Biomedical subjects

Heping Zhang

Publications and source records attributed to Heping Zhang.

At least 19 recordsLinked to original sources

PubMed2025

S-GMAS: Genome-Wide Mediation Analysis With Brain Subcortical Shape Mediators.

Mediation analysis is widely utilized in neuroscience to investigate the role of brain image phenotypes in the neurological pathways from genetic exposures to clinical outcomes. However, it is still difficult to conduct mediation analyses with whole genome-wide exposures and brain subcortical shape mediators due to several challenges including (i) large-scale genetic exposures, that is, millions of single-nucleotide polymorphisms (SNPs); (ii) nonlinear Hilbert space for shape mediators; and (iii) statistical inference on the direct and indirect effects. To tackle these challenges, this paper proposes a genome-wide mediation analysis framework with brain subcortical shape mediators. First, to address the issue caused by the high dimensionality in genetic exposures, a fast genome-wide association analysis is conducted to discover potential genetic variants with significant genetic effects on the clinical outcome. Second, the square-root velocity function representations are extracted from the brain subcortical shapes, which fall in an unconstrained linear Hilbert subspace. Third, to identify the underlying causal pathways from the detected SNPs to the clinical outcome implicitly through the shape mediators, we utilize a shape mediation analysis framework consisting of a shape-on-scalar model and a scalar-on-shape model. Furthermore, the bootstrap resampling approach is adopted to investigate both global and spatial significant mediation effects. Finally, our framework is applied to the corpus callosum shape data from the Alzheimer's Disease Neuroimaging Initiative.

Humans↗

PubMed2003

Cell and tumor classification using gene expression data: construction of forests.

The advent of gene chips has led to a promising technology for cell, tumor, and cancer classification. We exploit and expand the methodology of recursive partitioning trees for tumor and cell classification from microarray gene expression data. To improve classification and prediction accuracy, we introduce a deterministic procedure to form forests of classification trees and compare their performance with extant alternatives. When two published and commonly used data sets are used, we find that the deterministic forests perform similarly to the random forests in terms of the error rate obtained from the leave-one-out procedure, and all of the forests are far better than the single trees. In addition, we provide graphical presentations to facilitate interpretation of complex forests and compare our findings with the current biological literature. In addition to numerical improvement, the main advantage of deterministic forests is reproducibility and scientific interpretability of all steps in tree construction.

Cells↗

PubMed2003

Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome.

Obsessive-compulsive disorder (OCD) is an etiologically heterogeneous disorder. Recent factor analyses have consistently identified several symptom dimensions, two of which are associated with increased familial risk for OCD; aggressive, sexual, and religious obsessions and checking compulsions (FACTOR 1) and symmetry and ordering obsessions and compulsions (FACTOR 2). Both of these symptom dimensions are also frequently seen in association with Gilles de la Tourette syndrome (GTS). The purpose of this study was to determine whether these obsessive-compulsive (OC) symptom dimensions are correlated within families (between sibs and between parent-child pairs). Using data collected by the Tourette Syndrome Association International Consortium for Genetics Affected Sibling Pair Study, the authors selected all available GTS sib pairs and their parents for which these OC symptom dimensions (factor scores) could be generated. This group included 128 full sibs and their mothers (54) and fathers (54). Four OC symptom dimension scores were computed for each family member using an algorithm derived from item endorsements from the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) symptom checklist. In addition to a series of univariate analyses, complex segregation analyses were also completed using these quantitative OC symptom dimension scores. FACTOR 1 and FACTOR 2 scores were significantly correlated in sib pairs concordant for GTS. The mother-child correlations, but not father-child correlations, were also significant for these two factors. Segregation analyses were consistent with dominant major gene effects for both FACTOR 1 and FACTOR 2. We conclude that familial factors contribute significantly to OC symptom dimension phenotypes in GTS families. This familial contribution could be genetic or environmental.

Adolescent↗

PubMed2003

Basal Ganglia volumes in patients with Gilles de la Tourette syndrome.

