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In Print: Nov 3, 2009

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Microarray Papers of Note Published in October 2009

Journal: Bioinformatics. 2009 Oct 14. [Epub ahead of print]

Title: Integrated analysis of copy number alterations and gene expression: a bivariate assessment of equally directed abnormalities.

Authors: M Schäfer, et al.

The authors propose a new procedure for an integrated analysis of two different data types that searches for genes and genetic regions, which, for both inputs, display strong equally directed deviations from the reference median. In this paper, they employed the approach, which is based on a modified correlation coefficient and an explorative Wilcoxon test, to find DNA regions of such abnormalities in gene expression and copy number. In an application to acute myeloid leukemia, the authors found their procedure was able to identify various regions on different chromosomes with characteristic abnormalities in gene expression and copy number data and showed a higher sensitivity to differences in abnormalities than standard approaches. The code and data are available here.


Journal: Biostatistics. 2009 Oct;10(4):773-8.

Title: A continuous-index hidden Markov jump process for modeling DNA copy number data.

Authors: S Stjernqvist, et al.

In this paper, the authors devised a statistical model, based on a latent continuous-index Markov jump process, that is aimed to capture certain features of array comparative genomic hybridization data, including probes that are unevenly long, unevenly spaced, and overlapping. The model has a continuous state space, with one state representing a normal copy number of two, and the rest of the states being either amplifications or deletions. The authors also adopted a Bayesian approach and applied Markov chain Monte Carlo methods for estimating the parameters and the Markov process. The authors stated that the model can be applied to data from both tiling bacterial artificial chromosome arrays and oligonucleotide arrays.


Journal: BMC Bioinformatics. 2009 Oct 8;10 Suppl 11:S9.

Title: Comparing gene annotation enrichment tools for functional modeling of agricultural microarray data.

Authors: B van den Berg, et al.

The authors evaluated and compared four publicly available computational tools — Onto-Express, EasyGO, GOstat, and DAVID — that support the analysis of gene-expression datasets in agricultural species. The authors used AgBase as the functional annotation reference for agricultural species. The selected tools were evaluated based on a) available features, usage, and accessibility; b) implemented statistical computational methods; and c) annotation and enrichment performance analysis. Annotation was assessed using a randomly selected test gene annotation set and an experimental differentially expressed gene-set — both from chicken. The experimental set was also used to evaluate identification of enriched functional groups. Comparison of the tools showed that they produced different sets of annotations for the two datasets and different functional groups for the experimental dataset. The authors determined that tools for functionally annotating gene sets and identifying significantly enriched categories differ in their results when applied to a test annotation gene set and an experimental dataset from chicken. The authors emphasized the "need for care when interpreting the results of such analysis and the lack of standardization of approaches."


Journal: BMC Medical Genomics. 2009 Oct 30;2(1):64. [Epub ahead of print]

Title: Accurate molecular classification of cancer using simple rules.

Author: X Wang, et al.

The authors screened a small number of informative single genes and gene pairs on the basis of their depended degrees proposed in rough sets. Applying the decision rules induced by the selected genes or gene pairs, they constructed cancer classifiers. The authors tested the efficacy of the classifiers by leave-one-out cross-validation of training sets and classification of independent test sets. They applied their methods to five cancerous gene expression datasets: acute lymphoblastic leukemia, lung cancer, prostate cancer, breast cancer, and acute myelogenous leukemia. According to the authors, accurate classification outcomes were obtained by using just one or two genes. Some genes that correlated closely with the pathogenesis of relevant cancers were also identified.

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Journal: Clinical Cancer Research. 2009 Oct 1;15(19):6070-8.

Title: High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth.

Authors: K Iljin, et al.

The authors carried out a high-throughput cell-based screening with proliferation as a primary end point using a library of 4,910 drug-like small molecule compounds in four prostate cancer lines (VCaP, LNCaP, DU 145, and PC-3), and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). EC50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. The authors identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. They then validated DSF as a potential prostate cancer therapeutic agent.


Journal: Clinical Cancer Research. 2009 Oct 27. [Epub ahead of print]

Title: A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.

Authors: D Friedman, et al.

The authors used gene-expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflected progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. The authors validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients. A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could distinguish responding and nonresponding CLL patients.


Journal: European Journal of Human Genetics. 2009 Oct 7. [Epub ahead of print]

Title: High-resolution SNP arrays in mental retardation diagnostics: How much do we gain?

Authors: L Bernardini, et al.

