CiteULike: jyuh's Yu

Population Substructure and Control Selection in Genome-Wide Association Studies

Kai Yu — 2008-07-25T01:12:58-00:00

PLoS ONE, Vol. 3, No. 7. (2 July 2008), e2551.

Determination of the relevance of both demanding classical epidemiologic criteria for control selection and robust handling of population stratification (PS) represents a major challenge in the design and analysis of genome-wide association studies (GWAS). Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility (CGEMS) project were used to evaluate the impact of PS in studies with different control selection strategies. In each of the two original case-control studies nested in corresponding prospective cohorts, a minor confounding effect due to PS (inflation factor λ of 1.025 and 1.005) was observed. In contrast, when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy, the confounding effects were larger (λ of 1.090 and 1.062). A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium (pair-wise r2<0.004) was selected to infer population substructure with principal component analysis. A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error (to λ of 1.032 and 1.006, respectively) than currently used methods. The overlap between sets of SNPs in the bottom 5% of p-values based on the new test and the test without PS correction was about 80%, with the majority of discordant SNPs having both ranks close to the threshold. Thus, for the CGEMS GWAS of prostate and breast cancer conducted in European Americans, PS does not appear to be a major problem in well-designed studies. A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed.

Logical Analysis of Data (LAD) model for the early diagnosis of acute ischemic stroke

Anupama Reddy — 2008-07-11T03:37:38-00:00

BMC Medical Informatics and Decision Making, Vol. 8 (10 July 2008), 30.

Characterization of salivary RNA by cDNA library analysis

Noh Park — 2006-10-20T13:49:50-00:00

Archives of Oral Biology, Vol. In Press, Corrected Proof

Oral fluid (saliva) meets the demands for a noninvasive and accessible diagnostic medium. Recent reports by our group and others described the presence and use of human RNA in saliva as a diagnostic or forensic tool, including the use for oral cancer detection. To gain insights into the integrity of salivary RNA, we examined in detail the integrity of salivary RNA by generating a cDNA library from pooled supernatant saliva of 10 healthy donors. From a library with a primary library titer of 1.3 x 106 cfu/mL of which 95% of the clones had inserts, we successfully sequenced 117 random colonies containing recombinant clones. BLAST search results indicated that all of these clones contained sequences of human origin. Most of the salivary RNAs appeared to be endonucleolytically cleaved at random positions as indicated by comparisons to respective full length parental RNAs from the Genbank. Twelve of the insert sequences matched to the normal salivary core transcriptome sequences, which are highly abundant mRNAs present in healthy individuals. This study provides an in-depth molecular analysis of the saliva transcriptome and should be a useful resource for future basic and translational studies of RNA in human saliva. In addition, this paper presents unequivocal evidence for the presence of RNA in saliva as determined by the use of diverse techniques such as reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), in vitro translation, and the construction of a salivary cDNA library.

Characterization of LD structures and the utility of HapMap in genetic association studies.

CC Gu — 2008-07-10T09:52:54-00:00

Advances in genetics, Vol. 60 (2008), pp. 407-435.

Observed distribution of and variation in linkage disequilibrium (LD) with respect to the evolution history and disease transmission in a population is the driving force behind the current wave of genome-wide association (GWA) studies of complex human diseases. An extensive literature covers topics from haplotype analysis that utilizes local LD structures in candidate genes and regions to genome-wide organization of LD blocks (neighborhood) that led to the development of International HapMap Project and panels of "tagSNPs" used by current GWA studies. In this chapter, we examine the scenarios where each of the major types of analysis methods may be applicable and where the current popular genotyping platforms for GWA might come short. We discuss current association analysis methods by emphasizing their reliance on the local LD structures or the global organization of the LD structures, and highlight the need to consider individual marker information content in large-scale association mapping.

C-reactive protein gene polymorphism 1009A>G is associated with serum CRP levels in Chinese men: a TCVGHAGE study.

WH Sheu — 2008-07-10T02:02:51-00:00

Clinica chimica acta; international journal of clinical chemistry, Vol. 382, No. 1-2. (July 2007), pp. 117-123.

BACKGROUND: Increased concentrations of high-sensitivity CRP (hs-CRP) are associated with increased risk of cardiovascular disease. This increase might be caused by low-grade inflammation, but a number of studies have suggested that serum CRP concentrations are under genetic control. Since the relation between CRP concentration and cardiovascular diseases occurs across ethnicities, we determined whether CRP gene variants affect fasting hs-CRP concentrations in a cohort of Chinese men. METHODS: High-sensitivity CRP concentrations were measured in 369 Chinese men. Six polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing within the CRP gene: 969T>C, 1009A>G, and a 3-allele polymorphism 1440C>A>T in the 5' UTR (promoter region), 2667G>C in exon 2, and 3872A>G and 5992T>A in the 3' UTR. RESULTS: In a group of participants (n=328) whose fasting serum hs-CRP concentrations were within the 5th to 95th percentile, we found that the genetic polymorphism 1009A>G was significantly associated with fasting serum hs-CRP concentrations (GG vs. AG or AA genotypes, CRP concentrations 0.072+/-0.062 vs. 0.176+/-0.166 and 0.166+/-0.185 mg/dl, mean+/-S.D., both P=0.023). Furthermore, subjects carrying the 1009G bearing haplotype exhibited the lowest CRP concentrations (P=0.05). CONCLUSION: The CRP 1009A>G genotypes and associated haplotypes were associated with lower fasting serum hs-CRP concentrations in a group of elderly Chinese men.

A method of assessing the sensitivity of the Cochran-Mantel-Haenszel test to an unobserved confounder.

B Yu — 2008-07-01T01:52:09-00:00

Philosophical transactions. Series A, Mathematical, physical, and engineering sciences, Vol. 366, No. 1874. (13 July 2008), pp. 2377-2388.

Observational studies, including the case-control design frequently used in epidemiology, are subject to a number of biases and possible confounding factors. Failure to adjust with them may lead to an erroneous conclusion about the existence of a causal relationship between exposure and disease. The Cochran-Mantel-Haenszel (CMH) test is widely used to measure the strength of the association between an exposure and disease or response, after stratifying on the observed covariates. Thus, observed confounders are accounted for in the analysis. In practice, there may be causal variables that are unknown or difficult to obtain. Hence, they are not incorporated into the analysis. Sensitivity analysis enables investigators to assess the robustness of the findings. A method for assessing the sensitivity of the CMH test to an omitted confounder is presented here. The technique is illustrated by re-examining two datasets: one concerns the effect of maternal hypertension as a risk factor for low birth weight infants and the other focuses on the risk of allopurinol on having a rash. The computer code performing the sensitivity analysis is provided in appendix A.

Neuro-fuzzy technology as a predictor of parathyroid hormone level in hemodialysis patients.

