Dataset Information

A novel method incorporating gene ontology information for unsupervised clustering and feature selection.

ABSTRACT:

Background

Among the primary goals of microarray analysis is the identification of genes that could distinguish between different phenotypes (feature selection). Previous studies indicate that incorporating prior information of the genes' function could help identify physiologically relevant features. However, current methods that incorporate prior functional information do not provide a relative estimate of the effect of different genes on the biological processes of interest.

Results

Here, we present a method that integrates gene ontology (GO) information and expression data using Bayesian regression mixture models to perform unsupervised clustering of the samples and identify physiologically relevant discriminating features. As a model application, the method was applied to identify the genes that play a role in the cytotoxic responses of human hepatoblastoma cell line (HepG2) to saturated fatty acid (SFA) and tumor necrosis factor (TNF)-alpha, as compared to the non-toxic response to the unsaturated FFAs (UFA) and TNF-alpha. Incorporation of prior knowledge led to a better discrimination of the toxic phenotypes from the others. The model identified roles of lysosomal ATPases and adenylate cyclase (AC9) in the toxicity of palmitate. To validate the role of AC in palmitate-treated cells, we measured the intracellular levels of cyclic AMP (cAMP). The cAMP levels were found to be significantly reduced by palmitate treatment and not by the other FFAs, in accordance with the model selection of AC9.

Conclusions

A framework is presented that incorporates prior ontology information, which helped to (a) perform unsupervised clustering of the phenotypes, and (b) identify the genes relevant to each cluster of phenotypes. We demonstrate the proposed framework by applying it to identify physiologically-relevant feature genes that conferred differential toxicity to saturated vs. unsaturated FFAs. The framework can be applied to other problems to efficiently integrate ontology information and expression data in order to identify feature genes.

SUBMITTER: Srivastava S

PROVIDER: S-EPMC2585795 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Publications

A novel method incorporating gene ontology information for unsupervised clustering and feature selection.

Srivastava Shireesh S Zhang Linxia L Jin Rong R Chan Christina C

PloS one 20081204 12

<h4>Background</h4>Among the primary goals of microarray analysis is the identification of genes that could distinguish between different phenotypes (feature selection). Previous studies indicate that incorporating prior information of the genes' function could help identify physiologically relevant features. However, current methods that incorporate prior functional information do not provide a relative estimate of the effect of different genes on the biological processes of interest.<h4>Result ...[more]

PMID: 19052637

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Project description:Biological data are accumulating at a faster rate, but interpreting them still remains a problem. Classifying biological data into distinct groups is the first step in understanding them. Data classification in response to a certain treatment is an extremely important aspect for differentially expressed genes in making present/absent calls. Many feature selection algorithms have been developed including the support vector machine recursive feature elimination procedure (SVM-RFE) and its variants. Support vector machine RFEs are greedy methods that attempt to find superlative possible combinations leading to binary classification, which may not be biologically significant. To overcome this limitation of SVM-RFE, we propose a novel feature selection algorithm, termed as "sigFeature" (https://bioconductor.org/packages/sigFeature/), based on SVM and t statistic to discover the differentially significant features along with good performance in classification. The "sigFeature" R package is centered around a function called "sigFeature," which provides automatic selection of features for the binary classification. Using six publicly available microarray data sets (downloaded from Gene Expression Omnibus) with different biological attributes, we further compared the performance of "sigFeature" to three other feature selection algorithms. A small number of selected features (by "sigFeature") also show higher classification accuracy. For further downstream evaluation of its biological signature, we conducted gene set enrichment analysis with the selected features (genes) from "sigFeature" and compared it with the outputs of other algorithms. We observed that "sigFeature" is able to predict the signature of four out of six microarray data sets accurately, whereas the other algorithms predict less data set signatures. Thus, "sigFeature" is considerably better than related algorithms in discovering differentially significant features from microarray data sets.

Project description:MotivationDespite advances in the gene annotation process, the functions of a large portion of gene products remain insufficiently characterized. In addition, the in silico prediction of novel Gene Ontology (GO) annotations for partially characterized gene functions or processes is highly dependent on reverse genetic or functional genomic approaches. To our knowledge, no prediction method has been demonstrated to be highly accurate for sparsely annotated GO terms (those associated to fewer than 10 genes).ResultsWe propose a novel approach, information theory-based semantic similarity (ITSS), to automatically predict molecular functions of genes based on existing GO annotations. Using a 10-fold cross-validation, we demonstrate that the ITSS algorithm obtains prediction accuracies (precision 97%, recall 77%) comparable to other machine learning algorithms when compared in similar conditions over densely annotated portions of the GO datasets. This method is able to generate highly accurate predictions in sparsely annotated portions of GO, where previous algorithms have failed. As a result, our technique generates an order of magnitude more functional predictions than previous methods. A 10-fold cross validation demonstrated a precision of 90% at a recall of 36% for the algorithm over sparsely annotated networks of the recent GO annotations (about 1400 GO terms and 11,000 genes in Homo sapiens). To our knowledge, this article presents the first historical rollback validation for the predicted GO annotations, which may represent more realistic conditions than more widely used cross-validation approaches. By manually assessing a random sample of 100 predictions conducted in a historical rollback evaluation, we estimate that a minimum precision of 51% (95% confidence interval: 43-58%) can be achieved for the human GO Annotation file dated 2003.AvailabilityThe program is available on request. The 97,732 positive predictions of novel gene annotations from the 2005 GO Annotation dataset and other supplementary information is available at http://phenos.bsd.uchicago.edu/ITSS/.Supplementary informationSupplementary data are available at Bioinformatics online.

Dataset Information

A novel method incorporating gene ontology information for unsupervised clustering and feature selection.

Background

Results

Conclusions

Publications

A novel method incorporating gene ontology information for unsupervised clustering and feature selection.

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