CiteULike: jyuh's Liu

Fitting stratified proportional odds models by amalgamating conditional likelihoods.

Bhramar Mukherjee — 2008-07-27T05:49:16-00:00

Statistics in medicine (10 July 2008)

Classical methods for fitting a varying intercept logistic regression model to stratified data are based on the conditional likelihood principle to eliminate the stratum-specific nuisance parameters. When the outcome variable has multiple ordered categories, a natural choice for the outcome model is a stratified proportional odds or cumulative logit model. However, classical conditioning techniques do not apply to the general K-category cumulative logit model (K>2) with varying stratum-specific intercepts as there is no reduction due to sufficiency; the nuisance parameters remain in the conditional likelihood. We propose a methodology to fit stratified proportional odds model by amalgamating conditional likelihoods obtained from all possible binary collapsings of the ordinal scale. The method allows for categorical and continuous covariates in a general regression framework. We provide a robust sandwich estimate of the variance of the proposed estimator. For binary exposures, we show equivalence of our approach to the estimators already proposed in the literature. The proposed recipe can be implemented very easily in standard software. We illustrate the methods via three real data examples related to biomedical research. Simulation results comparing the proposed method with a random effects model on the stratification parameters are also furnished. Copyright (c) 2008 John Wiley & Sons, Ltd.

Association between betel-nut chewing and chronic kidney disease in men.

Che-Yi Chou — 2008-07-26T05:52:09-00:00

Public health nutrition (23 July 2008), pp. 1-5.

BACKGROUND: Betel-nut use is associated with metabolic syndrome and obesity. However, the association between betel-nut chewing and risk for chronic kidney disease (CKD) is unknown. The present study was conducted to determine the association between betel-nut chewing and CKD in men. METHODS: We retrospectively reviewed health-check records of 3264 men in a hospital-based cross-sectional screening programme from 2003 to 2006. CKD was defined as estimated glomerular filtration rate less than 60 ml/min/1.73 m2 calculated by the Modification of Diet in Renal Disease formula. Risk factors for CKD including diabetes, hypertension, BMI, smoking, alcohol consumption and age were also considered. RESULTS: A total of 677 (20.7 %) men were found to have CKD and 427 (13.1 %) participants reported a history of betel-nut use. The prevalence (24.8 %) of CKD in betel-nut users was significantly higher than that (11.3 %) of participants without betel-nut use (P = 0.026). In multivariate logistic regression analysis with adjustments for age, hypertension, diabetes and hyperlipidaemia, betel-nut use was independently associated with CKD (P < 0.001). The adjusted odds ratio for betel-nut use was 2.572 (95 % CI 1.917, 3.451). CONCLUSIONS: Betel-nut use is associated with CKD in men. The association between betel-nut use and CKD is independent of age, BMI, smoking, alcohol consumption, hypertension, diabetes and hyperlipidaemia.

Two-stage analysis for gene-environment interaction utilizing both case-only and family-based analysis.

Yi-Hau Chen — 2008-07-26T00:38:52-00:00

Genetic epidemiology (17 July 2008)

The case-only study and family-based study are two popular study designs for detecting gene-environment interactions. It is well known that the case-only analysis is efficient, but its validity relies crucially on the assumption of gene-environment independence in the study population. In contrast, the family-based analysis is robust to the violation of such an assumption, but is less efficient. We propose a two-stage study design for detecting gene-environment interactions, where a case-only study is performed at the first stage, and a case-parent/case-sibling study is performed at the second stage on a random subsample of the first-stage case sample as well as their parents/unaffected siblings. Statistical inference procedures are developed for the proposed two-stage study designs, which not only preserve the robustness property of the family-based analysis, but also utilize information from the case-only analysis to enhance estimation efficiency and testing power. Simulation results reveal both the robustness and efficiency of the proposed strategies. Genet. Epidemiol. 2008. (c) 2008 Wiley-Liss, Inc.

Improved detection of global copy number variation using high density, non-polymorphic oligonucleotide probes

Fan Shen — 2008-03-28T18:02:49-00:00

BMC Genetics, Vol. 9 (28 March 2008), 27.

Alignment of two-dimensional electrophoresis gels.

G Shi — 2008-07-24T09:22:16-00:00

Biochemical and biophysical research communications, Vol. 357, No. 2. (1 June 2007), pp. 427-432.

Two-dimensional electrophoresis is a major separating technique for proteins in proteomics. Alignment of gel images is critical for intra-laboratory or even more difficult inter-laboratory gel comparisons. In the paper, we propose a novel iterative closest point (ICP) method for 2D-gel electrophoresis image alignment. The paper seeks to introduce an information theoretic measure as one part of distance metric to gel image alignment. We combine intensity information of spots with geometric information of landmarks by applying information potential idea. The proposed method has been applied to both synthetic and real gel images accessible in public 2D-electrophoresis gel protein databases. The high accuracy and robustness of the algorithm indicate that it is promising for gel image alignment.

Estimation of progression of multi-state chronic disease using the Markov model and prevalence pool concept

Hui-Chuan Shih — 2007-11-09T09:46:59-00:00

BMC Medical Informatics and Decision Making, Vol. 7 (09 November 2007), 34.

A random effects four-part model, with application to correlated medical costs

Lei Liu — 2008-07-22T05:13:41-00:00

Computational Statistics & Data Analysis, Vol. 52, No. 9. (15 May 2008), pp. 4458-4473.

In this paper we propose a four-part random effects model, with application to correlated medical cost data. Four joint equations are used to model respectively: (1) the probability of seeking medical treatment, (2) the probability of being hospitalized (conditional on seeking medical treatment), and the actual amount of (3) outpatient and (4) inpatient costs. Our model simultaneously takes account of the inter-temporal (or within-cluster) correlation of each patient and the cross-equation correlation of the four equations, by means of joint linear mixed models and generalized linear mixed models. The estimation is accomplished by the high-order Laplace approximation technique in Raudenbush et al. [Raudenbush, S.W., Yang, M., Yosef, M., 2000. Maximum likelihood for generalized linear models with nested random effects via high-order, multivariate Laplace approximation. Journal of Computational and Graphical Statistics 9, 141-157] and Olsen and Schafer [Olsen, M.K., Schafer, J.L., 2001. A two-part random effects model for semicontinuous longitudinal data. Journal of the American Statistical Association 96, 730-745]. Our model is used to analyze monthly medical costs of 1397 chronic heart failure patients from the clinical data repository (CDR) at the University of Virginia.

A multi-level two-part random effects model, with application to an alcohol-dependence study.

