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1.  Modulated expression of human peripheral blood microRNAs from infancy to adulthood and its role in aging 
Aging Cell  2014;13(4):679-689.
Accumulating evidence suggests a role for microRNAs (miRNAs) in regulating various processes of mammalian postnatal development and aging. To investigate the changes in blood-based miRNA expression from preterm infants to adulthood, we compared 365 miRNA expression profiles in a screening set of preterm infants and adults. Approximately one-third of the miRNAs were constantly expressed from postnatal development to adulthood, another one-third were differentially expressed between preterm infants and adults, and the remaining one-third were not detectable in these two groups. Based on their expression in infants and adults, the miRNAs were categorized into five classes, and six of the seven miRNAs chosen from each class except one with age-constant expression were confirmed in a validation set containing infants, children, and adults. Comparing the chromosomal locations of the different miRNA classes revealed two hot spots: the miRNA cluster on 14q32.31 exhibited age-constant expression, and the one on 9q22.21 exhibited up-regulation in adults. Furthermore, six miRNAs detectable in adults were down-regulated in older adults, and four chosen for individual quantification were verified in the validation set. Analysis of the network functions revealed that differentially regulated miRNAs between infants and adults and miRNAs that decreased during aging shared two network functions: inflammatory disease and inflammatory response. Four expression patterns existed in the 11 miRNAs from infancy to adulthood, with a significant transition in ages 9–20 years. Our results provide an overview on the regulation pattern of blood miRNAs throughout life and the possible biological functions performed by different classes of miRNAs.
PMCID: PMC4326935  PMID: 24803090
aging; development; gene expression profiling; microRNA; network function; peripheral blood
2.  Clustering by neurocognition for fine-mapping of the schizophrenia susceptibility loci on chromosome 6p 
Genes, brain, and behavior  2009;8(8):785-794.
Chromosome 6p is one of the most commonly implicated regions in the genome-wide linkage scans of schizophrenia, whereas further association studies for markers in this region were inconsistent likely due to heterogeneity. This study aimed to identify more homogeneous subgroups of families for fine mapping on regions around markers D6S296 and D6S309 (both in 6p24.3) as well as D6S274 (in 6p22.3) by means of similarity in neurocognitive functioning. A total of 160 families of patients with schizophrenia comprising at least two affected siblings who had data for 8 neurocognitive test variables of the Continuous Performance Test (CPT) and the Wisconsin Card Sorting Test (WCST) were subjected to cluster analysis with data visualization using the test scores of both affected siblings. Family clusters derived were then used separately in family-based association tests for 64 single nucleotide polymorphisms covering the region of 6p24.3 and 6p22.3. Three clusters were derived from the family-based clustering, with deficit cluster 1 representing deficit on the CPT, deficit cluster 2 representing deficit on both the CPT and the WCST, and a third cluster of non-deficit. After adjustment using false discovery rate for multiple testing, SNP rs13873 and haplotype rs1225934-rs13873 on BMP6-TXNDC5 genes were significantly associated with schizophrenia for the deficit cluster 1 but not for the deficit cluster 2 or non-deficit cluster. Our results provide further evidence that the BMP6-TXNDC5 locus on 6p24.3 may play a role in the selective impairments on sustained attention of schizophrenia.
PMCID: PMC4286260  PMID: 19694819
endophenotype; sustained attention deficit; executive dysfunction; candidate gene; cluster analysis; schizophrenia
3.  Prenatal Exposure to Phthalate Esters and Behavioral Syndromes in Children at 8 Years of Age: Taiwan Maternal and Infant Cohort Study 
Environmental Health Perspectives  2014;123(1):95-100.
Background: Few studies have shown an association between prenatal phthalate exposure and adverse effects on neurodevelopment and behavior in young children.
Objectives: We aimed to assess the relationship between prenatal exposure to phthalate esters and behavior syndromes in children at 8 years of age.
Methods: A total of 122 mother–child pairs from the general population in central Taiwan were studied from 2000 to 2009. Mono-methyl phthalate (MMP), mono-ethyl phthalate (MEP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), and three di-(2-ethylhexyl) phthalate (DEHP) metabolites—mono-2-ethylhexyl, mono-2-ethyl-5-hydroxyhexyl, and mono-2-ethyl-5-oxohexyl phthalates (MEHP, MEHHP, and MEOHP)—were measured in maternal urine collected during the third trimester of pregnancy using liquid chromatography–electrospray ionization–tandem mass spectrometry. Behavioral syndromes of children at 8 years of age were evaluated using the Child Behavior Checklist (CBCL). Associations between log10-transformed creatinine-corrected phthalate concentrations and standardized scores of the CBCL were estimated using linear regression models or multinomial logistic regressions with adjustments for potential confounders.