BACKGROUND: Despite strong circumstantial evidence that the pathophysiology of Gilles de la Tourette syndrome (TS) involves structural and functional disturbances of the basal ganglia, inconsistent findings from relatively small in vivo TS imaging studies have supported contradictory conclusions concerning the role of abnormal anatomical characteristics of the basal ganglia in the pathophysiology of TS. METHODS: Basal ganglia volumes were measured on high-resolution magnetic resonance images acquired for 154 children and adults with TS and 130 healthy control subjects. Repeated-measures analyses tested hypotheses concerning regional specificity, age effects, and abnormal asymmetries in the basal ganglia of subjects with TS. Subjects with prior neuroleptic exposure had larger basal ganglia volumes and were excluded from further statistical analyses. RESULTS: Caudate nucleus volumes were significantly (P =.008) smaller in children and adults with TS. Lenticular nucleus volumes also were smaller in adults with TS and in children with TS who were diagnosed as having comorbid obsessive-compulsive disorder. Regional anatomical asymmetries did not differ across groups. Regional volumes did not correlate significantly with the severity of tic, obsessive-compulsive disorder, or attention-deficit/hyperactivity disorder symptoms. CONCLUSIONS: Reduced caudate nucleus volumes may be a good candidate marker for a trait abnormality in the structure of the basal ganglia in persons with TS. Smaller lenticular nucleus volumes may be an additional marker for the presence of comorbid obsessive-compulsive disorder and for the persistence of tic symptoms into adulthood. Brain regions other than the basal ganglia may have greater clinical relevance in determining the severity of tic symptoms.

Adolescent↗

PubMed2003

Longitudinal trajectories of depression and anxiety in a prospective community study: the Zurich Cohort Study.

BACKGROUND: The dearth of long-term follow-up studies of community-based samples and differences in methodology in existing studies highlight the need for research designed to examine the stability, comorbidity, and diagnostic thresholds of depression and anxiety in the community. METHODS: Prospective study of a community-based cohort aged 19 and 20 years from the canton of Zurich, Switzerland. Semistructured diagnostic interviews were administered by clinically experienced interviewers at 5 assessment points during a 15-year period. The format of the interview permitted assessment of major mental disorders at both the diagnostic and subthreshold levels. RESULTS: Comorbid anxiety and depression tended to be far more persistent than either syndrome alone. Individuals with anxiety states alone tended to develop either depression alone or comorbid anxiety and depression as they progressed through adulthood. In contrast, depression alone and depression comorbid with anxiety tended to be more stable than anxiety alone over time. The patterns of stability were similar for subthreshold- and threshold-level disorders. CONCLUSIONS: These findings have important implications for classification and treatment of affective disorders. The greater stability of comorbid anxiety and depression than either disorder alone illustrates the importance of further investigation of comorbid states compared with noncomorbid states in etiologic and treatment research. The persistence of subthreshold-level depression and anxiety from early to mid adulthood also suggests the importance of characterizing the continuum of expression of depression and anxiety rather than adhering to strict diagnostic thresholds.

Adult↗

PubMed2003

Tree-based disease classification using protein data.

A reliable and precise classification of diseases is essential for successful diagnosis and treatment. Using mass spectrometry from clinical specimens, scientists may find the protein variations among disease and use this information to improve diagnosis. In this paper, we propose a novel procedure to classify disease status based on the protein data from mass spectrometry. Our new tree-based algorithm consists of three steps: projection, selection and classification tree. The projection step aims to project all observations from specimens into the same bases so that the projected data have fixed coordinates. Thus, for each specimen, we obtain a large vector of 'coefficients' on the same basis. The purpose of the selection step is data reduction by condensing the large vector from the projection step into a much lower order of informative vector. Finally, using these reduced vectors, we apply recursive partitioning to construct an informative classification tree. This method has been successfully applied to protein data, provided by the Department of Radiology and Chemistry at Duke University.

Computational Biology↗

PubMed2003

Recurrence of bipolar disorders and major depression. A life-long perspective.