Lei Liu — 2008-04-30T09:33:54-00:00

Statistics in medicine (25 January 2008)

Two-part random effects models (J. Am. Statist. Assoc. 2001; 96:730-745; Statist. Methods Med. Res. 2002; 11:341-355) have been applied to longitudinal studies for semi-continuous outcomes, characterized by a large portion of zero values and continuous non-zero (positive) values. Examples include repeated measures of daily drinking records, monthly medical costs, and annual claims of car insurance. However, the question of how to apply such models to multi-level data settings remains. In this paper, we propose a novel multi-level two-part random effects model. Distinct random effects are used to characterize heterogeneity at different levels. Maximum likelihood estimation and inference are carried out through Gaussian quadrature technique, which can be implemented conveniently in freely available software-aML. The model is applied to the analysis of repeated measures of the daily drinking record in a randomized controlled trial of topiramate for alcohol-dependence treatment. Copyright (c) 2008 John Wiley & Sons, Ltd.

Summary of contributions to GAW15 Group 13: candidate gene association studies.

M de Andrade — 2008-07-22T00:55:06-00:00

Genetic epidemiology, Vol. 31 Suppl 1 (2007)

Here we summarize the contributions to Group 13 of the Genetic Analysis Workshop 15 held in St. Pete Beach, Florida, on November 12-14, 2006. The focus of this group was to identify candidate genes associated with rheumatoid arthritis or surrogate outcomes. The association methods proposed in this group were diverse, from better known approaches, such as logistic regression for single nucleotide polymorphism (SNP) analysis and haplotype sharing tests to methods less familiar to genetic epidemiologists, such as machine learning and visualization methods. The majority of papers analyzed Genetic Analysis Workshop 15 Problems 2 (rheumatoid arthritis data) and 3 (simulated data). The highlighted points of this group analyses were: (1) haplotype-based statistics can be more powerful than single SNP analysis for risk-locus localization; (2) considering linkage disequilibrium block structure in haplotype analysis may reduce the likelihood of false-positive results; and (3) visual representation of genetic models for continuous covariates may help identify SNPs associated with the underlying quantitative trait loci.

PDTD: a web-accessible protein database for drug target identification

Zhenting Gao — 2008-02-20T02:00:30-00:00

BMC Bioinformatics, Vol. 9 (19 February 2008), 104.

The complete genome of an individual by massively parallel DNA sequencing

David Wheeler — 2008-04-16T19:24:49-00:00

Nature, Vol. 452, No. 7189. (17 April 2008), pp. 872-876.

The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports.

LA Cupples — 2008-04-16T16:12:34-00:00

BMC medical genetics, Vol. 8 Suppl 1 (2007)

BACKGROUND: The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies.METHODS: Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests.RESULTS: The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 +/- 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency > or + 10%, genotype call rate > or = 80%, Hardy-Weinberg equilibrium p-value > or = 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.CONCLUSION: We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.

Association of tumour necrosis factor alpha (TNF-alpha) polymorphisms with Graves' disease: A meta-analysis.

N Li — 2008-07-15T14:50:38-00:00

Clinical biochemistry, Vol. 41, No. 10-11. (July 2008), pp. 881-886.

OBJECTIVE: To quantitatively summarize the association between tumour necrosis factor alpha (TNF-alpha) gene polymorphisms and Graves' disease. DESIGN AND METHODS: Relevant studies were identified from the following electronic databases: Cochrane Library, MEDLINE, EMBASE and Chinese Bio-medicine Database. A meta-analysis of relevant studies was performed. RESULTS: This meta-analysis included 10 case-control studies, which included 2271 Graves' disease cases and 2633 controls. The combined results based on all studies showed that there was significant difference in genotype distribution (-308A/G; -308G/G; -863C/C; -863C/A; -1031C/T) between Graves' disease and controls. When stratifying for race, statistically significant results were observed in three genotype distribution (-863C/C; -863C/A; -1031C/T) between Graves' disease and controls among Asians. Statistically significant results were observed in only two genotype distribution (-308A/G; -308G/G) between Graves' disease and controls among Caucasians. CONCLUSIONS: This meta-analysis suggests that TNF-alpha gene polymorphisms at positions -308 (G-308A), -863 (C-863A), and -1031 (T-1031C) were associated with Graves' disease.

SNP combinations in chromosome-wide genes are associated with bone mineral density in Taiwanese women.

GT Lin — 2008-07-15T14:03:14-00:00

The Chinese journal of physiology, Vol. 51, No. 1. (29 February 2008), pp. 32-41.

Osteoporosis is a major public health problem, mainly quantified by low BMD. Eleven polymorphisms were investigated in this study; TNFalpha-857 (rs1799724), TGFbeta1-509 (rs1800469), osteocalcin (rs1800247), TNFalpha-308 (rs1800629), PTH BstB I (rs6254), PTH Dra II (rs6256), IL-1ra (VNTR), HSP70 hom (rs2227956), HSP 70-2 (rs1061581), CTR (rs1801197), and BMP-4 (rs17563). The relationship between the combined polymorphisms in different genomic regions and BMD variation was investigated. Among the female subjects, the proportion of subjects with low BMD in low BMI group (< or = 18.50) was significantly higher than that of the middle (18.51-22.99) and high (> or = 23.00) BMI groups (P < 0.05). In post-menopausal women, there was a significant association between low BMD and genotypes ranging from 2 to approximately 7 SNPs. For two combined SNPs, the portion of subjects with low BMD was significantly higher in those with CC-AA genotypes in rs1799724-rs1800629, compared to those with non-CC-AA genotypes in post-menopausal women and the combination of all women. Similarly, part of the combined SNPs with rs1799724-rs1800629-rs6254-rs6256-IL-1ra-rs2227956-rs1801197 was significantly associated with reduced BMD. After controlling for age and BMI, post-menopausal women with certain specific SNP combination had a 3.54- to 4.68-fold increased risk for low BMD, comparing to other SNP combinations. In conclusion, our data suggest that several gene polymorphisms may be cooperatively involved in the development of osteoporosis.

MicroRNA expression profiling using microarrays.

CG Liu — 2008-05-21T12:41:03-00:00

Nature protocols, Vol. 3, No. 4. (2008), pp. 563-578.

Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once within tens of samples processed in parallel in a single experiment. To conduct a genome-wide analysis of miRNA expression of normal and disease samples, such as cancer, and to distinguish expression signatures associated with diagnosis, prognosis and therapeutic interventions, we have developed a unique miRNA microarray assay on a CodeLink platform. The miRNA array consists of 4,104 probes printed in duplicate. This array can simultaneously profile more than 1,500 mature miRNAs and their corresponding precursors from 474 human and 373 mouse miRNA genes. The full protocol details of the miRNA microarray assay developed by our group are described here, including miRNA oligo probe design, array fabrication and miRNA target preparation (by reverse transcription of total RNA), target-probe hybridization on array, signal detection and data analysis. The assay is simple, can be easily standardized and allows the reproducible profiling of up to 24 total RNA samples within 24 h.

