John Jen Tai

Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response.

OBJECTIVES The aim of this study was to investigate the association of the complex haplotype system of the adenosine triphosphate-binding cassette B1 (ABCB1) gene with the epilepsy treatment response. METHODS AND RESULTS Ten polymorphisms were genotyped in 108 drug-resistant epileptic patients, 223 seizure-free patients and 287 normal controls. Highly significant linkage disequilibrium was shown among exon 12 C1236T, exon 21 G2677T and exon 26 C3435T. Haplotypic analysis demonstrated that patients with the CGC, TGC, and TTT haplotypes were more likely to be drug resistant. Further analysis of haplotype combinations demonstrated that drug-resistant patients tended to have the CGC/CGC, CGC/TGC, CGC/TTT, and TGC/TTT haplotype combinations over the seizure-free patients and controls (all p-values < 0.0001). In contrast, patients with the TTC/TTC, TTC/CGT, TTC/TGT, CGT/CGT and TGT/CGT haplotype combinations were more likely to be seizure-free (all p-values<0.0001 except CGT/CGT [p=0.0063]). CONCLUSION Our results showed that the three loci, C1236T, G2677T and C3435T, jointly influenced the treatment response for epileptic patients. They should be regarded together as a complex polymorphic drug-response system. These findings suggest that examination of the haplotypes of the three loci could be useful in predicting drug resistance in epilepsy.

The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease

Background and aims: The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease (GORD), which remains elusive, was quantified. Methods: The population included 3669 subjects undergoing repeated upper endoscopy. Data were analysed using a three-state Markov model to estimate transition rates (according to the Los Angeles classification) regarding the natural course of the disease. Individual risk score together with the kinetic curve was derived by identifying significant factors responsible for the net force between progression and regression. Results: During three consecutive study periods, 12.2, 14.9 and 17.9% of subjects, respectively, progressed from non-erosive to erosive disease, whereas 42.5, 37.3 and 34.6%, respectively, regressed to the non-erosive stage. The annual transition rate from non-erosive to class A–B disease was 0.151 per person year (95% CI 0.136 to 0.165) and from class A–B to C–D was 0.079 per person year (95% CI 0.063 to 0.094). The regression rate from class A–B to non-erosive disease was 0.481 per person year (95% CI 0.425 to 0.536). Class C–D, however, appeared to be an absorbing state when not properly treated. Being male (relative risk (RR) 4.31; 95% CI 3.22 to 5.75), smoking (RR 1.20; 95% CI 1.03 to 1.39) or having metabolic syndrome (RR 1.75; 95% CI 1.29 to 2.38) independently increased the likelihood of progressing from a non-erosive to an erosive stage of disease and/or lowered the likelihood of disease regression. The short-term use of acid suppressants (RR 0.54; 95% CI 0.39 to 0.75) raised the likelihood of regression from erosive to non-erosive disease. Conclusions: Intraoesophageal damage is a dynamic and migratory process in which the metabolic syndrome is associated with accelerated progression to or attenuated regression from erosive states. These findings have important implications for the design of effective prevention and screening strategies.

Association of polymorphisms in NR1I2 and ABCB1 genes with epilepsy treatment responses.

OBJECTIVES The aim of this study was to investigate whether the polymorphisms in the NR1I2 and ABCB1 genes were associated with epilepsy treatment responses. METHODS & RESULTS NR1I2and ABCB1 polymorphisms were genotyped in 114 drug-resistant epileptic patients, 213 seizure-free patients and 287 normal controls. Highly specific real-time PCR was applied to detect the variants by using TaqMan allelic specific probe. For a single gene test, it was demonstrated that 3435C>T in the ABCB1 gene had a significant effect on epilepsy treatment responses, but polymorphisms in the NR1I2 gene did not. Further analysis using a logistic regression model revealed that only 2677G>T and 3435C>T in the ABCB1 gene and their interaction term were associated with drug-resistant epilepsy after adjustment for etiology and epilepsy classification. In the present study, the polymorphisms in the NR1I2 gene were not significantly associated with epilepsy treatment responses. CONCLUSION Our results indicated that 2677G>T and 3435C > T in the ABCB1 gene contributed to drug-resistant epilepsy. Although biologically plausible, the polymorphisms in NR1I2 investigated in the present study did not play a role in epilepsy treatment responses. Other unveiled genetic variants in the NR1I2 gene that may have the potential to affect ABCB1 gene expression are worth further investigation in future studies.

