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Aims Women with menopausal symptoms show evidence of accelerated epigenetic ageing, vascular aging and low‐grade systemic inflammation status. However, data are limited regarding menopausal symptoms and risk of heart failure (HF). We aimed to explore the impact of menopausal symptoms on risk of HF. Methods We included 14 340 symptomatic menopausal women without a history of coronary heart disease (CHD) or HF from the Taiwan National Health Insurance Research Database as the experimental cohort. We included 14 340 asymptomatic women matched for age and comorbidities as controls. We surveyed possible comorbidity‐attributable risks of HF and assessed whether menopausal symptoms play a role in risk of HF. Additional analyses were conducted to ascertain the association of CHD and HF in different risk factor burdens categories in both cohorts and CHD was applied as a sensitivity analysis. Results The incidence of HF was not significantly lower in the experimental than in the control cohort (4.87 vs. 5.06 per 1000 person‐years, P = 0.336). Participants with a higher comorbidity burden had a proportionally increased risk of HF and CHD in both cohorts. The burden of risk factors had a greater impact on risk of HF in the control than in the experimental cohort (≥five risk factors, adjusted hazard ratio 25.69 vs. 14.75). Participants undergoing hormone therapy had no significant effect on the risk of HF, regardless of the presence or absence of menopausal symptoms. Subgroup analysis revealed that compared with the control cohort, the risk of HF in the experimental cohort did not increase significantly in all subgroups. Conclusions Menopausal symptoms were associated with CHD risk but not with risk of HF. Traditional risk factors rather than menopausal symptoms play important roles in the HF risk among middle‐aged women.

Pi-Shan Hsu,1,2 Ie-Bin Lian,3,4 Day-Yu Chao2 1Department of Family Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 2Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan; 3Graduate Institute of Statistics and Information Science, National Changhua University of Education, Changhua, Taiwan; 4Department of Applied Math, National Chung-Hsing University, Taichung, TaiwanCorrespondence: Day-Yu ChaoGraduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung-Hsing University, Taichung 401, TaiwanTel +886-4-22840694Fax +886-4-22852186Email dychao@nchu.edu.twIe-Bin Lian Tel +886-4-7232105 ext. 3222Fax +886-4-7211192Email maiblian@cc.ncue.edu.twBackground: Influenza is a major cause of morbidity and mortality in the elderly worldwide. Influenza vaccination can prevent morbidity/mortality from influenza infection. A gap of 1– 2 years, before an epidemic strain is recommended by the World Health Organization (WHO) to be the vaccine strain in Southeast Asia, has been reported; this results in a high rate of vaccine mismatch and excess influenza-associated morbidity. The aim of the current study was to evaluate the effect of repeated vaccination on vaccine effectiveness (VE) among the elderly in Taiwan, during years with and without early appearance of antigenically drifted strains.Methods: A historical cohort study was conducted to evaluate the impact of repeated vaccination on the reduction of influenza-associated hospitalization among persons older than 64 years over two influenza seasons: 2007– 08, with all circulatingvirus strainsmismatched, and 2008– 09, with all virusstrainsmatched with the vaccine strains, considering four exposure effects, namely current vaccine effect, sequential vaccination effect, residual protection effect and no vaccination effect. Propensity score matching on vaccination status was performed to ensure similar baseline characteristics between the groups that received and did not receive vaccination.Results: Only current-year vaccination in combination with prior history of annual revaccination significantly reduced the risk of hospitalization, with adjusted hazard ratios of 0.68 (95% CI: 0.54, 0.85) and 0.74 (95% CI: 0.57, 0.95) during the 2007– 08 and 2008– 09 influenza seasons, respectively. Further stratification showed that even during the 2007– 08 influenza season, when all vaccinations weremismatched with the circulating strains, sequential vaccinations still significantly reduced influenza-associated hospitalization in thefemale population aged 68– 74 and 75– 84 years, with adjusted VE of 25.2% (95% CI: − 9.6, 49.0%) and 36.9% (95% CI: 17.1, 52.0%), respectively.Conclusion: Our study supports the recommendation of annual revaccination against influenza in theelderly, even though the circulating strain of influenza virus was antigenically mismatched with thevaccine strains.Keywords: vaccine effectiveness, trivalent influenza vaccine, elderly, prior vaccination history, repeated vaccination, propensity score matching

Background Invoices had been used in food product traceability, however, none have addressed the automated alarm system for food safety by utilizing electronic invoice big data. In this paper, we present an alarm system for edible oil manufacture that can prevent a food safety crisis rather than trace problematic sources post-crisis. Materials and methods Using nearly 100 million labeled e-invoices from the 2013‒2014 of 595 edible oil manufacturers provided by Ministry of Finance, we applied text-mining, statistical and machine learning techniques to “train” the system for two functions: (1) to sieve edible oil-related e-invoices of manufacturers who may also produce other merchandise and (2) to identify suspicious edible oil manufacture based on irrational transactions from the e-invoices sieved. Results The system was able to (1) accurately sieve the correct invoices with sensitivity >95% and specificity >98% via text classification and (2) identify problematic manufacturers with 100% accuracy via Random Forest machine learning method, as well as with sensitivity >70% and specificity >99% through simple decision-tree method. Conclusion E-invoice has bright future on the application of food safety. It can not only be used for product traceability, but also prevention of adverse events by flag suspicious manufacturers. Compulsory usage of e-invoice for food producing can increase the accuracy of this alarm system.

Background In Taiwan, Changhua County residents were exposed to high heavy metal pollution and exhibited high heavy metal levels in blood and urine. We examined associations between heavy metals in residential soil and renal outcomes of residents with chronic kidney disease (CKD). Method From January 01, 2003 to June 30, 2015, we retrospectively identified CKD patients with an estimated glomerular filtration rate of

We studied the combined effect of air pollutant concentrations and meteorological factors [e.g., temperature and atmospheric pressure (AP)] on the acute exacerbation of coronary obstructive pulmonary disease (COPD) in 277 older patients with COPD (240 men and 37 women; average age, 75.3 ± 9.3 years). Average air pollutant concentrations, AP, temperature, and relative humidity corresponding to each of the 7 days before the date of hospitalisation were identified as the case and the two other weekly averages, 4 and 8 weeks prior to admission, were considered the controls. During the warming-up season, COPD exacerbation more likely occurred on days of temperature increase or AP decrease than on other days. Increments in CO, NO2 and O3 concentrations were significantly associated with 5%, 11% and 4% increases in COPD exacerbation risks, respectively. During the cooling-down season, increments in PM10 concentrations were significant risk factors; the exacerbation likely occurred on days of temperature decreases than on other days. Air pollution with increased NO2, CO, O3 and PM10 concentrations and continual temperature changes (colder during cooling-down seasons or hotter during warning-up seasons) were associated with acute exacerbation of COPD in older patients.

