Search

The case-control study design is one of the main tools for detecting associations between genetic markers and diseases. It is well known that population substructure can lead to spurious association between disease status and a genetic marker if the prevalence of disease and the marker allele frequency vary across subpopulations. In this paper, we propose a novel statistical method to estimate the association in case-control studies with unmeasured population substructure. The proposed method takes two steps. First, the information on genomic markers and disease status is used to infer the population substructure; second, the association between the disease and the test marker adjusting for the population substructure is modeled and estimated parametrically through polytomous logistic regression. The performance of the proposed method, relative to the existing methods, on bias, coverage probability and computational time, is assessed through simulations. The method is applied to an end-stage renal disease study in African Americans population. [ABSTRACT FROM AUTHOR]

In a parametric model, parameters are often partitioned into parameters of interest and nuisance parameters. However, as the data structure becomes more complex, inference based on the full likelihood may be computationally intractable or sensitive to potential model misspecification. Alternative likelihood-based methods proposed in these settings include pseudo-likelihood and composite likelihood. We propose a simple adjustment to these likelihood functions to reduce the impact of nuisance parameters. The advantages of the modification are illustrated through examples and reinforced through simulations. The adjustment is still novel even if attention is restricted to the profile likelihood. The Canadian Journal of Statistics 42: 544-562; 2014 © 2014 Statistical Society of Canada [ABSTRACT FROM AUTHOR]

Summary We consider likelihood ratio tests (LRT) and their modifications for homogeneity in admixture models. The admixture model is a two-component mixture model, where one component is indexed by an unknown parameter while the parameter value for the other component is known. This model is widely used in genetic linkage analysis under heterogeneity in which the kernel distribution is binomial. For such models, it is long recognized that testing for homogeneity is nonstandard, and the LRT statistic does not converge to a conventional χ2 distribution. In this article, we investigate the asymptotic behavior of the LRT for general admixture models and show that its limiting distribution is equivalent to the supremum of a squared Gaussian process. We also discuss the connection and comparison between LRT and alternative approaches such as modifications of LRT and score tests, including the modified LRT (, Statistica Sinica 16, 805-823). The LRT is an omnibus test that is powerful to detect general alternative hypotheses. In contrast, alternative approaches may be slightly more powerful to detect certain type of alternatives, but much less powerful for others. Our results are illustrated by simulation studies and an application to a genetic linkage study of schizophrenia. [ABSTRACT FROM AUTHOR]

This paper considers the asymptotic distribution of the likelihood ratio statistic T for testing a subset of parameter of interest θ, , , based on the pseudolikelihood , where is a consistent estimator of , the nuisance parameter. We show that the asymptotic distribution of T under H0 is a weighted sum of independent chi-squared variables. Some sufficient conditions are provided for the limiting distribution to be a chi-squared variable. When the true value of the parameter of interest, , or the true value of the nuisance parameter, , lies on the boundary of parameter space, the problem is shown to be asymptotically equivalent to the problem of testing the restricted mean of a multivariate normal distribution based on one observation from a multivariate normal distribution with misspecified covariance matrix, or from a mixture of multivariate normal distributions. A variety of examples are provided for which the limiting distributions of T may be mixtures of chi-squared variables. We conducted simulation studies to examine the performance of the likelihood ratio test statistics in variance component models and teratological experiments. [ABSTRACT FROM PUBLISHER]

There has been much research on analysing multivariate failure times, but little that has accommodated failures that arise in the presence of a competing failure process. This paper studies the problem of describing associations among times to such failures. It proposes a modified conditional hazard ratio measure of association that is tailored to competing risks data, develops frailty models and a nonparametric method for describing the proposed measure, and contrasts estimation by proposed methods with the ‘standard’ of treating competing risks as independently censoring failure times due to targeted causes. The methods are investigated on simulated and real data. [ABSTRACT FROM PUBLISHER]

Presents information on a study which proposed a multipoint linkage-disequilibrium-mapping approach based on the case-parent trio design. Difference of the proposed method from the popular transmission/disequilibrium test approach; Preferential-transmission statistics; Results and discussion.

