Biomedical subjects

Kung-Yee Liang

Publications and source records attributed to Kung-Yee Liang.

At least 19 recordsLinked to original sources

PubMed2007

Factor analysis of the Yale-Brown Obsessive Compulsive Scale in a family study of obsessive-compulsive disorder.

Our objective in this study was to determine whether symptoms of obsessive-compulsive disorder (OCD) cluster into groups that can usefully subclassify OCD. Psychiatrists or psychologists interviewed 221 subjects using the Lifetime Anxiety Version of the Schedule for Affective Disorders and Schizophrenia (SADS-LA) for the diagnosis of DSM-IV disorders, and the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) for OCD symptoms. We analyzed 16 symptom categories from the Y-BOCS using exploratory factor analysis to identify latent symptom dimensions. The relationship between these symptom dimensions and clinical characteristics and familiality was investigated. A four-factor model emerged as the best classification of OCD symptoms in the Y-BOCS. These factors were labeled Pure Obsessions, Contamination, Symmetry/Order, and Hoarding. The contamination factor was least likely to be associated with other Axis I disorders. Whereas no significant relationship was found between the factor scores of probands and the presence of OCD in their first-degree relatives, the Symmetry/Order and Hoarding factors did breed true. Hoarding was found to predict poorer treatment response. A four-factor classification of OCD features best describes the symptom patterns of a sample of patients with OCD. There were specific clinical correlates for these factors, and significant intrafamilial sib-sib correlations were found for the Symmetry/Order and Hoarding factors.

Adult↗

PubMed2007

Utility of the Leyton Obsessional Inventory to distinguish OCD and OCPD.

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.

Adolescent↗

PubMed2007

Psychiatric and psychosocial predictors of substance use disorders among adolescents: longitudinal study.

BACKGROUND: Few studies have prospectively examined psychosocial and psychiatric predictors of adolescent substance use disorders simultaneously. AIMS: To identify psychosocial and psychiatric predictors of substance use disorders in adolescence. METHOD: School children aged 12 years (s.d.=0.3) free from any substance use disorder at grade 7 (n=428) were assessed in three consecutive years, using a standardised psychiatric interview. Their baseline psychosocial information was also collected. The outcome was the onset age of a substance use disorder. The Cox regression model was used for data analysis. RESULTS: The most significant predictive factors for adolescent substance use disorder included male gender, attention-deficit hyperactivity disorder, conduct disorder and sibling use of tobacco. Three protective factors against such morbidity included living in a household with two parents, a good academic grade at grade 7 and objection to the use of substances. CONCLUSIONS: Early intervention for disruptive behaviour disorders and specific psychosocial risk factors might prevent substance use disorders in early adolescence.

Adolescent↗

PubMed2006

Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD Collaborative Genetics Study.

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.

Comorbidity↗

PubMed2006

Epidemiological and genetic correlates of severe acute respiratory syndrome coronavirus infection in the hospital with the highest nosocomial infection rate in Taiwan in 2003.

Taiwan experienced a series of outbreaks of nosocomial severe acute respiratory syndrome (SARS) infections in 2003. Two months after the final outbreak, we recruited 658 employees from the hospital that suffered the first and most severe SARS infections to help us investigate epidemiological and genetic factors associated with the SARS coronavirus (SARS-CoV). SARS-CoV infections were detected by using enzyme immunoassays and confirmed by a combination of Western blot assays, neutralizing antibody tests, and commercial SARS tests. Risk factors were analyzed via questionnaire responses and sequence-specific oligonucleotide probes of human leukocyte antigen (HLA) alleles. Our results indicate that 3% (20/658) of the study participants were seropositive, with one female nurse identified as a subclinical case. Identified SARS-CoV infection risk factors include working in the same building as the hospital's emergency room and infection ward, providing direct care to SARS patients, and carrying a Cw*0801 HLA allele. The odds ratio for contracting a SARS-CoV infection among persons with either a homozygous or a heterozygous Cw*0801 genotype was 4.4 (95% confidence interval, 1.5 to 12.9; P = 0.007).

Adult↗

PubMed2005

Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.

Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.

Adolescent↗

PubMed2005

Power and robustness of linkage tests for quantitative traits in general pedigrees.