Objective Oral cancer (OC) is a leading cause of death from cancer in men between the ages of 25 and 44 years in Taiwan. The overall 5-year survival rates for the four OC stages (I–IV) in Taiwan are approximately 70%, 30%, 20%, and 10%, respectively, indicating the importance of the early diagnosis of oral potentially malignant disorders (OPMDs). Previous studies indicated an association between the OC incidence and certain environmental heavy metal concentrations. If these associations do exist for OC, they may also be observed for OPMD. The purpose of this study is to explore the association between the development of OPMD to OC and environmental heavy metals. Oral submucous fibrosis (OSF) and oral leukoplakia (OL) are two major types of OPMD in Taiwan. Materials and methods A retrospective cohort study was conducted by Changhua Christian Hospital, the sole medical center in Changhua County, where 2725 male adult patients diagnosed with either OSF or OL between 2000 and 2014 were recruited. Data were analyzed by Cox regression and adjusted for smoking and betel-quid chewing. Results and discussion OPMD patients who resided in areas with high nickel concentrations (polluted levels) exhibited hazard ratios of 1.8–2 for OC relative to those who lived in areas with low nickel levels ( P 0.01). Meanwhile, smokers with OPMDs had a hazard ratio of 2.8–2.9 relative to non-smokers. Betel-quid chewers had a 2.2–2.3 hazard ratio relative to non-chewers. Smoking, betel-quid chewing, and environmental nickel exposure are associated with an increased risk of OC development in OPMD patients. This study provides valuable findings on the environmental effects of heavy metals on human health. Enhanced surveillance of the condition of OPMD patients who have been exposed to high nickel concentrations may be crucial for OC prevention.

To investigate the incidence and prevalence of dry eye disease (DED) in Taiwan and to explore its potential risk factors. Population-based longitudinal data from 2000 to 2013 based on Taiwan National Health Insurance Research Database were used in this study. To explore potential risks factor of interest, patients who had DED diagnosis before the exposure were excluded. Each patient from the exposure and his/her matched non-exposure controls were followed until either the diagnosis of DED or censorship. Kaplan–Meier method was used to compare the hazard of DED between cohorts. Stratified Cox proportional hazard models were applied to estimate the adjusted effect. The age-adjusted prevalence for men and women were 6.81% and 16.16%, respectively. The age–gender rate of the same period was 549 per 105 person-years. The propensity-adjusted hazard ratio of DED is 1.816 for the presbyopia versus non-presbyopia (with 95% CI = [1.737, 1.897] with p value

Differential diagnosis for neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) is always doubtful. To differentiate these diseases, we studied the immune status in the blood of patients with MS ( n = 45) or NMOSD ( n = 23) at remission phase. Remitting NMOSD patients had increased levels of CXCL13 and memory B cells, while remitting MS patients had elevated levels of galectin-9 and Th1 cells. A diagnostic model with these four variables is built to distinguish remitting NMOSD from MS with a sensitivity of 91.30%. Our diagnostic model may help to improve the differentiation of remitting NMOSD from MS.

Background/Purpose: Chromium and nickel are important soil pollutants in Taiwan. Previously, we showed that blood chromium levels correlated strongly with soil chromium levels. Our observation that many patients with dry eyes or a dry mouth came from areas where soils contain high chromium levels prompted us to investigate whether incidence and prevalence of SS are higher in areas where soils contain high levels of heavy metals. Methods: We used a database from national health insurance (NHI) to study the epidemiology of SS. It was ascertained by at least 3 hospital visits with the diagnosis within 12 months. We then compared the results with the information about heavy metal contents in farm soils. Results: The incidence of SS was significantly increased (3.6 fold) in the areas where soils contained high levels of chromium and nickel. In contrast, lead, copper, or arsenic did not show such a strong association. Conclusion: Both the prevalence and incidence of SS are significantly increased in areas where soils contain high levels of chromium and nickel. Whether heavy metal, particularly chromium or nickel is a novel environmental risk factor for sicca syndrome needs more studies to confirm. Keywords: Sicca syndrome, Chromium, Nickel, Epidemiology

This study investigated the interaction effects of meteorological factors and air pollutants on the onset of acute coronary syndrome (ACS). Data of ACS patients were obtained from the Taiwan ACS Full Spectrum Registry and comprised 3164 patients with a definite onset date during the period October 2008 and January 2010 at 39 hospitals. Meteorological conditions and air pollutant concentrations at the 39 locations during the 488-day period were obtained. Time-lag Poisson and logistic regression were used to explore their association with ACS incidence. One-day lag atmospheric pressure (AP), humidity, particulate matter (PM2.5, and PM10), and carbon monoxide (CO) all had significant interaction effects with temperature on ACS occurrence. Days on which high temperatures (>26 °C) and low AP (

Some specific types of cancer still pose a severe threat to the health of Taiwanese women. This study focuses on determining the geographical locations of hot spots and causal factors related to the major categories of cancers in Taiwanese women. Cancer mortality data from 1972 to 2001 of 346 townships in Taiwan were obtained from the Atlas of Cancer Mortality. Principal component analysis was conducted to determine the primary categories of female cancers. The spatial patterns of hot spots and cold spots for each major cancer category were identified using the local indicator of spatial association. Finally, the regional differences between the hot spots and cold spots were compared to confirm the possible factors causing cancer throughout Taiwan. A total of 21 cancer types in women were divided into seven major categories, which accounted for 68.0% of the total variance. The results from the spatial autocorrelation analysis showed significant spatial clusters of the cancer categories. Based on the overall consistency of results between this study and those of previous research, this study further identified the high-risk locations and some specific risk factors for major cancer types among Taiwanese women.

To design and to manufacture in science learning are increasingly important in science education. Yet, evaluation techniques in school for evaluating students’ creative products are apparently left behind. With the aim of developing an evaluation method to evaluate creative products in science and technology class, this study constructed a set of criteria with data collected from teachers and students. The analytic hierarchy process (AHP), a multiple criteria decision-making tool for single rater, was selected for the purpose of weighting and evaluating students’ products. However, the traditional AHP used one rater’s pair-wise comparisons; its subjectivity and complexity limit its applications in school. For solving this problem, this study developed an advanced technique, called direct-rating AHP (DR-AHP), to extend the applicability of the traditional AHP. The DR-AHP is used to obtain weights or preferences for criteria/alternatives by a process of directly ranking criteria/alternatives by single/multi rater(s), checking consistency, and developing a rank vector matrix. The DR-AHP was implemented in obtaining criteria weights of a hierarchy framework for creative products evaluation by a group of science educators (N = 13) and field-tested in ranking creative products by another group of science teachers (N = 9). Results showed its superiority in objectivity and efficiency over traditional ways of evaluation. The results also demonstrate how the AHP and DR-AHP are capable of helping evaluators systematically construct criteria and/or to evaluate students’ creative products for classroom instruction as well as during many other activities.