Haplotype of signal transducer and activator of transcription 3 gene predicts cardiovascular disease in dialysis patients.

L Zhang — 2008-07-11T13:22:43-00:00

Journal of the American Society of Nephrology : JASN, Vol. 17, No. 8. (August 2006), pp. 2285-2292.

Signal transducer and activator of transcription 3 (STAT3) protein has been linked to cardiovascular disease (CVD) through multiple pathways in experimental and animal studies. STAT3 gene variation was examined as a predictor of incident CVD in a subcohort of 529 incident white dialysis patients. Fifteen single-nucleotide polymorphisms of the STAT3 gene were genotyped. Haplotypes were estimated using software PHASE 2.1, and associations with first CVD event were tested using Cox proportional hazards analysis. Adjusted global tests of haplotype association with incident CVD and inflammation markers were performed using permutated P value in R-package Haplo.score. An a priori specified additive genetic model was assumed for haplotype analysis. Both genotypes (four single nucleotide polymorphisms with P < 0.001) and haplotypes (P = 0.002 overall) were associated with incident CVD. Two major haplotype blocks, blocks A and C, were identified. Compared with common haplotype A-1, A-3 was associated with a hazard ratio (HR) of 0.70 (95% confidence interval [CI] 0.51 to 0.94) for CVD events after adjustment for covariates including C-reactive protein (CRP) and interleukin 6. Compared with common haplotype C-1, C-3 was associated with an adjusted HR of 2.12 (95% CI 1.25 to 3.57) for CVD events. Associations were independent of inflammation markers, but IL-6 levels were 14% lower (geometric mean ratio 0.86; 95% CI 0.77 to 0.96) per copy of haplotype A-3 compared with haplotype A-1 in block A after adjustment for CRP and other risk factors (P = 0.008). Variation in the STAT3 gene is associated with the risk for CVD among white dialysis patients independent of serum IL-6 and CRP levels.

Beta-fibrinogen haplotypes and the risk for cardiovascular disease in a dialysis cohort.

Y Liu — 2008-07-11T13:22:46-00:00

American journal of kidney diseases : the official journal of the National Kidney Foundation, Vol. 46, No. 1. (July 2005), pp. 78-85.

BACKGROUND: Elevated plasma fibrinogen levels are common in dialysis patients and may be related to an elevated risk for cardiovascular disease (CVD). We tested the hypothesis that genetic variation in the beta-fibrinogen ( FGB ) gene, shown to explain 1% to 5% of fibrinogen level variation in the general population, has an important role in elevated fibrinogen levels and excess CVD risk in dialysis patients. METHODS: Plasma fibrinogen was measured in 735 dialysis patients a median of 3 months from the start of dialysis therapy by using an automated clot-rate assay. Seven polymorphisms of the FGB gene were determined. Haplotype analysis was conducted using the Phase program to estimate haplotypes, with stratification for race. CVD events were ascertained from medical records. RESULTS: During a median follow-up of 2.1 years, 279 CVD events occurred. Genotype frequencies were in Hardy-Weinberg equilibrium. Four common haplotypes identified were not associated with fibrinogen levels or CVD risk in the entire cohort or after stratification by race. The -455A allele, known to increase gene expression in vitro, was marginally associated with fibrinogen levels only in patients without diabetes (regression coefficient [beta], 20 mg/dL [for +1 copy of the A allele; P = 0.06]), adjusted for age, sex, race, smoking, baseline dialysis modality, comorbidity, and history of diabetes and CVD. Post hoc analysis showed that -249C-->T (defining haplotype 3) was associated with greater fibrinogen levels and CVD risk among patients without diabetes and current smokers. CONCLUSION: The FGB gene likely does not have an important role in determining the variation in elevated plasma fibrinogen levels or excess CVD risk in dialysis patients.

Required sample size and nonreplicability thresholds for heterogeneous genetic associations.

R Moonesinghe — 2008-07-11T03:41:52-00:00

Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 2. (15 January 2008), pp. 617-622.

Many gene-disease associations proposed to date have not been consistently replicated across different populations. Nonreplication often reflects false positives in the original claims. However, occasionally, nonreplication may be due to heterogeneity due to biases or even genuine diversity of the genetic effects in different populations. Here, we propose methods for estimating the required sample size to replicate an association across many studies with different amounts of between-study heterogeneity, when data are summarized through metaanalysis. We demonstrate thresholds of between-study heterogeneity (tau(0)(2)) above which one cannot reach adequate power to replicate a proposed association at a specified level of statistical significance when k studies are performed (regardless of how large these studies are). Based on empirical evidence from 91 proposed gene-disease associations (50 on candidate genes and 41 from genome-wide association efforts), the observed between-study heterogeneity is often close to or even surpasses nonreplicability thresholds. With more modest between-study heterogeneity, the required sample size increases considerably compared with when no between-study heterogeneity exists. Increases are steep as tau(0)(2) is approached. Therefore, some true associations may not be practically possible to replicate with consistency, no matter how large studies are conducted. Efforts should be made to minimize between-study heterogeneity in targeted genetic effects.

A note on tree gatekeeping procedures in clinical trials.

A Dmitrienko — 2008-07-11T02:55:39-00:00

Statistics in medicine, Vol. 27, No. 17. (30 July 2008), pp. 3446-3451.

Dmitrienko et al. (Statist. Med. 2007; 26:2465-2478) proposed a tree gatekeeping procedure for testing logically related hypotheses in hierarchically ordered families, which uses weighted Bonferroni tests for all intersection hypotheses in a closure method by Marcus et al. (Biometrika 1976; 63:655-660). An algorithm was given to assign weights to the hypotheses for every intersection. The purpose of this note is to show that any weight assignment algorithm that satisfies a set of sufficient conditions can be used in this procedure to guarantee gatekeeping and independence properties. The algorithm used in Dmitrienko et al. (Statist. Med. 2007; 26:2465-2478) may fail to meet one of the conditions, namely monotonicity of weights, which may cause it to violate the gatekeeping property. An example is given to illustrate this phenomenon. A modification of the algorithm is shown to rectify this problem. Copyright (c) 2008 John Wiley & Sons, Ltd.

Common Variation in the FTO Gene Confers Risk of Obesity and Modulates Body Mass Index in the Chinese Population.