In recent years substantial research has been devoted to developing failure-time methodology which accounts for possible dependency between observations. An example is the univariate frailty model (Vaupel, Manton & Stallard, 1979), which incorporates an exchangeable dependence structure by the inclusion of cluster-specific random effects. In some studies it may be reasonable to expect more than one level of within-cluster association: for instance, association between a parent and child versus that between two siblings in studies of familial disease aggregation, or association between two village residents who live in different households versus that between residents of the same household in intervention studies. We propose a family of distributional models for failure-time data that accounts for multiple levels of clustering and reduces in the case of a single clustering level to a univariate frailty model. The resulting survival functions are constructed by a recursive nesting of univariate frailty-type distributions through which archimedean copula forms are determined for all bivariate margins. Properties of the proposed model are developed, illustrated and briefly contrasted with multivariate frailty model properties. In conclusion, we outline the application of our model to marginal risk regression problems. [ABSTRACT FROM AUTHOR]

Opinion. Presents the authors' view on historical preference for randomization inference and the regulatory benefit of a standardized approach to the analysis of clinical trial data, and focus in more detail on bias, proposing an alternative to E&F's estimate of treatment. Their objection related to the regulatory objective for a clinical trial to dictate a decision about a proposed therapy; Most important objection to controlling for compliance.

Psychiatric researchers tend to select the discordant co-twin design when they seek to hold constant genetic influence while estimating exposure-associated disease risk. The epidemiologic case-crossover research design developed for the past two decades represents a viable alternative, not often seen in psychiatric studies. Here, we turn to the epidemiologic case-crossover approach to examine the idea that cannabis onset is a proximal trigger for cocaine use, with the power of 'subject-as-own-control' research used to hold constant antecedent characteristics of the individual drug user, including genetic influence and other traits experienced up to the time of the observed hazard and control intervals. Data are from newly incident cocaine users identified in the 2002-2006 US National Surveys on Drug Use and Health. Among these cocaine users, 48 had both cannabis onset and cocaine onset in the same month-long hazard interval; the expected value is 30 users, based on the control interval we had pre-specified for case-crossover estimation (estimated relative risk, RR = 1.6; exact mid- p = 0.042). Within the framework of a subject-as-own-control design, the evidence is consistent with the hypothesis that cannabis onset is a proximal trigger for cocaine use, with genetic influences (and many environmental conditions and processes) held constant. Limitations are noted and implications are discussed. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate possible adverse effects of cannabis use on cognitive decline after 12 years in persons under age 65 years. This was a follow-up study of a probability sample of the adult household residents of East Baltimore. The analyses included 1,318 participants in the Baltimore, Maryland, portion of the Epidemiologic Catchment Area study who completed the Mini-Mental State Examination (MMSE) during three study waves in 1981, 1982, and 1993–1996. Individual MMSE score differences between waves 2 and 3 were calculated for each study participant. After 12 years, study participants' scores declined a mean of 1.20 points on the MMSE (standard deviation 1.90), with 66% having scores that declined by at least one point. Significant numbers of scores declined by three points or more (15% of participants in the 18–29 age group). There were no significant differences in cognitive decline between heavy users, light users, and nonusers of cannabis. There were also no male-female differences in cognitive decline in relation to cannabis use. The authors conclude that over long time periods, in persons under age 65 years, cognitive decline occurs in all age groups. This decline is closely associated with aging and educational level but does not appear to be associated with cannabis use. Am J Epidemiol 1999;149:794–800. [ABSTRACT FROM PUBLISHER]