CA Chen — 2008-06-30T01:59:33-00:00

The Tohoku journal of experimental medicine, Vol. 211, No. 1. (January 2007), pp. 81-87.

Measuring the plasma parathyroid hormone (PTH) concentration is crucial to evaluate renal bone disease in patients with renal failure. Although frequent measurement is needed to avoid inadequate prescription of phosphate binders and vitamin D preparations, artificial intelligence can repeatedly perform the forecasting tasks and may be a satisfactory substitute for laboratory tests. Neuro-fuzzy technology represents a promising forecasting application in clinical medicine. We therefore constructed a coactive neuro-fuzzy inference system (CANFIS) to predict plasma PTH concentrations in hemodialysis patients. The CANFIS was constructed with clinical parameters (patient age, plasma albumin, calcium, phosphorus, alkaline phosphatase, and calcium-phosphorus product) from a cohort of hemodialysis patients, and plasma PTH concentration measured by radioimmunoassay (RIA) was the supervised outcome. The accuracy of the CANFIS was prospectively compared with RIA in another hospital. Plasma PTH concentrations measured by RIA and predicted by CANFIS were 179.04 +/- 38.18 ng/l and 179.34 +/- 37.76 ng/l, respectively (p = 0.15). The CANFIS was able to precisely estimate plasma PTH concentrations in hemodialysis patients. These results suggest that the neuro-fuzzy technology, based on limited clinical parameters, is an excellent alternative to RIA for accurately predicting plasma PTH concentration in hemodialysis patients.

Effect of Kt/V on survival and clinical outcome in CAPD patients in a randomized prospective study.

WK Lo — 2008-06-29T06:57:28-00:00

Kidney international, Vol. 64, No. 2. (August 2003), pp. 649-656.

BACKGROUND: There has been a lack of randomized control study on the effect of Kt/V on patient outcome. This interventional study was designed to examine the effect of Kt/V on continuous ambulatory peritoneal dialysis (CAPD) patients' clinical outcome and nutritional status in a randomized prospective manner. METHOD: A total of 320 new CAPD patients with baseline renal Kt/V <1.0 were recruited from six centers in Hong Kong and were randomized into three Kt/V targets: group A, 1.5 to 1.7; group B, 1.7 to 2.0; and group C,>2.0. Kt/V and nutritional status were assessed every 6 months and dialysis prescription adjusted accordingly. Nutritional assessment included serum albumin and composite nutritional index (CNI). Patients were allowed to withdraw at the discretion of their physicians or themselves. RESULTS: Total Kt/V were significantly different between groups (P = 0.000) and the difference was contributed by peritoneal Kt/V only. The overall 2-year patient survival was 84.9%. There was no statistical difference in patient survival among the three groups (2-year survival in group A, 87.3%; group B, 86.1%; and group C, 81.5%). However, there were more patients withdrawn by physicians in group A (group A, 16; group B, 7; and group C, 6; P = 0.023). Total Kt/V or Kt did not significantly affect survival after adjustment to age and diabetes. There was no difference in serum albumin, CNI scores, and hospitalization rate, but there were more patients in group A requiring erythropoietin (EPO) treatment after 1 year. CONCLUSION: Patients with total Kt/V maintained below 1.7 had significantly more clinical problems and severe anemia but there was no difference in outcome demonstrated for patients with Kt/V maintained above 2.0 and between 1.7 and 2.0. We recommended that the minimal target of total Kt/V should be above 1.7.

Recombinant human growth hormone improves muscle amino acid uptake and whole-body protein metabolism in chronic hemodialysis patients.

LB Pupim — 2008-06-29T06:36:22-00:00

The American journal of clinical nutrition, Vol. 82, No. 6. (December 2005), pp. 1235-1243.

BACKGROUND: Intradialytic parenteral nutrition (IDPN), with or without exercise, has been shown to reverse the net negative whole-body and forearm muscle protein balances observed during hemodialysis. Pharmacologic doses of recombinant human growth hormone (rhGH) constitute another potential anabolic therapy in chronic hemodialysis patients. OBJECTIVE: Our goal was to examine the potential additive anabolic effects of rhGH compared with IDPN and exercise on protein and energy homeostasis. DESIGN: We studied 7 chronic hemodialysis patients in a crossover design study in which each subject participated in 2 protocols: GH (rhGH + IDPN + exercise) and no GH (IDPN + exercise). During the GH protocol, the subjects were studied after 3 daily doses of rhGH. Each subject was studied 2 h before, 4 h during, and 2 h after a hemodialysis session with the use of a primed, constant infusion of l-[1-(13)C]leucine. RESULTS: Whole-body net protein balance was -0.50 +/- 0.07 mg x kg fat-free mass(-1) x min(-1) when the patients did not receive rhGH and -0.39 +/- 0.04 mg x kg fat-free mass(-1) x min(-1) when the patients received rhGH, a 22% improvement in prehemodialysis whole-body protein homeostasis (P < 0.05). Essential amino acid muscle loss was also significantly less during the prehemodialysis period when rhGH was administered (-18 +/- 23 compared with -71 +/- 20 mmol/L; P < 0.05). The whole-body anabolic effects of rhGH observed during the prehemodialysis period persisted throughout the entire study, as evidenced by a lack of significant interaction or main effect of treatment during hemodialysis and in the posthemodialysis period. CONCLUSION: rhGH improves whole-body protein homeostasis in chronic hemodialysis patients.

Role of leptin and melanocortin signaling in uremia-associated cachexia.

W Cheung — 2008-06-29T01:57:36-00:00

The Journal of clinical investigation, Vol. 115, No. 6. (June 2005), pp. 1659-1665.

The pathogenesis of cachexia in patients with uremia is unknown. We tested the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R). We performed either subtotal nephrectomy (N) or sham operations in WT, leptin receptor-deficient (db/db), and MC4-R knockout (MC4-RKO) mice. The animals were on 17% protein diets, and none of the uremic animals were acidotic. WT-N mice produced a classic syndrome of cachexia characterized by decreased food intake, increased metabolic rate, and loss of lean body mass. Corrected leptin levels were elevated. db/db mice and MC4-RKO mice resisted the cachexic effects of uremia on weight gain, body composition, and metabolic rate. Likewise, treatment of WT mice with intracranial agouti-related peptide reversed the cachexic effects of uremia on appetite, weight gain, body composition, and metabolic rate. Gene expression of ubiquitin C and proteasome subunits C2, C3, and C9 was not changed in the uremic animals, suggesting that other pathways are involved in this model of nonacidotic uremic cachexia. The results of this study suggest that elevated circulating levels of cytokines such as leptin may be an important cause of uremia-associated cachexia via signaling through the central melanocortin system.

Determinants of C-reactive protein in chronic hemodialysis patients: Relevance of dialysis catheter utilization

Adriana Hung — 2008-04-08T07:01:15-00:00

Hemodialysis International, Vol. 12, No. 2. (April 2008), pp. 236-243.

