Salvatore Alaimo

Drug-target interaction prediction through domain-tuned network-based inference.

Motivation: The identification of drug–target interaction (DTI) represents a costly and time-consuming step in drug discovery and design. Computational methods capable of predicting reliable DTI play an important role in the field. Recently, recommendation methods relying on network-based inference (NBI) have been proposed. However, such approaches implement naive topology-based inference and do not take into account important features within the drug–target domain. Results: In this article, we present a new NBI method, called domain tuned-hybrid (DT-Hybrid), which extends a well-established recommendation technique by domain-based knowledge including drug and target similarity. DT-Hybrid has been extensively tested using the last version of an experimentally validated DTI database obtained from DrugBank. Comparison with other recently proposed NBI methods clearly shows that DT-Hybrid is capable of predicting more reliable DTIs. Availability: DT-Hybrid has been developed in R and it is available, along with all the results on the predictions, through an R package at the following URL: http://sites.google.com/site/ehybridalgo/. Contact: apulvirenti@dmi.unict.it Supplementary information: Supplementary data are available at Bioinformatics online.

ncPred: ncRNA-Disease Association Prediction through Tripartite Network-Based Inference.

Motivation: Over the past few years, experimental evidence has highlighted the role of microRNAs to human diseases. miRNAs are critical for the regulation of cellular processes, and, therefore, their aberration can be among the triggering causes of pathological phenomena. They are just one member of the large class of non-coding RNAs, which include transcribed ultra-conserved regions (T-UCRs), small nucleolar RNAs (snoRNAs), PIWI-interacting RNAs (piRNAs), large intergenic non-coding RNAs (lincRNAs) and, the heterogeneous group of long non-coding RNAs (lncRNAs). Their associations with diseases are few in number, and their reliability is questionable. In literature, there is only one recent method proposed by Yang et al. (2014) to predict lncRNA-disease associations. This technique, however, lacks in prediction quality. All these elements entail the need to investigate new bioinformatics tools for the prediction of high quality ncRNA-disease associations. Here, we propose a method called ncPred for the inference of novel ncRNA-disease association based on recommendation technique. We represent our knowledge through a tripartite network, whose nodes are ncRNAs, targets, or diseases. Interactions in such a network associate each ncRNA with a disease through its targets. Our algorithm, starting from such a network, computes weights between each ncRNA-disease pair using a multi-level resource transfer technique that at each step takes into account the resource transferred in the previous one. Results: The results of our experimental analysis show that our approach is able to predict more biologically significant associations with respect to those obtained by Yang et al. (2014), yielding an improvement in terms of the average area under the ROC curve (AUC). These results prove the ability of our approach to predict biologically significant associations, which could lead to a better understanding of the molecular processes involved in complex diseases. Availability: All the ncPred predictions together with the datasets used for the analysis are available at the following url: http://alpha.dmi.unict.it/ncPred/

DT-Web: a web-based application for drug-target interaction and drug combination prediction through domain-tuned network-based inference

BackgroundThe identification of drug-target interactions (DTI) is a costly and time-consuming step in drug discovery and design. Computational methods capable of predicting reliable DTI play an important role in the field. Algorithms may aim to design new therapies based on a single approved drug or a combination of them. Recently, recommendation methods relying on network-based inference in connection with knowledge coming from the specific domain have been proposed.DescriptionHere we propose a web-based interface to the DT-Hybrid algorithm, which applies a recommendation technique based on bipartite network projection implementing resources transfer within the network. This technique combined with domain-specific knowledge expressing drugs and targets similarity is used to compute recommendations for each drug. Our web interface allows the users: (i) to browse all the predictions inferred by the algorithm; (ii) to upload their custom data on which they wish to obtain a prediction through a DT-Hybrid based pipeline; (iii) to help in the early stages of drug combinations, repositioning, substitution, or resistance studies by finding drugs that can act simultaneously on multiple targets in a multi-pathway environment. Our system is periodically synchronized with DrugBank and updated accordingly. The website is free, open to all users, and available at http://alpha.dmi.unict.it/dtweb/.ConclusionsOur web interface allows users to search and visualize information on drugs and targets eventually providing their own data to compute a list of predictions. The user can visualize information about the characteristics of each drug, a list of predicted and validated targets, associated enzymes and transporters. A table containing key information and GO classification allows the users to perform their own analysis on our data. A special interface for data submission allows the execution of a pipeline, based on DT-Hybrid, predicting new targets with the corresponding p-values expressing the reliability of each group of predictions. Finally, It is also possible to specify a list of genes tracking down all the drugs that may have an indirect influence on them based on a multi-drug, multi-target, multi-pathway analysis, which aims to discover drugs for future follow-up studies.

Post-transcriptional knowledge in pathway analysis increases the accuracy of phenotypes classification.