Results: Externalizing problem scores were significantly higher in association with a 1-unit increase in log10-transformed creatinine-corrected concentrations of maternal MBP (β = 4.29; 95% CI: 0.59, 7.99), MEOHP (β = 3.74; 95% CI: 1.33, 6.15), and MEHP (β = 4.28 ; 95% CI: 0.03, 8.26) after adjusting for the child’s sex, intelligence, and family income. Meanwhile, MBP and MEOHP were significantly associated with Delinquent Behavior and Aggressive Behavior scores. The same pattern was found for borderline and/or clinical ranges.
Conclusions: Our findings suggest positive associations between maternal DEHP and dibutyl phthalate (DBP) exposure and externalizing domain behavior problems in 8-year-old children.
Citation: Lien YJ, Ku HY, Su PH, Chen SJ, Chen HY, Liao PC, Chen WJ, Wang SL. 2015. Prenatal exposure to phthalate esters and behavioral syndromes in children at 8 years of age: Taiwan Maternal and Infant Cohort Study. Environ Health Perspect 123:95–100;
PMCID: PMC4286269  PMID: 25280125
4.  Ketamine use among regular tobacco and alcohol users as revealed by respondent driven sampling in Taipei: prevalence, expectancy, and users’ risky decision making 
Journal of food and drug analysis  2013;21(4):S102-S105.
The popularity of ketamine for recreational use among young people began to increase, particularly in Asia, in 2000. To gain more knowledge about the use of ketamine among high risk individuals, a respondent-driven sampling (RDS) was implemented among regular alcohol and tobacco users in the Taipei metropolitan area from 2007 to 2010. The sampling was initiated in three different settings (i.e., two in the community and one in a clinic) to recruit seed individuals. Each participant was asked to refer one to five friends known to be regular tobacco smokers and alcohol drinkers to participate in the present study. Incentives were offered differentially upon the completion of an interview and successful referral. Information pertaining to drug use experience was collected by an audio computer-assisted self-interview instrument. Software built for RDS analyses was used for data analyses. Of the 1,115 subjects recruited, about 11.7% of the RDS respondents reported ever having used ketamine. Positive expectancy of ketamine use was positively associated with ketamine use; in contrast, negative expectancy inversely associated with ketamine use. Decision-making characteristics as measured on the Iowa Gambling Task using reinforcement learning models revealed that ketamine users learned less from the most recent event than both tobacco- and drug-naïve controls and regular tobacco and alcohol users. These findings about ketamine use among young people have implications for its prevention and intervention.
PMCID: PMC4175916  PMID: 25264412
ketamine; respondent-driven sampling (RDS); expectancy; decision making
5.  Second-Generation Antipsychotic Medications and Risk of Pneumonia in Schizophrenia 
Schizophrenia Bulletin  2012;39(3):648-657.
This study assessed the association between second-generation antipsychotic medications and risk of pneumonia requiring hospitalization in patients with schizophrenia because the evidence is limited in the population. We enrolled a nationwide cohort of 33 024 inpatients with schizophrenia ranged in age from 18 to 65 years, who were derived from the National Health Insurance Research Database in Taiwan from 2000 to 2008. Cases (n = 1741) were defined as patients who developed pneumonia after their first psychiatric admissions. Risk set sampling was used to match each case with 4 controls by age, sex, and the year of the first admission based on nested case-control study. Antipsychotic exposure was categorized by type, duration, and daily dose, and the association between exposure and pneumonia was assessed using conditional logistic regression. We found that current use of clozapine (adjusted risk ratio = 3.18, 95% CI: 2.62–3.86, P < .001) was associated with a dose-dependent increase in the risk. Although quetiapine, olanzapine, zotepine, and risperidone were associated with increased risk, there was no clear dose-dependent relationship. Amisulpride was associated with a low risk of pneumonia. The use of clozapine combined with another drug (olanzapine, quetiapine, zotepine, risperidone, or amisulpride), as assessed separately, was associated with increased risk for pneumonia. In addition, with the exception of amisulpride, each drug was associated with increased risk for pneumonia at the beginning of treatment. Clinicians who prescribe clozapine to patients with schizophrenia should closely monitor them for pneumonia, particularly at the start of therapy and when clozapine is combined with other antipsychotics.