MPDA: Microarray pooled DNA analyzer

Hsin-Chou Yang — 2008-04-15T18:39:14-00:00

BMC Bioinformatics, Vol. 9 (15 April 2008), 196.

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.

The application of cell-based label-free technology in drug discovery.

B Xi — 2008-06-25T06:02:58-00:00

Biotechnology journal, Vol. 3, No. 4. (April 2008), pp. 484-495.

Cell-based assays are an important part of the drug discovery process allowing for interrogation of targets and pathways in a more physiological setting compared to biochemical assays. One of the main hurdles in the cell-based assay field is to design sufficiently robust assays with adequate signal to noise parameters while maintaining the inherent physiology of the pathway or target being investigated. Conventional label and reporter-based cell assays may be more prone to artifacts due to considerable manipulation of the cell either by the label or over-expression of targets or reporter proteins. Cell-based label-free technologies preclude the need for cellular labeling or over-expression of reporter proteins, utilizing the inherent morphological and adhesive characteristics of the cell as a physiologically relevant and quantitative readout for various cellular assays. Furthermore, these technologies utilize non-invasive measurements allowing for time resolution and kinetics in the assay. In this article, we have reviewed the various label-free technologies that are being used in drug discovery settings and have focused our discussion on impedance-based label-free technologies and its main applications in drug discovery.

How many human genes can be defined as housekeeping with current expression data?

Jiang Zhu — 2008-04-16T11:53:22-00:00

BMC Genomics, Vol. 9, No. 1. (2008)

BACKGROUND:Housekeeping (HK) genes are ubiquitously expressed in all tissue/cell types and constitute a basal transcriptome for the maintenance of basic cellular functions. Partitioning transcriptomes into HK and tissue-specific (TS) genes relatively is fundamental for studying gene expression and cellular differentiation. Although many studies have aimed at large-scale and thorough categorization of human HK genes, a meaningful consensus has yet to be reached.RESULTS:We collected two latest gene expression datasets (both EST and microarray data) from public databases and analyzed the gene expression profiles in 18 human tissues that have been well-documented by both two data types. Benchmarked by a manually-curated HK gene collection (HK408), we demonstrated that present data from EST sampling was far from saturated, and the inadequacy has limited the gene detectability and our understanding of TS expressions. Due to a likely over-stringent threshold, microarray data showed higher false negative rate compared with EST data, leading to a significant underestimation of HK genes. Based on EST data, we found that 40.0% of the currently annotated human genes were universally expressed in at least 16 of 18 tissues, as compared to only 5.1% specifically expressed in a single tissue. Our current EST-based estimate on human HK genes ranged from 3,140 to 6,909 in number, a ten-fold increase in comparison with previous microarray-based estimates.CONCLUSIONS:We concluded that a significant fraction of human genes, at least in the currently annotated data depositories, was broadly expressed. Our understanding of tissue-specific expression was still preliminary and required much more large-scale and high-quality transcriptomic data in future studies. The new HK gene list categorized in this study will be useful for genome-wide analyses on structural and functional features of HK genes.

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.

Treatment of chronic hepatitis C in southern Taiwan.

WL Chuang — 2008-06-22T09:49:39-00:00

Intervirology, Vol. 49, No. 1-2. (2006), pp. 99-106.

Chronic hepatitis C virus (HCV) infection may lead to cirrhosis and hepatocellular carcinoma. Interferon (IFN)-alpha is effective in the treatment of chronic hepatitis C. The rate of response to IFN is enhanced by increasing the IFN dose. Extending the treatment duration can reduce the relapse rate. Addition of ribavirin to IFN increases the sustained virological response (SVR). Thus, combination therapy with IFN and ribavirin was adopted for the treatment of chronic hepatitis C in Kaohsiung Medical University Hospital in 1998. Approximately 60% of patients receiving IFN/ribavirin therapy gained SVR. IFN 6 million units three times per week combined with daily ribavirin for 6 months achieved SVR more frequently than combination therapy with 3 million units. Factors for SVR in these combination regimens were HCV genotype, viral load and early virological response. Long-term follow-up of patients treated with IFN has shown that SVR might reduce the risk of progression to cirrhosis and hepatocellular carcinoma. Pegylated (peg)-IFN has a longer half-life and better efficacy. Combination therapy with peg-IFN and ribavirin accomplished higher SVR than conventional IFN and ribavirin. A multicenter clinical trial was conducted in Taiwan to compare the efficacy of combination therapy between peg-IFN/ribavirin and conventional IFN/ribavirin for 6 months. SVR was higher in patients receiving peg-IFN and ribavirin, especially in those infected with HCV genotype 1b. Based on the results obtained, the national health insurance started to sponsor the combination therapy in October 2003, with a suggested duration for 6 months. Some small-scale studies in Taiwan have postulated higher SVR for treatment duration of 12 than of 6 months in patients with genotype 1b. Further investigation should be conducted in the near future.

A frailty mixture cure model with application to hospital readmission data.

B Yu — 2008-06-21T04:10:25-00:00

Biometrical journal. Biometrische Zeitschrift, Vol. 50, No. 3. (June 2008), pp. 386-394.

Mixture cure models have been utilized to analyze survival data with possible cure. This paper considers the inclusion of frailty into the mixture cure model to model recurrent event data with a cure fraction. An attractive feature of the proposed model is the allowance for heterogeneity in risk among those individuals experiencing the event of interest in addition to the incorporation of a cured component. Maximum likelihood estimates can be obtained using the Expectation Maximization algorithm and standard errors are calculated from the Bootstrap method. The model is applied to hospital readmission data among colorectal cancer patients.

A marginal regression model for multivariate failure time data with a surviving fraction

Yingwei Peng — 2008-06-20T09:39:09-00:00

Lifetime Data Analysis, Vol. 13, No. 3. (2007), pp. 351-369.

Abstract A marginal regression approach for correlated censored survival data has become a widely used statistical method. Examples of this approach in survival analysis include from the early work by Wei et al. (J Am Stat Assoc 84:1065–1073, 1989) to more recent work by Spiekerman and Lin (J Am Stat Assoc 93:1164–1175, 1998). This approach is particularly useful if a covariate’s population average effect is of primary interest and the correlation structure is not of interest or cannot be appropriately specified due to lack of sufficient information. In this paper, we consider a semiparametric marginal proportional hazard mixture cure model for clustered survival data with a surviving or “cure” fraction. Unlike the clustered data in previous work, the latent binary cure statuses of patients in one cluster tend to be correlated in addition to the possible correlated failure times among the patients in the cluster who are not cured. The complexity of specifying appropriate correlation structures for the data becomes even worse if the potential correlation between cure statuses and the failure times in the cluster has to be considered, and thus a marginal regression approach is particularly attractive. We formulate a semiparametric marginal proportional hazards mixture cure model. Estimates are obtained using an EM algorithm and expressions for the variance–covariance are derived using sandwich estimators. Simulation studies are conducted to assess finite sample properties of the proposed model. The marginal model is applied to a multi-institutional study of local recurrences of tonsil cancer patients who received radiation therapy. It reveals new findings that are not available from previous analyses of this study that ignored the potential correlation between patients within the same institution.