To investigate whether patients with central serous chorioretinopathy (CSCR) have increased risk of coronary heart disease (CHD).Population-based retrospective cohort and case control study. Longitudinal data from the Taiwan National Health Insurance Research Database (2000-2009) were analysed. The study cohort comprised 835 patients with a diagnosis of CSCR and 4175 age and gender matched patients without CSCR. Kaplan-Meier plots and log-rank tests were used to compare differences in the hazard rates of CHD between the CSCR and non-CSCR cohorts. Stratified Cox proportional hazard models were applied to examine the association between CSCR and CHD, adjusting for potential confounding factors.The 5-year CHD cumulative incidence for patients with CSCR was nearly twofold that of the non-CSCR cohort (6.12% vs 3.29%, p=0.004) from the log-rank test. The adjusted CHD HR of CSCR versus non-CSCR was 1.61 (95% CI 1.12 to 2.30, p=0.009) from the Cox model. Specifically, the HR for male patients was 1.72 (95% CI 1.14 to 2.59, p=0.010) and for female patients it was 1.34 (95% CI 0.64 to 2.84, p=0.438).Male patients with CSCR had a significantly higher CHD rate than those without CSCR, indicating that CSCR may be a potential risk factor for the development of CHD for men.

summary Background: Oral cancer (OC) is the leading cause of death from cancer in men between the ages of 25 and 44 in Taiwan. The survival rate for the last stage of OC is 75%, which suggests the importance of the diagnosis of oral precancerous lesions (OPLs) in reducing OC mortality. The aim of this study was to analyze the time to OC event after OPL diagnosis, and to suggest the surveillance period necessary according to OPL type. Materials and methods: This was a retrospective cohort study based on 1.0 million people randomly selected from the Taiwan National Health Insurance Database, which provided data on 3058 adult male patients aged P20 years who were diagnosed with OPL for the first time between 1996 and 2009. The patient population was divided into two groups according to the type of lesion: oral submucous fibrosis (OSF) or oral leukoplakia (OLE). Age-standardized incidence rate (ASIR) and hazards rate (HR) were then estimated. Results: The ASIR for OPL showed an increasing trend over the study period, the main contributor to this being OSF. The OSF group demonstrated a higher OC incidence rate than the OLE group. Conclusion: Patients with both OLE and OSF carry a higher risk for OC than those with either OLE or OSF alone, and they may also experience malignant transformation at an earlier date (mostly within 5 years). The 5- and 10-year OC rate for both OLE and OSF was found to be 5% and around 10%, respectively. However, 10 years after the diagnosis of OPL, OSF carries a higher risk of developing into OC than OLE.

Exogenous administration of coenzyme Q10 (CoQ10) has been shown in experimental models to have a protective effect against ischemia–reperfusion injury. However, it is unclear whether follow-up plasma CoQ10 concentration is prognostic of left ventricular (LV) performance after primary balloon angioplasty in patients with acute ST segment elevation myocardial infarction (STEMI). We prospectively recruited 55 patients with STEMI who were treated with primary coronary balloon angioplasty. Plasma CoQ10 concentrations were measured before primary angioplasty (baseline) and 3 days, 7 days, and 1 month after STEMI using high-performance liquid chromatography. Echocardiography was performed at baseline and at 6-month follow-up. The control group comprised 54 healthy age- and sex-matched volunteers. Serial circulating CoQ10 concentrations significantly decreased with time in the STEMI group. The LV ejection fraction at 6-month follow-up positively correlated with the 1-month plasma CoQ10 tertile. Higher plasma CoQ10 concentrations at 1 month were associated with favorable LV remodeling and systolic function 6 months after STEMI. Multiple linear regression analysis showed that changes in CoQ10 concentrations at 1-month follow-up were predictive of LV systolic function 6 months after STEMI. Changes in CoQ10 concentrations correlated negatively with baseline oxidized low-density lipoprotein and fibrinogen concentrations and correlated positively with leukocyte mitochondrial copy number at baseline. Patients with STEMI who had higher plasma CoQ10 concentrations 1 month after primary angioplasty had better LV performance at 6-month follow-up. In addition, higher plasma CoQ10 concentration was associated with lower grade inflammatory and oxidative stress status. Therefore, plasma CoQ10 concentration may serve as a novel prognostic biomarker of LV systolic function after revascularization therapy for acute myocardial infarction.

Background Traumatic brain injury (TBI) is an important cause of death and disability worldwide. The relationship between TBI and kidney diseases is largely unknown. Methods We aimed to determine whether TBI is associated with long-term adverse renal outcomes. We performed a nationwide, population-based, propensity score-matched cohort study of 32,152 TBI patients and 128,608 propensity score-matched controls. Data were collected by the National Health Insurance Research Database of Taiwan from 2000 to 2012. Our clinical outcomes were chronic kidney disease (CKD), end-stage renal disease (ESRD) and the composite endpoint of ESRD or all-cause mortality. Results The incidence rate of CKD was higher in the TBI than in the control cohort (8.99 vs. 7.4 per 1000 person-years). The TBI patients also showed higher risks of CKD (adjusted hazard ratio [aHR] 1.14, 95% confidence interval [CI] 1.08–1.20; P < 0.001) and composite endpoints (aHR 1.08, 95% CI 1.01–1.15; P = 0.022) than the control groups, but the ESRD was not significantly different between the groups. In subgroup analyses, the risks of incident CKD and composite endpoints were significantly raised in TBI patients aged < 65 years and/or without comorbidities. However, the risks of both CKD and composite outcome were little affected by the severity of TBI. Conclusions TBI has a modest but significant effect on incident CKD and composite endpoint, but not on ESRD alone. TBI patients under 65 are at greater risk of CKD and composite outcome than their older counterparts.

Background The statistical tests for single locus disease association are mostly under-powered. If a disease associated causal single nucleotide polymorphism (SNP) operates essentially through a complex mechanism that involves multiple SNPs or possible environmental factors, its effect might be missed if the causal SNP is studied in isolation without accounting for these unknown genetic influences. In this study, we attempt to address the issue of reduced power that is inherent in single point association studies by accounting for genetic influences that negatively impact the detection of causal variant in single point association analysis. In our method we use propensity score (PS) to adjust for the effect of SNPs that influence the marginal association of a candidate marker. These SNPs might be in linkage disequilibrium (LD) and/or epistatic with the target-SNP and have a joint interactive influence on the disease under study. We therefore propose a propensity score adjustment method (PSAM) as a tool for dimension reduction to improve the power for single locus studies through an estimated PS to adjust for influence from these SNPs while regressing disease status on the target-genetic locus. The degree of freedom of such a test is therefore always restricted to 1. Results We assess PSAM under the null hypothesis of no disease association to affirm that it correctly controls for the type-I-error rate ( 70%) and shows an average of 15% improvement in power as compared with commonly-used logistic regression method and PLINK under most simulated scenarios. Using the open-access multifactor dimensionality reduction dataset, PSAM displays improved significance for all disease loci. Through a whole genome study, PSAM was able to identify 21 SNPs from the GAW16 NARAC dataset by reducing their original trend-test p-values from within 0.001 and 0.05 to p-values less than 0.0009, and among which 6 SNPs were further found to be associated with immunity and inflammation. Conclusions PSAM improves the significance of single-locus association of causal SNPs which have had marginal single point association by adjusting for influence from other SNPs in a dataset. This would explain part of the missing heritability without increasing the complexity of the model due to huge multiple testing scenarios. The newly reported SNPs from GAW16 data would provide evidences for further research to elucidate the etiology of rheumatoid arthritis. PSAM is proposed as an exploratory tool that would be complementary to other existing methods. A downloadable user friendly program, PSAM, written in SAS, is available for public use.

