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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↗
PubMed2007

Generation of insulin-producing cells from PDX-1 gene-modified human mesenchymal stem cells.

Islet cell replacement is considered as the optimal treatment for type I diabetes. However, the availability of human pancreatic islets for transplantation is limited. Here, we show that human bone marrow-derived mesenchymal stem cells (hMSCs) could be induced to differentiate into functional insulin-producing cells by introduction of the pancreatic duodenal homeobox-1 (PDX-1). Recombinant adenoviral vector was used to deliver PDX-1 gene into hMSCs. After being infected with Ad-PDX-1, hMSCs were successfully induced to differentiate into insulin-secreting cells. The differentiated PDX-1+ hMSCs expressed multiple islet-cell genes including neurogenin3 (Ngn3), insulin, GK, Glut2, and glucagon, produced and released insulin/C-peptide in a weak glucose-regulated manner. After the differentiated PDX-1+ hMSCs were transplanted into STZ-induced diabetic mice, euglycemia can be obtained within 2 weeks and maintained for at least 42 days. These findings validate the hMSCs model system as a potential basis for enrichment of human beta cells or their precursors, and a possible source for cell replacement therapy in diabetes.

Adenoviridae↗
PubMed2006

Linkage analysis of longitudinal data and design consideration.

BACKGROUND: Statistical methods have been proposed recently to analyze longitudinal data in genetic studies. So far, little attention has been paid to examine the relationship among key factors in genetic longitudinal studies including power, the number of families or sibships, and the number of repeated measures per individual subjects. RESULTS: We proposed a variance component model that extends classic variance component models for a single quantitative trait to mapping longitudinal traits. Our model includes covariate effects and allows genetic effects to vary over time. Using our proposed model, we examined the power, pedigree structures, and sample size through simulation experiments. CONCLUSION: Our simulation results provide useful insights into the study design for genetic, longitudinal studies. For example, collecting a small number of large sibships is much more powerful than collecting a large number of small sibships or increasing the number of repeated measures, when the total number of measurements is comparable.

Computer Simulation↗
PubMed2006

A statistical framework for the classification of tensor morphologies in diffusion tensor images.

Tractography algorithms for diffusion tensor (DT) images consecutively connect directions of maximal diffusion across neighboring DTs in order to reconstruct the 3-dimensional trajectories of white matter tracts in vivo in the human brain. The performance of these algorithms, however, is strongly influenced by the amount of noise in the images and by the presence of degenerate tensors-- i.e., tensors in which the direction of maximal diffusion is poorly defined. We propose a simple procedure for the classification of tensor morphologies that uses test statistics based on invariant measures of DTs, such as fractional anisotropy, while accounting for the effects of noise on tensor estimates. Examining DT images from seven human subjects, we demonstrate that this procedure validly classifies DTs at each voxel into standard types (nondegenerate DTs, as well as degenerate oblate, prolate or isotropic DTs), and we provide preliminary estimates for the prevalence and spatial distribution of degenerate tensors in these brains. We also show that the P values for test statistics are more sensitive tools for classifying tensor morphologies than are invariant measures of anisotropy alone.

Algorithms↗
PubMed2006

Ascertainment adjustment in genetic studies of ordinal traits.

Most genetic studies recruit high risk families and the discoveries are based on non-random selected groups. We must consider the consequences of this ascertainment process in order to apply the results of genetic research to the general population. In previous reports, we developed a latent variable model to assess the familial aggregation and inheritability of ordinal-scaled diseases, and found a major gene component of alcoholism after applying the model to the data from the Yale family study of comorbidity of alcoholism and anxiety (YFSCAA). In this report, we examine the ascertainment effects on parameter estimates and correct potential bias in the latent variable model. The simulation studies for various ascertainment schemes suggest that our ascertainment adjustment is necessary and effective. We also find that the estimated effects are relatively unbiased for the particular ascertainment scheme used in the YFSCAA, which assures the validity of our earlier conclusion.

