Georgios N. Dimitrakopoulos

A Clustering based Method Accelerating Gene Regulatory Network Reconstruction

One important direction of Systems Biology is to infer Gene Regulatory Networks and many methods have been developed recently, but they cannot be applied effectively in full scale data. In this work we propose a framework based on clustering to handle the large dimensionality of the data, aiming to improve accuracy of inferred network while reducing time complexity. We explored the efficiency of this framework employing the newly proposed metric Maximal Information Coefficient (MIC), which showed superior performance in comparison to other well established methods. Utilizing both benchmark and real life datasets, we showed that our method is able to deliver accurate results in fractions of time required by other state of the art methods. Our method provides as output interactions among groups of highly correlated genes, which in an application on an aging experiment were able to reveal aging related pathways.

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.

Identification of gait-related brain activity using electroencephalographic signals

Restoring normal walking abilities following the loss of them is a challenge. Importantly, there is a growing need for a better understanding of brain plasticity and the neural involvements for the initiation and control of these abilities so as to develop better rehabilitation programmes and external support devices. In this paper, we attempt to identify gait-related neural activities by decoding neural signals obtained from electroencephalography (EEG) measurements while subjects performed three types of walking: without exoskeleton (free walking), and with exoskeleton support (zero force and assisting force). An average classification accuracy of 92.0% for training and 73.8% for testing sets was achieved using features extracted from mu and beta frequency bands. Furthermore, we found that mu band features contributed significantly to the classification accuracy and were localized mainly in sensorimotor regions that are associated with the control of the exoskeleton. These findings contribute meaningful insight on the neural dynamics associated with lower limb movements and provide useful information for future developments of orthotic devices and rehabilitation programs.

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.

Supervised method for construction of microRNA-mRNA networks: Application in cardiac tissue aging dataset

MicroRNAs play an important role in regulation of gene expression, but still detection of their targets remains a challenge. In this work we present a supervised regulatory network inference method with aim to identify potential target genes (mRNAs) of microRNAs. Briefly, the proposed method exploiting mRNA and microRNA expression trains Random Forests on known interactions and subsequently it is able to predict novel ones. In parallel, we incorporate different available data sources, such as Gene Ontology and ProteinProtein Interactions, to deliver biologically consistent results. Application in both benchmark data and an experiment studying aging showed robust performance.

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.

Functional Connectivity Analysis of Mental Fatigue Reveals Different Network Topological Alterations Between Driving and Vigilance Tasks

Despite the apparent importance of mental fatigue detection, a reliable application is hindered due to the incomprehensive understanding of the neural mechanisms of mental fatigue. In this paper, we investigated the topological alterations of functional brain networks in the theta band (4 - 7 Hz) of electroencephalography (EEG) data from 40 male subjects undergoing two distinct fatigue-inducing tasks: a low-intensity one-hour simulated driving and a high-demanding half-hour sustained attention task [psychomotor vigilance task (PVT)]. Behaviorally, subjects demonstrated a robust mental fatigue effect, as reflected by significantly declined performances in cognitive tasks prior and post these two tasks. Furthermore, characteristic path length presented a positive correlation with task duration, which led to a significant increase between the first and the last five minutes of both tasks, indicating a fatigue-related disruption in information processing efficiency. However, significantly increased clustering coefficient was revealed only in the driving task, suggesting distinct network reorganizations between the two fatigue-inducing tasks. Moreover, high accuracy (92% for driving; 97% for PVT) was achieved for fatigue classification with apparently different discriminative functional connectivity features. These findings augment our understanding of the complex nature of fatigue-related neural mechanisms and demonstrate the feasibility of using functional connectivity as neural biomarkers for applicable fatigue monitoring.

Driving Mental Fatigue Classification Based on Brain Functional Connectivity

EEG techniques have been widely used for mental fatigue monitoring, which is an important factor for driving safety. In this work, we performed an experiment involving one hour driving simulation. Based on EEG recordings, we created brain functional networks in alpha power band with three different methods, partial directed coherence (PDC), direct transfer function (DTF) and phase lag index (PLI). Then, we performed feature selection and classification between alertness and fatigue states, using the functional connectivity as features. High accuracy (84.7%) was achieved, with 22 discriminative connections from PDC network. The selected features revealed alterations of the functional network due to mental fatigue and specifically reduction of information flow among areas. Finally, a feature ranking is provided, which can lead to electrode minimization for real-time fatigue monitoring applications.

A mental fatigue index based on regression using mulitband EEG features with application in simulated driving

Development of accurate fatigue level prediction models is of great importance for driving safety. In parallel, a limited number of sensors is a prerequisite for development of applicable wearable devices. Several EEG-based studies so far have performed classification in two or few levels, while others have proposed indices based on power ratios. Here, we utilized a regression Random Forest model in order to provide more accurate continuous fatigue level prediction. In detail, multiband power features were extracted from EEG data recorded from one hour simulated driving task. Next, cross-subject regression was performed to obtain common fatigue-related discriminative features. We achieved satisfactory prediction accuracy and simultaneously we minimized required electrodes, proposing to use a set of 3 electrodes.