OBJECTIVE: It is not known whether the risk of recurrence declines with time in bipolar disorders and in major depression. This study describes the life-long recurrence risk of bipolar I, bipolar II and major depressive disorders. METHOD: 160 bipolar-I, 60 bipolar-II and 186 depressive patients hospitalised between 1959 and 1963 were followed up every five years from 1965 to 1985. The course prior to the index hospitalisation was assessed in retrospect. The recurrence risk was computed by the multiplicative intensity model (Aalen et al. 1980). RESULTS: The cumulative intensity curves for the transition from states of remission to new episodes remained linear over 30 to 40 years after onset, indicating a constant risk of recurrence over the life-span up to the age of 70 or more. The recurrence risk of bipolar disorders (0.40 episodes per year) was about twice that of depression (0.20 episodes per year); BP-II disorders had only a slightly higher recurrence risk than BP-I disorders. There were no significant gender differences in the course of either bipolar or depressive disorders. CONCLUSION: If long-term trials confirm its efficacy, these results support lifelong prophylactic treatment of severe types of mood disorders.

Adult↗

PubMed2003

Classification of dental caries patterns in the primary dentition: a multidimensional scaling analysis.

OBJECTIVE: Clinical patterns of early childhood caries (ECC) encompassing specific teeth or surfaces have been previously proposed on an a priori basis and have been used as case definitions. The underlying assumption is that the patterns result from different host response and environmental conditions. Identifying caries patterns has utility in refining case definitions of ECC. Well-defined caries patterns should enhance the ability of an analysis to identify meaningful associations between suspected risk factors and ECC. The purpose of this project was to identify patterns of caries in the dentition of preschool children using multidimensional scaling without a priori pattern delineation. METHODS: Between February 1994 and September 1995, five examiners visually examined 5171 Arizona preschool children aged 5-59 months old. Multidimensional scaling (MDS) was used as a classification/taxonomy technique to identify any underlying structure of the caries data. MDS provided a classification scheme for individual tooth surfaces based on the dissimilarity measures of squared Euclidean distance and of variance using an alscal analysis. Both two- and three-dimensional solutions were pursued; s-stress, stress, R-square and residual patterns were assessed in determining the best dimensional model, with the resulting quadrant positions of the tooth surfaces suggesting potential caries patterns. RESULTS: All models demonstrated excellent fit. Two- and three-dimensional solutions suggested four caries patterns: (i) any maxillary incisor surfaces, (ii) first molar occlusal surfaces, (iii) second molar pit and fissure surfaces, and (iv) any smooth surfaces, excluding the maxillary incisor surfaces. CONCLUSIONS: This is the first delineation of primary dentition caries patterns produced by a classification analysis without a priori pattern definitions. The identified caries patterns may arise from specific risk factors and/or be a function of the timing of various risk factor exposures. Use of these patterns as case definitions should enhance the ability to identify associations between suspected risk factors and ECC.

Child, Preschool↗

PubMed2003

Assessing sex differences on treatment effectiveness from the drug abuse treatment outcome study (DATOS).

Men and women entering drug treatment programs are known to differ in demographic characteristics and psychosocial behavioral patterns. To be effective, any such program that caters to individuals from both sexes should identify and address these gender-based variations. Studies have also reported clinical differences in the effect of drugs on men and women addicts. Here, we examine whether the treatment is equally effective on men and women, when several demographic covariates are controlled. We construct a "problem severity index" to categorize individuals based on how acute their problems were at the start of the program. We also examine how the choice of treatment modality affects treatment success. Cumulative logit models were used in our analysis. The choice of treatment modality is sex specific, although sex did not appear to be a significant factor for treatment effectiveness when we controlled for other explanatory variables.

Adolescent↗

PubMed2003

Disruptive behavior in children with Tourette's syndrome: association with ADHD comorbidity, tic severity, and functional impairment.