Yi-Cheng Chang — 2008-07-10T10:40:45-00:00

Diabetes (16 May 2008)

Objective: Genetic variants in the FTO gene have been associated with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO genetic variants in obesity and type 2 diabetes in the Chinese population. Methods: We genotyped 19 single nucleotide polymorphisms (SNPs) spanning from the 3' end of the neighboring RPGRIP1L gene to the 5' flanking region of the FTO gene. We analyzed their associations with obesity (638 cases and 1,610 controls), type 2 diabetes (759 cases and 784 controls), and obesity-related traits in non-diabetic subjects. Results: Among the 19 SNPs, the rs9939609 A allele was strongly associated with obesity (p= 7.0x10(-4)) and body mass index (BMI) (p= 0.0024) in the Chinese population. The odds ratio for obesity was 2.60 (95% CI: 1.24-5.46; p=0.011) for the AA genotype and 1.32 (95% CI: 1.05-1.66; p= 0.018) for the AT genotype as compared to the TT genotype. Each additional copy of the rs9936609 A allele was associated with a BMI increase of approximately 0.37 kg/m(2). The rs9939609 A allele was substantially less common in the Chinese population than in the European population (12.6% vs. 45%). We did not find significant associations of the 19 SNPs with type 2 diabetes or other obesity-related traits. Conclusions: Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. The risk variant is less common in the Chinese population but its effect size on BMI is comparable to that in the European population.

A low serum iron level is a predictor of poor outcome in hemodialysis patients.

K Kalantar-Zadeh — 2008-06-30T11:34:58-00:00

American journal of kidney diseases : the official journal of the National Kidney Foundation, Vol. 43, No. 4. (April 2004), pp. 671-684.

BACKGROUND: Iron administration has been implicated as a cause of poor clinical outcome in maintenance hemodialysis (MHD) patients. However, the role of low iron levels in the clinical outcome of MHD patients is not clear. METHODS: We examined the predicting value of baseline serum iron level on prospective mortality and hospitalization in a cohort of all 1,283 MHD patients from 10 DaVita dialysis facilities in Los Angeles County, CA. RESULTS: Patients aged 57.8 +/- 15.2 years included 49% men, 45% Hispanics, 25% African Americans, and 53% patients with diabetes. During the first 3 months of the cohort, 97% of patients were administered erythropoietin (EPO) and 60% were administered intravenous iron (gluconate and/or dextran) at least once. During a 12-month follow-up, mortality was significantly greater (23%) in the lowest serum iron quartile (<45.3 microg/dL [<8.1 micromol/L]) compared with other quartiles (10% to 12%). Multivariate Poisson and Cox models adjusted for demographic features, dialysis dose and vintage, serum albumin and ferritin and blood hemoglobin concentrations, and administered EPO and iron doses showed that both serum iron level and iron saturation ratio had significant, but inverse, associations with prospective mortality and hospitalization. There was a statistically significant trend toward greater rates of mortality and hospitalization with lower serum iron levels. This reverse association remained significant in a subcohort of 322 MHD patients after additional adjustments for comorbid conditions and serum C-reactive protein level to reflect inflammation. CONCLUSION: Low baseline serum iron indicators are associated with increased mortality and hospitalization in MHD patients independent of hemoglobin level, EPO and iron doses, indicators of nutrition and inflammation, and comorbid conditions. Clinical trials to examine the role of iron administration in improving morbidity and mortality by increasing serum iron levels in MHD patients are required.

The MTHFR gene polymorphism is associated with lean body mass but not fat body mass.

X Liu — 2008-06-28T23:48:07-00:00

Human genetics, Vol. 123, No. 2. (March 2008), pp. 189-196.

Along with aging, human body composition undergoes notable changes and may incur sarcopenia, obesity or osteoporosis. Sarcopenia is related to a wide series of human health problems and can be largely characterized by loss of lean body mass (LBM). Studies have showed relevance of methylenetetrahydrofolate reductase (MTHFR) with variation in LBM and fat body mass (FBM). To test if polymorphism of the MTHFR gene is underlying the pathology of sarcopenia and obesity, we concurrently tested five single nucleotide polymorphisms (SNPs) of the MTHFR gene for association with LBM, FBM and body mass index (BMI) in 405 Caucasian nuclear families comprising 1,873 individuals. After correction for multiple testing, we detected significant associations for LBM with rs2066470 (P = 0.0006), rs4846048 (P = 0.0007) and with rs3737964 (P = 0.004), as well as for BMI with rs4846048 (P = 0.009). Polymorphism of rs2066470 explains 3.67% of LBM variation in this sample. The association between BMI and rs4846048 diminished after adjusting for LBM, suggesting that the association between BMI and rs4846048 is largely due to LBM instead of the fat component. In concert, no significant associations were identified for FBM with any of the studied SNPs. The results of single-locus association analyses were corroborated by haplotype-based analyses. In summary, the MTHFR gene polymorphism is associated with LBM, suggesting that MTHFR may play an important role in LBM variation. In addition, the MTHFR gene polymorphism is not associated with FBM or obesity in this sample.

C-reactive protein predicts vascular access thrombosis in hemodialysis patients.

CY Chou — 2008-06-28T04:00:26-00:00

Blood purification, Vol. 24, No. 4. (2006), pp. 342-346.

BACKGROUND: Vascular access thrombosis (VAT) is one of the most common morbidity in hemodialysis patients. The development of arteriovenous fistula thrombosis is associated with vascular intimal hyperplasia. Some studies suggested that serum C-reactive protein (CRP) predicts the development of vascular intima hyperplasia that conduces vascular access stenosis and thrombosis. This study aimed to access the clinical usefulness of CRP in predicting VAT in hemodialysis patients. METHODS: We retrospectively reviewed all prevalent hemodialysis patients with native arteriovenous fistula (nAVF) between November 2001 and November 2004. The CRP levels and relation to the development of VAT was analyzed with Kaplan-Meier analysis in four groups of patients divided according to their serum CRP levels. Besides serum CRP levels, other factors possibly influencing vascular access thrombosis were also considered: gender, age, diabetes, aspirin, smoking, statin, serum albumin, hematocrit, cholesterol > 200 mg/dl, Calcium-phosphate product, and intact parathyroid hormone > 200 pg/ml. RESULTS: We retrospectively reviewed 223 chronic hemodialysis patients. 198 patients with forearm nAVF and 25 with upper arm nAVF were included. Of the above 223 patients, 51 experienced one or more VAT episodes. In Kaplan-Meier survival analysis, patients with serum CRP levels > 0.8 mg/dl were prone to develop VAT (log-rank, p < 0.001). In a multivariate Cox regression model, serum CRP greater than 0.8 mg/dl was confirmed to be an independent predictor of VAT with a relative risk of 16.6 times (95% CI, 7.85-35.1). The area under the receiver operator characteristic (ROC) curve of CRP > 0.8 mg/dl in predicting VAT events is 0.785 (95% CI, 0.712-0.858; p < 0.001). Sensitivity and specificity of CRP (> 0.8 mg/dl) in predicting VAT were 80.4 and 72.7%. CONCLUSIONS: The serum CRP levels not only predict cardiovascular disease and mortality in hemodialysis patients but also predict the development of vascular access thrombosis in chronic hemodialysis patients.

