on entry into substance abuse treatment within 24 months post release. We also describe primary drug use and services utilized for all the ex-inmates who accessed substance abuse services (N=1,383). Regression techniques were used to analyze the probability of utilizing substance abuse treatment services by various demographic, behavioral, and criminal involvement characteristics.
The prevalence of a history of substance use disorders is high in this population (69%; n = 1,285). Subsequently, at 24 months post release 61% (n = 1,383) of ex-inmates with open mental health cases utilized substance abuse treatment services. This group was disproportionately female, with a preincarceration history of substance abuse, an increased number of previous incarcerations, and more likely released under correctional supervision.
Substance abuse is a chronic relapsing disorder and dual diagnosis is common among individuals with mental disorders involved with the criminal justice system. Their service needs and contacts across substance abuse, mental health, and criminal justice systems highlight individuals caught up in the institutional circuit. Study results point to the need for expanded and targeted dual diagnosis treatment approaches and relapse prevention for ex-inmates with mental disorders post correctional release.
PMCID: PMC3608478  PMID: 23543790
mental illness; mental disorder; substance abuse; criminal justice; dual diagnosis; history of substance abuse services; substance abuse treatment services; ex-inmates
9.  Genetic Analysis of Low BMI Phenotype in the Utah Population Database 
PLoS ONE  2013;8(12):e80287.
The low body mass index (BMI) phenotype of less than 18.5 has been linked to medical and psychological morbidity as well as increased mortality risk. Although genetic factors have been shown to influence BMI across the entire BMI, the contribution of genetic factors to the low BMI phenotype is unclear. We hypothesized genetic factors would contribute to risk of a low BMI phenotype. To test this hypothesis, we conducted a genealogy data analysis using height and weight measurements from driver's license data from the Utah Population Data Base. The Genealogical Index of Familiality (GIF) test and relative risk in relatives were used to examine evidence for excess relatedness among individuals with the low BMI phenotype. The overall GIF test for excess relatedness in the low BMI phenotype showed a significant excess over expected (GIF 4.47 for all cases versus 4.10 for controls, overall empirical p-value<0.001). The significant excess relatedness was still observed when close relationships were ignored, supporting a specific genetic contribution rather than only a family environmental effect. This study supports a specific genetic contribution in the risk for the low BMI phenotype. Better understanding of the genetic contribution to low BMI holds promise for weight regulation and potentially for novel strategies in the treatment of leanness and obesity.
PMCID: PMC3859471  PMID: 24348998
10.  A Novel Intergenic ETnII-β Insertion Mutation Causes Multiple Malformations in Polypodia Mice 
PLoS Genetics  2013;9(12):e1003967.
Mouse early transposon insertions are responsible for ∼10% of spontaneous mutant phenotypes. We previously reported the phenotypes and genetic mapping of Polypodia, (Ppd), a spontaneous, X-linked dominant mutation with profound effects on body plan morphogenesis. Our new data shows that mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. In addition, we refined the Ppd genetic interval and discovered a novel ETnII-β early transposon insertion between the genes for Dusp9 and Pnck. The ETn inserted 1.6 kb downstream and antisense to Dusp9 and does not disrupt polyadenylation or splicing of either gene. Knock-in mice engineered to carry the ETn display Ppd characteristic ectopic caudal limb phenotypes, showing that the ETn insertion is the Ppd molecular lesion. Early transposons are actively expressed in the early blastocyst. To explore the consequences of the ETn on the genomic landscape at an early stage of development, we compared interval gene expression between wild-type and mutant ES cells. Mutant ES cell expression analysis revealed marked upregulation of Dusp9 mRNA and protein expression. Evaluation of the 5′ LTR CpG methylation state in adult mice revealed no correlation with the occurrence or severity of Ppd phenotypes at birth. Thus, the broad range of phenotypes observed in this mutant is secondary to a novel intergenic ETn insertion whose effects include dysregulation of nearby interval gene expression at early stages of development.