PMCID: PMC3627761  PMID: 22282455
second-generation antipsychotics; clozapine; pneumonia; dose-dependent
6.  Performance on the Wisconsin Card Sorting Test in Families of Schizophrenia Patients With Different Familial Loadings 
Schizophrenia Bulletin  2011;39(3):537-546.
Despite the consistent presence of performance deficits on the Wisconsin Card Sorting Test (WCST) in schizophrenia patients, whether poorer performance is also present in their nonpsychotic relatives is not certain. This study aimed to estimate both the recurrence risk ratio (λs) and the heritability of WCST scores in simplex and multiplex families, respectively, and to examine the influence of familial loading on these estimates. Participants were patients with schizophrenia and their nonpsychotic first-degree relatives from 168 simplex families and 653 multiplex families as well as 440 normal comparisons. On the basis of adjusted z scores, both the λs at a series of cutoff points and heritability estimates based on variance component modeling in the nonpsychotic relatives of schizophrenia patients were estimated. The WCST deficits in schizophrenia patients were more prominent in multiplex families than in simplex ones. Among relatives, WCST deficits were limited to parents of multiplex families for most WCST scores and siblings from multiplex families for total errors, perseverative responses, and perseverative errors. Pertaining to λs, the estimates for multiplex families (highest estimates ranging from 7.9 to 11.0) were greater than those for simplex ones (<2.5). Nevertheless, the heritability estimates were very similar between simplex (ranging from 0% to 17%) and multiplex (ranging from 0% to 21%) families, with the latter having slightly greater values than the former. There is only a small-to-modest familial aggregation on part of WCST scores in families of schizophrenia patients, and this may limit its use as endophenotypic markers to schizophrenia susceptibility.
PMCID: PMC3627779  PMID: 23196712
executive function; recurrence risk ratio; heritability; endophenotype; familial aggregation; prefrontal cortex
7.  Handedness and schizotypy in nonpsychotic relatives of patients with schizophrenia 
Laterality  2011;16(6):690-706.
Existing studies have found the relationship between handedness and schizotypy to be inconsistent and had limited generalizability since only highly homogeneous groups have been investigated. This study aimed to examine the relation between handedness and the four schizotypal factors identified from a previous confirmatory factor analysis in a population of high familial loading for schizophrenia. Study subjects consisted of nonpsychotic first-degree relatives (850 parents and 334 siblings) of sib-pairs who were co-affected with schizophrenia. All participants were interviewed with the Diagnostic Interview for Genetic Studies, which contains a section of the modified Structured Interview for Schizotypy, and the Annett handedness questionnaire. Both categorical and continuous indicators for handedness were examined. Non-right handed siblings of schizophrenia patients displayed more positive schizotypal features than their right handed counterparts when the two-way Annett's handedness classification was adopted. No association was found when handedness was treated as continuous. The relationship between handedness and schizotypy was insignificant for parents probably due to the strong social pressure against left-handedness. We concluded that categorical non-right handedness was associated with positive schizotypy in nonpsychotic siblings of schizophrenia patients. The results indicate that an atypical cerebral lateralization underlying non-right handedness may be also a contributing factor to positive schizotypy.
PMCID: PMC3175314  PMID: 21308606
positive schizotypy; handedness; familial loading; schizophrenia
8.  A Genome-wide Quantitative Linkage Scan of Niacin Skin Flush Response in Families With Schizophrenia 
Schizophrenia Bulletin  2011;39(1):68-76.
Schizophrenia patients frequently display reduced niacin flush responses, and similar characteristics are also observed in their nonpsychotic relatives. This study aimed to identify loci influencing flush response to niacin in schizophrenia using genome-wide quantitative linkage scan. In a nationwide sample of families with at least 2 siblings affected with schizophrenia in each family, 115 families that had at least 2 affected siblings with information on the niacin skin test were subjected to quantitative trait loci linkage analysis, either involving affected individuals only or the whole family. Nonparametric linkage z (NPL-Z) scores were calculated for each of 386 microsatellite markers spaced at an average of 9-cM intervals. Niacin patches of 3 concentrations (0.001M, 0.01, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. Determination of genome-wide empirical significance was implemented using 1000 simulated genome scans. One linkage peak attaining genome-wide significance was identified at chromosomal region 14q32.12 for 0.01M concentration at 5 minutes (NPL-Z scores = 3.39, genome-wide empirical P = .03) in affected individuals, and the corresponding linkage signal remained strong (NPL-Z scores = 2.87) for the analyses of the whole family. This locus is distinct from the chromosomal region identified in the previous genome-wide scan for the diagnosis of schizophrenia, and the signal was higher than the peak linkage signal in that study. These findings indicate that there might be modifier or susceptibility-modifier genes at 14q32.12 for schizophrenia-related attenuation of flush response to niacin.