This study uses growth curve analysis to examine whether disparities in the occupational standing of White men relative to women and minorities grew larger or smaller with advancing age during the 1980s and 1990s. The analyses are based on The National Longitudinal Survey of Youth 1979 and the Baltimore Epidemiologic Catchment Area Follow-Up. Results indicate that disparities in occupational standing stayed constant over the life course across all demographic groups except for African Americans, whose gap in occupational status relative to Whites and Hispanics grew significantly larger with advancing age. Implications of these findings for theories of occupational inequality are discussed. [ABSTRACT FROM AUTHOR]

Composite likelihood has been widely used in applications. The asymptotic distribution of the composite likelihood ratio statistic at the boundary of the parameter space is a complicated mixture of weighted χ2 distributions. In this paper we propose a conditional test with data-dependent degrees of freedom. We consider a modification of the composite likelihood which satisfies the second-order Bartlett identity.We show that the modified composite likelihood ratio statistic given the number of estimated parameters lying on the boundary converges to a simple χ2 distribution. This conditional testing procedure is validated through simulation studies. [ABSTRACT FROM AUTHOR]

Parametric and semiparametric mixture models have been widely used in applications from many areas, and it is often of interest to test the homogeneity in these models. However, hypothesis testing is non standard due to the fact that several regularity conditions do not hold under the null hypothesis. We consider a semiparametric mixture case–control model, in the sense that the density ratio of two distributions is assumed to be of an exponential form, while the baseline density is unspecified. This model was first considered by Qin and Liang (2011, biometrics), and they proposed a modified score statistic for testing homogeneity. In this article, we consider alternative testing procedures based on supremum statistics, which could improve power against certain types of alternatives. We demonstrate the connection and comparison among the proposed and existing approaches. In addition, we provide a unified theoretical justification of the supremum test and other existing test statistics from an empirical likelihood perspective. The finite-sample performance of the supremum test statistics was evaluated in simulation studies. [ABSTRACT FROM AUTHOR]

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10−6

Background: The Bone Morphogenetic Protein 4 gene (BMP4) is located in chromosome 14q22-q23 which has shown evidence of linkage for isolated nonsyndromic cleft lip with or without cleft palate (NSCL/P) in a genome wide linkage analysis of human multiplex families. BMP4 has been shown to play crucial roles in lip and palatal development in animal models. Several candidate gene association analyses also supported its potential risk for NSCL/P, however, results across these association studies have been inconsistent. The aim of the current study was to test for possible association between markers in and around the BMP4 gene and NSCL/P in Asian and Maryland trios. Methodology/Principal Findings: Family Based Association Test was used to test for deviation from Mendelian assortment for 12 SNPs in and around BMP4. Nominal significant evidence of linkage and association was seen for three SNPs (rs10130587, rs2738265 and rs2761887) in 221 Asian trios and for one SNP (rs762642) in 76 Maryland trios. Statistical significance still held for rs10130587 after Bonferroni correction (corrected p = 0.019) among the Asian group. Estimated odds ratio for carrying the apparent high risk allele at this SNP was 1.61 (95%CI = 1.20, 2.18). Conclusions: Our results provided further evidence of association between BMP4 and NSCL/P. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study is to determine whether neurocognitive performance distinguishes individuals with compulsive hoarding (CH) from those with obsessive-compulsive disorder (OCD). Compared to control subjects, OCD patients and CHs scored significantly worse on the Serial Reaction Time Task suggesting disturbed implicit memory in both patient groups. On the Iowa Gambling Task, an overall learning progression difference over time was found between the CHs, OCD group, and control subjects, suggesting differences in decision-making between the groups. The groups did not differ in performance on the Stop Signal Reaction Time Task (motor inhibition). This study found evidence for impaired implicit memory in CHs, but also in OCD patients, albeit less severe. There was evidence that OCD patients learned more slowly on a decision-making task than CHs and control subjects. This latter finding provides some evidence to suggest that CH and OCD have, at least on this one measure, differing cognitive substrates. [Copyright &y& Elsevier]