Author Summary
Mobile genetic elements, particularly early transposons (ETn), cause malformations by inserting within genes leading to disruption of exons, splicing or polyadenylation. Few mutagenic early transposon insertions have been found outside genes and the effects of such insertions on surrounding gene regulation is poorly understood. We discovered a novel intergenic ETnII-β insertion in the mouse mutant Polypodia (Ppd). We reproduced the mutant phenotype after engineering the mutation in wild-type cells with homologous recombination, proving that this early transposon insertion is Ppd. Mutant mice are not born in expected Mendelian ratios secondary to loss after E9.5. Embryonic stem cells from mutant mice show upregulated transcription of an adjacent gene, Dusp9. Thus, at an early and critical stage of development, dysregulated gene transcription is one consequence of the insertion mutation. DNA methylation of the ETn 5′ LTR is not correlated with phenotypic outcome in mutant mice. Polypodia is an example of an intergenic mobile element insertion in mice causing dramatic morphogenetic defects and fetal death.
PMCID: PMC3854779  PMID: 24339789
11.  Modelling Coral Reef Futures to Inform Management: Can Reducing Local-Scale Stressors Conserve Reefs under Climate Change? 
PLoS ONE  2013;8(11):e80137.
Climate change has emerged as a principal threat to coral reefs, and is expected to exacerbate coral reef degradation caused by more localised stressors. Management of local stressors is widely advocated to bolster coral reef resilience, but the extent to which management of local stressors might affect future trajectories of reef state remains unclear. This is in part because of limited understanding of the cumulative impact of multiple stressors. Models are ideal tools to aid understanding of future reef state under alternative management and climatic scenarios, but to date few have been sufficiently developed to be useful as decision support tools for local management of coral reefs subject to multiple stressors. We used a simulation model of coral reefs to investigate the extent to which the management of local stressors (namely poor water quality and fishing) might influence future reef state under varying climatic scenarios relating to coral bleaching. We parameterised the model for Bolinao, the Philippines, and explored how simulation modelling can be used to provide decision support for local management. We found that management of water quality, and to a lesser extent fishing, can have a significant impact on future reef state, including coral recovery following bleaching-induced mortality. The stressors we examined interacted antagonistically to affect reef state, highlighting the importance of considering the combined impact of multiple stressors rather than considering them individually. Further, by providing explicit guidance for management of Bolinao's reef system, such as which course of management action will most likely to be effective over what time scales and at which sites, we demonstrated the utility of simulation models for supporting management. Aside from providing explicit guidance for management of Bolinao's reef system, our study offers insights which could inform reef management more broadly, as well as general understanding of reef systems.
PMCID: PMC3832406  PMID: 24260347
12.  Optimized Dual Threshold Entity Resolution For Electronic Health Record Databases – Training Set Size And Active Learning 
Clinical databases may contain several records for a single patient. Multiple general entity-resolution algorithms have been developed to identify such duplicate records. To achieve optimal accuracy, algorithm parameters must be tuned to a particular dataset. The purpose of this study was to determine the required training set size for probabilistic, deterministic and Fuzzy Inference Engine (FIE) algorithms with parameters optimized using the particle swarm approach. Each algorithm classified potential duplicates into: definite match, non-match and indeterminate (i.e., requires manual review). Training sets size ranged from 2,000–10,000 randomly selected record-pairs. We also evaluated marginal uncertainty sampling for active learning. Optimization reduced manual review size (Deterministic 11.6% vs. 2.5%; FIE 49.6% vs. 1.9%; and Probabilistic 10.5% vs. 3.5%). FIE classified 98.1% of the records correctly (precision=1.0). Best performance required training on all 10,000 randomly-selected record-pairs. Active learning achieved comparable results with 3,000 records. Automated optimization is effective and targeted sampling can reduce the required training set size.