PMCID: PMC3523922  PMID: 21653277
endophenotype; relative pair; identical by descent; nonparametric linkage z score; modifier gene; susceptibility-modifier gene
9.  A stochastic inference of de novo CNV detection and association test in multiplex schizophrenia families 
Frontiers in Genetics  2013;4:185.
The copy number variation (CNV) is a type of genetic variation in the genome. It is measured based on signal intensity measures and can be assessed repeatedly to reduce the uncertainty in PCR-based typing. Studies have shown that CNVs may lead to phenotypic variation and modification of disease expression. Various challenges exist, however, in the exploration of CNV-disease association. Here we construct latent variables to infer the discrete CNV values and to estimate the probability of mutations. In addition, we propose to pool rare variants to increase the statistical power and we conduct family studies to mitigate the computational burden in determining the composition of CNVs on each chromosome. To explore in a stochastic sense the association between the collapsing CNV variants and disease status, we utilize a Bayesian hierarchical model incorporating the mutation parameters. This model assigns integers in a probabilistic sense to the quantitatively measured copy numbers, and is able to test simultaneously the association for all variants of interest in a regression framework. This integrative model can account for the uncertainty in copy number assignment and differentiate if the variation was de novo or inherited on the basis of posterior probabilities. For family studies, this model can accommodate the dependence within family members and among repeated CNV data. Moreover, the Mendelian rule can be assumed under this model and yet the genetic variation, including de novo and inherited variation, can still be included and quantified directly for each individual. Finally, simulation studies show that this model has high true positive and low false positive rates in the detection of de novo mutation.
PMCID: PMC3779856  PMID: 24065985
Bayesian model; CNV association test; de novo CNV detection; schizophrenia multiplex family; random mutation parameter
10.  Cardiac Complications Associated with Short-Term Mortality in Schizophrenia Patients Hospitalized for Pneumonia: A Nationwide Case-Control Study 
PLoS ONE  2013;8(7):e70142.
Pneumonia is one of most prevalent infectious diseases worldwide and is associated with considerable mortality. In comparison to general population, schizophrenia patients hospitalized for pneumonia have poorer outcomes. We explored the risk factors of short-term mortality in this population because the information is lacking in the literature.
In a nationwide schizophrenia cohort, derived from the National Health Insurance Research Database in Taiwan, that was hospitalized for pneumonia between 2000 and 2008 (n = 1,741), we identified 141 subjects who died during their hospitalizations or shortly after their discharges. Based on risk-set sampling in a 1∶4 ratio, 468 matched controls were selected from the study cohort (i.e., schizophrenia cohort with pneumonia). Physical illnesses were categorized as pre-existing and incident illnesses that developed after pneumonia respectively. Exposures to medications were categorized by type, duration, and defined daily dose. We used stepwise conditional logistic regression to explore the risk factors for short-term mortality.
Pre-existing arrhythmia was associated with short-term mortality (adjusted risk ratio [RR] = 4.99, p<0.01). Several variables during hospitalization were associated with increased mortality risk, including incident arrhythmia (RR = 7.44, p<0.01), incident heart failure (RR = 5.49, p = 0.0183) and the use of hypoglycemic drugs (RR = 2.32, p<0.01). Furthermore, individual antipsychotic drugs (such as clozapine) known to induce pneumonia were not significantly associated with the risk.
Incident cardiac complications following pneumonia are associated with increased short-term mortality. These findings have broad implications for clinical intervention and future studies are needed to clarify the mechanisms of the risk factors.
PMCID: PMC3726532  PMID: 23922940
11.  Inference of Cross-Level Interaction between Genes and Contextual Factors in a Matched Case-Control Metabolic Syndrome Study: A Bayesian Approach 
PLoS ONE  2013;8(2):e56693.