OBJECTIVE: To examine the association of disruptive behavior with social, adaptive, and family functioning in Tourette's syndrome (TS) with and without comorbid attention-deficit/hyperactivity disorder (ADHD). METHOD: The sample included 207 children (144 boys and 63 girls) between the ages of 7 and 18 years. Forty-two children received a diagnosis of TS-only, 52 received a diagnosis of ADHD-only, 52 children had TS+ADHD, and there were 61 unaffected control children. Best-estimate DSM-IV diagnoses were assigned on the basis of structured interviews and clinical ratings. Dependent measures included parent and teacher ratings of disruptive behavior, parent ratings of social and family functioning, and the Vineland Adaptive Behavior Scales. RESULTS: Children with TS-only did not differ from unaffected controls on the parent ratings of aggression and delinquent behavior or on the teacher ratings of conduct problems. By contrast, children with TS+ADHD were rated significantly above unaffected controls and similar to children with ADHD-only on these indices of disruptive behavior. Hierarchical regression analyses revealed that aggression and delinquency scores added unique contributions to impairment in social and family functioning, controlling for age, gender, and diagnostic status. CONCLUSIONS: Comorbid ADHD is highly associated with disruptive behavior and functional impairment in children with TS. When disruptive behavior problems are present, there is an additional burden on children's social and family functioning.

Adolescent↗

PubMed2003

Developmental trajectories of cocaine-and-other-drug-exposed and non-cocaine-exposed children.

Few data are available concerning the trajectories of mental and motor development across time for cocaine-exposed children compared with others. Findings are presented from individual group curve analyses of the mental and motor development measured by the Bayley Scales of Infant Development-II (BSID-II) on repeated visits from 3 through 36 months of a group of prenatally cocaine-and-other-drug-exposed children (n = 265) compared with those exposed to no drugs (n = 129) or no-cocaine-but-other-drugs (n = 66), including alcohol and/or tobacco. Across time, there was a general decline in motor performance but cocaine-exposed-infants showed a trend toward a greater decrease than children in the other two comparison groups. For mental performance, there was also a decline across age but only through 24 months and no differences in the trajectory of the cocaine-exposed group compared to the other two. And, across all assessment ages, cocaine-exposed-infants showed lower BSID-II mental performance compared to both non-drug and non-cocaine-exposed children. Results suggest that prenatally cocaine-exposed children show delayed developmental indices, particularly in their mental performance, but their trajectories across time are similar to those from impoverished, non-cocaine-exposed groups.

Child↗

PubMed2003

Development of the Yale Children's Global Stress Index (YCGSI) and its application in children and adolescents ith Tourette's syndrome and obsessive-compulsive disorder.

OBJECTIVE: The Yale Children's Global Stress Index (YCGSI) is a new clinical rating instrument designed to provide objective global clinician ratings of psychosocial stress in studies of children and adolescents. This study was designed to evaluate the psychometric properties of the YCGSI. METHOD: Independent ratings of clinical severity and psychosocial stress were obtained at two time points separated by 4 months from 33 subjects with Tourette's syndrome (TS) and/or early-onset obsessive-compulsive disorder (OCD), aged 7 to 17 years, and 25 age-matched control subjects. Parents and children were interviewed separately. Multiple measures of stress were obtained including the YCGSI and the Daily Life Stressors Scale (DLSS). RESULTS: Data support the interrater reliability and convergent and divergent validity of the YCGSI. At both time points, children and adolescents with TS and OCD had, on average, experienced significantly more psychosocial stress than did the controls. Cross-sectional ratings of tic and obsessive-compulsive symptom severity did not correlate with the YCGSI, but did correlate with self-report ratings of stress on the DLSS. In contrast, ratings on the YCGSI were associated with clinician ratings of depression. CONCLUSIONS: The YCGSI has acceptable psychometric properties. Children and adolescents with TS and OCD appear to be at increased risk of experiencing higher levels of psychosocial stress and adversities compared with their peers in the community. Future studies need to examine the possible differential contributions of distinctive forms of stress on the intramorbid course of these disorders.

Adolescent↗

PubMed2002

Disrupted synaptic development in the hypoxic newborn brain.