A generalized log-rank test for interval-censored failure time data via multiple imputation.

Jinlong Huang — 2008-06-16T04:29:23-00:00

Statistics in medicine (6 February 2008)

Interval-censored (IC) failure time data often occur in follow-up studies where subjects can only be followed periodically and the failure time can only be known to lie in an interval. In this paper we propose a modified log-rank test for the problem of comparing two or more IC samples. Our log-rank statistic and covariance matrix are calculated by a multiple imputation technique. Through simulation studies, we find that the performance of the proposed test is comparable to that of the test proposed by Finkelstein (Biometrics 1986; 42(4):845-854) and is better than that of the two existing log-rank type tests proposed by Sun (Lifetime Data Anal. 2001; 7:363-375) and Zhao and Sun (Stat. Med. 2004; 23(10):1621-1629) due to the differences in the method of multiple imputation and the covariance matrix estimation. Our covariance matrix estimator is similar to the estimator used by Follmann et al. (Biometrics 2003; 59:420-429) for clustered data. The proposed method is illustrated by means of an example involving patients with breast cancer. Copyright (c) 2008 John Wiley & Sons, Ltd.

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.

A SAS macro for sample size adjustment and randomization test for internal pilot study

Suzhen Wang — 2008-06-06T12:43:17-00:00

Computer Methods and Programs in Biomedicine, Vol. 90, No. 1. (April 2008), pp. 66-88.

An unnecessarily high or inadequately low sample size often occurs in clinical trials if the planned variance of the trials is overestimated or underestimated. Internal pilot study which utilizes the information from the patients recruited up to interim stage can solve this problem well by re-estimating the variance and re-calculating the sample size. The trial may get a satisfactory power but the type I error rate may be inflated while the t-test is adopted to make hypothesis test because condition of t-distribution is not sufficed any more with variation of the sample size resulted from internal pilot design. If blind variance estimators of the internal pilot are used for sample size recalculation and randomization test is used to accomplish the final hypothesis test, not only the blindness of the internal pilot is preserved but also the ability to control the type I error rate is guaranteed. A SAS macro is programmed to simulate the process of sample size adjustment and randomization test.

ENDEAVOUR update: a web resource for gene prioritization in multiple species

Leon-Charles Tranchevent — 2008-05-29T01:57:07-00:00

Nucl. Acids Res. (28 May 2008), gkn325.

ENDEAVOUR (http://www.esat.kuleuven.be/endeavourweb; this web site is free and open to all users and there is no login requirement) is a web resource for the prioritization of candidate genes. Using a training set of genes known to be involved in a biological process of interest, our approach consists of (i) inferring several models (based on various genomic data sources), (ii) applying each model to the candidate genes to rank those candidates against the profile of the known genes and (iii) merging the several rankings into a global ranking of the candidate genes. In the present article, we describe the latest developments of ENDEAVOUR. First, we provide a web-based user interface, besides our Java client, to make ENDEAVOUR more universally accessible. Second, we support multiple species: in addition to Homo sapiens, we now provide gene prioritization for three major model organisms: Mus musculus, Rattus norvegicus and Caenorhabditis elegans. Third, ENDEAVOUR makes use of additional data sources and is now including numerous databases: ontologies and annotations, protein-protein interactions, cis-regulatory information, gene expression data sets, sequence information and text-mining data. We tested the novel version of ENDEAVOUR on 32 recent disease gene associations from the literature. Additionally, we describe a number of recent independent studies that made use of ENDEAVOUR to prioritize candidate genes for obesity and Type II diabetes, cleft lip and cleft palate, and pulmonary fibrosis. 10.1093/nar/gkn325

MAX-rank: a simple and robust genome-wide scan for case-control association studies.

Qizhai Li — 2008-05-23T03:08:14-00:00

Human genetics (20 May 2008)

In genome-wide association studies (GWAS), single-marker analysis is usually employed to identify the most significant single nucleotide polymorphisms (SNPs). The trend test has been proposed for analysis of case-control association. Three trend tests, optimal for the recessive, additive and dominant models respectively, are available. When the underlying genetic model is unknown, the maximum of the three trend test results (MAX) has been shown to be robust against genetic model misspecification. Since the asymptotic distribution of MAX depends on the allele frequency of the SNP, using the P-value of MAX for ranking may be different from using the MAX statistic. Calculating the P-value of MAX for 300,000 (300 K) or more SNPs is computationally intensive and the software and program to obtain the P-value of MAX are not widely available. On the other hand, the MAX statistic is very easy to calculate without complex computer programs. Thus, we study whether or not one could use the MAX statistic instead of its P-value to rank SNPs in GWAS. The approaches using the MAX and its P-value to rank SNPs are referred to as MAX-rank and P-rank. By applying MAX-rank and P-rank to simulated and four real datasets from GWAS, we found the ranks of SNPs with true association are very similar using both approaches. Thus, we recommend to use MAX-rank for genome-wide scans. After the top-ranked SNPs are identified, their P-values based on MAX can be calculated and compared with the significance level.

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

K Rikova — 2008-01-24T11:57:39-00:00

Cell, Vol. 131, No. 6. (14 December 2007), pp. 1190-1203.

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

HuGE Watch: tracking trends and patterns of published studies of genetic association and human genome epidemiology in near-real time

Wei Yu — 2008-05-14T10:47:27-00:00

European Journal of Human Genetics, Vol. aop, No. current.

CSCDB: The cAMP and cGMP signaling components database.

Jianxin Lu — 2008-05-16T02:41:44-00:00

Genomics (7 May 2008)

Adenylate cyclases, guanylate cyclases, cyclic nucleotide phosphodiesterases, and cyclic nucleotide-binding proteins constitute the core of cAMP and cGMP signaling components. Using a combination of BLAST and profile search methods, we found that cyclic nucleotide-binding proteins exhibited diverse domain architectures. In addition to the domain architectures involved in the characterized functional groups, a cyclic nucleotide-binding domain was also fused to various domains involved in pyridine nucleotide-disulfide oxidoreductase, acetyltransferase, thioredoxin reductase, glutaminase, rhodanese, ferredoxin, and diguanylate cyclase, implying the versatile functions of cyclic nucleotide-binding proteins. We constructed the CSCDB database to accumulate the components of cAMP and cGMP signaling pathways in the complete genomes. User-friendly interfaces were created for easier browsing, searching, and downloading the data. Besides harboring the sequence itself, each entry provided detailed annotation information, such as sequence features, chromosomal localization, functional domains, transmembrane region, and sequence similarity against several major databases. Currently, CSCDB contains 4234 entries covering 466 organisms, including 35 eukaryotes, 382 bacteria, and 29 archaea. CSCDB can be freely accessible on the web at http://cscdb.com.cn.

Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications

Zongzhong Tong — 2008-05-13T23:41:12-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 19. (13 May 2008), pp. 6998-7003.

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10-3; Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10-8; and Boston: P = 2.1 x 10-2]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications. 10.1073/pnas.0800454105

Targeted pre-mRNA modification for gene silencing and regulation

Xinliang Zhao — 2007-12-29T05:58:20-00:00

Nature Methods, Vol. 5, No. 1. (09 December 2007), pp. 95-100.

Peak bagging for peptide mass fingerprinting

Zengyou He — 2008-05-07T10:39:14-00:00

Bioinformatics, Vol. 24, No. 10. (15 May 2008), pp. 1293-1299.

Motivation: Mass Spectrometry (MS)-based protein identification via peptide mass fingerprinting (PMF) is a key component in high-throughput proteome research. While PMF was the first commonly used protein identification method, provided higher throughput than the tandem MS-based method, its accuracy is lower than that of the tandem MS method. Thus, it is desirable to develop PMF-based algorithm with higher protein identification accuracy to facilitate proteome research. Results: We propose a peak bagging method for single MS-based protein identification. It combines results from multiple PMF algorithms, where each PMF algorithm takes a random peak subset as input. Evaluation with a set of real MALDI-TOF MS spectra shows that the new peak bagging method provides consistent improvements over the single PMF algorithm. Contact: eezyhe@ust.hk 10.1093/bioinformatics/btn123

Ischemia heart disease and greater waist circumference are risk factors of renal function deterioration in male gout patients.

BY Su — 2008-05-08T03:57:19-00:00

Clinical rheumatology, Vol. 27, No. 5. (May 2008), pp. 581-586.

We examined the incidence of renal function deterioration (RFD) in a population of male gout patients and to identify associated risk factors. Subjects who had been regularly followed up for more than 2 years and had visited Chang Gung Memorial Hospital-Kaohsiung Medical Center Rheumatology Clinic between June 1, 2006 and January 31, 2007 were enrolled. Four subjects were excluded as secondary gout was suspected. Group I (Gr I) comprised subjects without RFD and group II (Gr II) comprised subjects with RFD during the follow-up period. RFD was defined as absolute increment in creatinine (Cr) levels over 0.4 mg/dl for subjects with baseline Cr levels </=1.4 mg/dl or as more than 50% increment of baseline Cr level per 12-month interval in average for subjects with baseline Cr levels >1.4 mg/dl. Clinical parameters were analyzed to study the potential risk factors of RFD. Of 318 male gout patients, 296 (93.1%) were categorized as Gr I, and 22 (6.9%) were categorized as Gr II. The observation periods for Gr I and Gr II were 81.20 +/- 53.29 and 92.41 +/- 46.72 months, respectively (p = 0.338). Initial Cr levels are similar between the two groups (1.25 +/- 0.51 vs 1.25 +/- 0.61, p = 0.963). Multiple logistic regression analysis revealed that current age, age at disease onset, disease duration, treatment duration, body weight, height, family history of gout, tophi, urolithiasis, tobacco use, alcohol consumption, history of cerebral vascular accident, hypertension, diabetes mellitus, dyslipidemia, base-line and final Cr, blood urea nitrogen level, serum uric acid level, and body-mass index were not independent risk factors. However, history of ischemic heart disease [IHD; odds ratio (OR) 7.68, 95% confidence interval (CI) 1.99-29.70] and greater waist circumference (WC; OR 1.06, 95% CI 1.01-1.11) were two independent risk factors of RFD. Additionally, the Cox multivariable analysis disclosed that IHD (p < 0.001) and greater WC (p = 0.011) deteriorated kidney function in these patients. The incidence of RFD in male gout patients is 6.9%. History of IHD and greater WC are two independent risk factors for developing RFD.

Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism

Paul Yu — 2008-05-07T07:13:49-00:00

Nat Chem Biol, Vol. 4, No. 1. (January 2008), pp. 33-41.

Activation of a TGF-beta-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-beta Receptor II

Alexei Gratchev — 2008-05-06T02:26:53-00:00

J Immunol, Vol. 180, No. 10. (15 May 2008), pp. 6553-6565.

Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2IL-4/GC) but not M2IL-4 responds to TGF-1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF- cooperation revealed that surface expression of TGF-RII was high in M2GC and M2IL-4/GC, but absent from M2IL-4, whereas the expression of TGF-RI/II mRNA, TGF-RII total protein, and surface expression of TGF-RIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-RII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-1-treated M2IL-4/GC was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-RII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF- by GC-induced surface expression of TGF-RII activate in response to TGF-1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.

Circulating blood volume measurements correlate poorly with pulmonary artery catheter measurements.

H Yamauchi — 2008-05-05T03:00:27-00:00

Hawaii medical journal, Vol. 67, No. 1. (January 2008), pp. 8-11.

BACKGROUND: Determination of the intravascular volume status of a critically ill surgical patient is paramount for appropriate fluid and cardiovascular management. Many clinical parameters have been utilized to estimate intravascular volume but none are precise indicators of circulating blood volume. The purpose of this observational pilot study was to compare measured blood volume with hemodynamic parameters obtained from the pulmonary artery catheter and to determine if incorporation of these measurements altered treatment decisions in critically ill surgical patients. METHODS: Blood volume measurements were prospectively obtained in twenty surgical intensive care unit patients with a pulmonary artery catheter when intravascular volume status was deemed uncertain by traditional clinical parameters. RESULTS: There was a statistically significant, but weak, correlation between blood volume results and pulmonary artery occlusion pressure, but no correlation with central venous pressure, cardiac index, and stroke volume index. Blood volume information altered treatment in 21% of instances, and 5 of these 6 patients demonstrated a favorable clinical response. CONCLUSIONS: Circulating blood volume measurements may be useful in critically ill surgical patients when clinical appraisal of intravascular volume is uncertain. This remains to be validated in a larger, prospective randomized trial.

Exon-Level Expression Profiling: A Comprehensive Transcriptome Analysis of Oral Fluids

Zhanzhi Hu — 2008-05-01T02:30:00-00:00

Clin Chem, Vol. 54, No. 5. (1 May 2008), pp. 824-832.