There are numerous statistical methods for quantitative trait linkage analysis in human studies. An ideal such method would have high power to detect genetic loci contributing to the trait, would be robust to non-normality in the phenotype distribution, would be appropriate for general pedigrees, would allow the incorporation of environmental covariates, and would be appropriate in the presence of selective sampling. We recently described a general framework for quantitative trait linkage analysis, based on generalized estimating equations, for which many current methods are special cases. This procedure is appropriate for general pedigrees and easily accommodates environmental covariates. In this report, we use computer simulations to investigate the power and robustness of a variety of linkage test statistics built upon our general framework. We also propose two novel test statistics that take account of higher moments of the phenotype distribution, in order to accommodate non-normality. These new linkage tests are shown to have high power and to be robust to non-normality. While we have not yet examined the performance of our procedures in the context of selective sampling via computer simulations, the proposed tests satisfy all of the other qualities of an ideal quantitative trait linkage analysis method.

Algorithms↗

PubMed2005

Multipoint linkage mapping using sibpairs: non-parametric estimation of trait effects with quantitative covariates.

Multipoint linkage analysis using sibpair designs remains a common approach to help investigators to narrow chromosomal regions for traits (either qualitative or quantitative) of interest. Despite its popularity, the success of this approach depends heavily on how issues such as genetic heterogeneity, gene-gene, and gene-environment interactions are properly handled. If addressed properly, the likelihood of detecting genetic linkage and of efficiently estimating the location of the trait locus would be enhanced, sometimes drastically. Previously, we have proposed an approach to deal with these issues by modeling the genetic effect of the target trait locus as a function of covariates pertained to the sibpairs. Here the genetic effect is simply the probability that a sibpair shares the same allele at the trait locus from their parents. Such modeling helps to divide the sibpairs into more homogeneous subgroups, which in turn helps to enhance the chance to detect linkage. One limitation of this approach is the need to categorize the covariates so that a small and fixed number of genetic effect parameters are introduced. In this report, we take advantage of the fact that nowadays multiple markers are readily available for genotyping simultaneously. This suggests that one could estimate the dependence of the generic effect on the covariates nonparametrically. We present an iterative procedure to estimate (1) the genetic effect nonparametrically and (2) the location of the trait locus through estimating functions developed by Liang et al. ([2001a] Hum Hered 51:67-76). We apply this new method to the linkage study of schizophrenia to illustrate how the onset ages of each sibpair may help to address the issue of genetic heterogeneity. This analysis sheds new light on the dependence of the trait effect on onset ages from affected sibpairs, an observation not revealed previously. In addition, we have carried out some simulation work, which suggests that this method provides accurate inference for estimating the location of quantitative trait loci.

Algorithms↗

PubMed2005

Multipoint linkage disequilibrium mapping using case-control designs.

Case-control study has been and continues to be one of the most popular designs in epidemiology. More recently, this design has been adopted to test for candidate genes when searching for disease genetic etiology. In this report, we present a multipoint linkage disequilibrium (LD) mapping approach with the focus on estimating the location of the target trait locus. It builds upon a representation, which shows that the difference between a case and a control in probabilities of carrying the target allele of a marker is proportional to that of the trait locus and that the proportionality factor is simply a measure of LD between the trait locus and the marker. Our method has the desired properties that (1) there is no need to specify phases of genotypic data with multiple markers, (2) it provides an estimate of location of the disease locus along with sampling uncertainty to help investigators to narrow chromosomal regions, and (3) a single test statistic is provided to test for LD in the framed region rather than testing the hypothesis one marker at a time. Our simulation work suggests that the proposed method performs well in terms of bias and coverage probability. Extension of the proposed method to account for confounding and genetic heterogeneity is discussed. We apply the proposed method to a published case-control data set for cystic fibrosis.

Alleles↗

PubMed2005

Oral clefts, maternal smoking, and TGFA: a meta-analysis of gene-environment interaction.

OBJECTIVE: A meta-analysis was performed to examine the association among maternal cigarette smoking, infant genotype at the Taq1 site in the transforming growth factor alpha (TGFA) locus, and risk of nonsyndromic oral clefts, both cleft palate (CP) and cleft lip with or without cleft palate (CL/P). DESIGN: Five published case-control studies were included in the meta-analyis. Pooled Mantel-Haenszel odds ratios (OR) and 95% confidence intervals (CIs) were computed. Gene-environment interaction was also assessed by using the pooled data in a case-only analysis and polytomous logistic regression. RESULTS: Among nonsmoking mothers, there was no evidence of any increased risk for CP if the infant carried the TGFA Taq1 C2 allele. If the mother reported smoking, however, there was an overall increased risk for CP if the infant carried the C2 allele (ORsmokers = 1.95; 95% CI = 1.22 to 3.10). TGFA genotype did not increase risk to CL/P, regardless of maternal smoking status. Polytomous logistic regression revealed a significant overall smoking effect for CL/P (OR = 1.64, 95% CI = 1.33 to 2.02) and CP (OR = 1.42, 95% CI = 1.06 to 1.90). CONCLUSIONS: While maternal smoking was a consistent risk factor for both CL/P and CP across all studies, the suggestive evidence for gene-environment interaction between the infant's genotype at the Taq1 marker in TGFA and maternal smoking was limited to CP. Furthermore, evidence for such gene-environment interaction was strongest in a case-control study drawn from a birth defect registry where infants with non-cleft defects served as controls.