The authors used Affymetrix 6.0 GeneChip SNP arrays to characterize copy number variations in a cohort of 70 patients previously characterized on lower-density oligonucleotide arrays affected by idiopathic mental retardation and dysmorphic features. The SNP array platform includes approximately 900,000 SNP probes and 900,000 non-SNP oligonucleotide probes at an average distance of 0.7 kilobases, which the authors said facilitates coverage of the whole genome, including coding and noncoding regions. At the same time, they noted that the high density of probes is critical for detecting small CNVs, but can lead to data interpretation problems. To reduce the number of false positives, the authors set their parameters to consider only imbalances greater than 75 kb encompassing at least 80 probe sets. They found that the higher resolution of the SNP array platform confirmed the increased ability to detect small CNVs, although more than 80 percent of the CNVs overlapped to copy number neutral polymorphism regions and 4.4 percent of them did not contain known genes. In their cohort of 70 patients, of the 51 previously evaluated as "normal" on the Agilent 44K array, the SNP array platform disclosed six additional CNV changes, including three in three patients that may be pathogenic, the authors found. They suggested that about 6 percent of individuals classified as "normal" using a lower-density oligonucleotide array could be found to be affected by a genomic disorder when evaluated with a higher-density microarray platform.


Journal: Journal of Plant Physiology. 2009 Oct 26. [Epub ahead of print]

Title: Use of a custom array to study differentially expressed genes during blood orange (Citrus sinensis L. Osbeck) ripening.

Authors: J Bernardi, et al.

The authors designed a flesh-specific oligonucleotide custom array to study gene expression during blood orange ripening. The array included 301 probes derived from a subtracted SSH library, a cDNA-AFLP collection, and a set of regulatory genes from the Harvest citrus database. The custom array was hybridized using samples of Moro, a pigmented cultivar, and Cadenera, a common cultivar, at three different ripening stages: the immature phase, the halfway point of maturation, and the full ripening. Of the 301 probes, 27 in total, corresponding to 20 different transcripts, indicated differential expression in stage-to-stage and cultivar-to-cultivar comparisons. Transcripts encoding for anthocyanin biosynthesis represented most of the total over-expressed probes. The remaining differentially expressed transcripts were functionally associated with primary metabolism as flavor biosynthesis, defense, and signal transduction, the authors found. The expressed products associated with probes indicating differential expression were confirmed by qRT-PCR.

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Journal: Langmuir. 2009 Oct 19. [Epub ahead of print]

Title: Tandem surface microfluidic lithography and activation to generate patch pattern biospecific ligand and cell arrays.

Authors: A Pulsipher, et al.

The authors describe a methodology that combines microfluidic lithography and oxidative activation to pattern and chemically alter selective regions of self-assembled monolayers on gold for subsequent chemoselective ligand immobilization. We demonstrate that PCC, a mild oxidant, can be used to convert hydroxyl-terminated SAMs to aldehydes decorated with a variety of oxyamine-containing molecules. The authors used this method to create a biospecific ligand platform for peptide-mediated, cell adhesion arrays. By using a number of different ligands and characterization tools, they showed that the generation of both cell patterning and ligand microarray patterning can be achieved.


Journal: Malaria Journal. 2009 Oct 15;8:229.

Title: FlexiChip package: A universal microarray with a dedicated analysis software for high-throughput SNPs detection linked to anti-malarial drug resistance.

Authors: N Steenkeste, et al.

The authors took previously published microarray probes detecting SNPs associated with parasite resistance to anti-malarial drugs and adapted them for use in a universal microarray FlexiChip format. To evaluate the overall sensitivity of the FlexiChip microarray and software, the results of FlexiChip were compared to the older microarray, using the same extension probes and with the same PCR products. They determined that FlexiChip could be employed to monitor P. falciparum drug resistance markers with greater cost effectiveness and the possibility for high-throughput analysis.


Journal: Molecular and Cellular Probes. 2009 Oct 7. [Epub ahead of print]

Title: DNA microarray-based identification of bacterial and fungal pathogens in bloodstream infections.

Authors: S Yoo, et al.

The authors detail the development of a microarray for the identification of pathogens causing bloodstream infections. Specifically, species-specific and bacteria- and fungi-broad-ranged probes were designed to identify 50 bacteria and seven fungi. The specificities and sensitivities of the selected probes were validated by applying reference strains. To assess the performance of the array in a clinical setting, blind tests were performed using 112 blood culture specimens that showed preliminary presence of pathogenic microorganisms by a culture-based method, resulting in the correct identification of pathogens in 104 samples showing a sensitivity level of 93 percent.


Journal: Molecular and Cellular Probes. 2009 Oct 13. [Epub ahead of print]

Title: Development of an oligonucleotide-based microarray to detect multiple foodborne pathogens.

Authors: B Suo, et al.