Infants born prematurely risk significant life-long cognitive disability, representing a major pediatric health crisis. The neuropathology of this cohort is accurately modeled in mice subjected to sublethal postnatal hypoxia. Massively parallel transcriptome analysis using cDNA microchips (9,262 genes), combined with immunohistochemical and protein assays, reveals that sublethal hypoxia accentuates genes subserving presynaptic function, and it suppresses genes involved with synaptic maturation, postsynaptic function, and neurotransmission. Other significantly affected pathways include those involved with glial maturation, vasculogenesis, and components of the cortical and microtubular cytoskeleton. These patterns reveal a global dysynchrony in the maturation programs of the hypoxic developing brain, and offer insights into the vulnerabilities of processes that guide early postnatal cerebral maturation.

Animals↗

PubMed2002

Tree-based analysis of microarray data for classifying breast cancer.

DNA microarray data have provided us with the opportunity to assess the expression levels for thousands of genes simultaneously. One of the uses of this information is to classify cancer tumors. A noted challenge in using microarray information is analytical. Following the work of Zhang et al. (1), we further pursue the use of recursive partitioning in analyses of microarray data for cancer classification. Not only does the recursive partitioning technique create intuitive classification rules, but also it is most flexible as to the handling of a massive number of genes, missing expressions, and multi-class tissues. Using a published data set (2), we demonstrate that the recursive partitioning technique creates a more precise and simpler classification rule than other commonly used approaches. In particular, we introduce the concept of A-tree and propose a procedure to assess a large number of A-trees. One of the identified genes (ERBB2) is in the close region of BRCA1 (17q21.1) and has been shown by others to have altered expression levels in breast cancer. Nonetheless, our identified genes warrant further investigation as to whether they play a role in the etiology of breast cancer.

Breast Neoplasms↗

PubMed2002

Genomewide scan of hoarding in sib pairs in which both sibs have Gilles de la Tourette syndrome.

A genome scan of the hoarding phenotype (a component of obsessive-compulsive disorder) was conducted on 77 sib pairs collected by the Tourette Syndrome Association International Consortium for Genetics (TSAICG). All sib pairs were concordant for a diagnosis of Gilles de la Tourette syndrome (GTS). However, the analyses reported here were conducted for hoarding as both a dichotomous trait and a quantitative trait. Not all sib pairs in the sample were concordant for hoarding. Standard linkage analyses were performed using GENEHUNTER and Haseman-Elston methods. In addition, novel analyses with a recursive-partitioning technique were employed. Significant allele sharing was observed for both the dichotomous and the quantitative hoarding phenotypes for markers at 4q34-35 (P=.0007), by use of GENEHUNTER, and at 5q35.2-35.3 (P=.000002) and 17q25 (P=.00002), by use of the revisited Haseman-Elston method. The 4q site is in proximity to D4S1625, which was identified by the TSAICG as a region linked to the GTS phenotype. The recursive-partitioning technique examined multiple markers simultaneously. Results suggest joint effects of specific loci on 5q and 4q, with an overall P value of.000003. Although P values were not adjusted for multiple comparison, nearly all were much smaller than the customary significance level of.0001 for genomewide scans.

Alleles↗

PubMed2002

The spectrum of social phobia in the Zurich cohort study of young adults.

BACKGROUND: The goals of the present study are to describe the prevalence, risk factors, course, and impact of social phobia in a 15-year prospective longitudinal community study; and to examine an expanded conceptualization of social phobia with respect to clinical indicators of severity, as well as gender differences, personality traits, and stability over 15 years. METHODS: The sample is a cohort of 591 young adults aged 18-19 from the general population of Zurich, Switzerland at study entry who have been followed to age 35. RESULTS: Six percent of participants met lifetime criteria for social phobia at the diagnostic level, 12% at the subthreshold level, and 24% had social phobia symptoms alone. Women had higher lifetime rates of diagnostic and subthreshold-level social phobia, whereas there was an equal gender ratio of social phobia symptoms. There was a direct association between strictness of the diagnostic threshold and severity, such that work impairment, social impairment, treatment rate, medication use, and subjective distress decreased from the diagnostic to the symptom level. Similarly, family history of phobias, autonomic lability, and comorbidity decreased across the spectrum. Although there was a substantial degree of longitudinal stability at each level of the spectrum, significant oscillation across levels suggests that the spectrum concept better characterizes the longitudinal course of social phobia. CONCLUSIONS: These findings demonstrate the utility of the social phobia spectrum. Application of the spectrum concept provides coverage of treated but undiagnosed cases of social phobia as well as those who vacillate across the diagnostic threshold over time.

