Andrew Cheng

Psychosocial and psychiatric risk factors for suicide. Case-control psychological autopsy study.

BACKGROUND Few studies of suicide have simultaneously examined the individual and combined effects of psychosocial and psychiatric risk factors. AIMS To do so in a representative sample of suicides. METHOD A case-control psychological autopsy was conducted among 113 consecutive suicides and 226 living controls matched for age, gender, ethnicity and area of residence in Taiwan. RESULTS Five major risk factors (loss event, suicidal behaviour in first-degree relatives, ICD-10 major depressive episode, emotionally unstable personality disorder and substance dependence) were found to have independent effects on suicide from multivariate conditional logistic regression analysis. CONCLUSIONS Effective intervention and management for loss event and major depressive episode among emotionally unstable subjects with a family tendency of suicidal behaviour, frequently also comorbid with alcohol or other substance dependence, may prove to be most effective for suicide prevention in different populations.

Was the economic crisis 1997-1998 responsible for rising suicide rates in East/Southeast Asia? A time-trend analysis for Japan, Hong Kong, South Korea, Taiwan, Singapore and Thailand

In 1997-1998 a widespread economic crisis hit the economies of many East/Southeast Asian countries; its impact on suicide rates across the region has not been systematically documented. We investigated the impact of the Asian economic crisis (1997-1998) on suicide in Japan, Hong Kong, South Korea, Taiwan, Singapore and Thailand. Suicide and population data for the period 1985-2006 were extracted from the World Health Organisations mortality database and Taiwanese mortality statistics. Sex-specific age-standardised suicide rates for people aged 15years or above were analysed using joinpoint regression. Trends in divorce, marriage, unemployment, gross domestic product (GDP) per capita and alcohol consumption were compared with trends in suicide rates graphically and using time-series analysis. Suicide mortality decreased in the late 1980s and early 1990s but subsequently increased markedly in all countries except Singapore, which had steadily declining suicide rates throughout the study period. Compared to 1997, male rates in 1998 rose by 39% in Japan, 44% in Hong Kong and 45% in Korea; rises in female rates were less marked. Male rates also rose in Thailand, but accurate data were incomplete. The economic crisis was associated with 10,400 more suicides in 1998 compared to 1997 in Japan, Hong Kong and Korea. Similar increases in suicide rates were not seen in Taiwan and Singapore, the two countries where the economic crisis had a smaller impact on GDP and unemployment. Time-series analyses indicated that some of the crisiss impact on male suicides was attributable to increases in unemployment. These findings suggest an association of the Asian economic crisis with a sharp increase in suicide mortality in some, but not all, East/Southeast Asian countries, and that these increases were most closely associated with rises in unemployment.

Association between morningness-eveningness and behavioral/emotional problems among adolescents.

Adolescent eveningness is associated with age, parental monitoring, daytime sleepiness, sleep problems, moodiness, and the use of coffee. This study investigated the association between adolescent morningness-eveningness and psychopathology, substance use, and suicidality in 1332 students ages 12 to 13. Each student-participant completed the Chinese version of the Child Morningness/Eveningness Scale (CMES), the Pubertal Development Scale, and a questionnaire about their sleep schedule, trouble sleeping, habitual substance use, and suicidality. Their mothers completed the Child Behavioral Checklist and Chinese Health Questionnaire. The morning (n = 412), intermediate (n = 740), and evening (n = 180) groups were operationally defined by the CMES t scores. The mixed model was used for data analysis. The evening group had shorter weekday sleep time, longer weekend sleep time, more daytime napping, and greater sleep compensation on weekends and was more likely than the other 2 groups to have behavioral/emotional problems, suicidality, and habitual substance use. Internalizing and externalizing problems partially explained the association between eveningness, substance use, and suicidality. The findings suggest that eveningness may be an indicator for adolescents with behavioral/emotional problems and risky behaviors and suggest an investigation for possible intervention.