Genome-wide association studies (GWAS) have become the method of choice for identifying disease susceptibility genes in common disease genetics research. Despite successes in these studies, much of the heritability remains unexplained due to lack of power and low resolution. High-density genotyping arrays can now screen more than 5 million genetic markers. As a result, multiple comparison has become an important issue especially in the era of next-generation sequencing. We propose to use a two-stage maximal segmental score procedure (MSS) which uses region-specific empirical P-values to identify genomic segments most likely harboring the disease gene. We develop scoring systems based on Fisher's P-value combining method to convert locus-specific significance levels into region-specific scores. Through simulations, our result indicated that MSS increased the power to detect genetic association as compared with conventional methods provided type I error was at 5%. We demonstrated the application of MSS on a publicly available case-control dataset of Parkinson's disease and replicated the findings in the literature. MSS provides an efficient exploratory tool for high-density association data in the current era of next-generation sequencing. R source codes to implement the MSS procedure are freely available at http://www.csjfann.ibms.sinica.edu.tw/EAG/program/programlist.htm.

SUMMARYThe introduction and the widespread use of the varicella vaccine in Taiwan has led to a 75–80% decrease in the incidence of varicella in children. However the vaccine's long-term impact on the incidence of herpes zoster (HZ) has attracted attention. By controlling gender, underlying diseases, and age effects, a Poisson regression was applied on the 2000–2008 chart records of 240 000 randomly selected residents who enrolled in the Universal National Health Insurance. The results show that, as the vaccine coverage in children increases, the incidence of varicella decreases. However, the incidence of HZ increased even before the implementation of the free varicella vaccination programme in 2004, particularly in females. The increase in the incidence of HZ cannot be entirely and directly attributed to the widespread vaccination of children. Continuous monitoring is needed to understand the secular trends in HZ before and after varicella vaccination in Taiwan and in other countries.

The varicella vaccine has been available in the Taiwan market since July 1997. Beginning 1998-1999, Taipei City and Taichung City/County as the early launch areas included the varicella vaccine in their free pediatric vaccination programs. By contrast, the national free vaccination program was not implemented until 2004. We aim to investigate the changing epidemiology of varicella incidence through an analysis of age-period-cohort effects. With the greatest decrease in varicella incidence occurring in children aged below 6, the incidence of varicella shifted to older age groups as reflected in different birth cohorts. The current study provides important implications for the current vaccination policy.

Excessive arsenic intake has a detrimental effect on human health, as reflected in an increase in cancer incidence. In an area on the southwest coast of Taiwan, arsenic intake from well water since the 1920s had caused an exceptionally high mortality from cancer. Municipal water has become available to people living in the arseniasis endemic area since the early 1970s. This study explored the impacts of reduction in arsenic intake from water on lung cancer and bladder cancer in the arseniasis endemic area in Taiwan. Chart records of 23,013 patients diagnosed with bladder cancer and 93,633 patients with lung cancer from 1979 to 2003 were retrieved from the Taiwan Cancer Registry Center. We used the age-period-cohort model to study the changes in the incidence of lung cancer and bladder cancer in the arseniasis endemic area and the rest of Taiwan. Three decades after municipal water supply to the arseniasis and black foot disease endemic area (BFDEA), we saw a marked decrease in the incidence of both bladder cancer and lung cancer in the area, especially for those in the later cohorts. The relative risk (RR) of getting a bladder cancer for people living in BFDEA when compared with those in the rest of Taiwan has dropped from 20 for the early cohorts to 5 for the late cohorts. As to lung cancer, the RR has decreased from 8 to between 1.5 and 2. Reduction in arsenic intake from water has a positive impact on the incidence of both lung and bladder cancer; however, while RR for lung cancer has dropped to below 2, RR for bladder cancer remained at around 5. The difference may be because (1) there are other risk factors beside the well-water intake or (2) bladder cancer may have longer latency period for excessive arsenic exposure than lung cancer. More studies are required to understand the causes behind the difference in RR for these two types of cancer.

Central and Eastern Taiwan have alarmingly high oral cancer (OC) mortality rates, however, the effect of lifestyle factors such as betel chewing cannot fully explain the observed high-risk. Elevated concentrations of heavy metals in the soil reflect somewhat the levels of exposure to the human body, which may promote cancer development in local residents. This study assesses the space-time distribution of OC mortality in Taiwan, and its association with prime factors leading to soil heavy metal content. The current research obtained OC mortality data from the Atlas of Cancer Mortality in Taiwan, 1972–2001, and derived soil heavy metals content data from a nationwide survey carried out by ROCEPA in 1985. The exploratory data analyses showed that OC mortality rates in both genders had high spatial autocorrelation (Moran’s I = 0.6716 and 0.6318 for males and females). Factor analyses revealed three common factors (CFs) representing the major pattern of soil pollution in Taiwan. The results for Spatial Lag Models (SLM) showed that CF1 (Cr, Cu, Ni, and Zn) was most spatially related to male OC mortality which implicates that some metals in CF1 might play as promoters in OC etiology.

Smoking and betel quid chewing are established risk factors for oral cancer in Taiwan. The prevalence of these risk factors in the central county of Changhua falls within the middle range nationally, yet the county has the highest incidence of oral cancer in Taiwan. The purpose of this study, therefore, was to identify if patients' ages and prognoses at diagnosis were related to their place of residence and, if so, to explore environmental and geographical factors which might explain local variance in the incidence of oral cancers within Changhua and their prevalence in the county as a whole. The paper contains results from a retrospective review of medical records for patients diagnosed with oral cancer in Changhua County who were treated at the Changhua Christian Hospital (CCH) between 1994 and 2005. The Wilcoxon signed rank test, ANOVA, t-test, Kaplan-Meier curve and log-rank tests were carried out to examine the association between patients' places of residence, their ages at diagnosis, and their overall prognoses. A total of 1363 oral cancer cases were diagnosed in the study period. These consisted of 1272 males and 91 females. A steady increase in the number of patients diagnosed with oral cancer annually was noted. The tongue and buccal mucosa were the two most frequently affected sites constituting 56% of cases, while squamous cell carcinoma was diagnosed in nearly 80% of the study population. The mean ages at diagnosis were 53.1 and 52.8 years for patients living in the northern and central areas of Changhua, and 55.1 years for those living in the south. Patients living in the northern and central areas of Changhua had poorer long-term prognoses as indicated by Kaplan-Meier survival curves and the log-rank test, and it appears that differences in the level, type and distribution of industry in these areas distinguish these patients from those living in the south of the county. In particular, the density of electroplating factories in northern and central Changhua is significantly higher than in the south. Patients living in northern and central areas of Changhua have their oral cancers diagnosed at a younger age and have poorer long-term prognoses than those living in the south of the county in spite of their being treated at the same hospital. We conclude that factors explaining local differences in the prognosis of oral cancer patients in this part of Taiwan require further investigation, as does Changhua's high overall incidence for these cancers.