Different prevalence rates of Parkinson's disease in urban and rural areas: a population-based study in Taiwan.

Background: Rural living has long been debated as a risk factor for idiopathic Parkinson’s disease (IPD). But few community-based studies compared this difference between urban and rural areas. Methods: Population-based surveys by neurologists using a standardized diagnostic protocol were conducted in the urban areas of Keelung City and compared the prevalence rates of IPD with those we had previously determined in the rural area of Ilan County, Taiwan. Subjects were diagnosed with IPD when at least 2 of the 4 cardinal signs of parkinsonism were present and by exclusion of secondary parkinsonism. Gender-specific age-standardized prevalence rates of IPD by using the 1970 and 2000 US censuses were calculated for comparison. Results: The participation rate was 84.9%. The crude prevalence rate of IPD in persons aged 40 years and over was 706 (95% CI: 551–864) per 100,000 population. The age-adjusted prevalence rates by using the 1970 US census were 633 (95% CI: 620–646) for people aged 40 and over and 230 (95% CI: 227–234) for all ages. Our results were similar to those obtained in Sicily, Rotterdam, and 3 communities in China. Moreover, the prevalence rates of IPD in Keelung, the urban area studied, were twice as high as those in Ilan, the rural area studied (p < 0.001). Conclusions: Our results suggest that urban living is more important as a risk factor for IPD development than rural living in Taiwan.

Association of genetic variants in six candidate genes with valproic acid therapy optimization

AIMS Valproic acid (VPA) is one of the most widely used antiepileptic drugs. The aim of the study was to investigate whether polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of VPA were associated with the large interindividual variability in dosages and concentrations. METHODS & RESULTS Genetic polymorphisms in six candidate genes were detected in 162 epileptic patients under maintenance with VPA monotherapy and stable seizure control by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant UGT1A6 19T>G, 541A>G and 552A>C allele tended to require higher VPA dosages and lower ln(concentration-to-dose ratios [CDRs]) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher VPA dosages and lower lnCDRs (p < 0.0001). On the other hand, carriers of the variant GRIN2B -200T>G allele were more likely to require lower VPA dosages than noncarriers (p < 0.0001) and the homozygous carriers also tended to require lower dosages and higher lnCDRs (p < 0.0001). In addition, the regression model of CDR of VPA also revealed that genetic variants in UGT1A6, GRIN2B and UGT2B7 genes interactively affect CDRs of VPA (adjusted r² = 47%). CONCLUSION Although there was a limited sample size, the study identified genetic factors associated with VPA therapy optimization that has not been revealed, and provided useful information for individualized VPA therapy in epileptic patients.

Association of polymorphisms in EPHX1, UGT2B7, ABCB1, ABCC2, SCN1A and SCN2A genes with carbamazepine therapy optimization.

AIM Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. The aim of the present study is to investigate the impacts of polymorphisms in genes related to pharmacokinetic and pharmacodynamic pathways of CBZ on the large interindividual variability in dosages and concentrations. METHODS & RESULTS Genetic polymorphisms in the candidate genes were detected in 234 epileptic patients under maintenance CBZ monotherapy by real-time PCR and PCR-RFLP. Results of statistical analysis demonstrated that carriers of the variant SCN1A IVS5-91G>A and EPHX1 c.337T>C allele tended to require higher CBZ dosages and lower ln(concentration-dose ratios) than noncarriers (p < 0.0001) and the homozygous carriers also seemed to require higher CBZ dosages and lower ln(concentration-dose ratios) (p < 0.0001). In addition, the multiple regression model of concentration-dose ratio of CBZ also revealed that genetic variants in SCN1A, EPHX1 and UGT2B7 genes interactively affect the concentration-dose ratio of CBZ (adjusted r(2) = 55%). CONCLUSION The present study identified genetic factors associated with CBZ therapy optimization and provided useful information for individualized CBZ therapy in epileptic patients. Further studies in larger populations are needed to confirm our results.