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial

Context Resistance to antiretroviral drugs is a leading cause of treatment failure in HIV-1infected patients. Contribution In this multicenter, double-blind trial, 552 treatment-experienced patients with detectable RNA levels despite continuing antiretroviral therapy were randomly assigned to receive tenofovir DF (a nucleotide analogue) or placebo. At 6 months, patients given tenofovir DF had greater reductions in HIV-1 RNA levels than those given placebo. Nearly 15% of patients in both groups had clinical adverse events, such as severe diarrhea, pain, or depression. Implications In HIV-infected patients with suboptimal viral suppression, adding tenofovir DF to ongoing antiretroviral therapy reduces viral loads. The Editors Combination antiretroviral therapy has decreased mortality rates for patients with HIV-1 infection (1, 2). Suppression of HIV-1 viral load has been shown to be highly predictive of slower clinical disease progression (3). However, the clinical utility of a combination antiretroviral regimen typically wanes, often because of one or more factors such as drug resistance or poor adherence (4). These factors are even more important for patients who have previously used antiretroviral drugs. This difficult-to-treat population has limited treatment options and often experiences drug-related adverse effects due to previous antiretroviral therapy regimens (5-7). Given these limitations, novel potent agents that combine ease of dosing with favorable safety and resistance profiles are needed to increase the long-term durability of combination antiretroviral therapy (8, 9). Simplifying HIV treatment regimens using once-daily antiretroviral drugs may improve adherence and therapeutic outcomes (10, 11). Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2 (12, 13). Unlike nucleoside analogues, tenofovir is active in both active and resting lymphoid cells and macrophages (13). In rhesus macaques acutely infected with simian immunodeficiency virus, tenofovir administered as monotherapy 24 hours after inoculation eradicated viral DNA from lymph nodes, plasma, and leukocytes (14). Tenofovir has also demonstrated in vitro activity against wild-type and lamivudine-resistant hepatitis B virus (15). In a 186-patient phase II dose-ranging study, Schooley and colleagues (16) demonstrated the potency and favorable safety profile of tenofovir DF, 300 mg, highlighting its potential for further study in larger phase III trials. Tenofovir has a favorable resistance profile with activity against most nucleoside analogueresistant viruses and infrequent (3%) emergence of the K65R resistance mutation through 96 weeks (17-21). Our study was designed to confirm the antiviral efficacy and safety of tenofovir DF compared with placebo in treatment-experienced patients who had detectable HIV-1 RNA levels despite combination antiretroviral therapy. Methods Study Sample Institutional review boards at all study sites approved the study protocol and informed consent statements. Recruitment began in October 1999 and continued until June 2000 at 75 HIV clinics in western Europe, North America, and Australia. All patients gave written informed consent. Patients 18 to 65 years of age were eligible if they had received antiretroviral therapy (four agents or fewer) for at least 8 weeks before randomization and had stable plasma HIV-1 RNA levels of 400 to 10 000 copies/mL on the Roche Amplicor HIV-1 Monitor UltraSensitive test, version 1.0 (Roche Diagnostics, Branchburg, New Jersey). The lower limit of quantification for this test was 50 copies/mL. We placed no entry restrictions on CD4 cell count. Additional inclusion criteria were serum creatinine concentration of 133 mol/L or less ( 1.5 mg/dL), calculated creatinine clearance (using the CockcroftGault formula [22]) of at least 1.00 mL/s ( 60 mL/min), absolute neutrophil count of at least 1.000 109 cells/L, platelet count of at least 50.0 109 cells/L, hemoglobin level of at least 80 g/L, total bilirubin level of 26 mol/L or less ( 1.5 mg/dL), serum phosphorus level of at least 0.71 mmol/L ( 2.2 mg/dL), alanine aminotransferase level less than 108 U/L, aspartate aminotransferase level less than 90 U/L, negative results on a serum pregnancy test for women of childbearing potential, and life expectancy of more than 1 year. We excluded patients who had previously participated in clinical trials with intravenous tenofovir, tenofovir DF, or adefovir dipivoxil; had been immunized within 30 days of baseline; had an active AIDS-defining condition within 30 days of baseline; or were receiving aminoglycoside antibiotics, amphotericin B, cidofovir, cisplatin, foscarnet, intravenous pentamidine, vancomycin, ganciclovir, systemic chemotherapeutic agents, oral corticosteroids, probenecid, or other investigational agents on an ongoing basis. Patients who were receiving their first antiretroviral regimen were not excluded. We assessed 976 patients for eligibility and randomly assigned 552 to study groups (Figure). Four hundred twenty-four patients were excluded. Of the 380 who did not meet inclusion criteria, the most common reason (n = 269) was HIV-1 RNA levels outside the range of 400 to 10 000 copies/mL. Among the remaining 44 patients, 22 elected not to participate in the study and the other 22 were excluded because of investigator decision, concomitant participation in other investigational studies, screening after the cutoff date for enrollment, incomplete laboratory values, lack of follow-up, or family emergency. No statistical analyses were performed for patients who were not randomly assigned to a study group. Figure. Recruitment and disposition flow chart. Design Through an interactive voice response system that centralized patient randomization, Interactive Clinical Technologies, Inc. (San Francisco, California), generated the random allocation sequence, assigned patients to their treatment groups, and blinded kit numbers to conceal the allocation sequence. Patients were stratified according to HIV-1 RNA level (<5000 copies/mL or 5000 copies/mL), CD4 cell count (<0.2 109 cells/L or 0.2 109 cells/L), and number of antiretroviral drugs taken before study entry (fewer than four or at least four). Patients were then randomly assigned in a 2-to-1 ratio to add tenofovir DF, 300 mg, or identical-appearing placebo to their existing antiretroviral regimen. Randomization was not stratified by study center. Changes to the background regimen were discouraged during the first 24 weeks. After week 24, all patients received open-label tenofovir DF for the remainder of the 48-week study. As predefined in both the study protocol and the statistical analysis plan, the single end point for primary efficacy was the time-weighted average change in HIV-1 RNA level from baseline to week 24. Secondary efficacy end points included the proportion of patients with HIV-1 RNA levels of 50 copies/mL or less and 400 copies/mL or less at weeks 24 and 48, the time-weighted average change in HIV-1 RNA level from baseline to week 48, and CD4 cell count at weeks 24 and 48. Adherence to treatment was measured by using pill counts at each study visit, but pill counts were not formally analyzed and drug concentrations were not measured during routine study visits. Approximately half of the patients (n = 274) were randomly assigned to a virologic genotyping substudy at baseline. HIV-1 reverse transcriptase nucleotides 1 to 1200 and all of the HIV-1 protease gene were sequenced by following the reverse transcriptase polymerase chain reaction from plasma HIV-1 RNA (Vircogen, Virco, Mechelen, Belgium). All plasma HIV-1 samples that were obtained at baseline, at week 24 or 48, or at early study termination and had more than 50 copies of HIV-1 RNA per mL were analyzed in a blinded fashion. A polymerase chain reaction product could not be obtained from 21 patients at baseline (14 in the tenofovir DF group, 7 in the placebo group). Plasma HIV-1 RNA was insufficient for genotypic analysis in 58 patients at week 24 (43 patients in the tenofovir DF group, 15 in the placebo group) and 129 patients at week 48. Assessments The incidences of grade 3 or 4 clinical adverse events or laboratory abnormalities were evaluated as safety end points. At each postbaseline study visit (weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), the investigator assessed and recorded all adverse events found during history and physical examination as well as laboratory toxicities found on chemical and hematologic tests and urinalysis, including date of onset and resolution, severity, relationship to study drug, outcome, and action taken with study medication. Severity was recorded and graded according to the modified severity grading for adult adverse experiences outlined by the National Institutes of Allergy and Infectious Diseases, Division of AIDS. Plasma levels of HIV-1 RNA and CD4 cell counts were measured at all study visits except weeks 28, 36, and 44. Statistical Analysis Data were analyzed for the intention-to-treat sample and the as-treated sample. The intention-to-treat sample included all enrolled patients who received at least one dose of study medication and was the primary sample for analyses of efficacy. The as-treated sample included patients who received at least one dose of study medication but excluded all data obtained after permanent discontinuation of assigned study medication or addition of other antiretroviral medication. The safety analysis sample included all patients who received at least one dose of study medication. As the primary efficacy end point, the time-weighted average change in HIV-1 RNA level from baseline to week 24 represents the difference between the time-weighted average postbaseline values and values at baseline. This difference is defined as follows (23, 24). If the area under the curve (AUC) at week 24 (