When using microarray analysis to determine gene dependence, one of the goals is to identify differentially expressed genes. However, the inherent variations make analysis challenging. We propose a statistical method (SRA, swapped and regression analysis) especially for dye-swapped design and small sample size. Under general assumptions about the structure of the channels, scanner, and target effects from the experiment, we prove that SRA removes bias caused by these effects. We compare our method with ANOVA, using both simulated and real data. The results show that SRA has consistent sensitivity for the identification of differentially expressed genes in dye-swapped microarrays, particularly when the sample size is small. The program for the proposed method is available at http://www.ibms.sinica.edu.tw/~csjfann/firstflow/program.htm.

Supplemental Digital Content is available in the text, End stage renal disease (ESRD) has been reported to be an important risk factor for systemic vascular disease. Retinal vein occlusion (RVO) is closely related with cardiovascular diseases; however, its association with ESRD had not been reported. The aim of the study was to investigate whether ESRD is a risk factor for RVO, including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO). This population-based study is based on the longitudinal data from Taiwan National Health Insurance Research Database. The study cohort comprised 5344 patients with diagnosis of ESRD on hemodialysis or peritoneal dialysis during the period from January 1996 to December 2011. For each ESRD patient, we selected 20 non-ESRD patients matched on age and sex. Each ESRD patient and his/her controls were followed from the initiation of renal dialysis until either the diagnosis of RVO or censorship. Kaplan–Meier method was used to compare the hazard of RVO between cohorts. Stratified Cox proportional hazard models were applied to estimate the hazard ratio (HR) adjusted by the comorbidities of RVO including diabetes mellitus (DM), hypertension, hypercholesteremia, and hypertriglyceridemia. After stratifying by DM status, the statistics were applied again to examine the associations among the DM cohort and non-DM cohort. The 16-year RVO cumulative incidence for ESRD cohort was 2-fold to the non-ESRD (1.01% vs 0.46%). After matching with age, sex, hypertension, and hypercholesteremia, the adjusted HR was 1.46 (95% confidence interval = 1.07–2.01, P value = 0.018). By further excluding patients with DM, the adjusted HR escalated to 2.43 (95% confidence interval = 1.54–3.83, P

To estimate the incidence and clinical characteristics of rhegmatogenous retinal detachment (RRD) in Taiwan.This was a nationwide, population-based retrospective study of patients with RRD. Data from the Taiwan National Health Insurance Research Database (2000-2012), which represents 4% of the total population in Taiwan, were analysed. The incidence of RRD and its associations with age, gender and high myopia were analysed.A total of 2359 patients with RRD (1336 men and 1023 women) were identified from 2000-2012. The age-standardised incidence rate of RRD over the 13-year period was 16.40±1.06 per 10(5) person-years (18.89 and 13.93 for men and women, respectively, p0.0001) and an average age of 47.76±0.67 years. The incidence in both genders had an obvious peak at 50-69 years of age, and a secondary peak at 20-29 years in women. Concomitant high myopia was noted in 10.51% of the patients, with an average of 39.72±1.95 years. Prior cataract extraction was noted in 11.06% of the patients, including 17.64% in the patients RRD aged ≥50 years and 4.04% in those younger than 50 years. The average age of the patients with pseudophakic or aphakic RRD was 61.85±1.60 years.The annual incidence of RRD in Taiwan is comparable to most Western countries, with a relatively younger mean age. The male patients were more susceptible to retinal detachment in almost all age groups. Retinal detachment in patients with high myopia was associated with a younger age at onset.

Background Despite dengue dynamics being driven by complex interactions between human hosts, mosquito vectors and viruses that are influenced by climate factors, an operational model that will enable health authorities to anticipate the outbreak risk in a dengue non-endemic area has not been developed. The objectives of this study were to evaluate the temporal relationship between meteorological variables, entomological surveillance indices and confirmed dengue cases; and to establish the threshold for entomological surveillance indices including three mosquito larval indices [Breteau (BI), Container (CI) and House indices (HI)] and one adult index (AI) as an early warning tool for dengue epidemic. Methodology/Principal Findings Epidemiological, entomological and meteorological data were analyzed from 2005 to 2012 in Kaohsiung City, Taiwan. The successive waves of dengue outbreaks with different magnitudes were recorded in Kaohsiung City, and involved a dominant serotype during each epidemic. The annual indigenous dengue cases usually started from May to June and reached a peak in October to November. Vector data from 2005–2012 showed that the peak of the adult mosquito population was followed by a peak in the corresponding dengue activity with a lag period of 1–2 months. Therefore, we focused the analysis on the data from May to December and the high risk district, where the inspection of the immature and mature mosquitoes was carried out on a weekly basis and about 97.9% dengue cases occurred. The two-stage model was utilized here to estimate the risk and time-lag effect of annual dengue outbreaks in Taiwan. First, Poisson regression was used to select the optimal subset of variables and time-lags for predicting the number of dengue cases, and the final results of the multivariate analysis were selected based on the smallest AIC value. Next, each vector index models with selected variables were subjected to multiple logistic regression models to examine the accuracy of predicting the occurrence of dengue cases. The results suggested that Model-AI, BI, CI and HI predicted the occurrence of dengue cases with 83.8, 87.8, 88.3 and 88.4% accuracy, respectively. The predicting threshold based on individual Model-AI, BI, CI and HI was 0.97, 1.16, 1.79 and 0.997, respectively. Conclusion/Significance There was little evidence of quantifiable association among vector indices, meteorological factors and dengue transmission that could reliably be used for outbreak prediction. Our study here provided the proof-of-concept of how to search for the optimal model and determine the threshold for dengue epidemics. Since those factors used for prediction varied, depending on the ecology and herd immunity level under different geological areas, different thresholds may be developed for different countries using a similar structure of the two-stage model., Author Summary With the continuously high levels of worldwide dengue transmission, predicting dengue outbreaks in advance of their occurrence or identifying specific locations where outbreak risks are highest is of critical importance. However, only few studies have been conducted in dengue non-endemic countries to evaluate the association of vector index with the occurrence of dengue cases; and the establishment of an early warning signal would significantly enhance the public health intervention. Our study here provided the proof-of-concept results, utilizing a two-stage model to identify the best set of lag effects of meteorological and entomological variables, explaining dengue epidemics based on the data obtained from Taiwan, which is a dengue-non-endemic country. Each of the vector indices when combined with the meteorological factors has better performance compared to the prediction using AI, BI, CI and HI alone, with 83.8, 87.8, 88.3 and 88.4% accuracy, respectively. Because of the complex interplays between the size of human hosts and movement, environmental factors and dynamic changes of mosquito population and density, each country should consider its own individual data and situation and apply this two-stage model to find the optimal predictive models for allocating public health resources and prevention strategies.

The distribution of the length of the longest run has wide applications in regard to reliability and DNA sequencing. Statistical tests based on the longest well-matching run are usually considered to be more reasonable than tests based on the perfect-matching run. In this paper, a method adopted from Fu and Koutras (J. Amer. Statist. Assoc. 89 (1994) 1050) is proposed to improve the efficiency of computing the exact distribution of length. We used the result to investigate the accuracy of some approximations of the distribution.