Alleles↗

PubMed2004

Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a severe psychiatric illness that is characterized by intrusive and senseless thoughts and impulses (obsessions) and by repetitive behaviors (compulsions). Family, twin, and segregation studies support the presence of both genetic and environmental susceptibility factors, and the only published genome scan for OCD identified a candidate region on 9p24 at marker D9S288 that met criteria for suggestive significance (Hanna et al. 2002). In an attempt to replicate this finding, we genotyped 50 pedigrees with OCD, using microsatellite markers spanning the 9p24 candidate region, and analyzed the data, using parametric and nonparametric linkage analyses under both a narrow phenotype model (DSM-IV OCD definite; 41 affected sib pairs) and a broad phenotype model (DSM-IV OCD definite and probable; 50 affected sib pairs). Similar to what was described by Hanna et al. (2002), our strongest findings came with the dominant parameters and the narrow phenotype model: the parametric signal peaked at marker D9S1792 with an HLOD of 2.26 ( alpha =0.59), and the nonparametric linkage signal (NPL) peaked at marker D9S1813 with an NPL of 2.52 (P=.006). These findings are striking in that D9S1813 and D9S1792 lie within 0.5 cM (<350 kb) of the original 9p24 linkage signal at D9S288; furthermore, pedigree-based association analyses also implicated the 9p24 candidate region by identifying two markers (D9S288 and GATA62F03) with modest evidence (P=.046 and .02, respectively) for association.

Chromosome Mapping↗

PubMed2004

Genomewide linkage scan for bipolar-disorder susceptibility loci among Ashkenazi Jewish families.

The relatively short history of linkage studies in bipolar disorders (BPs) has produced inconsistent findings. Implicated regions have been large, with reduced levels of significance and modest effect sizes. Both phenotypic and genetic heterogeneity may have contributed to the failure to define risk loci. BP is part of a spectrum of apparently familial affective disorders, which have been organized by severity. Heterogeneity may arise because of insufficient data to define the spectrum boundaries, and, in general, the less-severe disorders are more difficult to diagnose reliably. To address the inherent complexities in detecting BP susceptibility loci, we have used restricted diagnostic classifications and a genetically more homogeneous (Ashkenazi Jewish) family collection to perform a 9-cM autosomal genomewide linkage scan. Although they are genetically more homogeneous, there are no data to suggest that the rate of illness in the Ashkenazim differs from that in other populations. In a genome scan of 41 Ashkenazi pedigrees with a proband affected with bipolar I disorder (BPI) and at least one other member affected with BPI or bipolar II disorder (BPII), we identified four regions suggestive of linkage on chromosomes 1, 3, 11, and 18. Follow-up genotyping showed that the regions on chromosomes 1, 3, and 18 are also suggestive of linkage in a subset of pedigrees limited to relative pairs affected with BPI. Furthermore, our chromosome 18q22 signal (D18S541 and D18S477) overlaps with previous BP findings. This research is being conducted in parallel with our companion study of schizophrenia, in which, by use of an identical approach, we recently reported significant evidence for a schizophrenia susceptibility locus in the Ashkenazim on chromosome 10q22.

Bipolar Disorder↗

PubMed2004

An indirect test of the new mutation hypothesis associating advanced paternal age with the etiology of schizophrenia.

Two studies by Malaspina et al. [2001: Arch Gen Psychiatr 58:361-367]; [2002: Am J Med Genet 114:299-303] have put forward the hypothesis that advanced paternal age with concomitant mutations in the male germ line is associated with sporadic schizophrenia in offspring. The hypothesis was supported by an observation of a monotonic increase in the risk for schizophrenia with increased paternal age, and a second observation in a separate sample of greater paternal mean age at birth among cases of apparent sporadic schizophrenia. The present study did not test the association of the risk of schizophrenia with advanced paternal age, but repeated the test of paternal age at birth among sporadic versus familial schizophrenic probands. We also examined the risk of schizophrenia, psychosis, and broad psychosis among paternal 1st and 2nd degree relatives of schizophrenic probands as a function of paternal age at birth of the proband, reasoning that if probands born to older fathers are more likely to be sporadic cases, the risk of schizophrenia (or psychosis) should be lower on the paternal side of the family. Results indicate a lack of support for the previous finding that sporadic probands tend to have older fathers at birth than familial probands. Results also failed to support the related hypothesis that increased paternal age is associated with the lower risk of schizophrenia (or psychosis) in the relatives of schizophrenic probands. The failure to support the paternal age hypothesis may be a function of heterogeneous samples, but calls for further research in the context of family studies.