Genotypic and Phenotypic Predictors of the Magnitude of Response to Tenofovir Disoproxil Fumarate Treatment in Antiretroviral-Experienced Patients

Results from 2 placebo-controlled intensification trials of tenofovir disoproxil fumarate (DF) in treatment-experienced human immunodeficiency type 1 (HIV-1)-infected patients (n=332) were integrated to determine the effects of resistance at baseline on HIV-1 RNA response. In these trials, there was a high prevalence of HIV-1 resistance mutations, with 94% of patients having nucleoside-associated mutations and 71% having thymidine analogue-associated mutations (TAMs). Statistically significant HIV-1 RNA reductions associated with tenofovir DF treatment, relative to placebo (P<.001), were observed for patients without TAMs (n=97) or for patients with 1-2 (n=88) or >or=3 TAMs (n=147). Response to tenofovir DF was reduced among patients with HIV-1 with >or=3 TAMs inclusive of either the M41L or L210W mutation (n=86) or patients who had a preexisting K65R mutation (n=6). Slightly increased treatment responses were observed when the M184V mutation was present. Phenotypic cutoffs were established at 1.4-fold and 4-fold, respectively, for the beginning of reduced response to tenofovir DF and for a strongly reduced response. The results from these controlled clinical trials provide guidance for the use of tenofovir DF for treatment-experienced patients.