PMCID: PMC3900213  PMID: 24551372
13.  The Reinforcing and Rewarding Effects of Methylone, a Synthetic Cathinone Commonly Found in “Bath Salts” 
Methylone is a member of the designer drug class known as synthetic cathinones which have become increasingly popular drugs of abuse in recent years. Commonly referred to as “bath salts”, these amphetamine-like compounds are sold as “legal” alternatives to illicit drugs such as cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy). Following their dramatic rise in popularity along with numerous reports of toxicity and death, several of these drugs were classified as Schedule I drugs in the United States in 2012. Despite these bans, these drugs and other new structurally similar analogues continue to be abused. Currently, however, it is unknown whether these compounds possess the potential for compulsive use and addiction. The present study sought to determine the relative abuse liability of methylone by employing intravenous self-administration (IVSA) and intracranial self-stimulation (ICSS) paradigms in rats. We demonstrate that methylone (0.05, 0.1, 0.2, and 0.5 mg/kg/infusion) dose-dependently functions as a reinforcer, and that there is a significant positive relationship between methylone dose and reinforcer efficacy. Furthermore, responding during short access sessions (ShA, 2 hr/day) appeared more robust than previous IVSA studies with MDMA. However, unlike previous findings with abused stimulants such as cocaine or methamphetamine, long access sessions (LgA, 6 hr/day) did not lead to escalated drug intake or increased reinforcer efficacy. Finally, methylone produced a dose-dependent, but statistically non-significant, trend towards reductions in ICSS thresholds. Together these results reveal that methylone may possess an addiction potential similar to or greater than MDMA, yet patterns of self-administration and effects on brain reward function suggest that this drug may have a lower potential for abuse and compulsive use than prototypical psychostimulants.
PMCID: PMC3828752  PMID: 24244886
Methylone; Self-administration; Intracranial self-stimulation; Reward; Reinforcement; Monoamine; Stimulant
14.  Harmonizing Databases? Using a Quasi-Experimental Design to Evaluate a Public Mental Health Re-entry Program1 
Evaluation and Program Planning  2012;35(4):461-472.
Our study is the first-ever initiative to merge administrative databases in Massachusetts to evaluate an important public mental health program. It examines post-incarceration outcomes of adults with serious mental illness (SMI) enrolled in the Massachusetts Department of Mental Health (DMH) Forensic Transition Team (FTT) program. The program began in 1998 with the goal of transitioning offenders with SMI released from state and local correctional facilities utilizing a core set of transition activities. In this study we evaluate the program’s effectiveness using merged administrative data from various state agencies for the years 2007 – 2011, comparing FTT clients to released prisoners who, despite having serious mental health disorders, did not meet the criterion for DMH services. By systematically describing our original study design and the barriers we encountered, this report will inform future efforts to evaluate public programs using merged administrative databases and electronic health records.
PMCID: PMC3371126  PMID: 22436598
Serious mental illness; released prisoners; re-entry program effectiveness; administrative data
15.  Distinct gene expression profiles of viral- and non-viral associated Merkel cell carcinoma revealed by transcriptome analysis 
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine tumor with high mortality rates. Merkel cell polyomavirus (MCPyV), identified in the majority of MCC, may drive tumorigenesis via viral T antigens. However, mechanisms underlying pathogenesis in MCPyV-negative MCC remain poorly understood. To nominate genes contributing to pathogenesis of MCPyV-negative MCC, we performed DNA microarray analysis on 30 MCCs. MCPyV status of MCCs was determined by PCR for viral DNA and RNA. 1593 probe-sets were differentially expressed between MCPyV-negative and -positive MCC, with significant differential expression defined as at least 2-fold change in either direction and p-value of ≤ 0.05. MCPyV-negative tumors showed decreased RB1 expression, whereas MCPyV-positive tumors were enriched for immune response genes. Validation studies included immunohistochemistry demonstration of decreased RB protein expression in MCPyV-negative tumors and increased peritumoral CD8+ T lymphocytes surrounding MCPyV-positive tumors. In conclusion, our data suggest that loss of RB1 expression may play an important role in tumorigenesis of MCPyV-negative MCC. Functional and clinical validation studies are needed to determine whether this tumor suppressor pathway represents an avenue for targeted therapy.
PMCID: PMC3597750  PMID: 23223137
16.  Effects of a Range-Expanding Sea Urchin on Behaviour of Commercially Fished Abalone 
PLoS ONE  2013;8(9):e73477.
Global climate change has resulted in a southerly range expansion of the habitat modifying sea urchin Centrostephanus rodgersii to the east coast of Tasmania, Australia. Various studies have suggested that this urchin outcompetes black-lipped abalone (Haliotis rubra) for resources, but experiments elucidating the mechanisms are lacking.
Methodology/Principal Findings
We outline a new framework involving experimental manipulations and Markov chain and Pareto modelling to examine the effects of interspecific competition between urchins and abalone and the effect of intraspecific competition in abalone, assessed as effects on behaviour. Manipulations of abalone densities had no detectable effect on urchin behavioural transitions, movement patterns or resightability through time. In contrast, additions of urchins resulted in abalone shifting microhabitats from exposed to sheltered positions, an increase in the proportion of mobile abalone, and declines in abalone resightability through time relative to controls without the urchins. Our results support the hypothesis of asymmetrical competitive interactions between urchins and abalone.