A family of simultaneous confidence intervals for multinomial proportions

A family of simultaneous confidence intervals (SCIs) for multinomial proportions is proposed by inverting the power-divergence statistics and the best SCIs in the family is determined by Monte-Carlo technique. Numerical comparisons of this method with the other alternatives are presented. Simulation results indicate that the new procedure is preferable to all its competitors in most cases.

An endoscopic training model to improve accuracy of colonic polyp size measurement

PurposeMost studies of colonic polyps rely on visual estimation when regarding polyp size; however, the reliability of a visual estimate is questionable. Our study aims to develop a training model to improve the accuracy of size estimation of colonic polyps in vivo.MethodsColon polyps were recorded on 160 video clips during colonoscopy. The size of each polyp was estimated by visual inspection and subsequently measured with a flexible linear measuring probe. The study included a pretest, an intervention, and a posttest. The pretest included 160 video clips, which comprised the visual-estimation portion of the study. The intervention was an educational model consisting of 30 video clips which included a visual-estimation section and a linear-measuring-probe section, designed to help the endoscopists to compare their visual estimate of size with the measured size of the polyps. The posttest included the 160 video clips used in the pretest, presented in random order. Intraobserver agreement and diagnostic accuracy were compared before and after the training session.ResultsEight beginners and four experienced colonoscopists were enrolled. The overall kappa (κ) values of intraobserver agreement for pretest and posttest were 0.74 and 0.85 for beginner group as well as 0.83 and 0.88 for experienced group, respectively. The overall diagnostic accuracy improved from 0.52 to 0.78 for beginner group and 0.71 to 0.87 for experienced group (P < 0.05) after education with the training model.ConclusionsThis training model could help endoscopists improve the accuracy of measurement of polyps on colonoscopy in a short period. The durability of learning effect needs further investigation.

Testing the nonrandomness of chromosomal breakpoints using highest observed breakages

Abstract To determine whether a chromosomal band is a fragile site rather than a spontaneous breakpoint, an essential step is to test the nonrandomness of breakage at the region. In this paper, the nonapplicability of the testing procedure introduced by Bohm et al. is discussed, and a new detection procedure is proposed. This new procedure considers the relations of one site with the others, and can be applied to tests of the nonrandomness of breakpoints under either the proportional probability model, or the equiprobability model. A data set for Chinese patients with colorectal carcinoma is analyzed as an illustration of the proposed method.

Gene-wide tagging study of the effects of common genetic polymorphisms in the α subunits of the GABAA receptor on epilepsy treatment response

AIM We aimed to identify the effect of SNPs in the α-subunits of GABAA receptors on epilepsy treatment outcomes by using a gene-wide tagging method. MATERIALS & METHODS There were 720 epileptic patients included in the present study. A total of 136 tagging SNPs in GABRA1, GABRA2, GABRA3, GABRA4, GABRA5 and GABRA6 were genotyped by Illumina(®)GoldenGate(®) Genotyping platform. Clinical information, such as prescribed antiepileptic drugs, height, weight, epilepsy syndrome classification, etiology, number of attacks, renal function and liver function were collected. The associations between SNPs and epilepsy treatment outcomes were analyzed using SAS(®) version 9.1.3. Both multivariate logistic regression and multifactor dimensionality reduction analyses were performed. RESULTS The results of single gene effects did not remain significant after Bonferronis corrections. Further multivariate logistic regression and multifactor dimensionality reduction analyses of interactions between these genes showed that under adjustment of clinical factors, the epilepsy treatment outcomes were significantly associated with the genotype combinations of GABRA1 rs6883877, GABRA2 rs511310 and GABRA3 rs4828696 (p < 0.0001; adjusted r(2) = 0.149). CONCLUSION Our results indicated that genetic variants in the α subunits of GABA(A) receptors may interactively affect the treatment responses of antiepileptic drugs. Further replication using an independent sample collection would be essential to confirm our findings.