Background: The application of global gene expression profiling to saliva samples is hampered by the presence of partially fragmented and degraded RNAs that are difficult to amplify and detect with the prevailing technologies. Moreover, the often limited volume of saliva samples is a challenge to quantitative PCR (qPCR) validation of multiple candidates. The aim of this study was to provide proof-of-concept data on the combination of a universal mRNA-amplification method with exon arrays for candidate selection and a multiplex preamplification method for easy validation. Methods: We used a universal mRNA-specific linear-amplification strategy in combination with Affymetrix Exon Arrays to amplify salivary RNA from 18 healthy individuals on the nanogram scale. Multiple selected candidates were preamplified in one multiplex reverse transcription PCR reaction, cleaned up enzymatically, and validated by qPCR. Results: We defined a salivary exon core transcriptome (SECT) containing 851 transcripts of genes that have highly similar expression profiles in healthy individuals. A subset of the SECT transcripts was verified by qPCR analysis. Informatics analysis of the SECT revealed several functional clusters and sequence motifs. Sex-specific salivary exon biomarkers were identified and validated in tests with samples from healthy individuals. Conclusions: It is feasible to use samples containing fragmented RNAs to conduct high-resolution expression profiling with coverage of the entire transcriptome and to validate multiple targets from limited amounts of sample. 10.1373/clinchem.2007.096164

GAPscreener: An Automatic Tool for Screening Human Genetic Association Literature in PubMed Using the Support Vector Machine Technique

Wei Yu — 2008-04-23T07:16:11-00:00

BMC Bioinformatics, Vol. 9 (22 April 2008), 205.

Systematic identification and analysis of mammalian small ubiquitin-like modifier substrates.

CB Gocke — 2007-02-07T20:46:18-00:00

J Biol Chem, Vol. 280, No. 6. (11 February 2005), pp. 5004-5012.

Small ubiquitin-like modifier (SUMO) regulates diverse cellular processes through its reversible, covalent attachment to target proteins. Many SUMO substrates are involved in transcription and chromatin structure. Sumoylation appears to regulate the functions of target proteins by changing their subcellular localization, increasing their stability, and/or mediating their binding to other proteins. Using an in vitro expression cloning approach, we have identified 40 human SUMO1 substrates. The spectrum of human SUMO1 substrates identified in our screen suggests general roles of sumoylation in transcription, chromosome structure, and RNA processing. We have validated the sumoylation of 24 substrates in living cells. Analysis of this panel of SUMO substrates leads to the following observations. 1) Sumoylation is more efficient in vitro than in living cells. Polysumoylation occurs on several substrates in vitro. 2) SUMO isopeptidases have little substrate specificity. 3) The SUMO ligases, PIAS1 and PIASxbeta, have broader substrate specificities than does PIASy. 4) Although SUMO1 and SUMO2 are equally efficiently conjugated to a given substrate in vitro, SUMO1 conjugation is more efficient in vivo. 5) Most SUMO substrates localize to the nucleus, and sumoylation does not generally affect their subcellular localization. Therefore, sumoylation appears to regulate the functions of its substrates through multiple, context-dependent mechanisms.

Investigating differential item functioning by chronic diseases in the SF-36 health survey: a latent trait analysis using MIMIC models.

YF Yu — 2008-04-15T07:45:23-00:00

Medical care, Vol. 45, No. 9. (September 2007), pp. 851-859.

OBJECTIVES: Differential item functioning (DIF) is present when respondents of unique subgroups endorse certain items differently given the respondents have the same underlying ability. This study investigates the presence of DIF regarding chronic illnesses among items of the physical functioning (PF) and mental health (MH) domains of the SF-36 health survey. METHODS: Multiple indicators multiple causes (MIMIC) model was applied to data extracted from the Kaiser Permanente database for members who completed the SF-36 during 1994-1995 (N = 7538). DIF effects were evaluated for sociodemographic variables and for indicators of 5 chronic conditions: hypertension, rheumatic conditions, diabetes, respiratory diseases, and depression. An iterative strategy with backward selection was applied to build DIF models, which were estimated by weighted least squares. The Hochberg procedure was applied to P values for multiple tests. RESULTS: After controlling for the selected covariates and the latent ability, DIF was present in 3 items for hypertension, one for respiratory diseases, and one for diabetes. Adjusting for DIF did not modify the overall pattern of exogenous variables' effects on PF or MH, except Hispanic and other ethnicity on PF, education on MH became insignificant; and black ethnicity on PF, old ages and other ethnicity on MH became significant. CONCLUSIONS: Considering the number of items and disease subgroups compared, the presence of DIF was minimal among items of the PF and MH domains of the SF-36. DIF had little effect on comparisons of sociodemographic or disease groups.

Increased utilization of peritoneal dialysis to cope with mounting demand for renal replacement therapy--perspectives from Asian countries.

PK Li — 2008-04-14T01:42:54-00:00

Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis, Vol. 27 Suppl 2 (June 2007)

With the number of end-stage renal disease (ESRD) patients growing, one of the crucial questions facing health care professionals and funding agencies in Asia is whether funding for dialysis will be sufficient to keep up with demand. During the ISPD's 2006 Congress, academic nephrologists and government officials from China, Hong Kong, India, Indonesia, Japan, Macau, Malaysia, Philippines, Singapore, Taiwan, Thailand, and Vietnam participated in a roundtable discussion on dialysis economics in Asia. The focus was policy and health care financing. The roundtable addressed ESRD growth in Asia and how to obtain enough funding to keep up with the growth in patient numbers. Various models were presented: the "peritoneal dialysis (PD) first" policy model, incentive programs, nongovernmental organizations providing PD, and PD reimbursement in a developing economy. This article summarizes the views of the participant nephrologists on how to increase the utilization of PD to improve on clinical and financial management of patients with ESRD.

Using support vector machine combined with auto covariance to predict protein-protein interactions from protein sequences

Yanzhi Guo — 2008-04-14T01:37:18-00:00

Nucl. Acids Res. (4 April 2008), gkn159.

Compared to the available protein sequences of different organisms, the number of revealed proteinprotein interactions (PPIs) is still very limited. So many computational methods have been developed to facilitate the identification of novel PPIs. However, the methods only using the information of protein sequences are more universal than those that depend on some additional information or predictions about the proteins. In this article, a sequence-based method is proposed by combining a new feature representation using auto covariance (AC) and support vector machine (SVM). AC accounts for the interactions between residues a certain distance apart in the sequence, so this method adequately takes the neighbouring effect into account. When performed on the PPI data of yeast Saccharomyces cerevisiae, the method achieved a very promising prediction result. An independent data set of 11 474 yeast PPIs was used to evaluate this prediction model and the prediction accuracy is 88.09%. The performance of this method is superior to those of the existing sequence-based methods, so it can be a useful supplementary tool for future proteomics studies. The prediction software and all data sets used in this article are freely available at http://www.scucic.cn/Predict_PPI/index.htm. 10.1093/nar/gkn159

Multiple imputation methods for modelling relative survival data.

B Yu — 2008-04-11T04:20:41-00:00

Statistics in medicine, Vol. 25, No. 17. (15 September 2006), pp. 2946-2955.