In this study, a pathogen-detection microarray was developed using various 70-mer oligonucleotides specifically targeting Escherichia coli O157:H7, Salmonella enterica, Listeria monocytogenes, and Campylobacter jejuni. To reduce the cost of detection, each chip was designed and fabricated to accommodate 12 identical arrays that could be used for screening up to 12 different samples. To achieve high detection, sensitivity, and specificity, target-specific DNA amplification instead of whole-genome random amplification was used prior to microarray analysis. The authors found that the microarray combined with multiplex PCR method was able to effectively screen single or multiple pathogens in food samples and to provide important genotypic information related to pathogen virulence.


Journal: Nature. 2009 Oct 8;461(7265):802-8.

Title: A genome-wide linkage and association scan reveals novel loci for autism.

Authors: L Weiss, et al.

The authors of this paper initiated a linkage and association mapping study using half a million genome-wide SNPs in a common set of 1,031 multiplex autism families with 1,553 affected offspring. They identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations. However, genotyping of top hits in additional families revealed a SNP on chromosome 5p15 that was significantly associated with autism. The authors also demonstrated that expression of the gene, SEMA5A, is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene.

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Journal: Nature. 2009 Oct 7. [Epub ahead of print]

Title: Origins and functional impact of copy number variation in the human genome.

Authors: D Conrad, et al.

The authors used tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations greater than 443 base pairs, of which 8,599 have been validated independently. For 4,978 of these CNVs, the authors generated reference genotypes from 450 individuals of European, African, or East Asian ancestry. By correlation with known trait-associated SNPs, the authors identified 30 loci with CNVs that are candidates for influencing disease susceptibility. They also determined that for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.


Journal: Nature Genetics. 2009 Oct 18. [Epub ahead of print]

Title: Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus

Authors: JW Han, et al.

The authors of this paper performed a genome-wide association study of systemic lupus erythematosus in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts of 3,152 cases and 7,050 controls. They identified nine new susceptibility loci and confirmed seven previously reported loci. The authors also compared their findings with previous GWAS results, and noted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations.


Journal: PLoS Genetics. 2009 Oct;5(10):e1000676.

Title: Oncogenic pathway combinations predict clinical prognosis in gastric cancer.

Authors: C Ooi, et al.

The authors of this paper sought to identify major oncogenic pathways in gastric cancer with significant relationships to patient survival. Using gene-expression signatures, they devised an in silico strategy to map patterns of oncogenic pathway activation in 301 primary gastric cancers. The authors identified three oncogenic pathways deregulated in more than 70 percent of gastric cancers. They also functionally validated the pathway predictions in a panel of gastric cancer cell lines. The authors determined that patient stratification by oncogenic pathway combinations showed reproducible and significant survival differences in multiple cohorts, suggesting that pathway interactions may play an important role in influencing disease behavior.


Journal: PLoS One. 2009 Oct 23;4(10):e7431.

Title: Can survival prediction be improved by merging gene expression data sets?

Authors: H Yasrebi, et al.

The authors attempted to determine the merits of integrating breast cancer data sets from different studies. They used survival prediction based on Cox regression as an assay to measure the added value of merged data sets. They found that merging did not deteriorate performance on average despite: a) the diversity of microarray platforms used; b) the heterogeneity of patient cohorts; c) The heterogeneity of breast cancer disease; d) substantial variation of time to death or relapse; and e) the reduced number of genes in the merged data sets. Instead, predictors derived from the merged data sets were "more robust, consistent and reproducible across microarray platforms."


Journal: PLoS One. 2009 Oct 28;4(10):e7088.

Title: Human cell chips: adapting DNA microarray spotting technology to cell-based imaging assays.

Authors: T Hart, et al.

The authors describe human-spotted cell chips, a technology for determining cellular state across arrays of cells subjected to chemical or genetic perturbation. According to the paper, cells are grown and treated under standard tissue culture conditions before being fixed and printed onto replicate glass slides, decoupling the experimental conditions from the assay technique. Each slide is then probed using immunofluorescence or other optical reporter and assayed by automated microscopy.


Journal: Stroke. 2009 Oct;40(10):3173-9.

Title: Multi-ethnic genetic association study of carotid intima-media thickness using a targeted cardiovascular SNP microarray.

Authors: M Lanktree, et al.

The authors sought to test the association between subclinical atherosclerosis measured by intima-media thickness and approximately 50,000 SNPs by densely mapping approximately 2,100 genes found on the gene-centric Illumina cardiovascular-disease BeadChip in a multi-ethnic population-based sample. According to the authors, IMT was measured by B-mode ultrasound and DNA was collected from a population-based sample of South Asian, Chinese, and European Caucasian participants. Genetic association was measured using multivariate linear regression including adjustment for covariates. The authors identified some novel loci that they believe require further evaluation in follow-up studies.

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