The introduction of urchins to intact algal beds causes abalone to flee and seek shelter in cryptic microhabitat which will negatively impact both their accessibility to such microhabitats, and productivity of the abalone fishery, and will potentially affect their growth and survival, while the presence of the abalone has no detectable effect on the urchin. Our approach involving field-based experiments and modelling could be used to test the effects of other invasive species on native species behaviour.
PMCID: PMC3779227  PMID: 24073195
To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes.
The EATATE, a retrospective assessment of childhood perfectionism, and the Eating Disorder Inventory (EDI-2) were administered to 728 AN participants.
EATATE responses revealed General Childhood Perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; School Work Perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; Childhood Order and Symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and Global Childhood Rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 Drive for Thinness and Body Dissatisfaction were present with four EATATE subscales.
Global Childhood Rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.
PMCID: PMC3418385  PMID: 22488115
18.  The Genetics of Anorexia Nervosa Collaborative Study: Methods and Sample Description 
Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN).
Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders.
We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives.
These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.
PMCID: PMC3755506  PMID: 18236451
anorexia nervosa; eating disorders; bulimia nervosa; psychiatric disorders; genetics; linkage analysis; genomics
19.  Microbial Biofilms and Breast Tissue Expanders 
BioMed Research International  2013;2013:254940.
We previously developed and validated a vortexing-sonication technique for detection of biofilm bacteria on the surface of explanted prosthetic joints. Herein, we evaluated this technique for diagnosis of infected breast tissue expanders and used it to assess colonization of breast tissue expanders. From April 2008 to December 2011, we studied 328 breast tissue expanders at Mayo Clinic, Rochester, MN, USA. Of seven clinically infected breast tissue expanders, six (85.7%) had positive cultures, one of which grew Propionibacterium species. Fifty-two of 321 breast tissue expanders (16.2%, 95% CI, 12.3–20.7%) without clinical evidence of infection also had positive cultures, 45 growing Propionibacterium species and ten coagulase-negative staphylococci. While vortexing-sonication can detect clinically infected breast tissue expanders, 16 percent of breast tissue expanders appear to be asymptomatically colonized with normal skin flora, most commonly, Propionibacterium species.
PMCID: PMC3730356  PMID: 23956974
20.  Normal left ventricular myocardial thickness for middle aged and older subjects with SSFP cardiac MR: The Multi-Ethnic Study of Atherosclerosis 
Increased left ventricular myocardial thickness (LVMT) is a feature of several cardiac diseases. The purpose of this study was to establish standard reference values of normal LVMT with cardiac MR (CMR) and to assess variation with image acquisition plane, demographics and LV function.
Methods and Results
End-diastolic LVMT was measured on CMR steady-state free precession cine long and short axis images in 300 consecutive participants free of cardiac disease (169 women; 65.6±8.5 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Mean LVMT on short axis images at the mid-cavity level was 5.3±0.9mm and 6.3±1.1mm for women and men, respectively. The average of the maximum LVMT at the mid-cavity for women/men were 7mm/9mm (long axis) and 7mm/8mm (short axis). Mean LVMT was positively associated with weight (0.02mm/kg, p=0.01) and body-surface-area (1.1mm/m2, p<0.001). No relationship was found between mean LVMT and age or height. Greater mean LVMT was associated with lower LV end-diastolic volume (0.01mm/ml, p<0.01), a lower LV end-systolic volume (−0.01mm/ml, p=0.01) and lower LV stroke volume (−0.01mm/ml, p<0.05). LVMT measured on long axis images at the basal and mid-cavity level were slightly greater (by 6% and 10%, respectively) than measurements obtained on short axis images; apical LVMT values on long axis images were 20% less than those on short axis images.
Normal values for wall thickness are provided for middle-aged and older subjects. Normal LVMT is lower for women than men. Observed values vary depending on the imaging plane for measurement.