Family Health↗

PubMed2004

Clinical correlates of recurrent major depression in obsessive-compulsive disorder.

Major depressive disorder is the most frequent comorbid condition in obsessive-compulsive disorder (OCD). This study investigated factors associated with the development of recurrent major depressive disorder (RDD) in patients with OCD. Eighty OCD cases and 73 control probands were examined by psychiatrists or clinical psychologists using the Schedule for Affective Disorders and Schizophrenia-Lifetime Anxiety (SADS-LA). Two experienced psychiatrists independently reviewed all clinical materials and made final consensus diagnoses using DSM-IV criteria. Family history of OCD and RDD, additional comorbid disorders, OCD symptoms and illness severity were compared between persons with OCD alone (n = 21) and OCD with RDD (n = 41). Compared to OCD probands without RDD, OCD probands with RDD had earlier age at first diagnosis, more severe obsessive-compulsive symptoms, and were more likely to have a family history of RDD. Social phobia, separation anxiety disorder, and body dysmorphic disorder occurred more frequently in the comorbid group. In a multiple logistic regression model, only early age of OCD diagnosis was significantly associated with RDD. Early age at onset of OCD increases the risk of depressive disorder in individuals with OCD.

Adult↗

PubMed2004

Conditional multipoint linkage analysis using affected sib pairs: an alternative approach.

Recently, Liang et al. ([2001b] Genet. Epidemiol. 21:105-122) proposed a conditional approach to assess linkage evidence on the target region by incorporating linkage information from an unlinked (reference) region using allele shared IBD (identity-by-decent) from affected sib pairs. This is carried out by conditioning on the IBD sharing value at the estimated trait locus of the reference region. Since markers considered are typically non-fully informative, the IBD sharing at each marker needs to be estimated (or imputed). In this report, we propose an alternative approach to deal with the IBD sharing in the reference region. This new approach makes full use of the observed data without having to categorize the imputed IBD sharing as needed in Liang et al. ([2001b] Genet. Epidemiol. 21:105-122). We compare these two approaches by simulating data from a variety of two-locus models including heterogeneity, additive and multiplicative with either fully informative markers or non-fully informative markers. The performance of both approaches is quite comparable showing consistent estimates of the trait locus and key genetic parameters.

Alleles↗

PubMed2004

Quantitative trait linkage analysis by generalized estimating equations: unification of variance components and Haseman-Elston regression.

Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these were viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al. ([2002] Am. J. Hum. Genet. 71:238-253) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. First, this work provides new insight regarding the connection between these methods. Second, asymptotic approximations for power and sample size allow clear comparisons regarding the relative efficiency of the different methods. Third, our general framework suggests important extensions to the Haseman-Elston approach which make more complete use of the data in extended pedigrees and allow a natural incorporation of environmental and other covariates.

Algorithms↗

PubMed2004

Empirically derived latent classes of tobacco dependence syndromes observed in recent-onset tobacco smokers: epidemiological evidence from a national probability sample survey.

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.

Adolescent↗

PubMed2004

Five latent factors underlying schizophrenia: analysis and relationship to illnesses in relatives.

Clinical signs and symptoms in a sample of 1,043 individuals with schizophrenia or schizoaffective disorder were subjected to latent class factor analysis. Positive, negative, disorganized, and affective factors were similar in content to factors described in a number of other studies, while a fifth factor representing early onset/developmental signs provided a new area for investigation. The five sets of factor scores were logistically regressed on psychiatric illness indicators in first and second degree relatives. Relatives of probands with higher positive or negative symptom factor scores had a lower risk of depressive illness. Higher affective factor scores in probands predicted more mania and depression in relatives. Both the disorganized and the early onset/developmental factors were related to increased risk of psychiatric hospitalization in relatives, as well as increased risk of psychosis (marginally so for the disorganization factor). Increased early onset/developmental signs in the proband were also associated with increased risk for depression in relatives. These findings suggest a possible endophenotypic role for the factor scores in future studies.

Adult↗