Adolescent↗

PubMed2002

Toward validation of atypical depression in the community: results of the Zurich cohort study.

AIMS: This paper (1) examines the validity of the atypical subtype of depression in a community-based longitudinal cohort study, (2) presents estimates of the prevalence and sex differences of DSM-IV atypical depression and a newly more broadly defined atypical syndrome in the community and (3) compares the clinical correlates and treatment patterns of those with atypical depression with other depressives. METHODS: The Zurich cohort study is comprised of 591 subjects selected from a population-based cohort of young adults representative of the canton of Zurich in Switzerland, who were screened in 1978 with the Symptom Checklist 90-R [L.R. Derogatis (1977)] and followed prospectively with five interviews between 1979 and 1993. Atypical depression was defined on a spectrum ranging from atypical major to minor to atypical depressive symptoms alone. RESULTS: The rate of DSM-IV atypical major depressive episodes in this community is 4.8% and for major atypical depression syndrome is 7.3%. Whereas there was no marked sex difference for nonatypical features, there was a significant female preponderance for DSM-IV and broadly defined atypical depressive subtypes. Systematic investigation of the diagnostic criteria for atypical depression revealed that a nonhierarchical definition of atypical depression with respect to mood reactivity yielded as valid a syndromic definition as the current hierarchy based on mood reactivity as an essential feature. Very high comorbidity (odd ratios>2.0) was found with seasonality, bipolar II, social phobia, binge eating, neurasthenia and sociopathy. LIMITATIONS: Atypical depression was not defined à priori, its criteria were derived from two sections of the Zurich interview. CONCLUSIONS: Atypical depression has high population prevalence and substantial significance in terms of clinical severity, impairment, and service use. The intriguing finding that the sex difference in depression may be attributed to atypical features of depression will need further investigation. Overall, our data indicate that the atypical subtype of depression is a valid entity based on evidence from such traditional indicators of validity as inclusion criteria and indicators of course. However, there are some problems with discriminatory validity from other disorders. Although comorbidity with these disorders may in part reflect an operational artifact of symptom overlap, further work needs to be done in distinguishing atypical depression from bipolar II.

Adult↗

PubMed2002

A functional magnetic resonance imaging study of language processing and its cognitive correlates in prematurely born children.

OBJECTIVE: Abnormalities in brain structure, cognition, and behavior have been described in children born prematurely. However, no direct in vivo evidence has yet demonstrated abnormal neural processing in these children. Our aim was to compare brain activity associated with phonologic and semantic processing of language between term and preterm children using functional magnetic resonance imaging (fMRI). METHODS: fMRI scans were acquired during a passive language comprehension task in 26 preterm children at 8 years of age and in 13 term community control children who were comparable in age, sex, maternal education, and minority status. IQ was assessed using a standard measure of intelligence. RESULTS: The pattern of brain activity identified in a semantic processing task in the preterm children closely resembled the pattern of brain activity identified in a phonologic processing task in term controls. The greater this resemblance in the preterm children, the lower their verbal comprehension IQ scores and the poorer their language comprehension during the scanning task. CONCLUSIONS: Preterm children with the poorest language comprehension seemed not to fully engage normal semantic processing pathways in a language comprehension task. These children instead engaged pathways that normal term children used to process meaningless phonologic sounds. Aberrant processing of semantic content in these preterm children may account in part for their lower verbal IQ scores.

Benzophenones↗