PMCID: PMC3412148  PMID: 22705587
magnetic resonance imaging; myocardial thickness; normal values
21.  The Significance of Repetitive Hair-Pulling Behaviors in Eating Disorders 
Journal of clinical psychology  2011;67(4):391-403.
We studied the relation between intrusive and repetitive hair-pulling, the defining feature of trichotillomania, and compulsive and impulsive features in 1453 individuals with anorexia nervosa and bulimia nervosa. We conducted a series of regression models examining the relative influence of compulsive features associated with obsessive compulsive disorder; compulsive features associated with eating disorders; trait features related to harm avoidance, perfectionism and novelty seeking; and self harm. A final model with a reduced sample (n=928) examined the additional contribution of impulsive attributes. One out of 20 individuals endorsed hair-pulling. Evidence of a positive association with endorsement of compulsive behavior of the obsessive compulsive spectrum emerged. Hair-pulling may be more consonant with ritualistic compulsions than impulsive urges in those with eating disorders.
PMCID: PMC3664303  PMID: 21365638
eating disorders; trichotillomania; hair-pulling; anorexia nervosa; bulimia nervosa; impulsivity; compulsivity
22.  Trabeculated (Non-Compacted) and Compact Myocardium in Adults: The Multi-Ethnic Study of Atherosclerosis 
A high degree of non-compacted (trabeculated) myocardium in relationship to compact myocardium (T/M ratio >2.3) has been associated with a diagnosis of left ventricular non-compaction (LVNC). The purpose of this study was to determine the normal range of the T/M ratio in a large population-based study and to examine the relationship to demographic and clinical parameters.
Methods and Results
The thickness of trabeculation and the compact myocardium were measured in eight LV regions on long axis cardiac magnetic resonance (CMR) steady-state free precession cine images in 1000 participants (551 women; 68.1±8.9 years) of the Multi-Ethnic Study of Atherosclerosis cohort. Of 323 participants without cardiac disease or hypertension and with all regions evaluable 140 (43%) had a T/M ratio >2.3 in at least one region; in 20/323 (6%), T/M>2.3 was present in more than two regions. Multivariable linear regression model revealed no association of age, gender, ethnicity, height and weight with maximum T/M ratio in participants without cardiac disease or hypertension (p>0.05). In the entire cohort (n=1000) LVEF (β=−0.02/%; p=0.015), LVEDV (β=0.01/ml; p=<0.0001) and LVESV (β=0.01/ml; p<0.001) were associated with maximum T/M ratio in adjusted models while there was no association with hypertension or myocardial infarction (p>0.05). At the apical level T/M ratios were significantly lower when obtained on short- compared to long-axis images (p=0.017).
A ratio of trabeculated to compact myocardium of more than 2.3 is common in a large population based cohort. These results suggest reevaluation of the current CMR criteria for LVNC may be necessary.
PMCID: PMC3399115  PMID: 22499849
cardiovascular magnetic resonance imaging; cardiomyopathy; non-compaction; trabeculation
23.  Understanding the Association of Impulsivity, Obsessions, and Compulsions with Binge Eating and Purging Behaviors in Anorexia Nervosa 
To further refine our understanding of impulsivity, obsessions, and compulsions in anorexia nervosa (AN) by isolating which behaviors—binge eating, purging, or both—are associated with these features.
We conducted regression analyses with binge eating, purging, and the interaction of binge eating with purging as individual predictors of scores for impulsivity, obsessions, and compulsions in two samples of women with AN (n = 1373).
Purging, but not binge eating, was associated with higher scores of impulsivity, obsessions and compulsions. Purging was also associated with worst eating rituals and with worst eating preoccupations.
Our results suggest that purging, compared with binge eating, may be a stronger correlate of impulsivity, obsessions, and compulsions in AN.
PMCID: PMC3443865  PMID: 22351620
anorexia nervosa; impulsivity; compulsivity; binge eating; purging
24.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
PMCID: PMC3612981  PMID: 18243217
25.  Challenges in Conducting A Multi-Site Randomized Clinical Trial Comparing Treatments for Adolescent Anorexia Nervosa 
To describe obstacles in the implementation of a controlled treatment trial of adolescent anorexia nervosa (AN).
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.
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.
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.
PMCID: PMC3140589  PMID: 21495052
Anorexia nervosa; adolescents; Behavioral Family Therapy; Systems Family Therapy; RIAN trial

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