In population-based cancer survival studies, the cause-specific survival measures the net survival (excess mortality) due to cancer when the cause of death information is available and reliable. In contrast, when the cause of death is uncertain or unavailable, relative survival, the ratio of the survival rate due to all causes to the expected survival rate, is more appropriate. There is a large body of work on the modelling and hypothesis testing of cause-specific survival, but many of these methods are not directly applicable to relative survival. In this paper, we extend the multiple imputation (MI) methods (Stat. Methods Med. Res. 1999; 8:3-15) to the case of relative survival data. The MI methodology is combined with relative survival to estimate the net survival by changing relative survival data to cause-specific data. This facilitates the direct application to statistical methods developed for the cause-specific survival to the special situation of relative survival. The parameter estimates and the log-rank statistics are obtained by combining the results from multiple imputed cause-specific data. The likelihood-based methods for modelling relative survival data have been implemented by a Windows application called CANSURV (Comput. Meth. Prog. Biomed 2005). Although these methods produce accurate parameter estimates, the choice for models and diagnostic tools is limited. The MI method is presented as a simpler alternative. The relative survival data for the colorectal cancer patients from Surveillance, Epidemiology, and End Results (SEER) program (SEER Cancer Statistics Review, 1973-1999. National Cancer Institute: Bethesda, 2002) is used as an illustration. The results are compared with those obtained from the likelihood-based relative survival analysis methods. A sample SAS macro for the MI method is provided.

Prolonged [beta]-catenin stabilization and tcf-dependent transcriptional activation in hyperplastic cutaneous wounds

Sophia Cheon — 2005-01-18T07:29:09-00:00

Laboratory Investigation, Vol. aop, No. current. (17 January 2005)

Familial Risk of Hepatocellular Carcinoma Among Chronic Hepatitis B Carriers and Their Relatives

Ming-Whei Yu — 2008-04-03T09:52:57-00:00

J. Natl. Cancer Inst., Vol. 92, No. 14. (19 July 2000), pp. 1159-1164.

Background: Familial predisposition as a risk factor for hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers has not been thoroughly explored. Methods: The HCC risk associated with having parents and/or siblings with HCC was evaluated by use of a cohort study of 4808 male HBV carriers. A case-control family study was also conducted on data from first-degree relatives of 553 HBV carriers who had newly diagnosed HCC (case subjects) and 4684 HBV carriers without HCC (control subjects). Results: In the cohort study, HBV carriers with a family history of HCC had a multivariate-adjusted rate ratio for HCC of 2.41 (95% confidence interval [CI] = 1.47-3.95) compared with HBV carriers without a family history of HCC. For carriers with two or more affected relatives, the ratio increased to 5.55 (95% CI = 2.02-15.26). Cumulative HCC risk by age 70 years was 235.6 per 1000 (95% CI = 95.3-375.9 per 1000) for HBV carriers with family history compared with 88.9 per 1000 (95% CI = 67.9-109.9 per 1000) for those without. In the case-control family study, first-degree relatives of case subjects were more likely to have HCC (age-sex-adjusted odds ratio [OR] = 2.57; 95% CI = 2.03-3.25) than first-degree relatives of control subjects. The excess risk of HCC among relatives was particularly evident in siblings (sisters--age-adjusted OR = 4.55 [95% CI = 2.22-9.31]; brothers--age-adjusted OR = 3.73 [95% CI = 2.64-5.27]), but it was also observed in parents. The cumulative risk of HCC to age 80 years was 83.0 per 1000 among relatives of case subjects and 42.0 per 1000 among relatives of control subjects. Among relatives of case subjects, the cumulative risk of HCC was greater if the case subjects were diagnosed before age 50 years (two-sided P = .047). Liver cirrhosis was 2.29 (95% CI = 1.68-3.11) times more frequent in relatives of case subjects than in relatives of control subjects. Conclusions: First-degree relatives of patients with HBV-related HCC appear to be at increased risk of HCC and should be considered in the formulation of HCC-screening programs. 10.1093/jnci/92.14.1159

Investigations of the cytotoxicity of epigallocatechin-3-gallate against PC-3 cells in the presence of Cd(2+)in vitro.

Lan-Cui Zhang — 2008-04-02T03:52:42-00:00

Toxicology in vitro : an international journal published in association with BIBRA (15 February 2008)

The epidemiological studies and recent data have provided convinced evidence that green tea and its major constituent epigallocatechin gallate (EGCG) might have the potential to lower the risk of cancers in humans. Metal ions, such as zinc and cadmium, which are necessary to our health, are important factors inducing many diseases including prostate cancer in the condition of absence or excess. EGCG can satisfactorily exhibit complex chemistry with metal ions because of multiple hydroxyl states, which in turn changes their bioactivities and metabolism pathways. This paper presents the results of an investigation of the cytotoxicity of EGCG against PC-3 prostate cancer cells in the presence and absence of Cd(2+)in vitro. The results showed that both EGCG and Cd(2+) suppressed viability and clonegenecity of PC-3 cells, and the suppression effect was enhanced when EGCG added with Cd(2+). Although Cd(2+) up-regulated the 67kDa laminin receptor (67LR), which is a migration-associated protein, the cell migration ability was not significantly increased after each treatment. We also found that EGCG and Cd(2+) directly interacted with mitochondrial, and the mixture of EGCG and Cd(2+) (EGCG+Cd(2+)) significantly caused loss of the mitochondrial membrane potential, decrease of the ATP content and activation of caspase-9 compared with EGCG treated alone. Taken together, these findings suggest that Cd(2+) enhanced the cytotoxicity of EGCG to PC-3 cells by up-regulating the 67LR and the mitochondria-mediated apoptosis pathway.

Angiotensin-converting enzyme gene 2350 G/A polymorphism is associated with left ventricular hypertrophy but not essential hypertension.

M Pan — 2008-03-31T12:37:14-00:00

Hypertens Res, Vol. 30, No. 1. (January 2007), pp. 31-37.

The angiotensin-converting enzyme (ACE) gene (ACE) is one of the most studied candidate genes related to essential hypertension (EH) and left ventricular hypertrophy (LVH). ACE rs4343 synonymous coding polymorphism (2350 G/A) is known among the polymorphisms of this gene to have the most significant effect on plasma ACE concentrations. The aim of the present study was to investigate the association of this polymorphism with EH and LVH in 440 subjects (246 EH patients and 194 controls) from a Chinese Han population. In this study, 2350 G/A genotypes were identified by polymerase chain reaction and restriction digestion in all study participants, and left ventricular mass was assessed by 2-mode echocardiography in 178 untreated EH patients. There was no significant difference in either genotype distribution (p=0.3659) or allele frequency (p=0.1453) between EH and control groups. In addition, the 2350 G/A polymorphism had no effect on blood pressure in either controls or untreated EH patients. The distribution of genotypes differed significantly when patients with LVH were examined, i.e., 14.71% GG, 54.41% GA, and 30.88% AA patients had this complication, and 36.36% GG, 42.73% GA, and 20.91% AA patients did not (p=0.0070). The LVH patients had a higher A allele frequency (58.09%) than patients without LVH (42.27%) (p=0.0037). Logistic regression analysis revealed that the association between the A allele and LVH was independent of age, blood pressure, and body mass index. The relative risk of LVH in patients bearing the A allele (GA+AA group) compared with that of GG hypertensive patients was 3.31 (95% confidence interval [CI]: 1.43 to 7.68). These findings suggest an association between LVH and the 2350A allele in hypertensive patients.