Motivation Prediction of phenotypes from high-dimensional data is a crucial task in precision biology and medicine. Many technologies employ genomic biomarkers to characterize phenotypes. However, such elements are not sufficient to explain the underlying biology. To improve this, pathway analysis techniques have been proposed. Nevertheless, such methods have shown lack of accuracy in phenotypes classification. Results Here we propose a novel methodology called MITHrIL (Mirna enrIched paTHway Impact anaLysis) for the analysis of signaling pathways, which extends the work of Tarca et al., 2009. MITHrIL augments pathways with missing regulatory elements, such as microRNAs, and their interactions with genes. The method takes as input the expression values of genes and/or microRNAs and returns a list of pathways sorted according to their degree of deregulation, together with the corresponding statistical significance (p-values). Our analysis shows that MITHrIL outperforms its competitors even in the worst case. In addition, our method is able to correctly classify sets of tumor samples drawn from TCGA. Availability MITHrIL is freely available at the following URL: http://alpha.dmi.unict.it/mithril/

Neutrophil-To-Lymphocyte Ratio: An Emerging Marker Predicting Prognosis in Elderly Adults with Community-Acquired Pneumonia

To explore the performance of the neutrophil‐to‐lymphocyte ratio (NLR), an index of systemic inflammation that predicts prognosis of several diseases, in a cohort of elderly adults with community‐acquired pneumonia (CAP).

A novel computational method for inferring competing endogenous interactions

Posttranscriptional cross talk and communication between genes mediated by microRNA response element (MREs) yield large regulatory competing endogenous RNA (ceRNA) networks. Their inference may improve the understanding of pathologies and shed new light on biological mechanisms. A variety of RNA: messenger RNA, transcribed pseudogenes, noncoding RNA, circular RNA and proteins related to RNA-induced silencing complex complex interacting with RNA transfer and ribosomal RNA have been experimentally proved to be ceRNAs. We retrace the ceRNA hypothesis of posttranscriptional regulation from its original formulation [Salmena L, Poliseno L, Tay Y, et al. Cell 2011;146:353-8] to the most recent experimental and computational validations. We experimentally analyze the methods in literature [Li J-H, Liu S, Zhou H, et al. Nucleic Acids Res 2013;42:D92-7; Sumazin P, Yang X, Chiu H-S, et al. Cell 2011;147:370-81; Sarver AL, Subramanian S. Bioinformation 2012;8:731-3] comparing them with a general machine learning approach, called ceRNA predIction Algorithm, evaluating the performance in predicting novel MRE-based ceRNAs.

Detecting Disease Specific Pathway Substructures through an Integrated Systems Biology Approach

In the era of network medicine, pathway analysis methods play a central role in the prediction of phenotype from high throughput experiments. In this paper, we present a network-based systems biology approach capable of extracting disease-perturbed subpathways within pathway networks in connection with expression data taken from The Cancer Genome Atlas (TCGA). Our system extends pathways with missing regulatory elements, such as microRNAs, and their interactions with genes. The framework enables the extraction, visualization, and analysis of statistically significant disease-specific subpathways through an easy to use web interface. Our analysis shows that the methodology is able to fill the gap in current techniques, allowing a more comprehensive analysis of the phenomena underlying disease states.

Recommendation Techniques for Drug–Target Interaction Prediction and Drug Repositioning

The usage of computational methods in drug discovery is a common practice. More recently, by exploiting the wealth of biological knowledge bases, a novel approach called drug repositioning has raised. Several computational methods are available, and these try to make a high-level integration of all the knowledge in order to discover unknown mechanisms. In this chapter, we review drug-target interaction prediction methods based on a recommendation system. We also give some extensions which go beyond the bipartite network case.

Knowledge in the Investigation of A-to-I RNA Editing Signals

RNA editing is a post-transcriptional alteration of RNA sequences that is able to affect protein structure as well as RNA and protein expression. Adenosine-to-inosine (A-to-I) RNA editing is the most frequent and common post-transcriptional modification in human, where adenosine (A) deamination produces its conversion into inosine (I), which in turn is interpreted by the translation and splicing machineries as guanosine (G). The disruption of the editing machinery has been associated to various human diseases such as cancer or neurodegenerative diseases. This biological phenomenon is catalyzed by members of the adenosine deaminase acting on RNA (ADAR) family of enzymes and occurs on dsRNA structures. Despite the enormous efforts made in the last decade, the real biological function underlying such a phenomenon, as well as ADAR’s substrate features still remain unknown. In this work, we summarize the major computational aspects of predicting and understanding RNA editing events. We also investigate the detection of short motif sequences potentially characterizing RNA editing signals and the use of a logistic regression technique to model a predictor of RNA editing events. The latter, named AIRlINER, an algorithmic approach to assessment of A-to-I RNA editing sites in non-repetitive regions, is available as a web app at: http://alpha.dmi.unict.it/airliner/. Results and comparisons with the existing methods encourage our findings on both aspects.

Current Knowledge and Computational Techniques for Grapevine Meta-Omics Analysis

Growing grapevine (Vitis vinifera) is a key contribution to the economy of many countries. Tools provided by genomics and bioinformatics did help researchers in obtaining biological knowledge about the different cultivars. Several genetic markers for common diseases were identified. Recently, the impact of microbiome has been proved to be of fundamental importance both in humans and in plants for its ability to confer protection or induce diseases. In this review we report current knowledge about grapevine microbiome, together with a description of the available computational methodologies for meta-omics analysis.