Renal safety of tenofovir in HIV treatment-experienced patients.

The safety of tenovir disoproxil fumarate (TDF) was assessed in two double-blind, placebo-controlled studies. Furthermore, we retrospectively collected 19 cases of TDF-associated tubular dysfunction. The incidence of renal events was similar among the active TDF groups and the placebo group in the two double-blind, placebo-controlled studies. Proximal tubulopathy was diagnosed 6.89 +/- 5.51 months after TDF therapy started. All abnormalities normalized within 4.7 +/- 2.94 weeks after drug discontinuation.

Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 (LBA1), LMAN2L and PTGFR. In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1, was significant at the P=2.4 × 10−11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

Genome-wide association study of bipolar I disorder in the Han Chinese population

We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10−7 (rs2709736) and 6.05 × 10−6 (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10−6) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10−5), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10−5 and P=1.48 × 10−5, respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

Han Chinese Cell and Genome Bank in Taiwan: Purpose, Design and Ethical Considerations

a Institute of Biomedical Sciences, Academia Sinica, b Department of Political Sciences, National Taiwan University, c Research Center for Humanities and Social Sciencies, Academia Sinica, d Center for Survey Research, Research Center for Humanities and Social Sciencies, Academia Sinica, and e Department of Philosophy, National Chengchi University, Taipei , Taiwan, ROC goal is to develop Taiwan’s competitive edge in medical research particularly for prognosis, diagnosis, and treatment of Taiwanese important genetic diseases. The Han Chinese cell and Genome Bank project was jointly supported by NRPGM and Academia Sinica. Comprehensive cores have been established in NRPGM to complement relevant studies. The National Clinical Core and National High-throughput Genotyping Core, funded by NSC and directed by the Institute of Biomedical Sciences, Academia Sinica, Taiwan, played major roles in carrying out fi eld work and in the genotyping of the genetic material. A policy and mechanisms for the release of DNA information have been established for genetic research communities in Taiwan and abroad. In order to obtain a representative sample of genetic material for the bank; a stratifi ed, 3-staged, probability clustering sampling scheme (see appendix, table 1 , and fi g. 1 ) was adopted. Sampling was designed to have around 278 male and 278 female subjects respectively in each of the 6 age groups (20–, 30–, 40–, 50–, 60–, 70–) so that there would be suffi cient numbers of sex/age matched controls for a range of diseases. Of the people living in the registered households that were contacted, a total of 73.4% took part in the study. Plasma, DNA, and lymphocytes were collected and banked, and measurements including basic blood chemistry, blood pressure, peak fl ow, and anthropometric parameters were taken (see table 2 ). A questionnaire ( table 2 ) on ethnicity, disease history and medication, life styles, and cognitive function of the elderly was administered by trained nurses in a door-to-door survey, following a standardized protocol. Complete questionnaire and bio-specimen data were available for 3,380 people. This information can be used to defi ne phenotypes for association study and to select controls. The EBV-transformed lymphoblastoid cell lines had been established by the Bioresource Collection and Research Center, Hsinchu, Taiwan. From October 1, 2002 to January 14, 2004, the Institute of Biomedical Sciences, Academia Sinica, Taiwan, conducted fi eld work involving interviewing and recruiting 3,380 Han Chinese in order to establish a Han Chinese Cell and Genome Bank in Taiwan. The aims of this undertaking were several fold: (1) to collect representative genetic material for population genetic research, particularly for use as controls in disease association studies in Chinese people, (2) to document the genetic diversity of Han Chinese in Taiwan at the beginning of the 21st century, and (3) to create a bank of material that will prevent the repetitive collection of genetic material from the general public by the academic and medical community. The National Science Council (NSC) in Taiwan has launched the ‘National Research Program for Genomic Medicine (NRPGM)’ in 2002 as the fi rst phase of Taiwan’s Biotechnology Initiative in response to the deciphering of the human genome in 2000. The

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).