Objectives Metabolic factors are major risk factors for non-alcoholic fatty liver disease although other factors may also contribute to development of fatty liver disease. We explored the association between exposure to soil heavy metals and prevalence of fatty liver disease. Methods We retrospectively analysed data from patients diagnosed with fatty liver disease in 2014 at the Health Evaluation Centre of Chang-Hua Christian Hospital (n=1137). We used residency data provided in the records of the Health Evaluation Centre and data for soil metal concentrations from a nationwide survey conducted by the Environmental Protection Administration of Taiwan. We studied the correlations between the severity of fatty liver disease and concentrations of soil heavy metals (arsenic, mercury, cadmium, chromium, copper, nickel, lead and zinc). Results The prevalence of moderate to severe fatty liver disease in our study was 26.5%. Using univariate and multivariate analysis, we demonstrated that the presence of soil heavy metals was a significant risk factor for fatty liver disease in men (OR 1.83, 95% CI 1.161 to 2.899, p=0.009). With stratification by body mass index (BMI) and gender, lean men with a BMI

Purpose: To investigate peptic ulcer disease and other possible risk factors in patients with central serous chorioretinopathy (CSR) using a population-based database. Methods: In this population-based retrospective cohort study, longitudinal data from the Taiwan National Health Insurance Research Database were analyzed. The study cohort comprised 835 patients with CSR and the control cohort comprised 4175 patients without CSR from January 2000 to December 2009. Conditional logistic regression was applied to examine the association of peptic ulcer disease and other possible risk factors for CSR, and stratified Cox regression models were applied to examine whether patients with CSR have an increased chance of peptic ulcer disease and hypertension development. Results: The identifiable risk factors for CSR included peptic ulcer disease (adjusted odd ratio: 1.39, P = 0.001) and higher monthly income (adjusted odd ratio: 1.30, P = 0.006). Patients with CSR also had a significantly higher chance of developing peptic ulcer disease after the diagnosis of CSR (adjusted odd ratio: 1.43, P = 0.009). Conclusion: Peptic ulcer disease and higher monthly income are independent risk factors for CSR. Whereas, patients with CSR also had increased risk for peptic ulcer development.

Background Genome-wide association studies have been successful in identifying common genetic variants for human diseases. However, much of the heritable variation associated with diseases such as Parkinson’s disease remains unknown suggesting that many more risk loci are yet to be identified. Rare variants have become important in disease association studies for explaining missing heritability. Methods for detecting this type of association require prior knowledge on candidate genes and combining variants within the region. These methods may suffer from power loss in situations with many neutral variants or causal variants with opposite effects. Results We propose a method capable of scanning genetic variants to identify the region most likely harbouring disease gene with rare and/or common causal variants. Our method assigns a score at each individual variant based on our scoring system. It uses aggregate scores to identify the region with disease association. We evaluate performance by simulation based on 1000 Genomes sequencing data and compare with three commonly used methods. We use a Parkinson’s disease case–control dataset as a model to demonstrate the application of our method. Our method has better power than CMC and WSS and similar power to SKAT-O with well-controlled type I error under simulation based on 1000 Genomes sequencing data. In real data analysis, we confirm the association of α-synuclein gene (SNCA) with Parkinson’s disease (p = 0.005). We further identify association with hyaluronan synthase 2 (HAS2, p = 0.028) and kringle containing transmembrane protein 1 (KREMEN1, p = 0.006). KREMEN1 is associated with Wnt signalling pathway which has been shown to play an important role for neurodegeneration in Parkinson’s disease. Conclusions Our method is time efficient and less sensitive to inclusion of neutral variants and direction effect of causal variants. It can narrow down a genomic region or a chromosome to a disease associated region. Using Parkinson’s disease as a model, our method not only confirms association for a known gene but also identifies two genes previously found by other studies. In spite of many existing methods, we conclude that our method serves as an efficient alternative for exploring genomic data containing both rare and common variants. Electronic supplementary material The online version of this article (doi:10.1186/s12929-014-0088-9) contains supplementary material, which is available to authorized users.

Advances in biotechnology have resulted in large-scale studies of DNA methylation. A differentially methylated region (DMR) is a genomic region with multiple adjacent CpG sites that exhibit different methylation statuses among multiple samples. Many so-called “supervised” methods have been established to identify DMRs between two or more comparison groups. Methods for the identification of DMRs without reference to phenotypic information are, however, less well studied. An alternative “unsupervised” approach was proposed, in which DMRs in studied samples were identified with consideration of nature dependence structure of methylation measurements between neighboring probes from tiling arrays. Through simulation study, we investigated effects of dependencies between neighboring probes on determining DMRs where a lot of spurious signals would be produced if the methylation data were analyzed independently of the probe. In contrast, our newly proposed method could successfully correct for this effect with a well-controlled false positive rate and a comparable sensitivity. By applying to two real datasets, we demonstrated that our method could provide a global picture of methylation variation in studied samples. R source codes to implement the proposed method were freely available at http://www.csjfann.ibms.sinica.edu.tw/eag/programlist/ICDMR/ICDMR.html.

Globally, influenza infection is a major cause of morbidity and mortality in the elderly, who are suggested to be the major target group for trivalent influenza vaccine (TIV) vaccination by World Health Organization. In spite of an increasing trend in vaccine coverage rates in many countries, the effect of vaccination among the elderly in reducing hospitalization and mortality remains controversial. In this study, we conducted a historical cohort study to evaluate the temporal pattern of influenza-associated morbidity among persons older than 64 years over a decade. The temporal patterns of influenza-associated morbidity rates among the elderly older than 64 years indicated that Taiwan's elderly P&I outpatient visits have been decreasing since the beginning of the 1999–2000 influenza season; however, hospitalization has been increasing despite significant increases in vaccine coverage. The propensity score logistic regression model was implemented to evaluate the source of bias and it was found that the TIV-receiving group had a higher propensity score than the non-receiving group (P

In educational testing problems, some natural restriction on the coefficients may arise in maximizing the correlation or variance of linear combinations of sets of variables. In this article, two statistics based on restricted principal component and restricted canonical correlation (Das & Sen, 1994) are proposed to measure the intra- and inter-group concordance of variables. We also propose using these statistics as criteria for clustering variables. The analysis of encyclopedia data is provided as an illustration.

In the construction of phylogenetic tree, the choice of a metric for measuring the distance of pairs of objects, and linkages for measuring distance between groups are both crucial. For stepwise methods, different linkages usually produce different trees, and for exhaustive methods, the computation is time-consuming when the number of objects to be classified is large. In this paper, we propose an ultrametric fuzzy distance, and show that under this distance, the correspondent distance tree is additive and linkage-free, and therefore has a one-to-one correspondence between the distance matrix and trees. The algorithm is easy to implement even for a large sample of objects; however, it may mildly increase the chance of misclassification due to the loss of information.