Computer Simulation↗
PubMed2006

Adulthood outcome of tic and obsessive-compulsive symptom severity in children with Tourette syndrome.

BACKGROUND: Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder that is characterized by both motor and phonic tics. One half to two thirds of children with TS experience a reduction or complete resolution of tic symptoms during adolescence. At least one third of adults with TS have comorbid obsessive-compulsive disorder (OCD). OBJECTIVES: To clarify the clinical course of tic and OCD symptoms in children with TS and determine if baseline clinical measurements in childhood are associated with future symptom severity in late adolescence and early adulthood. DESIGN: Prospective cohort study. SETTING: Yale Child Study Center tic and OCD outpatient specialty clinic. PARTICIPANTS: Forty-six children with TS who received a structured clinical evaluation prior to age 14 years. MAIN OUTCOME MEASURES: Expert-rated tic and OCD symptom severity at follow-up interview an average of 7.6 years later (range, 3.8-12.8 years). RESULTS: Eighty-five percent of subjects reported a reduction in tic symptoms during adolescence. Only increased tic severity in childhood was associated with increased tic severity at follow-up. The average age at worst-ever tic severity was 10.6 years. Forty-one percent of patients with TS reported at one time experiencing at least moderate OCD symptoms. Worst-ever OCD symptoms occurred approximately 2 years later than worst-ever tic symptoms. Increased childhood IQ was strongly associated with increased OCD severity at follow-up. CONCLUSION: Obsessive-compulsive disorder symptoms in children with TS became more severe at a later age and were more likely to persist than tic symptoms.

Adolescent↗
PubMed2006

Family-based association tests for ordinal traits adjusting for covariates.

We present a class of family-based association tests (FBATs) for ordinal traits that adjust for the effects of covariates. For complex diseases, especially mental health conditions including nicotine dependence and substance use, the outcome variables are often recorded in an ordinal rather than quantitative scale. The naturally recorded ordinal traits are commonly analyzed either as quantitative traits or are dichotomized. It has been demonstrated repeatedly in recent studies that these commonly used approaches to dealing with ordinal traits are inadequate and result in loss of power. In this report, we make use of conditional likelihood to derive score test statistics that belong to a general class of FBATs. We conducted simulation studies to compare the type I error and power of our proposed test with existing tests. The empirical result suggests that our test produces reasonable type I errors and has power far exceeding (often doubling) those of existing tests. We applied our proposed test to a data set on alcohol dependence and found that six single nucleotide polymorphisms (SNPs) are significantly associated (P-values < or =0.001) with alcohol dependence after adjusting for gender and age. Three of the SNPs (rs619, rs1972373, and rs1571423) or their tightly linked regions have been suggested in the literature from the analysis of the same data, demonstrating the consistent findings between various methods. The other three SNPs (rs485874, rs718251, and rs1869907) are identified for the first time using this data set, underscoring the potential power of our proposed test.

Alcoholism↗
PubMed2006

Recursive partitioning-based preoperative risk stratification for atrial fibrillation after coronary artery bypass surgery.

BACKGROUND: Knowledge of the risk of atrial fibrillation (AF) for patients undergoing coronary artery bypass graft surgery (CABG) can guide decisions about prophylactic therapy. Accordingly, we sought to use tree-based methods to stratify patients into groups that will have similar risk of AF after CABG and informed decision making regarding aggressive prophylaxis of AF. METHODS: We studied 1209 consecutive patients with isolated CABG performed in 1998-1999 at Yale-New Haven Hospital. Patients with preoperative AF were excluded. Tree-based analysis was carried out to stratify patients into similar groups regarding the risk of AF. Relative risks (RRs) and 95% CIs were calculated at each level of stratification. RESULTS: Age was the most important variable. The importance of other risk factors seemed to be different for younger and older patients. Although in the younger age group (< or =60 years) severity of coronary artery disease (RR 2.19, 95% CI 1.12-3.34) followed by hypertension (RR 1.82, 95% CI 1.23-2.68) were important predictors, in the older age subgroups (61-69 and > or =70 years), nothing or only ejection fraction <40% (RR 1.31, 95% CI 1.08-1.59) was important. In the highest-risk group, AF occurrence was 55% and, in the lowest-risk group, it was 10%. In the low-risk groups, aggressive prophylaxis may not be justified in light of the smaller number of events that would be prevented, possible adverse events, and costs. CONCLUSION: Age and variables related to heart disease severity are predictors of AF. The tree-based method may be a useful tool for clinicians who seek to determine who is more or less likely to benefit from aggressive arrhythmia prophylaxis.