Association between cholesterol level and mortality in dialysis patients: role of inflammation and malnutrition.

Y Liu — 2008-06-26T10:15:04-00:00

JAMA : the journal of the American Medical Association, Vol. 291, No. 4. (28 January 2004), pp. 451-459.

CONTEXT: Total cholesterol level is inversely associated with mortality in dialysis patients, a group at high risk of cardiovascular disease (CVD). This paradox may be explained by systemic inflammation and/or malnutrition, which are associated with lower cholesterol levels and higher mortality. OBJECTIVE: To determine the relationship between cholesterol level and outcome in patients undergoing dialysis, accounting for inflammation and malnutrition. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 823 patients enrolled from October 1995 to June 1998 who recently initiated dialysis, from 79 clinics, classified by absence or presence of inflammation and/or malnutrition (defined as serum albumin levels <3.6 mg/dL, C-reactive protein > or =10 mg/L, or interleukin 6 > or =3.09 pg/mL). MAIN OUTCOME MEASURES: All-cause and cardiovascular disease mortality. RESULTS: During a median follow-up of 2.4 years, 324 deaths (159 CVD deaths), 153 renal transplantations, and 10 losses to follow-up occurred. Average serum cholesterol level was lower in the presence of inflammation/malnutrition than in its absence. In a Cox model adjusted for age, race, and sex, a 40-mg/dL (1.0-mmol/L) increment in baseline total serum cholesterol level was associated with a decreased risk of all-cause mortality overall (relative hazard [RH], 0.92; 95% confidence interval [CI], 0.87-0.98) and in the presence of inflammation/malnutrition (RH, 0.89; CI, 0.84-0.95). In contrast, serum cholesterol level was associated with an increased risk in the absence of inflammation/malnutrition (RH, 1.32; 95% CI, 1.07-1.63). For CVD mortality, an inverse trend was not statistically significant in the presence of inflammation/malnutrition, and a positive association was evident in the absence of inflammation/malnutrition (RH, 1.41; 95% CI, 1.04-1.89). Further adjustment for traditional CVD risk factors, dialysis modality, comorbidity, and inflammatory markers attenuated the inverse association but strengthened the positive association. CONCLUSIONS: The inverse association of total cholesterol level with mortality in dialysis patients is likely due to the cholesterol-lowering effect of systemic inflammation and malnutrition, not to a protective effect of high cholesterol concentrations. These findings support treatment of hypercholesterolemia in this population.

TiGER: a database for tissue-specific gene expression and regulation

Xiong Liu — 2008-06-10T19:46:24-00:00

BMC Bioinformatics, Vol. 9 (09 June 2008), 271.

Porcine transcriptome analysis based on 97 non-normalized cDNA libraries and assembly of 1,021,891 ESTs

Jan Gorodkin — 2007-04-03T22:50:40-00:00

Genome Biology, Vol. 8 (02 April 2007), R45.

Gene expression analysis in LLC-PK1 renal tubular cells by atrial natriuretic peptide (ANP): correlation of homologous human genes with renal response

Rosa Liu — 2008-06-25T05:26:36-00:00

Journal of Biomedical Science, Vol. 14, No. 3. (31 May 2007), pp. 383-393.

Summary We used human DNA microarray to explore the differential gene expression profiling of atrial natriuretic peptide (ANP)-stimulated renal tubular epithelial kidney cells (LLC-PK1) in order to understand the biological effect of ANP on renal kidney cell’s response. Gene expression profiling revealed 807 differentially expressed genes, consisting of 483 up-regulated and 324 down-regulated genes. The bioinformatics tool was used to gain a better understanding of differentially expressed genes in porcine genome homologous with human genome and to search the gene ontology and category classification, such as cellular component, molecular function and biological process. Four up-regulated genes of ATP1B1, H3F3A, ITGB1 and RHO that were typically validated by real-time quantitative PCR (RT-qPCR) analysis serve important roles in the alleviation of renal hypertrophy as well as other related effects. Therefore, the human array can be used for gene expression analysis in pig kidney cells and we believe that our findings of differentially expressed genes served as genetic markers and biological functions can lead to a better understanding of ANP action on the renal protective system and may be used for further therapeutic application.

Gut-enriched Krüppel-like factor interaction with Smad3 inhibits myofibroblast differentiation.

B Hu — 2008-06-24T03:19:22-00:00

American journal of respiratory cell and molecular biology, Vol. 36, No. 1. (January 2007), pp. 78-84.

Gut-enriched Krüppel-like factor (GKLF) has been reported to partially inhibit alpha-smooth muscle actin (alpha-SMA) gene transcription by competing for binding to the TGF-beta control element (TCE) with known activators such as Sp1 and other Krüppel-like factors. This incomplete inhibition via the TCE suggests an additional mechanism, which was evaluated in this study. The results showed that an alpha-SMA promoter mutated in the TCE remained susceptible to inhibition by GKLF in rat lung fibroblasts consistent with the existence of an additional TCE-independent mechanism. Since TGF-beta- induced alpha-SMA expression is Smad3-dependent, potential interaction between GKLF and Smad3 was examined as a basis for this additional inhibitory mechanism. Co-immunoprecipitation and yeast two-hybrid assays revealed that GKLF could bind Smad3 through the Smad3 MH2 domain. Electrophoretic mobility shift assays and ChIP assay indicated that this GKLF-Smad3 interaction inhibited Smad3 binding to the Smad3-binding element (SBE) in the alpha-SMA promoter, and the activity of an SBE containing artificial promoter. Further analysis using smad3(-/-) fibroblasts confirmed that the TCE-independent inhibition by GKLF was dependent on Smad3. These data taken together suggest that in addition to inhibition via the TCE, GKLF represses alpha-SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3, a key intracellular mediator of TGF-beta signaling, which should lead to a clearer understanding of the mechanism of how GKLF regulates TGF-beta-induced gene expression.