Abstract: Background: The serotonin transporter (SERT) polymorphism (5HTTLPR) has been reported to be associated with several psychiatric conditions. Specific personality disorders could be intermediate factors in the known relationship between 5HTTLPR and psychiatric disorders. This is the first study to test the association between this polymorphism and dimensions of all DSM-IV personality disorders in a community sample. Methods: 374 white participants were assessed by clinical psychologists using the International Personality Disorder Examination (IPDE). Associations between dimensions of each DSM-IV personality disorder and the long (l) and short (s) alleles of the 5HTTLPR were evaluated using non-parametric tests and regression models. Results: The s allele of the 5HTTLPR polymorphism was significantly associated with higher avoidant personality trait scores in the whole sample. Males with the s allele had a significantly lower likelihood of higher obsessive–compulsive personality disorder (OCPD) trait scores, whereas females with the s allele were likely to have higher OCPD personality trait scores. Conclusion: This paper provides preliminary data on the relationship between personality disorders and the 5HTTLPR polymorphism. The relationship of the s allele and avoidant PD is consistent with findings of a nonspecific relationship of this polymorphism to anxiety and depressive disorders. Concerning the unusual sexual dimorphic result with OCPD, several hypotheses are presented. These findings need further replication, including a more detailed study of additional variants in SERT. [Copyright &y& Elsevier]

Background: A history of separation anxiety disorder (SAD) is frequently reported by patients with obsessive-compulsive disorder (OCD). The purpose of this study was to determine if there are clinical differences between OCD-affected individuals with, versus without, a history of SAD. Methods: Using data collected during the OCD Collaborative Genetic Study, we studied 470 adult OCD participants; 80 had a history of SAD, whereas 390 did not. These two groups were compared as to onset and severity of OCD, lifetime prevalence of Axis I disorders, and number of personality disorder traits. Results: OCD participants with a history of SAD were significantly younger than the non-SAD group (mean, 34.2 versus 42.2 years; P<.001). They had an earlier age of onset of OCD symptoms (mean, 8.0 versus 10.5 years; P<.003) and more severe OCD, as measured by the Yale-Brown Obsessive Compulsive Scale (mean, 27.5 versus 25.0; P<.005). In addition, those with a history of SAD had a significantly greater lifetime prevalence of agoraphobia (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.4-4.6, P<.003), panic disorder (OR = 1.84, CI = 1.03-3.3 P<.04), social phobia (OR = 1.69, CI 1.01-2.8, P<.048), after adjusting for age at interview, age at onset of OCD, and OCD severity in logistic regression models. There was a strong relationship between the number of dependent personality disorder traits and SAD (adjusted OR = 1.42, CI = 1.2-1.6, P<.001). Conclusions: A history of SAD is associated with anxiety disorders and dependent personality disorder traits in individuals with OCD. Depression and Anxiety 28:256-262, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Context: Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression.Objective: To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data.Data Sources: Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis.Study Selection: Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data.Data Extraction: Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression.Results: In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.Conclusion: This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined. [ABSTRACT FROM AUTHOR]

Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10-5), we performed a peakwide association fine mapping study by using 1414 SNPs across -12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10-7. We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10-2), with a combined p value of 2.30 x 10-7. After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10-3. NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ. [ABSTRACT FROM AUTHOR]

Abstract: Background: The aim of the current study is to estimate the association between parenting factors derived from the Parental Bonding Instrument (PBI) and a lifetime DSM-IV diagnosis of OCD. Method: Data were from approximately 1200 adults from 465 families assessed as part of a large family and genetic study of OCD. The association of three parenting factors, for fathers and mothers, with offspring OCD status were examined; analyses were stratified by parental OCD status and family loading for OCD (multiplex versus sporadic). Results: Three factors were derived by principal components factor analysis of the PBI (maternal and paternal care, overprotection and control). Maternal overprotection was associated with OCD in offspring with familial OCD (familial cases) but only if neither parent was affected with OCD, which suggests independent but additive environmental and genetic risk (OR=5.9, 95% CI 1.2, 29.9, p =0.031). Paternal care was a protective factor in those not at high genetic risk (sporadic cases) (OR=0.2, 95% CI 0.0, 0.8, p =0.027). Maternal overprotection was also associated with offspring OCD in sporadic families (OR=2.9, 95% CI 1.3, 6.6, p =0.012). The finding that parental overprotection and care were not associated with offspring OCD when at least one parent had OCD addressed directly the hypothesis of maternal or paternal OCD adversely impacting parenting. Conclusions: This study provides evidence that aspects of parenting may contribute to the development of OCD among offspring. Prospective studies of children at risk for OCD are needed to explore the direction of causality. [Copyright &y& Elsevier]