Aged↗
PubMed2006

Cortical neurogenesis enhanced by chronic perinatal hypoxia.

Most regions of the mature mammalian brain, including the cerebral cortex, appear to be unable to support the genesis of new neurons. Here, we report that a low level of neurogenesis occurs in the cerebral cortex of the infant mouse brain and is enhanced by chronic perinatal hypoxia. When mice were reared in a low-oxygen environment from postnatal days 3 to 11, approximately 30% of the cortical neurons were lost after the insult; yet this damage was transient. The loss of cortical neuron number, cortical volume, and brain weight were all reversed during the recovery period. At P18, 7 days after the cessation of hypoxia, there was a marked increase in astroglial cell proliferation within the SVZ, as assessed by 5-bromodeoxyuridine (BrdU) incorporation in S-phase cells. One month after BrdU incorporation, 40% more BrdU-positive cells were found in the cerebral cortex of hypoxic-reared as compared to normoxic control mice. Among these newly generated cortical cells, approximately 45% were oligodendrocytes, 35% were astrocytes, and 10% were neurons in both hypoxic and normoxic mice. However, twice as many BrdU-labeled cells expressed neuronal markers in the neocortex in mice recovering from hypoxia as compared to controls. In both hypoxic-reared and normoxic infant/juvenile mice, putative neuroblasts could be seen detaching from the forebrain subventricular zone, migrating through the subcortical white matter and entering the lower cortical layers, 5 to 11 days after their last mitotic division. We suggest that cortical neurogenesis may play a significant role in repairing neuronal losses after neonatal injury.

Age Factors↗
PubMed2006

Substance-abusing mothers and disruptions in child custody: an attachment perspective.

Using an attachment framework, we examined (1) whether substance-abusing mothers' perceptions of how they were parented were related to the severity of their substance abuse and psychological maladjustment and (2) whether these two factors mediated the association between mothers' perceptions of how they were parented and their children's placement out of home. There were 108 mothers of 248 children who completed interviews upon admission to a methadone maintenance program for women. Measures included lifetime risk composite scores derived from the Addiction Severity Index, the Parental Bonding Instrument, and a demographics questionnaire. A multilevel modeling approach was used to model effects of the hierarchically organized data (e.g., children nested within families). Findings are consistent with an attachment perspective on parenting suggesting that the internal psychological processes of a parent play a critical role in the continuity of parenting.

Adjustment Disorders↗
PubMed2006

A randomized controlled trial of a coping group intervention for adults with HIV who are AIDS bereaved: longitudinal effects on grief.

The authors sought to study the longitudinal effects of a cognitive-behavioral group intervention for coping with AIDS bereavement among a diverse sample of adults who were HIV positive. Participants (N = 267) were randomly assigned to receive the 12-week intervention or individual therapy upon request. Measures were administered at baseline, postintervention, and 4-, 8-, and 12-month follow-ups. Longitudinal data were analyzed with linear mixed models to examine change in grief by condition across the study period and the effect of the intervention on grief through its interaction with psychiatric distress. The authors used the Grief Reaction Index to assess grief and the Symptom Checklist-90-Revised to assess global psychiatric distress. Participants in both conditions reported decreases in grief severity. However, among those with higher levels of psychiatric distress, participants in the group intervention had significantly lower grief severity scores compared with participants in the individual therapy condition. The long-term effectiveness of this AIDS-bereavement intervention for psychiatrically distressed people with HIV/AIDS supports the need for tailored interventions among those at risk for complicated grief responses.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Longitudinal effects of coping on outcome in a randomized controlled trial of a group intervention for HIV-positive adults with AIDS-related bereavement.