Genes, environment, and the interaction between them are each known to play an important role in the risk for developing complex diseases such as metabolic syndrome. For environmental factors, most studies focused on the measurements observed at the individual level, and therefore can only consider the gene-environment interaction at the same individual scale. Indeed the group-level (called contextual) environmental variables, such as community factors and the degree of local area development, may modify the genetic effect as well. To examine such cross-level interaction between genes and contextual factors, a flexible statistical model quantifying the variability of the genetic effects across different categories of the contextual variable is in need. With a Bayesian generalized linear mixed-effects model with an unconditional likelihood, we investigate whether the individual genetic effect is modified by the group-level residential environment factor in a matched case-control metabolic syndrome study. Such cross-level interaction is evaluated by examining the heterogeneity in allelic effects under various contextual categories, based on posterior samples from Markov chain Monte Carlo methods. The Bayesian analysis indicates that the effect of rs1801282 on metabolic syndrome development is modified by the contextual environmental factor. That is, even among individuals with the same genetic component of PPARG_Pro12Ala, living in a residential area with low availability of exercise facilities may result in higher risk. The modification of the group-level environment factors on the individual genetic attributes can be essential, and this Bayesian model is able to provide a quantitative assessment for such cross-level interaction. The Bayesian inference based on the full likelihood is flexible with any phenotype, and easy to implement computationally. This model has a wide applicability and may help unravel the complexity in development of complex diseases.
PMCID: PMC3577698  PMID: 23437214
12.  Causes of Death of Patients with Methamphetamine Dependence: A Record-Linkage Study 
Drug and alcohol review  2010;30(6):621-628.
Introduction and Aims
Methamphetamine use leads to increased likelihood of premature death. The authors investigated the causes of death and risk of mortality in a large cohort of patients with methamphetamine dependence.
Design and Methods
A cohort of 1,254 subjects with methamphetamine dependence, admitted to a psychiatric center in Taiwan from January 1990 to December 2007, was retrospectively studied. Diagnostic and sociodemographic data for each subject were extracted from the medical records based on a chart review process. Mortality data were obtained by linking to the National Death Certification System and standardised mortality ratios (SMRs) were estimated. The risk and protective factors for all-cause deaths were explored by means of survival analyses.
During the study period, 130 patients died. Of them, 63.1% died unnatural deaths, while the remaining 36.9% died natural deaths. The 1-year cumulative rates for unnatural and natural deaths were 0.018 and 0.006, respectively and the 5-year rates were 0.046 and 0.023, respectively. The cohort had excessive mortality (SMR = 6.02), and women had a higher SMR for unnatural deaths than men (26.19 vs. 9.82, P = 0.001). For all-cause deaths, comorbiditywith other substance use disorders was associated with increased risk of death, despite that being married was associated with a reduced risk.
Discussion and Conclusions
A substantial proportion of the deceased died natural deaths, but most died unnatural deaths. The findings show significant evidence to provide valuable insight into premature deaths among methamphetamine-dependent users. This information is valuable for development of prevention and intervention programs.
PMCID: PMC3117111  PMID: 21355920
methamphetamine; cohort; mortality; natural death; unnatural death
13.  Correction: Elevated Aspartate and Alanine Aminotransferase Levels and Natural Death among Patients with Methamphetamine Dependence 
PLoS ONE  2012;7(1):10.1371/annotation/85803bd9-3be6-4450-b70f-cd4104b87817.
PMCID: PMC3267787
14.  Correction: Elevated Aspartate and Alanine Aminotransferase Levels and Natural Death among Patients with Methamphetamine Dependence 
PLoS ONE  2012;7(1):10.1371/annotation/3bca7672-2fca-4a7e-942d-cc1b4aaa7b60.
PMCID: PMC3267788
15.  Genetic polymorphisms of nerve growth factor receptor (NGFR) and the risk of Alzheimer's disease 
Loss of basal forebrain cholinergic neurons is attributable to the proapoptotic signaling induced by nerve growth factor receptor (NGFR) and may link to Alzheimer's disease (AD) risk. Only one study has investigated the association between NGFR polymorphisms and the risk of AD in an Italian population. Type 2 diabetes mellitus (DM) may modify this association based on previous animal and epidemiologic studies.
This was a case-control study in a Chinese population. A total of 264 AD patients were recruited from three teaching hospitals between 2007 to 2010; 389 controls were recruited from elderly health checkup and volunteers of the hospital during the same period of time. Five common (frequency≥5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected from NGFR to test the association between NGFR htSNPs and the risk of AD.
Variant NGFR rs734194 was significantly associated with a decreased risk of AD [GG vs. TT copies: adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.20-0.95]. Seven common haplotypes were identified. Minor haplotype GCGCG was significantly associated with a decreased risk of AD (2 vs. 0 copies: adjusted OR = 0.39, 95% CI = 0.17-0.91). Type 2 DM significantly modified the association between rs2072446, rs741072, and haplotype GCTTG and GTTCG on the risk of AD among ApoE ε4 non-carriers (Pinteraction < 0.05).