Abstract: Little is known about whether the clinical correlates of hoarding behavior are different in men and women with obsessive-compulsive disorder (OCD). In the current study, we evaluated the association of hoarding with categories of obsessions and compulsions, psychiatric disorders, personality dimensions, and other clinical characteristics separately in 151 men and 358 women with OCD who were examined during the OCD Collaborative Genetics Study. We found that, among men but not women, hoarding was associated with aggressive, sexual, and religious obsessions and checking compulsions. In men, hoarding was associated with generalized anxiety disorder and tics whereas, among women, hoarding was associated with social phobia, post-traumatic stress disorder, body dysmorphic disorder, nail biting, and skin picking. In women but not men, hoarding was associated with schizotypal and dependent personality disorder dimensions, and with low conscientiousness. These findings indicate that specific clinical correlates of hoarding in OCD are different in men and women and may reflect sex-specific differences in the course, expression, and/or etiology of hoarding behavior in OCD. [Copyright &y& Elsevier]

Abstract: Despite progress in identifying homogeneous subphenotypes of obsessive-compulsive disorder (OCD) through factor analysis of the Yale Brown Obsessive-Compulsive Scale Symptom Checklist (YBOCS-SC), prior solutions have been limited by a reliance on presupposed symptom categories rather than discrete symptoms. Furthermore, there have been few attempts to evaluate the familiality of OCD symptom dimensions. The purpose of this study was to extend prior work by this collaborative group in category-based dimensions by conducting the first-ever exploratory dichotomous factor analysis using individual OCD symptoms, comparing these results to a refined category-level solution, and testing the familiality of derived factors. Participants were 485 adults in the six-site OCD Collaborative Genetics Study, diagnosed with lifetime OCD using semi-structured interviews. YBOCS-SC data were factor analyzed at both the individual item and symptom category levels. Factor score intraclass correlations were calculated using a subsample of 145 independent affected sib pairs. The item- and category-level factor analyses yielded nearly identical 5-factor solutions. While significant sib–sib associations were found for four of the five factors, Hoarding and Taboo Thoughts were the most robustly familial (r ICC ≥0.2). This report presents considerable converging evidence for a five-factor structural model of OCD symptoms, including separate factor analyses employing individual symptoms and symptom categories, as well as sibling concordance. The results support investigation of this multidimensional model in OCD genetic linkage studies. [Copyright &y& Elsevier]

Abstract: Little is known about the prevalence and correlates of hoarding behavior in the community. We estimated the prevalence and evaluated correlates of hoarding in 742 participants in the Hopkins Epidemiology of Personality Disorder Study. The prevalence of hoarding was nearly 4% (5.3%, weighted) and was greater in older than younger age groups, greater in men than women, and inversely related to household income. Hoarding was associated with alcohol dependence; paranoid, schizotypal, avoidant, and obsessive–compulsive personality disorder traits; insecurity from home break-ins and excessive physical discipline before 16 years of age; and parental psychopathology. These findings suggest that hoarding may be relatively prevalent and that alcohol dependence, personality disorder traits, and specific childhood adversities are associated with hoarding in the community. [Copyright &y& Elsevier]