A Transforming Growth Factor-beta Control Element Required for SM alpha-Actin Expression in Vivo Also Partially Mediates GKLF-dependent Transcriptional Repression

Yan Liu — 2008-06-24T03:15:53-00:00

J. Biol. Chem., Vol. 278, No. 48. (28 November 2003), pp. 48004-48011.

We previously demonstrated that a conserved transforming growth factor-beta control element (TCE) within the 5'-region of the smooth muscle cell (SMC) differentiation marker gene SM alpha-actin could mediate both transcriptional activation and repression in cultured SMCs through interaction with members of the zinc finger Kruppel-like transcription factor (KLF) family. The aims of the present studies were to: 1) determine the role of the SM alpha-actin TCE in vivo through mutagenesis studies in transgenic mice and 2) further characterize the possible role and mechanisms by which the TCE-binding factor GKLF/KLF4 induces repression of SMC marker genes in various SMC model systems in vitro. Our results showed that the TCE was required for SM alpha-actin promoter activity in transgenic mice in vivo. Results of transient transfection studies showed that GKLF-induced repression of a SM alpha-actin promoter/luciferase reporter gene partially depended on the TCE. Furthermore, a GKLF overexpressing adenovirus inhibited whereas GKLF morpholino antisense oligos increased expression of endogenous SMC marker genes. Results of chromatin immunoprecipitation assays showed GKLF binding to TCE containing regions of various SMC marker gene promoters within intact chromatin. Finally, results of co-transfection studies showed that overexpression of IKLF/KLF5 reversed GKLF-dependent repression thus supporting a model of reciprocal activation-repression of SMC gene expression by different members of the KLF gene family. 10.1074/jbc.M301902200

A Joint Frailty Model for Survival and Gap Times Between Recurrent Events

Huang — 2007-08-10T17:31:23-00:00

Biometrics, Vol. 63, No. 2. (June 2007), pp. 389-397.

The use of Gaussian quadrature for estimation in frailty proportional hazards models.

L Liu — 2008-06-21T04:33:47-00:00

Statistics in medicine, Vol. 27, No. 14. (30 June 2008), pp. 2665-2683.

In this paper, we propose a novel Gaussian quadrature estimation method in various frailty proportional hazards models. We approximate the unspecified baseline hazard by a piecewise constant one, resulting in a parametric model that can be fitted conveniently by Gaussian quadrature tools in standard software such as SAS Proc NLMIXED. We first apply our method to simple frailty models for correlated survival data (e.g. recurrent or clustered failure times), then to joint frailty models for correlated failure times with informative dropout or a dependent terminal event such as death. Simulation studies show that our method compares favorably with the well-received penalized partial likelihood method and the Monte Carlo EM (MCEM) method, for both normal and Gamma frailty models. We apply our method to three real data examples: (1) the time to blindness of both eyes in a diabetic retinopathy study, (2) the joint analysis of recurrent opportunistic diseases in the presence of death for HIV-infected patients, and (3) the joint modeling of local, distant tumor recurrences and patients survival in a soft tissue sarcoma study. The proposed method greatly simplifies the implementation of the (joint) frailty models and makes them much more accessible to general statistical practitioners. Copyright (c) 2007 John Wiley & Sons, Ltd.

Analysis of Longitudinal Data in the Presence of Informative Observational Times and a Dependent Terminal Event, with Application to Medical Cost Data.

Lei Liu — 2008-06-20T08:44:50-00:00

Biometrics (20 December 2007)

In longitudinal observational studies, repeated measures are often taken at informative observation times. Also, there may exist a dependent terminal event such as death that stops the follow-up. For example, patients in poorer health are more likely to seek medical treatment and their medical cost for each visit tends to be higher. They are also subject to a higher mortality rate. In this article, we propose a random effects model of repeated measures in the presence of both informative observation times and a dependent terminal event. Three submodels are used, respectively, for (1) the intensity of recurrent observation times, (2) the amount of repeated measure at each observation time, and (3) the hazard of death. Correlated random effects are incorporated to join the three submodels. The estimation can be conveniently accomplished by Gaussian quadrature techniques, e.g., SAS Proc NLMIXED. An analysis of the cost-accrual process of chronic heart failure patients from the clinical data repository at the University of Virginia Health System is presented to illustrate the proposed method.

Shared frailty models for recurrent events and a terminal event.

L Liu — 2008-06-17T08:52:44-00:00

Biometrics, Vol. 60, No. 3. (September 2004), pp. 747-756.

There has been an increasing interest in the analysis of recurrent event data (Cook and Lawless, 2002, Statistical Methods in Medical Research 11, 141-166). In many situations, a terminating event such as death can happen during the follow-up period to preclude further occurrence of the recurrent events. Furthermore, the death time may be dependent on the recurrent event history. In this article we consider frailty proportional hazards models for the recurrent and terminal event processes. The dependence is modeled by conditioning on a shared frailty that is included in both hazard functions. Covariate effects can be taken into account in the model as well. Maximum likelihood estimation and inference are carried out through a Monte Carlo EM algorithm with Metropolis-Hastings sampler in the E-step. An analysis of hospitalization and death data for waitlisted dialysis patients is presented to illustrate the proposed methods. Methods to check the validity of the proposed model are also demonstrated. This model avoids the difficulties encountered in alternative approaches which attempt to specify a dependent joint distribution with marginal proportional hazards and yields an estimate of the degree of dependence.

Paricalcitol Inhibits Renal Inflammation by Promoting Vitamin D Receptor-Mediated Sequestration of NF-kappaB Signaling.

Xiaoyue Tan — 2008-06-17T04:49:43-00:00

Journal of the American Society of Nephrology : JASN (4 June 2008)

Inflammation is a pathologic feature of a variety of chronic kidney diseases. Several lines of evidence suggest a potential anti-inflammatory role for vitamin D in chronic kidney disease, but the underlying mechanism remains unknown. Here, the effect of the synthetic vitamin D analogue paricalcitol on renal inflammation was investigated in a mouse model of obstructive nephropathy. Paricalcitol reduced infiltration of T cells and macrophages in the obstructed kidney. This inhibition of inflammatory cell infiltration was accompanied by a decreased expression of RANTES and TNF-alpha. Induction of RANTES was localized primarily to the tubular epithelium, underscoring a role for tubular cells in renal inflammation. In a human proximal tubular cell line (HKC-8), paricalcitol inhibited RANTES mRNA and protein expression and abolished the ability of tubular cells to recruit lymphocytes and monocytes after TNF-alpha stimulation. Although RANTES induction depended on NF-kappaB signaling, paricalcitol affected neither TNF-alpha-mediated IkappaBalpha phosphorylation and degradation nor p65 NF-kappaB activation and nuclear translocation. Instead, chromatin immunoprecipitation assay showed that paricalcitol abolished the binding of p65 to its cognate cis-acting element in the RANTES promoter. The vitamin D receptor (VDR) and p65 formed a complex in tubular cells after paricalcitol treatment, which inhibited the ability of p65 to trans-activate gene transcription. In vivo, paricalcitol did not block NF-kappaB nuclear translocation after obstructive injury but did increase the expression and nuclear distribution of VDR. These results suggest that paricalcitol inhibits renal inflammatory infiltration and RANTES expression by promoting VDR-mediated sequestration of NF-kappaB signaling.

