Biomedical subjects

Natalie J Blades

Publications and source records attributed to Natalie J Blades.

3 recordsLinked to original sources

PubMed2005

Improved statistical tests for differential gene expression by shrinking variance components estimates.

Combining information across genes in the statistical analysis of microarray data is desirable because of the relatively small number of data points obtained for each individual gene. Here we develop an estimator of the error variance that can borrow information across genes using the James-Stein shrinkage concept. A new test statistic (FS) is constructed using this estimator. The new statistic is compared with other statistics used to test for differential expression: the gene-specific F test (F1), the pooled-variance F statistic (F3), a hybrid statistic (F2) that uses the average of the individual and pooled variances, the regularized t-statistic, the posterior odds statistic B, and the SAM t-test. The FS-test shows best or nearly best power for detecting differentially expressed genes over a wide range of simulated data in which the variance components associated with individual genes are either homogeneous or heterogeneous. Thus FS provides a powerful and robust approach to test differential expression of genes that utilizes information not available in individual gene testing approaches and does not suffer from biases of the pooled variance approach.

Animals↗

PubMed2003

A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: application to Mycobacterium tuberculosis.

We describe a postgenomic in silico approach for identifying genes that are likely to be essential and estimate their proportion in haploid genomes. With the knowledge of all sites eligible for mutagenesis and an experimentally determined partial list of nonessential genes from genome mutagenesis, a Bayesian statistical method provides reasonable predictions of essential genes with a subsaturation level of random mutagenesis. For mutagenesis, a transposon such as Himar1 is suitable as it inserts randomly into TA sites. All of the possible insertion sites may be determined a priori from the genome sequence and with this information, data on experimentally hit TA sites may be used to predict the proportion of genes that cannot be mutated. As a model, we used the Mycobacterium tuberculosis genome. Using the Himar1 transposon, we created a genetically defined collection of 1,425 insertion mutants. Based on our Bayesian statistical analysis using Markov chain Monte Carlo and the observed frequencies of transposon insertions in all of the genes, we estimated that the M. tuberculosis genome contains 35% (95% confidence interval, 28%-41%) essential genes. This analysis further revealed seven functional groups with high probabilities of being enriched in essential genes. The PE-PGRS (Pro-Glu polymorphic GC-rich repetitive sequence) family of genes, which are unique to mycobacteria, the polyketide/nonribosomal peptide synthase family, and mycolic and fatty acid biosynthesis gene families were disproportionately enriched in essential genes. At subsaturation levels of mutagenesis with a random transposon such as Himar1, this approach permits a statistical prediction of both the proportion and identities of essential genes of sequenced genomes.

Anti-Bacterial Agents↗

PubMed2002

Relationships and differentially expressed genes among pancreatic cancers examined by large-scale serial analysis of gene expression.

Pancreatic adenocarcinoma is among the most fatal of cancers, in part because of late diagnosis and a lack of effective therapies. Comprehensive studies are needed to better understand and address the cellular mechanisms and pathways of tumorigenesis. Serial analysis of gene expression was used to analyze gene expression profiles of pancreatic cancer cell lines, short-term cultures of normal pancreatic ductal epithelium, and primary pancreatic cancer tissue. A total of 294,920 tags representing 77,746 genes in 10 serial analysis of gene expression libraries were analyzed. A pancreatic cancer cell line (Hs766T) that exhibited a "normoid" profile of gene expression was identified. Several genes that may be involved in the fundamental nature of malignant changes in pancreatic ductal epithelium were suggested from those differentially and highly expressed in pancreatic cancer cells as compared with normal epithelium. Some overexpressed genes, such as S100A4, prostate stem cell antigen, carcinoembryonic antigen-related cell adhesion molecule 6, and mesothelin, suggest potential use as diagnostic markers. Others suggest potential novel therapeutic targets.

Carcinoma, Pancreatic Ductal↗