Highlights d Time-resolved single-cell RNA-seq of EWSR1-FLI1 induction in an Ewing sarcoma cell line d Highly specific transcriptomic signature of EWSR1-FLI1 chimeric oncogene d Sources of transcriptomic heterogeneity in Ewing tumors d Correlations between EWSR1-FLI1 activity and metabolic and other phenotypic states
Independent component analysis (ICA) is a matrix factorization approach where the signals captured by each individual matrix factors are optimized to become as mutually independent as possible. Initially suggested for solving source blind separation problems in various fields, ICA was shown to be successful in analyzing functional magnetic resonance imaging (fMRI) and other types of biomedical data. In the last twenty years, ICA became a part of the standard machine learning toolbox, together with other matrix factorization methods such as principal component analysis (PCA) and non-negative matrix factorization (NMF). Here, we review a number of recent works where ICA was shown to be a useful tool for unraveling the complexity of cancer biology from the analysis of different types of omics data, mainly collected for tumoral samples. Such works highlight the use of ICA in dimensionality reduction, deconvolution, data pre-processing, meta-analysis, and others applied to different data types (transcriptome, methylome, proteome, single-cell data). We particularly focus on the technical aspects of ICA application in omics studies such as using different protocols, determining the optimal number of components, assessing and improving reproducibility of the ICA results, and comparison with other popular matrix factorization techniques. We discuss the emerging ICA applications to the integrative analysis of multi-level omics datasets and introduce a conceptual view on ICA as a tool for defining functional subsystems of a complex biological system and their interactions under various conditions. Our review is accompanied by a Jupyter notebook which illustrates the discussed concepts and provides a practical tool for applying ICA to the analysis of cancer omics datasets.
BackgroundIndependent Component Analysis (ICA) is a method that models gene expression data as an action of a set of statistically independent hidden factors. The output of ICA depends on a fundamental parameter: the number of components (factors) to compute. The optimal choice of this parameter, related to determining the effective data dimension, remains an open question in the application of blind source separation techniques to transcriptomic data.ResultsHere we address the question of optimizing the number of statistically independent components in the analysis of transcriptomic data for reproducibility of the components in multiple runs of ICA (within the same or within varying effective dimensions) and in multiple independent datasets. To this end, we introduce ranking of independent components based on their stability in multiple ICA computation runs and define a distinguished number of components (Most Stable Transcriptome Dimension, MSTD) corresponding to the point of the qualitative change of the stability profile. Based on a large body of data, we demonstrate that a sufficient number of dimensions is required for biological interpretability of the ICA decomposition and that the most stable components with ranks below MSTD have more chances to be reproduced in independent studies compared to the less stable ones. At the same time, we show that a transcriptomics dataset can be reduced to a relatively high number of dimensions without losing the interpretability of ICA, even though higher dimensions give rise to components driven by small gene sets.ConclusionsWe suggest a protocol of ICA application to transcriptomics data with a possibility of prioritizing components with respect to their reproducibility that strengthens the biological interpretation. Computing too few components (much less than MSTD) is not optimal for interpretability of the results. The components ranked within MSTD range have more chances to be reproduced in independent studies.Electronic supplementary materialThe online version of this article (10.1186/s12864-017-4112-9) contains supplementary material, which is available to authorized users.
MotivationMatrix factorization (MF) methods are widely used in order to reduce dimensionality of transcriptomic datasets to the action of few hidden factors (metagenes). MF algorithms have never been compared based on the between-datasets reproducibility of their outputs in similar independent datasets. Lack of this knowledge might have a crucial impact when generalizing the predictions made in a study to others.ResultsWe systematically test widely used MF methods on several transcriptomic datasets collected from the same cancer type (14 colorectal, 8 breast and 4 ovarian cancer transcriptomic datasets). Inspired by concepts of evolutionary bioinformatics, we design a novel framework based on Reciprocally Best Hit (RBH) graphs in order to benchmark the MF methods for their ability to produce generalizable components. We show that a particular protocol of application of independent component analysis (ICA), accompanied by a stabilization procedure, leads to a significant increase in the between-datasets reproducibility. Moreover, we show that the signals detected through this method are systematically more interpretable than those of other standard methods. We developed a user-friendly tool for performing the Stabilized ICA-based RBH meta-analysis. We apply this methodology to the study of colorectal cancer (CRC) for which 14 independent transcriptomic datasets can be collected. The resulting RBH graph maps the landscape of interconnected factors associated to biological processes or to technological artifacts. These factors can be used as clinical biomarkers or robust and tumor-type specific transcriptomic signatures of tumoral cells or tumoral microenvironment. Their intensities in different samples shed light on the mechanistic basis of CRC molecular subtyping.Availability and implementationThe RBH construction tool is available from http://goo.gl/DzpwYpSupplementary information Supplementary data are available at Bioinformatics online.
Two blind source separation methods (Independent Component Analysis and Non-negative Matrix Factorization), developed initially for signal processing in engineering, found recently a number of applications in analysis of large-scale data in molecular biology. In this short review, we present the common idea behind these methods, describe ways of implementing and applying them and point out to the advantages compared to more traditional statistical approaches. We focus more specifically on the analysis of gene expression in cancer. The review is finalized by listing available software implementations for the methods described.
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