Identifying susceptibility genes that influence complex diseases is extremely difficult because loci often influence the disease state through genetic interactions. Numerous approaches to detect disease-associated SNP-SNP interactions have been developed, but none consistently generates high-quality results under different disease scenarios. Using summarizing techniques to combine a number of existing methods may provide a solution to this problem. Here we used three popular non-parametric methods-Gini, absolute probability difference (APD), and entropy-to develop two novel summary scores, namely principle component score (PCS) and Z-sum score (ZSS), with which to predict disease-associated genetic interactions. We used a simulation study to compare performance of the non-parametric scores, the summary scores, the scaled-sum score (SSS; used in polymorphism interaction analysis (PIA)), and the multifactor dimensionality reduction (MDR). The non-parametric methods achieved high power, but no non-parametric method outperformed all others under a variety of epistatic scenarios. PCS and ZSS, however, outperformed MDR. PCS, ZSS and SSS displayed controlled type-I-errors (0.05) compared to GS, APDS, ES (0.05). A real data study using the genetic-analysis-workshop 16 (GAW 16) rheumatoid arthritis dataset identified a number of interesting SNP-SNP interactions.

Objective.The incidence of type 2 diabetes (T2D) in adults with rheumatoid arthritis (RA) was investigated, and the results were compared with non-RA controls to confirm whether RA is a risk factor for diabetes mellitus (DM) in Taiwan.Methods.We used a databank of 1 million individuals randomly selected from 23 million Taiwanese citizens covered by the National Health Insurance plan in 2005. All persons older than age 20 years in 1998 and not diagnosed with either RA or T2D before 1998 were included. They were divided into 2 cohorts, 1 with RA and the other without. Those who had T2D before RA were excluded. Each patient in the RA cohort was followed from the RA diagnosis until the end of 2009, or until dropping out of the insurance coverage. RA was ascertained by at least 3 visits using ICD-9 code 714.0, plus at least 2 visits with prescription of antirheumatic drugs in a period of 12 months. T2D was ascertained by at least 3 visits with diabetes codes within 1 year, while hypertension (HTN) and disorders of lipid metabolism (DLM) were determined by at least 3 visits using corresponding ICD codes during the study period. Kaplan-Meier plots, log-rank tests, and Cox regression were used to study the effects of age, sex, glucocorticoid use, HTN, DLM, and RA on T2D risk.Results.The subjects include 600,695 adults. Of these, 4193 were diagnosed with RA, and among them 799 were diagnosed with T2D. The RA to non-RA risk ratio for T2D was 1.68 (95% CI 1.53–1.84) in men and 1.46 (95% CI 1.39–1.54) in women.Conclusion.RA appears to be associated with an increased risk for T2D in Taiwan.

Background There is little information about the association between stroke and kidney diseases. We aimed to investigate the impact of stroke on long-term renal outcomes. Methods In this large population-based retrospective cohort study, we identified 100,353 subjects registered in the National Health Insurance Research Database of Taiwan from January 1, 2000, through December 31, 2012, including 33,451 stroke patients and 66,902 age-, sex- and Charlson’s comorbidity index score-matched controls. Results The incidence rate of chronic kidney disease (CKD) was higher in the stroke than in the control cohort (17.5 vs. 9.06 per 1000 person-years). After multivariate adjustment, the risk of developing CKD was significantly higher in patients with stroke (adjusted hazard ratio [aHR] 1.43, 95% confidence interval [CI] 1.36–1.50, P

Freedman, Navidi and Peters (1988) had shown that when a two-stage variable selection procedure is used to screen linear regression equations, the type I error rate of the t-test for a forced-in-first estimator is inflated if the ratio of the number of parameters to number of data points is large, In this paper, we investigate the asymptotic distribution of the “force-in-last” estimator, and show that this estimator is bias toward zero asymptotically and its asymptotic standard error is close to the nominal standard error under certain conditions. To remedy the bias and reduce the inflation of the type I error rate, two estimators involved with propensity score (Rubin and Rosenbaum, 1983) were introduced.

Chi-Ting Chiang1,*, Tsun-Kuo Chang2, Ie-Bin Lian3, Che-Chun Su4, Kuo-Yang Tsai5 and Yaw-Huei Hwang6 1Green Energy and Environment Research Laboratories, Industrial Technology Research Institute, 2Department of Bioenvironmental Systems Engineering, National Taiwan University, 3Graduate Institute of Statistics and Information Science, National Changhua University of Education, 4Department of Internal Medicine, Changhua Christian Hospital, 5Department of Oral and Maxillofacial Surgery, Changhua Christian Hospital, 6Department of Public Health, National Taiwan University Taiwan

Oral cancer is one of the most common cancers in Taiwan. Changhua County, in central Taiwan, has an extremely high prevalence of oral cancer, along with a high concentration of metal-related industries and soil metal contamination. The aim of this study was to clarify the possible association between metals and oral cancer within this specific area. This study recruited 101 oral cancer patients and 104 controls from the Changhua Christian Hospital. All subjects completed a questionnaire that asked about demographic information; cigarette, alcohol, and betel quid use; and environmental and occupational exposure history. Blood samples were collected and tested for metal concentrations with inductively coupled plasma mass spectrometry. A multiple logistic regression model illustrated that oral cancer was significantly associated with the blood levels of nickel and chromium (both with P

The growing incidence of oral cancer (OC) in Taiwan has become a crucial public health concern. In particular, Changhua, a county in central Taiwan, carries persistently high OC incidence rate, with an alarmingly high male/female ratio of OC incidence. Previous epidemiological studies had found that the incidence is spatially correlated with the level of soil content to certain heavy metals in the central Taiwan area. Soil and the human body both intake environmental heavy metals, which can be absorbed through various ways. The soil metal concentration is an index of possible environmental exposure to heavy metal, and the blood metal concentration somewhat reflects the level of the exposure on the human body. Metallic carcinogen is likely to generate free radicals and play a role in many cancers, and many studies had reported that environmental exposure to heavy metals is an important risk factor for developing cancer. Studies on animals showed that chronic intake of chromium (Cr) could induce OC. This study aims to explore the association between the Cr concentration in the farm soil and in the blood of OC patients. We recruited 79 OC patients from Changhua County, with their lifestyle being adjusted in regression analysis. The results showed that the Cr concentration in the blood of OC patients is significantly higher than the background value, and is positively associated with the Cr concentration in the soil surrounding their residence (p-value

summary The incidence of oral cancer has increased rapidly over the past 20 years in Taiwan. Cigarette smoking and betel quid chewing are considered as the most important risk factors. However, we found that Changhua, a county in Taiwan, had the highest oral cancer incidence, but a modest prevalence of smoking and betel quid chewing. Our previous study found that the incidence of oral cancer in Taiwan has a strong spatial correlation with the heavy metal concentrations in farm soils of patients’ residential areas. A high content of heavy metals in farm soil is likely the result of industrial activities. If exposure to heavy metals is a risk factor for oral cancer, we would expect to find evidence from epidemiologic trends. The age– period–cohort model was used to analyze chart records from the Taiwan Cancer Registry of 21,135 male patients diagnosed with oral cancer from 1983 to 2002. Although the incidence increased in both Changhua and Taiwan overall, Changhua had a similar incidence to that in Taiwan as a whole until 1990, when the incidence in Changhua began to speed up, leaving a marked difference with that in Taiwan. Exposure to the heavy metal pollution for a period of more than 10 years has an impact on the incidence of oral cancer. This novel factor can explain the extremely high incidence in Changhua.

