Dataset Information

Network and data integration for biomarker signature discovery via network smoothed T-statistics.

ABSTRACT: Predictive, stable and interpretable gene signatures are generally seen as an important step towards a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinics is the typical low reproducibility of signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approaches that try to integrate information from molecular interaction networks. We here propose a technique that integrates network information as well as different kinds of experimental data (here exemplified by mRNA and miRNA expression) into one classifier. This is done by smoothing t-statistics of individual genes or miRNAs over the structure of a combined protein-protein interaction (PPI) and miRNA-target gene network. A permutation test is conducted to select features in a highly consistent manner, and subsequently a Support Vector Machine (SVM) classifier is trained. Compared to several other competing methods our algorithm reveals an overall better prediction performance for early versus late disease relapse and a higher signature stability. Moreover, obtained gene lists can be clearly associated to biological knowledge, such as known disease genes and KEGG pathways. We demonstrate that our data integration strategy can improve classification performance compared to using a single data source only. Our method, called stSVM, is available in R-package netClass on CRAN (http://cran.r-project.org).

SUBMITTER: Cun Y

PROVIDER: S-EPMC3760887 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

Network and data integration for biomarker signature discovery via network smoothed T-statistics.

Cun Yupeng Y Fröhlich Holger H

PloS one 20130903 9

Predictive, stable and interpretable gene signatures are generally seen as an important step towards a better personalized medicine. During the last decade various methods have been proposed for that purpose. However, one important obstacle for making gene signatures a standard tool in clinics is the typical low reproducibility of signatures combined with the difficulty to achieve a clear biological interpretation. For that purpose in the last years there has been a growing interest in approache ...[more]

PMID: 24019896

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Project description:Biomarker detection presents itself as a major means of translating biological data into clinical applications. Due to the recent advances in high throughput sequencing technologies, an increased number of metagenomics studies have suggested the dysbiosis in microbial communities as potential biomarker for certain diseases. The reproducibility of the results drawn from metagenomic data is crucial for clinical applications and to prevent incorrect biological conclusions. The variability in the sample size and the subjects participating in the experiments induce diversity, which may drastically change the outcome of biomarker detection algorithms. Therefore, a robust biomarker detection algorithm that ensures the consistency of the results irrespective of the natural diversity present in the samples is needed.Toward this end, this paper proposes a novel Regularized Low Rank-Sparse Decomposition (RegLRSD) algorithm. RegLRSD models the bacterial abundance data as a superposition between a sparse matrix and a low-rank matrix, which account for the differentially and non-differentially abundant microbes, respectively. Hence, the biomarker detection problem is cast as a matrix decomposition problem. In order to yield more consistent and solid biological conclusions, RegLRSD incorporates the prior knowledge that the irrelevant microbes do not exhibit significant variation between samples belonging to different phenotypes. Moreover, an efficient algorithm to extract the sparse matrix is proposed. Comprehensive comparisons of RegLRSD with the state-of-the-art algorithms on three realistic datasets are presented. The obtained results demonstrate that RegLRSD consistently outperforms the other algorithms in terms of reproducibility performance and provides a marker list with high classification accuracy.The proposed RegLRSD algorithm for biomarker detection provides high reproducibility and classification accuracy performance regardless of the dataset complexity and the number of selected biomarkers. This renders RegLRSD as a reliable and powerful tool for identifying potential metagenomic biomarkers.

Project description:BackgroundThe human immune system is responsible for protecting the host from infection. However, in immunocompromised individuals the risk of infection increases substantially with possible drastic consequences. In extreme, systemic infection can lead to sepsis which is responsible for innumerous deaths worldwide. Amongst its causes are infections by bacteria and fungi. To increase survival, it is mandatory to identify the type of infection rapidly. Discriminating between fungal and bacterial pathogens is key to determine if antifungals or antibiotics should be administered, respectively. For this, in situ experiments have been performed to determine regulation mechanisms of the human immune system to identify biomarkers. However, these studies led to heterogeneous results either due different laboratory settings, pathogen strains, cell types and tissues, as well as the time of sample extraction, to name a few.MethodsTo generate a gene signature capable of discriminating between fungal and bacterial infected samples, we employed Mixed Integer Linear Programming (MILP) based classifiers on several datasets comprised of the above mentioned pathogens.ResultsWhen combining the classifiers by a joint optimization we could increase the consistency of the biomarker gene list independently of the experimental setup. An increase in pairwise overlap (the number of genes that overlap in each cross-validation) of 43% was obtained by this approach when compared to that of single classifiers. The refined gene list was composed of 19 genes and ranked according to consistency in expression (up- or down-regulated) and most of them were linked either directly or indirectly to the ERK-MAPK signalling pathway, which has been shown to play a key role in the immune response to infection. Testing of the identified 12 genes on an unseen dataset yielded an average accuracy of 83%.ConclusionsIn conclusion, our method allowed the combination of independent classifiers and increased consistency and reliability of the generated gene signatures.

Dataset Information

Network and data integration for biomarker signature discovery via network smoothed T-statistics.

Publications

Network and data integration for biomarker signature discovery via network smoothed T-statistics.

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