Inherited polymorphisms of NGFR were associated with the risk of AD; results were not significant after correction for multiple tests. This association was further modified by the status of type 2 DM.
PMCID: PMC3362783  PMID: 22236693
NGFR; Alzheimer's disease; htSNP; haplotype
16.  Elevated Aspartate and Alanine Aminotransferase Levels and Natural Death among Patients with Methamphetamine Dependence 
PLoS ONE  2012;7(1):e29325.
Methamphetamine is one of the fastest growing illicit drugs worldwide, causing multiple organ damage and excessive natural deaths. The authors aimed to identify potential laboratory indices and clinical characteristics associated with natural death through a two-phase study.
Methamphetamine-dependent patients (n = 1,254) admitted to a psychiatric center in Taiwan between 1990 and 2007 were linked with a national mortality database for causes of death. Forty-eight subjects died of natural causes, and were defined as the case subjects. A time-efficient sex- and age-matched nested case-control study derived from the cohort was conducted first to explore the potential factors associated with natural death through a time-consuming standardized review of medical records. Then the identified potential factors were evaluated in the whole cohort to validate the findings.
In phase I, several potential factors associated with natural death were identified, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), comorbid alcohol use disorder, and the prescription of antipsychotic drugs. In phase II, these factors were confirmed in the whole cohort using survival analysis. For the characteristics at the latest hospital admission, Cox proportional hazards models showed that the adjusted hazard ratios for natural death were 6.75 (p<0.001) in the group with markedly elevated AST (>80 U/L) and 2.66 (p<0.05) in the group with mildly elevated AST (40–80 U/L), with reference to the control group (<40 U/L). As for ALT, the adjusted hazard ratios were 5.41 (p<0.001), and 1.44 (p>0.05). Comorbid alcohol use disorder was associated with an increased risk of natural death, whereas administration of antipsychotic drugs was not associated with lowered risk.
This study highlights the necessity of intensive follow-up for those with elevated AST and ALT levels and comorbid alcohol use disorder for preventing excessive natural deaths.
PMCID: PMC3252311  PMID: 22242166
17.  A Genome-Wide Linkage Scan for Distinct Subsets of Schizophrenia Characterized by Age at Onset and Neurocognitive Deficits 
PLoS ONE  2011;6(8):e24103.
As schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits.
Patients with schizophrenia (n  =  1,207) and their first-degree relatives (n  =  1,035) from 557 families with schizophrenia were recruited from six data collection field research centers throughout Taiwan. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT), the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome.
A maximum nonparametric logarithm of odds (LOD) score of 4.17 at 2q22.1 was found in 295 families ranked by increasing age at onset, which had significant increases in the maximum LOD score compared with those obtained in initial linkage analyses using all available families. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based LOD on 2q22.1, with a score of 7.36 in 228 families and 7.71 in 243 families, respectively.
We found possible evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with more CPT false alarm rates nested within the families with younger age at onset. These results highlight the importance of incorporating genetically informative phenotypes in unraveling the complex genetics of schizophrenia.
PMCID: PMC3163684  PMID: 21897869
18.  Using an Uncertainty-Coding Matrix in Bayesian Regression Models for Haplotype-Specific Risk Detection in Family Association Studies 
PLoS ONE  2011;6(7):e21890.
Haplotype association studies based on family genotype data can provide more biological information than single marker association studies. Difficulties arise, however, in the inference of haplotype phase determination and in haplotype transmission/non-transmission status. Incorporation of the uncertainty associated with haplotype inference into regression models requires special care. This task can get even more complicated when the genetic region contains a large number of haplotypes. To avoid the curse of dimensionality, we employ a clustering algorithm based on the evolutionary relationship among haplotypes and retain for regression analysis only the ancestral core haplotypes identified by it. To integrate the three sources of variation, phase ambiguity, transmission status and ancestral uncertainty, we propose an uncertainty-coding matrix which combines these three types of variability simultaneously. Next we evaluate haplotype risk with the use of such a matrix in a Bayesian conditional logistic regression model. Simulation studies and one application, a schizophrenia multiplex family study, are presented and the results are compared with those from other family based analysis tools such as FBAT. Our proposed method (Bayesian regression using uncertainty-coding matrix, BRUCM) is shown to perform better and the implementation in R is freely available.
PMCID: PMC3137600  PMID: 21789192
19.  MicroRNA Expression Aberration as Potential Peripheral Blood Biomarkers for Schizophrenia 
PLoS ONE  2011;6(6):e21635.