Background Combining data from different ethnic populations in a study can increase efficacy of methods designed to identify expression quantitative trait loci (eQTL) compared to analyzing each population independently. In such studies, however, the genetic diversity of minor allele frequencies among populations has rarely been taken into account. Due to the fact that allele frequency diversity and population-level expression differences are present in populations, a consensus regarding the optimal statistical approach for analysis of eQTL in data combining different populations remains inconclusive. Results In this report, we explored the applicability of a constrained two-way model to identify eQTL for combined ethnic data that might contain genetic diversity among ethnic populations. In addition, gene expression differences resulted from ethnic allele frequency diversity between populations were directly estimated and analyzed by the constrained two-way model. Through simulation, we investigated effects of genetic diversity on eQTL identification by examining gene expression data pooled from normal quantile transformation of each population. Using the constrained two-way model to reanalyze data from Caucasians and Asian individuals available from HapMap, a large number of eQTL were identified with similar genetic effects on the gene expression levels in these two populations. Furthermore, 19 single nucleotide polymorphisms with inter-population differences with respect to both genotype frequency and gene expression levels directed by genotypes were identified and reflected a clear distinction between Caucasians and Asian individuals. Conclusions This study illustrates the influence of minor allele frequencies on common eQTL identification using either separate or combined population data. Our findings are important for future eQTL studies in which different datasets are combined to increase the power of eQTL identification.

Background: Betel quid chewing and cigarette smoking are two of the risk factors for some dental diseases as well as oral cavity cancer in Taiwan. The aim of the study was to quantify these factors in oral cavity cancer patients and compare the prevalence of these factors in patients and the general population. Methods: A questionnaire was designed to evaluate betel quid chewing, cigarette smoking and alcohol drinking in 254 patients, who had squamous cell carcinoma of the oral cavity, and had received surgical excision at the Changhua Christian Hospital in Taiwan between 2005 and 2008. The results were compared with those of population of Taiwan, based on a nation-wide survey with sample of 26 744 people. Results: We found that more than 80% of the male patients were both betel quid chewers and smokers. Few women in the survey practiced betel quid chewing, cigarette smoking or alcohol drinking. Chewers and smokers usually started the habits in their 20s. On average, a chewer patient consumed 12 508 betel quid pieces per year, for 23.3 years before the diagnosis of oral cavity cancer, making the total amount of betel quid consumed nearly 310 000 pieces; and a smoker patient consumed 469 packs per year, for 28.5 years before diagnosis, making the total number of about 14 000 packs. Patients with both habits had the age at diagnosis 4 years earlier than the smoker-only patients, 5 years earlier than the chewer-only patients, and 6 years earlier than those with neither. Conclusions: On average, it took two decades of betel quid chewing and cigarette smoking before oral cavity cancer diagnosis, making the life-time consumption of these substances an astonishing amount. Betel quid chewing and cigarette smoking patients are more likely to be diagnosed with oral cavity cancer at a younger age than those who have just one habit or none. Patients that smoke more are not only more likely to be diagnosed at a younger age, but also at an advanced stage.

Background Association testing is a powerful tool for identifying disease susceptibility genes underlying complex diseases. Technological advances have yielded a dramatic increase in the density of available genetic markers, necessitating an increase in the number of association tests required for the analysis of disease susceptibility genes. As such, multiple-tests corrections have become a critical issue. However the conventional statistical corrections on locus-specific multiple tests usually result in lower power as the number of markers increases. Alternatively, we propose here the application of the longest significant run (LSR) method to estimate a region-specific p-value to provide an index for the most likely candidate region. Results An advantage of the LSR method relative to procedures based on genotypic data is that only p-value data are needed and hence can be applied extensively to different study designs. In this study the proposed LSR method was compared with commonly used methods such as Bonferroni's method and FDR controlling method. We found that while all methods provide good control over false positive rate, LSR has much better power and false discovery rate. In the authentic analysis on psoriasis and asthma disease data, the LSR method successfully identified important candidate regions and replicated the results of previous association studies. Conclusion The proposed LSR method provides an efficient exploratory tool for the analysis of sequences of dense genetic markers. Our results show that the LSR method has better power and lower false discovery rate comparing with the locus-specific multiple tests.

Background/purposeOral cancer is one of the fastest increasing malignancies in Taiwan. Among the counties on the island, Changhua has been ranked in the top three in the list of oral cancer incidence. This study was performed to better characterize the epidemiology of oral cancer in Changhua county.MethodsWe used the complete registered records of oral cancer from the Department of Health data bank, and studied the trends in incidence rate, age of distribution, and anatomic sites of oral cancer in Taiwan. In addition, we correlated the incidence rate with known risk factors (betel quid chewing, smoking, and alcohol drinking) by regression analysis.ResultsAmong neoplasms, oral cancer is one of the fastest increasing malignancies in Taiwan. In the past two decades from 1982 to 2001, Taiwan had an alarming 5.3-fold increase in the incidence of male oral cancer. Among the 23 counties, Changhua has ranked top in oral cancer incidence in recent years. The incidence of male oral cancer in Changhua is also among the highest in the world (45.07/105/year in 2001). The most common site was the buccal mucosa, while it was the tongue in other counties. Finally, Changhua was the only outlier in our regression model, indicating that possible interference factors may interact with oral cancer incidence and prevalence of betel quid chewing in Changhua.ConclusionWe conclude that the high incidence and buccal mucosa preponderance of oral cancer in Changhua may have an exceptionally close relation with patients' betel quid chewing habit, and other unknown etiologic factors may also be present locally. [J Formos Med Assoc 2007;106(3):225-233]

Third-party payer systems are consistently associated with health care cost escalation. Taiwan’s single-payer, universal coverage National Health Insurance (NHI) adopted global budgeting (GB) to achieve cost control. This study captures ophthalmologists’ response to GB, specifically service volume changes and service substitution between low-revenue and high-revenue services following GB implementation, the subsequent Bureau of NHI policy response, and the policy impact. De-identified eye clinic claims data for the years 2000, 2005, and 2007 were analyzed to study the changes in Simple Claim Form (SCF) claims versus Special Case Claims (SCCs). The 3 study years represent the pre-GB period, post-GB but prior to region-wise service cap implementation period, and the post-service cap period, respectively. Repeated measures multilevel regression analysis was used to study the changes adjusting for clinic characteristics and competition within each health care market. SCF service volume (low-revenue, fixed-price patient visits) remained constant throughout the study period, but SCCs (covering services involving variable provider effort and resource use with flexibility for discretionary billing) increased in 2005 with no further change in 2007. The latter is attributable to a 30% cap negotiated by the NHI Bureau with the ophthalmology association and enforced by the association. This study demonstrates that GB deployed with ongoing monitoring and timely policy responses that are designed in collaboration with professional stakeholders can contain costs in a health insurance–financed health care system.