Methods to impute missing genotypes for population data.

Z Yu — 2008-03-29T11:52:29-00:00

Hum Genet, Vol. 122, No. 5. (December 2007), pp. 495-504.

For large-scale genotyping studies, it is common for most subjects to have some missing genetic markers, even if the missing rate per marker is low. This compromises association analyses, with varying numbers of subjects contributing to analyses when performing single-marker or multi-marker analyses. In this paper, we consider eight methods to infer missing genotypes, including two haplotype reconstruction methods (local expectation maximization-EM, and fastPHASE), two k-nearest neighbor methods (original k-nearest neighbor, KNN, and a weighted k-nearest neighbor, wtKNN), three linear regression methods (backward variable selection, LM.back, least angle regression, LM.lars, and singular value decomposition, LM.svd), and a regression tree, Rtree. We evaluate the accuracy of them using single nucleotide polymorphism (SNP) data from the HapMap project, under a variety of conditions and parameters. We find that fastPHASE has the lowest error rates across different analysis panels and marker densities. LM.lars gives slightly less accurate estimate of missing genotypes than fastPHASE, but has better performance than the other methods.

Efficient Approximation of P-value of the Maximum of Correlated Tests, with Applications to Genome-Wide Association Studies.

Qizhai Li — 2008-03-28T09:44:55-00:00

Ann Hum Genet (3 March 2008)

Genome-wide association study (GWAS), typically involving 100,000 to 500,000 single-nucleotide polymorphisms (SNPs), is a powerful approach to identify disease susceptibility loci. In a GWAS, single-marker analysis, which tests one SNP at a time, is usually used as the first stage to screen SNPs across the genome in order to identify a small fraction of promising SNPs with relatively low p-values for further and more focused studies. For single-marker analysis, the trend test derived for an additive genetic model is often used. This may not be robust when the additive assumption is not appropriate for the true underlying disease model. A robust test, MAX, based on the maximum of three trend test statistics derived for recessive, additive, and dominant models, has been proposed recently for GWAS. But its p-value has to be evaluated through a resampling-based procedure, which is computationally challenging for the analysis of GWAS. Obtaining the p-value for MAX with adjustment for the covariates can be even more time-consuming. In this article, we provide a simple approximation for the p-value of the MAX test with or without adjusting for the covariates. The new method avoids resampling steps and thus makes the MAX test readily applicable to GWAS. We use simulation studies as well as real datasets on 17 confirmed disease-associated SNPs to assess the accuracy of the proposed method. We also apply the method to the GWAS of coronary artery disease.

Identification of pollution source of cadmium in soil: application of material flow analysis and a case study in Taiwan.

LT Lu — 2008-03-25T09:21:38-00:00

Environ Sci Pollut Res Int, Vol. 14, No. 1. (January 2007), pp. 49-59.

BACKGROUND: Since the 1970s, at least 200 hectares (ha) of farm-land has been polluted by the heavy metal cadmium (Cd). Consequently, the Cd pollution has led to contaminate the rice production and caused acute social panic. According to the recent investigation results performed by the Taiwan Environmental Protection Administration (TEPA), it is indicated that most of the Cd pollution incidents in Taiwan resulted from the waste-water discharge of stearate Cd factories. To prevent the Cd pollution incidents from spreading, the TEPA has either forced these factories to close down or assisted them in improving their production processes since the 1980s. Unfortunately, accidental incidents of Cd pollution still emerge in an endless stream, despite the strict governmental controls placed on these questionable factories. Whether this pollution has resulted from undetected or hidden pollution sources stemming from two decades ago or comes from some new source, will be an outstanding issue. Therefore, this study attempts to identify the pollution sources of Cd in soil in Taiwan as well as to find the solution to the above-mentioned, outstanding issue by way of a methodology termed Material Flow Analysis (MFA). METHODOLOGY: The MFA has proved to be a useful tool on providing quantitative information of the flow of substances through an economic to an environmental system. Based upon the supply-and-demand theory of MFA, researchers have successfully conducted an overview of the use of materials in many industries, the construction industry being one of these. Therefore, this study tries to establish a set of analytical processes by way of MFA for identifying the pollution source of Cd in soil in Taiwan. In addition, the spirit of Life Cycle Assessment (LCA) technique was also employed to identify the materials, and products should be ignored as a crucial pollution source in this study. RESULTS AND DISCUSSION: According to the MFA methodology applied in this study and on the basis of related studies performed by Taiwanese governmental authorities, we arrive at the following analysis results: (1) the total amount of Cd from the economic perspective of material and product flow was approximately 441.2 tons; (2) the wastewater directly discharged into irrigation water can be concluded to be the major pollution route of Cd in farmland soil in Taiwan; (3) material plastic stabilizer (cadmium oxide, CdO), Zn-Pd compounds and Cu compounds should be the crucial pollution sources to contaminate environment through the route of wastewater in Cd flow analysis; (4) the crucial pollution sources to contaminate environment through the route of wastewater in Cd flow analysis were five factories, Coin, Jili, Taiwan Dye, Guangzheng and Mingguan, and they were all categorized as stearate Cd industries; (5) the typical source of the Cd pollution in soil in Changhua County through the pollution route of wastewater should be the metal surfacing process industries. CONCLUSIONS: This study proved that MFA can be a good tool for identifying Cd flow as well as for recognizing the crux of the problem concerning incidents of Cd pollution. This study led to the conclusion that the causal relationship between farmland pollution caused by Cd and stearate Cd factories in Taiwan seemed quite close by way of MFA methodology. In addition, this study also found that the wastewater discharged from a single metal surfacing process factory will not cause remarkable farmland pollution. However, the wastewater simultaneously discharged from a group of pollution factories can result in a significant pollution incident. RECOMMENDATIONS AND OUTLOOK: This case study is only a small contribution to the understanding of the toxic material flow related to Cd in the environment. This study recommends that Taiwanese governmental authorities should not deal with problems on an ad hoc basis, but should instead deal with Cd pollution problems overall employing control measures. Finally, the more accurate information or data we can collect, the more reliable results we can identify. Therefore, the quality and quantity of related data used in this MFA model should be closely scrutinized in order to ensure the most correct and comprehensive investigation on the toxic material flow.