Aristidis G. Vrahatis

DEsubs: an R package for flexible identification of differentially expressed subpathways using RNA-seq experiments

DEsubs is a network-based systems biology R package that extracts disease-perturbed subpathways within a pathway network as recorded by RNA-seq experiments. It contains an extensive and customized framework with a broad range of operation modes at all stages of the subpathway analysis, enabling so a case-specific approach. The operation modes include pathway network construction and processing, subpathway extraction, visualization and enrichment analysis with regard to various biological and pharmacological features. Its capabilities render DEsubs a tool-guide for both the modeler and experimentalist for the identification of more robust systems-level drug targets and biomarkers for complex diseases. AVAILABILITY AND IMPLEMENTATION DEsubs is implemented as an R package following Bioconductor guidelines: http://bioconductor.org/packages/DEsubs/ CONTACT: tassos.bezerianos@nus.edu.sgSupplementary information: Supplementary data are available at Bioinformatics online.

Integromics network meta-analysis on cardiac aging offers robust multi-layer modular signatures and reveals micronome synergism

BackgroundThe avalanche of integromics and panomics approaches shifted the deciphering of aging mechanisms from single molecular entities to communities of them. In this orientation, we explore the cardiac aging mechanisms – risk factor for multiple cardiovascular diseases - by capturing the micronome synergism and detecting longevity signatures in the form of communities (modules).For this, we developed a meta-analysis scheme that integrates transcriptome expression data from multiple cardiac-specific independent studies in mouse and human along with proteome and micronome interaction data in the form of multiple independent weighted networks. Modularization of each weighted network produced modules, which in turn were further analyzed so as to define consensus modules across datasets that change substantially during lifespan. Also, we established a metric that determines - from the modular perspective - the synergism of microRNA-microRNA interactions as defined by significantly functionally associated targets.ResultsThe meta-analysis provided 40 consensus integromics modules across mouse datasets and revealed microRNA relations with substantial collective action during aging. Three modules were reproducible, based on homology, when mapped against human-derived modules. The respective homologs mainly represent NADH dehydrogenases, ATP synthases, cytochrome oxidases, Ras GTPases and ribosomal proteins. Among various observations, we corroborate to the involvement of miR-34a (included in consensus modules) as proposed recently; yet we report that has no synergistic effect. Moving forward, we determined its age-related neighborhood in which HCN3, a known heart pacemaker channel, was included. Also, miR-125a-5p/-351, miR-200c/-429, miR-106b/-17, miR-363/-92b, miR-181b/-181d, miR-19a/-19b, let-7d/-7f, miR-18a/-18b, miR-128/-27b and miR-106a/-291a-3p pairs exhibited significant synergy and their association to aging and/or cardiovascular diseases is supported in many cases by a disease database and previous studies. On the contrary, we suggest that miR-22 has not substantial impact on heart longevity as proposed recently.ConclusionsWe revised several proteins and microRNAs recently implicated in cardiac aging and proposed for the first time modules as signatures. The integromics meta-analysis approach can serve as an efficient subvening signature tool for more-oriented better-designed experiments. It can also promote the combinational multi-target microRNA therapy of age-related cardiovascular diseases along the continuum from prevention to detection, diagnosis, treatment and outcome.

OLYMPUS: An automated hybrid clustering method in time series gene expression. Case study: Host response after Influenza A (H1N1) infection

The increasing flow of short time series microarray experiments for the study of dynamic cellular processes poses the need for efficient clustering tools. These tools must deal with three primary issues: first, to consider the multi-functionality of genes; second, to evaluate the similarity of the relative change of amplitude in the time domain rather than the absolute values; third, to cope with the constraints of conventional clustering algorithms such as the assignment of the appropriate cluster number. To address these, we propose OLYMPUS, a novel unsupervised clustering algorithm that integrates Differential Evolution (DE) method into Fuzzy Short Time Series (FSTS) algorithm with the scope to utilize efficiently the information of population of the first and enhance the performance of the latter. Our hybrid approach provides sets of genes that enable the deciphering of distinct phases in dynamic cellular processes. We proved the efficiency of OLYMPUS on synthetic as well as on experimental data. The discriminative power of OLYMPUS provided clusters, which refined the so far perspective of the dynamics of host response mechanisms to Influenza A (H1N1). Our kinetic model sets a timeline for several pathways and cell populations, implicated to participate in host response; yet no timeline was assigned to them (e.g. cell cycle, homeostasis). Regarding the activity of B cells, our approach revealed that some antibody-related mechanisms remain activated until day 60 post infection. The Matlab codes for implementing OLYMPUS, as well as example datasets, are freely accessible via the Web (http://biosignal.med.upatras.gr/wordpress/biosignal/).