Regulation of the sumoylation system in gene expression.

B Liu — 2008-06-17T03:48:13-00:00

Current opinion in cell biology, Vol. 20, No. 3. (June 2008), pp. 288-293.

Protein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the small ubiquitin-like modifier (SUMO) conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other post-translational modifications, including phosphorylation, ubiquitination, and acetylation.

Time to target haemoglobin concentration (11 g/dl)--risk of hospitalization and mortality among incident dialysis patients.

A Ishani — 2008-06-16T03:16:21-00:00

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Vol. 22, No. 8. (August 2007), pp. 2247-2255.

BACKGROUND: Haemoglobin levels <11 g/dl are associated with increased costs, morbidity and mortality. We aimed to determine if time required to reach 11 g/dl was associated with increased risk of hospitalization or death among incident dialysis patients. METHODS: We studied 29 131 patients initiating dialysis in 2002 and surviving >or=9 months. Demographic, comorbid and health care use data were extracted from Medicare claims from months 4-9 post-dialysis initiation. Logistic regression was used to calculate a propensity score for odds of longer than mean time to target. Proportional hazard models were used to assess effects of longer time on hospitalization and death. Other models were stratified for quartile of propensity score. RESULTS: Mean time to target haemoglobin was 1.3 months and 36% of participants required longer. These were more likely to be younger and minority, to use a dialysis catheter, and to have more comorbidity and hospitalization days during the entry period. Longer time to target was associated with increased risk for hospitalization (hazards ratio 1.15; 95% confidence interval 1.12-1.19) and mortality (1.26; 1.20-1.33) in the following year. Associations did not change when stratified by quartile of propensity score. CONCLUSIONS: Longer time required to reach the target haemoglobin level was associated with significantly higher risk of hospitalization and mortality. Whether observed associations resulted from residual confounding by more severe illness remains unclear. Future trials should determine if rapidity of haemoglobin correction influences outcomes.

PI3K/PTEN signaling in tumorigenesis and angiogenesis.

BH Jiang — 2008-06-14T23:46:05-00:00

Biochimica et biophysica acta, Vol. 1784, No. 1. (January 2008), pp. 150-158.

The phosphatidyl inositol 3-kinase (PI3K) can be activated by a variety of extracellular signals and involved in a number of cellular processes including cell proliferation, survival, protein synthesis, and tumor growth. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is an antagonist of PI3K. The alterations of PI3K pathway such as activation of oncogenes, gene amplification, and inactivation of tumor suppressors, commonly occur in many human cancers. Angiogenesis is required for tumor growth and metastasis when the tumor reaches more than 1 mm in diameter. Recent studies have shown that PI3K and Akt play an important role in regulating tumor growth and angiogenesis through VEGF and HIF-1 expression. PI3K regulates the expression of these two proteins through HDM2 and p70S6K1 in human cancer cells. The frequent dysregulation of the PI3K/PTEN pathway in human cancer demonstrates that this pathway is an appropriate target for cancer therapeutics. In this review, we describe the recent advances in understanding the PI3K/PTEN pathway, the role and mechanism of PI3K in regulating tumor growth and angiogenesis, and the potential therapeutic opportunities for targeting this pathway for cancer treatment.

The quality of reporting of randomized controlled trials of traditional Chinese medicine: a survey of 13 randomly selected journals from mainland China.

G Wang — 2008-06-12T02:12:31-00:00

Clinical therapeutics, Vol. 29, No. 7. (July 2007), pp. 1456-1467.

BACKGROUND: The number of randomized controlled trials (RCTs) of traditional Chinese medicine (TCM) is increasing. However, there have been few systematic assessments of the quality of reporting of these trials. Objective: This study was undertaken to evaluate the quality of reporting of RCTs in TCM journals published in mainland China from 1999 to 2004. METHODS: Thirteen TCM journals were randomly selected by stratified sampling of the approximately 100 TCM journals published in mainland China. All issues of the selected journals published from 1999 to 2004 were hand-searched according to guidelines from the Cochrane Centre. All reviewers underwent training in the evaluation of RCTs at the Chinese Centre of Evidence-based Medicine. A comprehensive quality assessment of each RCT was completed using a modified version of the Consolidated Standards of Reporting Trials (CONSORT) checklist (total of 30 items) and the Jadad scale. Disagreements were resolved by consensus. RESULTS: Seven thousand four hundred twenty-two RCTs were identified. The proportion of published RCTs relative to all types of published clinical trials increased significantly over the period studied, from 18.6% in 1999 to 35.9% in 2004 (P < 0.001). The mean (SD) Jadad score was 1.03 (0.61) overall. One RCT had a Jadad score of 5 points; 14 had a score of 4 points; and 102 had a score of 3 points. The mean (SD) Jadad score was 0.85 (0.53) in 1999 (746 RCTs) and 1.20 (0.62) in 2004 (1634 RCTs). Across all trials, 39.4% of the items on the modified CONSORT checklist were reported, which was equivalent to 11.82 (5.78) of the 30 items. Some important methodologic components of RCTs were incompletely reported, such as sample-size calculation (reported in 1.1% of RCTs), randomization sequence (7.9%), allocation concealment (0.3 %), implementation of the random-allocation sequence (0%), and analysis of intention to treat (0%). CONCLUSION: The findings of this study indicate that the quality of reporting of RCTs of TCM has improved, but remains poor.

Joint Analysis of Longitudinal Data with Informative Right Censoring

Liu — 2007-08-10T17:31:24-00:00

Biometrics, Vol. 63, No. 2. (June 2007), pp. 363-371.

Two-stage procedures for selecting the best diagnostic biomarkers.

A Liu — 2008-06-08T01:31:29-00:00

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Vol. 366, No. 1874. (13 July 2008), pp. 2293-2299.

Considered in the paper is the problem of selecting a diagnostic biomarker that has the highest classification rate among several candidate markers with dichotomous outcomes. The probability of correct selection depends on a number of nuisance parameters from the joint distribution of the biomarkers and thus can be substantially affected if these nuisance parameters are misspecified. A two-stage procedure is proposed to compute the needed sample size that achieves the desired level of correct selection, as so confirmed by simulation results.