The Leyton Obsessional Inventory (LOI) is a self-report questionnaire that assesses obsessional symptoms. The ability of the LOI to distinguish between obsessive–compulsive disorder (OCD) and obsessive–compulsive personality disorder (OCPD) has not been adequately addressed. Our purpose is to identify dimensions of obsessional symptoms from the LOI and determine how well they distinguish between OCD and OCPD. The LOI was completed by 488 participants diagnosed by trained clinicians. Factor analysis was performed on responses to the interference items of the LOI. The relationship between the factors, OCD and OCPD was evaluated using logistic regression. Five factors underlying the LOI were identified: (I) obsessional ruminations and compulsions, (II) ordering and arranging, (III) organizing activities, (IV) contamination, and (V) parsimony. Factors I, III, and IV were strongly associated with OCD. Only Factor II was associated with OCPD. Factor IV was negatively associated with obsessive–compulsive personality traits. LOI factors are useful in discriminating between OCD and OCPD. Obsessional ruminations and compulsions, organizing activities, and contamination fears may indicate OCD, and ordering and arranging symptoms may indicate OCPD rather than OCD. Parsimony may indicate neither disorder, and contamination, the absence of OCPD traits compared with the other LOI factors. These findings may contribute to effective diagnosis and treatment by allowing the LOI to screen for OCD and OCPD in a population exhibiting obsessional symptoms and traits. Depression and Anxiety 24:301–306, 2007. Published ©2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Hoarding behavior occurs frequently in obsessive–compulsive disorder (OCD). Results from previous studies suggest that individuals with OCD who have hoarding symptoms are clinically different than non-hoarders and may represent a distinct clinical group. In the present study, we compared 235 hoarding to 389 non-hoarding participants, all of whom had OCD, collected in the course of the OCD Collaborative Genetics Study. We found that, compared to non-hoarding individuals, hoarders were more likely to have symmetry obsessions and repeating, counting, and ordering compulsions; poorer insight; more severe illness; difficulty initiating or completing tasks; and indecision. Hoarders had a greater prevalence of social phobia and generalized anxiety disorder. Hoarders also had a greater prevalence of obsessive–compulsive and dependent personality disorders. Five personality traits were independently associated with hoarding: miserliness, preoccupation with details, difficulty making decisions, odd behavior or appearance, and magical thinking. Hoarding and indecision were more prevalent in the relatives of hoarding than of non-hoarding probands. Hoarding in relatives was associated with indecision in probands, independently of proband hoarding status. The findings suggest that hoarding behavior may help differentiate a distinct clinical subgroup of people with OCD and may aggregate in some OCD families. Indecision may be a risk factor for hoarding in these families. [Copyright &y& Elsevier]

Background: Identification of familial, more homogenous characteristics of obsessive–compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. Methods: Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale–Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. Results: After controlling for sex, age, and age of onset, robust sib–sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor II (symmetry/ordering/arranging; p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor II (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor II (p < .01). Conclusions: Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD. [Copyright &y& Elsevier]

This study pursued a line of large-sample epidemiological research on tobacco dependence syndromes that may appear during the first 2 years of tobacco smoking, as clinical features begin to emerge. Focusing on smokers who just recently started using tobacco may provide insights into the transitions that lead from initial smoking toward tobacco dependence. A specific focus was a possible excess risk of tobacco dependence associated with early-onset smoking. Data came from public use files of the 1995-1998 National Household Surveys on Drug Abuse. Analyses were based on responses from 2,993 smokers, that is, those whose age at onset of tobacco smoking was either equal to the age at the time of the interview (n=1,030) or within 1 year of the age at the interview (n=1,963). Seven clinical features were assessed for a measure of the tobacco dependence syndrome, elicited during a standardized assessment. Findings from latent class analysis best support a model with three classes of smokers; features of tobacco dependence are prominent in just two of these classes, which in aggregate constitute 29% of the recent-onset smokers. Earlier-onset tobacco smokers may have a modestly higher probability of expressing dependence features within 2 years of smoking onset, compared with later-onset smokers (i.e., those starting after age 20). Clinical features of tobacco dependence emerge within 1-2 years after the onset of smoking. If the three-class model of tobacco dependence is correct, early-onset smoking may confer modest excess risk of becoming tobacco dependent during the first 2 years after smoking onset. [ABSTRACT FROM AUTHOR]

