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      Independent Component Analysis for Unraveling the Complexity of Cancer Omics Datasets

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          Abstract

          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.

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          Most cited references63

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          A general and flexible method for signal extraction from single-cell RNA-seq data

          Single-cell RNA-sequencing (scRNA-seq) is a powerful high-throughput technique that enables researchers to measure genome-wide transcription levels at the resolution of single cells. Because of the low amount of RNA present in a single cell, some genes may fail to be detected even though they are expressed; these genes are usually referred to as dropouts. Here, we present a general and flexible zero-inflated negative binomial model (ZINB-WaVE), which leads to low-dimensional representations of the data that account for zero inflation (dropouts), over-dispersion, and the count nature of the data. We demonstrate, with simulated and real data, that the model and its associated estimation procedure are able to give a more stable and accurate low-dimensional representation of the data than principal component analysis (PCA) and zero-inflated factor analysis (ZIFA), without the need for a preliminary normalization step.
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            A module map showing conditional activity of expression modules in cancer.

            DNA microarrays are widely used to study changes in gene expression in tumors, but such studies are typically system-specific and do not address the commonalities and variations between different types of tumor. Here we present an integrated analysis of 1,975 published microarrays spanning 22 tumor types. We describe expression profiles in different tumors in terms of the behavior of modules, sets of genes that act in concert to carry out a specific function. Using a simple unified analysis, we extract modules and characterize gene-expression profiles in tumors as a combination of activated and deactivated modules. Activation of some modules is specific to particular types of tumor; for example, a growth-inhibitory module is specifically repressed in acute lymphoblastic leukemias and may underlie the deregulated proliferation in these cancers. Other modules are shared across a diverse set of clinical conditions, suggestive of common tumor progression mechanisms. For example, the bone osteoblastic module spans a variety of tumor types and includes both secreted growth factors and their receptors. Our findings suggest that there is a single mechanism for both primary tumor proliferation and metastasis to bone. Our analysis presents multiple research directions for diagnostic, prognostic and therapeutic studies.
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              Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

              The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                07 September 2019
                September 2019
                : 20
                : 18
                : 4414
                Affiliations
                [1 ]Institut Curie, PSL Research University, 75005 Paris, France (N.S.) (U.C.) (E.B.) (F.R.)
                [2 ]INSERM U900, 75248 Paris, France
                [3 ]CBIO-Centre for Computational Biology, Mines ParisTech, PSL Research University, 75006 Paris, France
                [4 ]Centre de Recherches Interdisciplinaires, Université Paris Descartes, 75004 Paris, France
                [5 ]Multiomics Data Science Research Group, Quantitative Biology Unit, Luxembourg Institute of Health (LIH), L-1445 Strassen, Luxembourg
                [6 ]Computational Systems Biology Team, Institut de Biologie de l’Ecole Normale Supérieure, CNRS UMR8197, INSERM U1024, Ecole Normale Supérieure, PSL Research University, 75005 Paris, France
                [7 ]Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI, USR 3756 Institut Pasteur et CNRS), 75015 Paris, France
                [8 ]Laboratory of Bioinformatics and Systems Biology, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, 010000 Nur-Sultan, Kazakhstan (A.M.) (Z.Z.) (U.K.)
                [9 ]University Medical Center, Nazarbayev University, 010000 Nur-Sultan, Kazakhstan
                [10 ]CNRS, UMR 144, 75248 Paris, France
                [11 ]Center for Mathematical Modeling, University of Leicester, Leicester LE1 7RH, UK
                [12 ]Lobachevsky University, 603022 Nizhny Novgorod, Russia
                Author notes
                Author information
                https://orcid.org/0000-0001-8759-2077
                https://orcid.org/0000-0002-5244-0708
                https://orcid.org/0000-0003-2724-2002
                https://orcid.org/0000-0001-8511-8064
                Article
                ijms-20-04414
                10.3390/ijms20184414
                6771121
                31500324
                f6ea7c22-ceb3-4a98-96bb-aa1f30a99e33
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 August 2019
                : 04 September 2019
                Categories
                Review

                Molecular biology
                independent component analysis,cancer,omics data,dimension reduction,data analysis,data integration

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