Convolutional Neural Networks for Toxic Comment Classification

Flood of information is produced in a daily basis through the global internet usage arising from the online interactive communications among users. While this situation contributes significantly to the quality of human life, unfortunately it involves enormous dangers, since online texts with high toxicity can cause personal attacks, online harassment and bullying behaviors. This has triggered both industrial and research community in the last few years while there are several attempts to identify an efficient model for online toxic comment prediction. However, these steps are still in their infancy and new approaches and frameworks are required. On parallel, the data explosion that appears constantly, makes the construction of new machine learning computational tools for managing this information, an imperative need. Thankfully advances in hardware, cloud computing and big data management allow the development of Deep Learning approaches appearing very promising performance so far. For text classification in particular the use of Convolutional Neural Networks (CNN) have recently been proposed approaching text analytics in a modern manner emphasizing in the structure of words in a document. In this work, we employ this approach to discover toxic comments in a large pool of documents provided by a current Kaggles competition regarding Wikipedias talk page edits. To justify this decision we choose to compare CNNs against the traditional bag-of-words approach for text analysis combined with a selection of algorithms proven to be very effective in text classification. The reported results provide enough evidence that CNN enhance toxic comment classification reinforcing research interest towards this direction.

Tensor-Based Semantically-Aware Topic Clustering of Biomedical Documents

Biomedicine is a pillar of the collective, scientific effort of human self-discovery, as well as a major source of humanistic data codified primarily in biomedical documents. Despite their rigid structure, maintaining and updating a considerably-sized collection of such documents is a task of overwhelming complexity mandating efficient information retrieval for the purpose of the integration of clustering schemes. The latter should work natively with inherently multidimensional data and higher order interdependencies. Additionally, past experience indicates that clustering should be semantically enhanced. Tensor algebra is the key to extending the current term-document model to more dimensions. In this article, an alternative keyword-term-document strategy, based on scientometric observations that keywords typically possess more expressive power than ordinary text terms, whose algorithmic cornerstones are third order tensors and MeSH ontological functions, is proposed. This strategy has been compared against a baseline using two different biomedical datasets, the TREC (Text REtrieval Conference) genomics benchmark and a large custom set of cognitive science articles from PubMed.

Aging Integromics: Module-Based Markers of Heart Aging from Multi-omics Data

In the emerging Systems Medicine field, the study of aging is re-evaluated and contextualized through the combination of ‘omics’ investigations (i.e. transcriptomic, proteomic, metabolomics, fluxomic). In particular, heart aging is a highly complex process in terms of molecular changes and the role of microRNAs (miRNAs) as key gene regulators has recently arisen.

Detecting Perturbed Subpathways towards Mouse Lung Regeneration Following H1N1 Influenza Infection

It has already been established by the systems-level approaches that the future of predictive disease biomarkers will not be sketched by plain lists of genes or proteins or other biological entities but rather integrated entities that consider all underlying component relationships. Towards this orientation, early pathway-based approaches coupled expression data with whole pathway interaction topologies but it was the recent approaches that zoomed into subpathways (local areas of the entire biological pathway) that provided more targeted and context-specific candidate disease biomarkers. Here, we explore the application potential of PerSubs, a graph-based algorithm which identifies differentially activated disease-specific subpathways. PerSubs is applicable both for microarray and RNA-Seq data and utilizes the Kyoto Encyclopedia of Genes and Genomes (KEGG) database as reference for biological pathways. PerSubs operates in two stages: first, identifies differentially expressed genes (or uses any list of disease-related genes) and in second stage, treating each gene of the list as start point, it scans the pathway topology around to build meaningful subpathway topologies. Here, we apply PerSubs to investigate which pathways are perturbed towards mouse lung regeneration following H1N1 influenza infection.

Identifying disease network perturbations through regression on gene expression and pathway topology analysis

In Systems Biology, network-based approaches have been extensively used to effectively study complex diseases. An important challenge is the detection of network perturbations which disrupt regular biological functions as a result of a disease. In this regard, we introduce a network based pathway analysis method which isolates casual interactions with significant regulatory roles within diseased-perturbed pathways. Specifically, we use gene expression data with Random Forest regression models to assess the interactivity strengths of genes within disease-perturbed networks, using KEGG pathway maps as a source of prior-knowledge pertaining to pathway topology. We deliver as output a network with imprinted perturbations corresponding to the biological phenomena arising in a disease-oriented experiment. The efficacy of our approach is demonstrated on a serous papillary ovarian cancer experiment and results highlight the functional roles of high impact interactions and key gene regulators which cause strong perturbations on pathway networks, in accordance with experimentally validated knowledge from recent literature.

Age-related subpathway detection through meta-analysis of multiple gene expression datasets

A novel perspective of systems biology is the incorporation of pathway structure data along with transcriptomics studies. In parallel, the plethora of high-throughput experimental studies necessitates employment of meta-analysis approaches in order to obtain more biologically consistent results. Towards this orientation we developed a subpathway-based meta-analysis method that integrates human pathway maps along with multiple human mRNA expression experiments. Our method succeeded to identify known age-related subpathways as differentially expressed exploiting several independent muscle-specific aging studies. Finally, our method is applicable in several complex biological problems where massive amount of time series expression data is available.

Network-based modular markers of aging across different tissues

Aging is a highly complex biological process and a risk factor for many diseases. Motivated by the high availability of diverse high-throughput data in the mouse model organism, we provide a systemic view of the age-related mechanisms. In particular, we present a robust network-based integrative approach that provides, based on protein interaction and microarray data, reliable modules that alter significantly in terms of expression during aging. Our modular meta-analysis provides novel information about the involvement of several established as well as recently reported longevity-associated pathways across different tissues.