: BackgroundIndividuals with obsessive–compulsive disorder (OCD) frequently have other psychiatric disorders. This study employed latent class analysis (LCA) to explore whether there are underlying clinical constructs that distinguish “OCD-related” subgroups.: MethodsThe study included 450 subjects, case and control probands and their first-degree relatives, and LCA was used to derive empirically based subgroups of 10 disorders: OCD, obsessive–compulsive personality disorder (OCPD), recurrent major depressive disorder (RMDD), separation anxiety disorder, panic disorder or agoraphobia (PD/AG), tic disorders (TD), generalized anxiety disorder (GAD), somatoform disorders (hypochondriasis or body dysmorphic disorder), pathologic skin picking or nail biting (PSP/NB), and eating disorders (EDs). The derived classes were compared on several clinical variables.: ResultsThe best fitting model is a four-class structure: minimal disorder, predominant RMDD and GAD, “highly comorbid,” and PD/AG and TD. The nature and number of disorders represented suggests that the first classes are distributed ordinally on a dimension of severity, and the fourth class is qualitatively distinct. Support for this structure is based on the number of disorders, age at onset of OCD, neuroticism, and extraversion.: ConclusionsIn this OCD enriched sample, LCA identified four classes of disorder. These classes appear to conform to two subgroups that may prove useful in investigating the etiology of OCD. [Copyright &y& Elsevier]

: PurposeFor physical activity to reduce the risk of cardiovascular disease, it must be sustained throughout life. We sought to determine the relation between the ability of young adults in different sports and their continued physical activity in midlife, and subsequent cardiovascular disease.: Subjects and methodsBaseline self-reported ability in tennis, golf, football, baseball, and basketball was assessed in a cohort study involving 1019 male medical students (median age, 22 years). Physical activity and sports participation were assessed 22 years later. The incidence of cardiovascular disease was assessed during a median follow-up of 40 years, using annual questionnaires, medical records, and death certificates.: ResultsSubjects with high ability in tennis as young adults had the highest participation in the sport in midlife (median age, 48 years). In the midlife questionnaire administered in 1978, 33% reported playing tennis within the past week and 51% within the past year. Tennis was the only sport in which a higher ability during medical school was associated with a lower risk of cardiovascular disease. After adjustment for father’s occupation, parental incidence of cardiovascular disease, serum cholesterol level, cigarette smoking, body mass index, and hypertension during follow-up, the relative hazard of developing cardiovascular disease was 0.56 (95% confidence interval [CI]: 0.35 to 0.89) in the high-ability group and 0.67 (95% CI: 0.47 to 0.96) in the low-ability group, compared with the no-ability group.: ConclusionOur results support the association between sustained activity in aerobic sports and a lower risk of cardiovascular disease. Sustainability of activity should be considered when developing physical education programs for young adults. [Copyright &y& Elsevier]

Background: Whether the increase in blood pressure with coffee drinking seen in clinical trials persists over time and translates into an increased incidence of hypertension is not known. Methods: We assessed coffee intake in a cohort of 1017 white male former medical students (mean age, 26 years) in graduating classes from 1948 to 1964 up to 11 times over a median follow-up of 33 years. Blood pressure and incidence of hypertension were determined annually by self-report, demonstrated to be accurate in this cohort. Results: Consumption of 1 cup of coffee a day raised systolic blood pressure by 0.19 mm Hg (95% confidence interval, 0.02-0.35) and diastolic pressure by 0.27 mm Hg (95% confidence interval, 0.15-0.39) after adjustment for parental incidence of hypertension and time-dependent body mass index, cigarette smoking, alcohol drinking, and physical activity in analyses using generalized estimating equations. Compared with nondrinkers at baseline, coffee drinkers had a greater incidence of hypertension during follow-up (18.8% vs 28.3%; P= .03). Relative risk (95% confidence interval) of hypertension associated with drinking 5 or more cups a day was 1.35 (0.87-2.08) for baseline intake and 1.60 (1.06-2.40) for intake over follow-up. After adjustment for the variables listed above, however, these associations were not statistically significant. Conclusion: Over many years of follow-up, coffee drinking is associated with small increases in blood pressure, but appears to play a small role in the development of hypertension. [ABSTRACT FROM AUTHOR]

