Search

Network-based approaches are an emerging field in the biomedical domain since various complex biological processes and complex human diseases can be interpreted more effectively through biological networks. Identifying groups of interconnected molecular components causing perturbations in the entire network topology for a given under-study disease, these can be considered as potential disease biomarkers, alternatively as «Network Biomarkers». Although there has been remarkable progress with computational systems-based approaches in the road for network biomarkers discovery, this field is still in its infancy, especially in quite complex diseases such as Alzheimer’s Disease (AD). Towards this direction, we proposed a network-based approach for the identification of AD-related network biomarkers. The core of the methodology is a constructed intracellular network integrated with RNA-sequencing expression profiles. Following various functional and topological rules, interconnected co-expressed subnetworks were exported, with differential expression during the transition from a control to a disease state. Isolating the most active subnetworks from the entire network topology, we offer potential network biomarkers that may cause an under-study disease. The methodology was applied using RNA-seq data from a study that examined the behavior of gamma oscillations before the cognitive decline in an AD mouse model. Our results were promising by opening new roads for new frameworks under the perspective of Network Biomarkers discovery.

Network-based computational approaches under the Systems biology perspective offer important insights to explore deeper the various biological processes and complex human diseases. The predominant process of these networks is the Pathway Analysis, a family of Systems Biology methods, intended to give meaning to high-throughput biological data. Nowadays, the Pathway Analysis area has shifted to a new generation, the fourth, which identifies “active subpathways” - in the form of local substructures within pathways – related to a case under study. Although subpathway-based methods have been extensively reviewed, this field remains up to date, and shortly its popularity will skyrocket because of the growth rate of experimental data at the molecular level, such as the single-cell RNA-seq data. Towards this direction, in this work, we highlight the current state of the emerging subpathway analysis field while we identify major challenges that the next generation of methods should consider.

We are in the big data era which has affected several domains including biomedicine and healthcare. This revolution driven by the explosion of biomedical data offers the potential for better understanding of biology and human diseases. An illustrative example is the emerging single-cell sequencing technologies, which isolate and measure each cell individually, taking a step beyond the traditional techniques where consider their measurements from a bulk of cell. Although big single-cell RNA sequencing (scRNA-seq) data promises valuable insights into the cellular level, their volume poses several challenges related to the ultra-high dimensionality. Furthermore, to further elucidate the potential of these data, more insight into gene regulatory networks (GRN) is required. Network-based approaches can tackle part of the inherent complexity of human diseases, however, the challenges related to the ultra-high dimensionality are increased. Towards this direction, we propose the NIRP, an algorithm that copes with the high dimensionality of scRNA-data using a workflow based on fast multiple random projections and a radius-based nearest neighbors search. NIRP infers a gene regulatory network (GRN) from big scRNA-seq data by transforming the original data space to a lower dimensions space and capturing the similarities among gene expressions. The network is further analyzed using a random walk approach in order to achieve dense subgraphs, active to the case under study. The performance of NIRP is evaluated in a real single-cell experimental study among three well-established GRN tools. Our results make NIRP a reliable tool, able to handle big single-cell data with ultra-high dimensionality and complexity. he main advantage of this method is that it is not affected by the volume, as much as it increases, since it transforms the data space to a specific low dimensional space.

We are in the era of single-cell RNA sequencing technology, which offers a great potential for uncovering cellular differences with a higher resolution, shedding light in various complex biological processes and complex human diseases. However, such studies create extremely high dimensional data isolating expression profiles for thousands or even millions of cells. Consequently, dealing with single-cell RNA-seq (scRNA-seq) data is considered the main challenge for unsupervised clustering, which can be used in order to identify grouped cell types. Towards this direction, we present a framework that enhances hierarchical clustering utilizing Proximity Learning on Random Projected spaces (PLRP). The proposed method's efficiency lies in the fact that we exploit the distances from multiple significantly lower dimension spaces defined by Random Projections using ensembles of k-nearest neighbor searches. In the transformed data we applied hierarchical agglomerative clustering (HAC) improving significantly its performance when compared against using the original space. The performance of the proposed PLRP was evaluated in a publicly available experimental dataset with scRNA-seq expression profiles, against three well-established clustering tools. The results showed that our approach greatly enhances clustering performance exposing its applicability in ultra-high dimensions and imposing further development towards this direction.

The recent advent in Next Generation Sequencing has created a huge data source which offers a great potential for elucidating complex disease mechanisms and biological processes. A recent technology is the single-cell RNA sequencing, which allows transcriptomics measurements in individual cells, having promising results. However, such studies measure the entire genome for thousands of cells, creating datasets with extremely high dimensionality and complexity. Following this perspective, we propose a dimensionality reduction approach, called RGt-SNE, which visualizes single-cell RNA-seq data in two dimensions. Initially, RGt-SNE defines a cell-cell distance matrix based on Random Projections and Geodesic Distances. The first is used to define the pairwise cells distances in a low dimensional projected space avoiding the difficulties that exist in data with ultra-high dimensionality. The latter is used to better define the large pairwise cells distances. Subsequently, the t-SNE method is applied in the customized distance matrix for two dimensional visualization. RGt-SNE was evaluated in two real experimental single-cell RNA-seq data against three well-known methods, such as t-SNE, Multidimensional scaling, and ISOMAP. Outcomes provide the superiority of RGt-SNE suggesting it as a reliable tool for single-cell RNA-seq data analysis and visualization.

Biomedicine is undergoing a revolution driven by the explosion of biomedical data, which are generated by emerged medical imaging, sensor technologies and high-throughput technologies. An indicative example is the single cell sequencing technology which concerns the genome sequencing examination of hundreds of separate cells in a single tumor. Consequently, open challenges arising from this emerged technology and generally from the evolution of biomedical technologies under the big data perspective. Also, given the fact that approaches based on high-performance computing require high computing resources and advanced developers, solutions that reduce the problem complexity remain very attractive. Following this direction, in this paper a classification scheme based on Multiple Random Projections and Voting is presented. Random Projections offer a platform not only for a low computational time analysis by significantly reducing the data dimensionality, but also for an accurate analysis which may well exceed classical classification approaches. The proposed method was applied on real biomedical high dimensional data and compared against well-known classification schemes as to Random Projection-based cutting-edge methods. Specifically, we applied it on expression profiles for single-cell RNA-seq data from non-diabetic and type 2 diabetic human samples. Experimental results showed that based on simplistic tools we can create a computationally fast, simple, yet effective approach for biomedical Big Data analysis and knowledge discovery.

In the road for network medicine the newly emerged systems-level subpathway-based analysis methods offer new disease genes, drug targets and network-based biomarkers. In parallel, paired miRNA/mRNA expression data enable simultaneously monitoring of the micronome effect upon the signaling pathways. Towards this orientation, we present a methodological pipeline for the identification of differentially expressed subpathways along with their miRNA regulators by using KEGG signaling pathway maps, miRNA-target interactions and expression profiles from paired miRNA/mRNA experiments. Our pipeline offered new biological insights on a real application of paired miRNA/mRNA expression profiles with respect to the dynamic changes from colostrum to mature milk whey; several literature supported genes and miRNAs were recontextualized through miRNA-mediated differentially expressed subpathways.

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.