Since brain tissue is not readily accessible, a new focus in search of biomarkers for schizophrenia is blood-based expression profiling of non-protein coding genes such as microRNAs (miRNAs), which regulate gene expression by inhibiting the translation of messenger RNAs. This study aimed to identify potential miRNA signature for schizophrenia by comparing genome-wide miRNA expression profiles in patients with schizophrenia vs. healthy controls. A genome-wide miRNA expression profiling was performed using a Taqman array of 365 human miRNAs in the mononuclear leukocytes of a learning set of 30 cases and 30 controls. The discriminating performance of potential biomarkers was validated in an independent testing set of 60 cases and 30 controls. The expression levels of the miRNA signature were then evaluated for their correlation with the patients' clinical symptoms, neurocognitive performances, and neurophysiological functions. A seven-miRNA signature (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) was derived from a supervised classification with internal cross-validation, with an area under the curve (AUC) of receiver operating characteristics of 93%. The putative signature was then validated in the testing set, with an AUC of 85%. Among these miRNAs, miR-34a was differentially expressed between cases and controls in both the learning (P = 0.005) and the testing set (P = 0.002). These miRNAs were differentially correlated with patients' negative symptoms, neurocognitive performance scores, and event-related potentials. The results indicated that the mononuclear leukocyte-based miRNA profiling is a feasible way to identify biomarkers for schizophrenia, and the seven-miRNA signature warrants further investigation.
PMCID: PMC3126851  PMID: 21738743
20.  Genetic Polymorphisms of a Novel Vascular Susceptibility Gene, Ninjurin2 (NINJ2), Are Associated with a Decreased Risk of Alzheimer's Disease 
PLoS ONE  2011;6(6):e20573.
Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.
A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n = 423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association.
Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR) = 0.43; 95% confidence interval (CI)  = 0.23–0.80; rs12425791: AOR  = 0.33, 95% CI  = 0.12–0.96]. Five common haplotypes (cumulative frequency  = 97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p = 0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR  = 0.32, 95% CI  = 0.11–0.94). No associations were observed for VaD.
Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.
PMCID: PMC3108950  PMID: 21674003
21.  Differential relationships of family drinking with alcohol expectancy among urban school children 
BMC Public Health  2011;11:87.
Positive alcohol outcome expectancy has consistently been linked with problematic drinking, but there is little population-based evidence on its role on early stages of drinking in childhood. The present study seeks to understand the extent to which drinking of family members is differentially associated with the endorsement of alcohol expectancy in late childhood.
A representative sample of 4th and 6th graders (N = 2455) drawn from 28 public schools in an urban region of Taiwan completed a self-administered paper-and-pencil questionnaire. Each student provided information on alcohol expectancy, drinking experiences, and individual and family attributes. Complex survey analyses were performed to evaluate the relationship, with stratification by children's alcohol drinking history.
An estimated 29% of the 4th graders and 43% of the 6th graders had initiated alcohol consumption (over 40% of them had drank on three or more occasions). Alcohol drinking-related differences appear in both the endorsement and the correlates of alcohol expectancy. Positive alcohol expectancy was strongly associated with family drinking, particularly the dimension of "enhanced social behaviors"; negative alcohol expectancy was inversely associated with drinking frequency. Among alcohol naïve children, significant connections appear between paternal drinking and three dimensions of positive alcohol expectancy (i.e., enhanced social behaviors:βwt = 0.15, promoting relaxation or tension reduction:βwt = 0.18, and global positive transformation:βwt = 0.22).
Individual tailored strategies that address family influences on alcohol expectancy may be needed in prevention programs targeting drinking behaviors in children.
PMCID: PMC3042940  PMID: 21303522
22.  Running away experience and psychoactive substance use among adolescents in Taiwan: multi-city street outreach survey 
BMC Public Health  2010;10:29.
This study aimed to examine: 1) the relationship between being a runaway and the time since the first absconding event and adolescent substance use; 2) whether different kinds of psychoactive substances have a different temporal relationship to the first absconding event; and 3) whether the various reasons for the first absconding event are associated with different risks of substance use.
Participants were drawn from the 2004-2006 nationwide outreach programs across 26 cities/towns in Taiwan. A total of 17,133 participants, age 12-18 years, who completed an anonymous questionnaire on their experience of running away and substances use and who were now living with their families, were included in the analysis.