Frailty is a well-recognized geriatric syndrome with various definitions and conceptual frameworks. This study aimed to use latent class analysis to discover potential subtypes of pre-frail and frail older people. Data from the I-Lan Longitudinal Aging Study (ILAS), a community-based cohort study was used for analysis. Latent class analysis was applied to characterize classes or subgroups with different frailty phenotypes among ILAS participants targeting older adults aged 65 and above, capable of completing a 6-meter walk, without severe major or life threatening diseases, and not institutionalized. Latent class analysis identified three distinct subgroups with different frailty phenotypes: non-mobility-type (weight loss and exhaustion), mobility-type frailty (slowness and weakness), and low physical activity. Comparing these groups with the robust group, people with mobility-type frailty had poorer body composition, worse bone health, poorer cognitive function, lower survival (hazard ratio: 6.82, p = 0.019), and poorer overall health outcomes (hazard ratio: 1.67, p = 0.040). People in the non-mobility-type group had poorer bone health and more metabolic serum abnormalities. In conclusion, mobility-type frailty was a better predictor of adverse outcomes. However, further investigation is needed to evaluate how these phenotypic subgroups may help in predicting prognosis or in developing interventions. [ABSTRACT FROM AUTHOR]

A correction to the article "A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4" that was published in the July 12, 2010 is presented.

Background: The increased risk of cardiovascular disease associated with higher serum cholesterol levels in middle-aged persons has been clearly established, but there have been few opportunities to examine a potential link between serum cholesterol levels measured in young men and clinically evident premature cardiovascular disease later in life. Methods: We performed a prospective study of 1017 young men (mean age, 22 years) followed for 27 to 42 years to quantify the risk of cardiovascular disease and total mortality associated with serum cholesterol levels during early adult life. The mean serum cholesterol level at entry was 192 mg per deciliter (5.0 mmol per liter). Results: During a median follow-up of 30.5 years, there were 125 cardiovascular-disease events, 97 of which were due to coronary heart disease. The serum cholesterol level at base line was strongly associated with the incidence of events related to coronary heart disease and cardiovascular disease, as well as to total mortality and mortality due to cardiovascular disease. The risks were similar whether the events occurred before or after the age of 50. In a proportional-hazards analysis adjusted for age, body-mass index (the weight in kilograms divided by the square of the height in meters), the level of physical activity, coffee intake, change in smoking status, and the incidence of diabetes and hypertension during follow-up, a difference in the serum cholesterol level at base line of 36 mg per deciliter (0.9 mmol per liter) -- the difference between the 25th and 75th percentiles of cholesterol level in the study population at base line -- was associated with an increased risk of cardiovascular disease (relative risk, 1.72; 95 percent confidence interval, 1.39 to 2.14), coronary heart disease (relative risk, 2.01; 95 percent confidence interval, 1.59 to 2.53), and mortality due to cardiovascular disease (relative risk, 2.02; 95 percent confidence interval, 1.23 to 3.32). A difference in the base-line serum cholesterol level of 36 mg per deciliter was significantly associated with an increased risk of death before the age of 50 (relative risk, 1.64; 95 percent confidence interval, 1.03 to 2.61), but not with the overall risk of death (relative risk, 1.21; 95 percent confidence interval, 0.93 to 1.58). Conclusions: These findings indicate a strong association between the serum cholesterol level measured early in adult life in men and cardiovascular disease in midlife. (N Engl J Med 1993;328:313-8.) [ABSTRACT FROM AUTHOR]