This study examined the longitudinal effects of coping on outcome one year following completion of a randomized, controlled trial of a group coping intervention for AIDS-related bereavement. Bereaved HIV-positive participants (N = 267) were administered measures of grief, psychiatric distress, quality of life, and coping at baseline, post-intervention, and at 4-, 8-, and 12-month follow-ups. Coping strategies directly impacted all outcome variables for both study conditions. Additionally, the coping intervention moderated the relationship between avoidant coping and the longitudinal course of grief and psychiatric distress, resulting in greater reductions in grief and distress for intervention participants after accounting for avoidant coping strategies.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Associations of ethnicity/race and socioeconomic status with early childhood caries patterns.

OBJECTIVES: The purpose of this project was to evaluate ethnicity/race, household income and caregiver education level as predictors of (1) any early childhood caries, and (2) each of four proposed patterns of primary dentition caries. METHODS: Between February 1994 and September 1995, five examiners visually examined Arizona pre-school children ages 5-59 months old. Self-reported demographic information including family income, caregiver education level and ethnicity/race were obtained at the time of examination. Multivariate analyses were conducted to assess the association of income, education and ethnicity/race with a child having any caries and with each of the proposed caries patterns seen in 3850 examinations. RESULTS: Income and education were inversely associated with: (1) any early childhood caries, and (2) the maxillary incisor caries pattern. A positive association between these caries patterns and minority ethnicity/race status was also identified. Three additional caries intraoral patterns demonstrated more varied associations with socioeconomic status (SES), ethnicity/race and income and education. CONCLUSIONS: This study supports the association of both ethnicity/race and social status with any early childhood caries. The patterns of caries were each found to be associated with specific and different socioeconomic-demographic indicators. The practical importance of these findings is that global measurement of ECC, without regard to specific caries pattern, leads to the potential for substantial non-differential misclassification of disease. The consequence of this is the potential for important ECC-SES-ethnicity/race associations to be masked. This, in turn, decreases the ability of surveys and investigations to accurately identify sub-groups of the population at greatest risk of developing ECC.

Arizona↗
PubMed2006

Familial and genetic susceptibility to major neonatal morbidities in preterm twins.

BACKGROUND: Intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia remain significant causes of morbidity and mortality in preterm newborns. OBJECTIVES: Our goal was to assess the familial and genetic susceptibility to intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia. METHODS: Mixed-effects logistic-regression and latent variable probit model analysis were used to assess the contribution of several covariates in a multicenter retrospective study of 450 twin pairs born at < or =32 weeks of gestation. To determine the genetic contribution, concordance rates in a subset of 252 monozygotic and dizygotic twin pairs were compared. RESULTS: The study population had a mean gestational age of 29 weeks and birth weight of 1286 g. After controlling for effects of covariates, the twin data showed that 41.3%, 51.9%, and 65.2%, respectively, of the variances in liability for intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia could be accounted for by genetic and shared environmental factors. Among the 63 monozygotic twin pairs, the observed concordance for bronchopulmonary dysplasia was significantly higher than the expected concordance; 12 of 18 monozygotic twin pairs with > or =1 affected member had both members affected versus 3.69 expected. After controlling for covariates, genetic factors accounted for 53% of the variance in liability for bronchopulmonary dysplasia. CONCLUSIONS: Twin analyses show that intraventricular hemorrhage, necrotizing enterocolitis, and bronchopulmonary dysplasia are familial in origin. These data demonstrate, for the first time, the significant genetic susceptibility for bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary Dysplasia↗
PubMed2006

Genetic susceptibility to retinopathy of prematurity.