The lifetime risk of tobacco, alcohol, betel nut, and illegal drug/inhalant use increased steadily from adolescents who had experienced a trial runaway episode (one time lasting ≤ 1 day), to those with extended runaway experience (≥ 2 times or lasting > 1 day), when compared to those who had never ran away. Adolescents who had their first running away experience > 6 months previously had a greater risk of betel nut or illegal drug/inhalant use over the past 6-months than those with a similar experience within the last 6 months. Both alcohol and tobacco use were most frequently initiated before the first running away, whereas both betel nut and illegal drug/inhalant use were most frequently initiated after this event. When adolescents who were fleeing an unsatisfactory home life were compared to those who ran away for excitement, the risk of alcohol use was similar but the former tended to have a higher risk of tobacco, betel nut, and illegal drug/inhalant use.
More significant running away and a longer time since the first absconding experience were associated with more advanced substance involvement among adolescents now living in a family setting. Once adolescents had left home, they developed additional psychoactive substance problems, regardless of their reasons for running away. These findings have implications for caregivers, teachers, and healthcare workers when trying to prevent and/or intervening in adolescent substance use.
PMCID: PMC2823700  PMID: 20089181
23.  Travel Distance and the Use of Inpatient Care among Patients with Schizophrenia 
This study examines the variations in the use of inpatient care that can be explained by travel distance among patients with schizophrenia living in Taiwan. Data were drawn from the Psychiatric Inpatient Medical Claims Database. We used mediation analysis and multilevel analysis to identify associations. Travel distance did not significantly account for lower readmission rates after an index admission, but significantly explained the longer length of stay of an index admission by 9.3 days (P < 0.001, 85% of variation) between remote and non-remote regions. Policies are discussed aimed at reducing the impact of travel distance on rural mental health care through inter-disciplinary collaboration and telepsychiatry.
PMCID: PMC2794377  PMID: 18512144
Schizophrenia; Travel distance; Remote; Length of stay; Readmission
24.  A new regularized least squares support vector regression for gene selection 
BMC Bioinformatics  2009;10:44.
Selection of influential genes with microarray data often faces the difficulties of a large number of genes and a relatively small group of subjects. In addition to the curse of dimensionality, many gene selection methods weight the contribution from each individual subject equally. This equal-contribution assumption cannot account for the possible dependence among subjects who associate similarly to the disease, and may restrict the selection of influential genes.
A novel approach to gene selection is proposed based on kernel similarities and kernel weights. We do not assume uniformity for subject contribution. Weights are calculated via regularized least squares support vector regression (RLS-SVR) of class levels on kernel similarities and are used to weight subject contribution. The cumulative sum of weighted expression levels are next ranked to select responsible genes. These procedures also work for multiclass classification. We demonstrate this algorithm on acute leukemia, colon cancer, small, round blue cell tumors of childhood, breast cancer, and lung cancer studies, using kernel Fisher discriminant analysis and support vector machines as classifiers. Other procedures are compared as well.
This approach is easy to implement and fast in computation for both binary and multiclass problems. The gene set provided by the RLS-SVR weight-based approach contains a less number of genes, and achieves a higher accuracy than other procedures.
PMCID: PMC2669483  PMID: 19187562
25.  Use of ecstasy and other psychoactive substances among school-attending adolescents in Taiwan: national surveys 2004–2006 
BMC Public Health  2009;9:27.
With the backdrop of a global ecstasy epidemic, this study sought to examine the trend, correlates, and onset sequence of ecstasy use among adolescents in Taiwan, where a well-established gateway drug such as marijuana is much less popular.
A multistage probability survey of school-attending adolescents in grades 7, 9, 10, and 12, aged 11–19 years, was conducted in 2004, 2005, and 2006. A self-administered anonymous questionnaire elicited response rates ranging from 94.3% to 96.6%. The sample sizes were 18232 respondents in 2004, 17986 in 2005, and 17864 in 2006.
In terms of lifetime prevalence and incidence, ecstasy and ketamine by and large appeared as the first and second commonly used illegal drugs, respectively, among middle (grades 7 and 9) and high school students (grades 10 and 12) during the 3-year survey period; however, this order was reversed in the middle school-aged students starting in 2006. Having sexual experience, tobacco use, and betel nut use were factors consistently associated with the onset of ecstasy use across years. The majority of ecstasy users had been involved in polydrug use, such as the use of ketamine (41.4%–53.5%), marijuana (12.7%–18.7%), and methamphetamine (4.2%–9.5%).
From 2004 to 2006, a decline was noted in the prevalence and incidence rate of ecstasy, a leading illegal drug used by school-attending adolescents in Taiwan since the early 2000s. The emerging ketamine use trend may warrant more attention in the future.
PMCID: PMC2636802  PMID: 19159468

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