Blood and urine cadmium levels in relation to demographic and life style in middle aged and elderly men.

YC Chen — 2008-06-03T09:15:31-00:00

Bulletin of environmental contamination and toxicology, Vol. 66, No. 3. (March 2001), pp. 287-294.

Ectopic Notch Activation in Developing Podocytes Causes Glomerulosclerosis

Aoife Waters — 2008-06-02T03:13:33-00:00

J Am Soc Nephrol, Vol. 19, No. 6. (1 June 2008), pp. 1139-1157.

10.1681/ASN.2007050596

Berberine inhibits aldose reductase and oxidative stress in rat mesangial cells cultured under high glucose.

Weihua Liu — 2008-05-30T02:47:53-00:00

Archives of biochemistry and biophysics (29 April 2008)

Diabetic nephropathy (DN), one of the most serious microvascular complications of diabetes mellitus, is a major cause of end-stage renal disease. Berberine is one of the main constituents of Coptidis rhizoma and Cortex phellodendri. In the present study, we examined effects of berberine (BBR) on renal injury in streptozotocin-induced diabetic rats, and on the changes of aldose reductase (AR) and oxidative stress in cultured rat mesangial cells exposed to high glucose. Fasting blood glucose, blood urea nitrogen, creatinine, and urine protein over 24h were detected by using the commercially available kits. Cell proliferation, collagen synthesis, aldose reductase (AR), superoxide anion, superoxide dismutase (SOD), and malondialdehyde (MDA) were detected, respectively, by different methods. In streptozotocin-induced diabetic rats, fasting blood glucose, blood urea nitrogen, creatinine, and urine protein over 24h were significantly decreased in rats treated with 200mg/kg berberine for 12 weeks compared with diabetic control rats (P<0.05). This was accompanied by a reduced AR activity and gene expression at both mRNA and protein levels. In cultured rat mesangial cells exposed to high glucose, incubation of BBR significantly decreased cell proliferation, collagen synthesis and AR activity as well as its mRNA and protein levels compared with control cells (P<0.05). In vitro, BBR also significantly increased SOD activity and decreased superoxide anion and MDA compared with control cells (P<0.05). These results suggested that BBR could ameliorate renal dysfunction in DN rats, which may be ascribed to inhibition of AR in mesangium, reduction of oxidative stress, and amelioration of extracellular matrix synthesis and cell proliferation. Further studies are warranted to explore the role of AR in DN and the therapeutic implications by AR inhibitors such as BBR.

Reducing Microarray Data via Nonnegative Matrix Factorization for Visualization and Clustering Analysis

Weixiang Liu — 2008-01-09T19:53:05-00:00

Journal of Biomedical Informatics, Vol. In Press, Accepted Manuscript

Pathway Analysis of Microarray Data via Regression

AJ Adewale — 2008-03-13T09:21:31-00:00

Journal of Computational Biology, Vol. 0, No. 0. (0), pp. 1-9.

Pathway analysis of microarray data evaluates gene expression profiles of a priori defined biological pathways in association with a phenotype of interest. We propose a unified pathway-analysis method that can be used for diverse phenotypes including binary, multiclass, continuous, count, rate, and censored survival phenotypes. The proposed method also allows covariate adjustments and correlation in the phenotype variable that is encountered in longitudinal, cluster-sampled, and paired designs. These are accomplished by combining the regression-based test statistic for each individual gene in a pathway of interest into a pathway-level test statistic. Applications of the proposed method are illustrated with two real pathway-analysis examples: one evaluating relapse-associated gene expression involving a matched-pair binary phenotype in children with acute lymphoblastic leukemia; and the other investigating gene expression in breast cancer tissues in relation to patients' survival (a censored survival phenotype). Implementations for various phenotypes are available in R. Additionally, an Excel Add-in for a user-friendly interface is currently being developed.

Minimum information specification for in situ hybridization and immunohistochemistry experiments (MISFISHIE)

Eric Deutsch — 2008-03-09T04:13:07-00:00

Nature Biotechnology, Vol. 26, No. 3. (07 March 2008), pp. 305-312.

In silico Biochemical Reaction Network Analysis (IBRENA): a package for simulation and analysis of reaction networks.

G Liu — 2008-05-17T09:26:40-00:00

Bioinformatics (Oxford, England), Vol. 24, No. 8. (15 April 2008), pp. 1109-1111.

SUMMARY: We present In silico Biochemical Reaction Network Analysis (IBRENA), a software package which facilitates multiple functions including cellular reaction network simulation and sensitivity analysis (both forward and adjoint methods), coupled with principal component analysis, singular-value decomposition and model reduction. The software features a graphical user interface that aids simulation and plotting of in silico results. While the primary focus is to aid formulation, testing and reduction of theoretical biochemical reaction networks, the program can also be used for analysis of high-throughput genomic and proteomic data. AVAILABILITY: The software package, manual and examples are available at http://www.eng.buffalo.edu/~neel/ibrena

Protein interaction predictions from diverse sources.

Y Liu — 2008-05-16T13:03:09-00:00

Drug discovery today, Vol. 13, No. 9-10. (May 2008), pp. 409-416.

Protein-protein interactions play an important role in many cellular processes. The availability of a comprehensive and accurate list of protein interactions can facilitate drug target discovery. Recent advances in high-throughput experimental technologies have generated enormous amounts of data and provided valuable resources for studying protein interactions. However, these technologies suffer from high error rates because of their inherent limitations. Therefore, computational approaches capable of incorporating multiple data sources are needed to fully take advantage of the rapid accumulation of data. In this review, we focus on the computational methods that integrate multiple data sources by combining direct measurements on protein interactions from diverse organisms, and by integrating different types of indirect information from various genomic and proteomic approaches.

GenoWatch: a disease gene mining browser for association study.

Yan-Hau Chen — 2008-05-16T04:27:58-00:00

Nucleic acids research (25 April 2008)

A human gene association study often involves several genomic markers such as single nucleotide polymorphisms (SNPs) or short tandem repeat polymorphisms, and many statistically significant markers may be identified during the study. GenoWatch can efficiently extract up-to-date information about multiple markers and their associated genes in batch mode from many relevant biological databases in real-time. The comprehensive gene information retrieved includes gene ontology, function, pathway, disease, related articles in PubMed and so on. Subsequent SNP functional impact analysis and primer design of a target gene for re-sequencing can also be done in a few clicks. The presentation of results has been carefully designed to be as intuitive as possible to all users. The GenoWatch is available at the website http://genepipe.ngc.sinica.edu.tw/genowatch.