OBJECTIVES: The goals were to isolate and to estimate the genetic susceptibility to retinopathy of prematurity. METHODS: A retrospective study (1994-2004) from 3 centers was performed with zygosity data for premature twins who were born at a gestational age of < or = 32 weeks and survived beyond a postmenstrual age of 36 weeks. Retinopathy of prematurity was diagnosed and staged by pediatric ophthalmologists at each center. Data analyses were performed with mixed-effects logistic regression analysis and latent variable probit modeling. RESULTS: A total of 63 monozygotic and 137 dizygotic twin pairs were identified and analyzed. Data on gestational age, birth weight, gender, respiratory distress syndrome, retinopathy of prematurity, bronchopulmonary dysplasia, duration of ventilation and supplemental oxygen use, and length of stay were comparable between monozygotic and dizygotic twins. In the mixed-effects logistic regression analysis for retinopathy of prematurity, gestational age and duration of supplemental oxygen use were significant covariates. After controlling for known and unknown nongenetic factors, genetic factors accounted for 70.1% of the variance in liability for retinopathy of prematurity. CONCLUSION: In addition to prematurity and environmental factors, there is a strong genetic predisposition to retinopathy of prematurity.

Female↗
PubMed2006

DOPA decarboxylase gene is associated with nicotine dependence.

INTRODUCTION: Cigarette smoking is a prevalent and harmful behavior. Although the heritability of nicotine dependence (ND) is well documented and many candidate genetic regions have been identified, few of them were confirmed. This may be, in part, due to analytic methods that sacrifice power. METHODS: Using a recently developed, more powerful method for testing association between a genetic marker and an ordinal trait, we analyzed data from 1879 smokers and nonsmokers from 600 nuclear families of African- or European-American (AA or EA) ancestry. This method increases power principally by accounting for differences in severity between affected subjects. RESULTS: To demonstrate the more powerful method, we re-analyzed an existing dataset, which confirmed the association of the DOPA decarboxylase (DDC) gene on chromosome 7p11 with measures of nicotine dependence. Although none of the eight single nucleotide polymorphisms (SNPs) studied were found to be significantly associated with nicotine dependence (unadjusted p-value > 0.01), we identified haplotypes from those SNPs that were significantly associated with nicotine dependence in both AA and EA samples. CONCLUSION: The associated haplotypes differed in the AA and EA samples. The strongest association (p-value = 0.003) was identified between the 'heaviness of smoking index' and haplotype C-A-T-G in SNPs rs921451-rs3735273-rs1451371-rs2060762. However, this association was not found significant in a previous report (p-value = 0.19) that used the same sample, underscoring the importance of using the statistical methods that use more of the available phenotypic information, and thereby better reflect the distribution of the phenotypes.

Black or African American↗
PubMed2005

Multivariate linkage analysis using the electrophysiological phenotypes in the COGA alcoholism data.

Multivariate linkage analysis using several correlated traits may provide greater statistical power to detect susceptibility genes in loci whose effects are too small to be detected in univariate analysis. In this analysis, we apply a new approach and perform a linkage analysis of several electrophysiological phenotypes of the Collaborative Study on the Genetics of Alcoholism data of the Genetic Analysis Workshop 14. Our approach is based on a variance-component model to map candidate genes using repeated or longitudinal measurements. It can take into account covariate effects and time-dependent genetic effects in general pedigree data. We compare our results with the ones obtained by SOLAR using single measurement data. Our multivariate linkage analysis found linkage evidence on two regions on chromosome 4: around marker GABRB1 at 51.4 cM and marker FABP2 at 116.8 cM (unadjusted p-value = 0.00006).

Alcoholism↗