Multilayer network alignment based on topological assessment via embeddings.

BACKGROUND: Network graphs allow modelling the real world objects in terms of interactions. In a multilayer network, the interactions are distributed over layers (i.e., intralayer and interlayer edges). Network alignment (NA) is a methodology that allows mapping nodes between two or multiple given networks, by preserving topologically similar regions. For instance, NA can be applied to transfer knowledge from one biological species to another. In this paper, we present DANTEml, a software tool for the Pairwise Global NA (PGNA) of multilayer networks, based on topological assessment. It builds its own similarity matrix by processing the node embeddings computed from two multilayer networks of interest, to evaluate their topological similarities. The proposed solution can be used via a user-friendly command line interface, also having a built-in guided mode (step-by-step) for defining input parameters. RESULTS: We investigated the performance of DANTEml based on (i) performance evaluation on synthetic multilayer networks, (ii) statistical assessment of the resulting alignments, and (iii) alignment of real multilayer networks. DANTEml over performed a method that does not consider the distribution of nodes and edges over multiple layers by 1193.62%, and a method for temporal NA by 25.88%; we also performed the statistical assessment, which corroborates the significance of its own node mappings. In addition, we tested the proposed solution by using a real multilayer network in presence of several levels of noise, in accordance with the same outcome pursued for the NA on our dataset of synthetic networks. In this case, the improvement is even more evident: +4008.75% and +111.72%, compared to a method that does not consider the distribution of nodes and edges over multiple layers and a method for temporal NA, respectively. CONCLUSIONS: DANTEml is a software tool for the PGNA of multilayer networks based on topological assessment, that is able to provide effective alignments both on synthetic and real multi layer networks, of which node mappings can be validated statistically. Our experimentation reported a high degree of reliability and effectiveness for the proposed solution.

An Exploratory Application of Multilayer Networks and Pathway Analysis in Pharmacogenomics.

Over the years, network analysis has become a promising strategy for analysing complex system, i.e., systems composed of a large number of interacting elements. In particular, multilayer networks have emerged as a powerful framework for modelling and analysing complex systems with multiple types of interactions. Network analysis can be applied to pharmacogenomics to gain insights into the interactions between genes, drugs, and diseases. By integrating network analysis techniques with pharmacogenomic data, the goal consists of uncovering complex relationships and identifying key genes to use in pathway enrichment analysis to figure out biological pathways involved in drug response and adverse reactions. In this study, we modelled omics, disease, and drug data together through multilayer network representation. Then, we mined the multilayer network with a community detection algorithm to obtain the top communities. After that, we used the identified list of genes from the communities to perform pathway enrichment analysis (PEA) to figure out the biological function affected by the selected genes. The results show that the genes forming the top community have multiple roles through different pathways.

Aligning Cross-Species Interactomes for Studying Complex and Chronic Diseases.

Neurodegenerative diseases (NDs) are a group of complex disorders characterized by the progressive degeneration and dysfunction of neurons in the central nervous system. NDs encompass many conditions, including Alzheimer's disease and Parkinson's disease. Alzheimer's disease (AD) is a complex disease affecting almost forty million people worldwide. AD is characterized by a progressive decline of cognitive functions related to the loss of connections between nerve cells caused by the prevalence of extracellular Aß plaques and intracellular neurofibrillary tangles plaques. Parkinson's disease (PD) is a neurodegenerative disorder that primarily affects the movement of an individual. The exact cause of Parkinson's disease is not fully understood, but it is believed to involve a combination of genetic and environmental factors. Some cases of PD are linked to mutations in the LRRK2, PARKIN and other genes, which are associated with familial forms of the disease. Different research studies have applied the Protein Protein Interaction (PPI) networks to understand different aspects of disease progression. For instance, Caenorhabditis elegans is widely used as a model organism for the study of AD due to roughly 38% of its genes having a human ortholog. This study's goal consists of comparing PPI network of C. elegans and human by applying computational techniques, widely used for the analysis of PPI networks between species, such as Local Network Alignment (LNA). For this aim, we used L-HetNetAligner algorithm to build a local alignment among two PPI networks, i.e., C. elegans and human PPI networks associated with AD and PD built-in silicon. The results show that L-HetNetAligner can find local alignments representing functionally related subregions. In conclusion, since local alignment enables the extraction of functionally related modules, the method can be used to study complex disease progression.

A Python Clustering Analysis Protocol of Genes Expression Data Sets.

Gene expression and SNPs data hold great potential for a new understanding of disease prognosis, drug sensitivity, and toxicity evaluations. Cluster analysis is used to analyze data that do not contain any specific subgroups. The goal is to use the data itself to recognize meaningful and informative subgroups. In addition, cluster investigation helps data reduction purposes, exposes hidden patterns, and generates hypotheses regarding the relationship between genes and phenotypes. Cluster analysis could also be used to identify bio-markers and yield computational predictive models. The methods used to analyze microarrays data can profoundly influence the interpretation of the results. Therefore, a basic understanding of these computational tools is necessary for optimal experimental design and meaningful data analysis. This manuscript provides an analysis protocol to effectively analyze gene expression data sets through the K-means and DBSCAN algorithms. The general protocol enables analyzing omics data to identify subsets of features with low redundancy and high robustness, speeding up the identification of new bio-markers through pathway enrichment analysis. In addition, to demonstrate the effectiveness of our clustering analysis protocol, we analyze a real data set from the GEO database. Finally, the manuscript provides some best practice and tips to overcome some issues in the analysis of omics data sets through unsupervised learning.

A statistical network pre-processing method to improve relevance and significance of gene lists in microarray gene expression studies.

BACKGROUND: Microarrays can perform large scale studies of differential expressed gene (DEGs) and even single nucleotide polymorphisms (SNPs), thereby screening thousands of genes for single experiment simultaneously. However, DEGs and SNPs are still just as enigmatic as the first sequence of the genome. Because they are independent from the affected biological context. Pathway enrichment analysis (PEA) can overcome this obstacle by linking both DEGs and SNPs to the affected biological pathways and consequently to the underlying biological functions and processes. RESULTS: To improve the enrichment analysis results, we present a new statistical network pre-processing method by mapping DEGs and SNPs on a biological network that can improve the relevance and significance of the DEGs or SNPs of interest to incorporate pathway topology information into the PEA. The proposed methodology improves the statistical significance of the PEA analysis in terms of computed p value for each enriched pathways and limit the number of enriched pathways. This helps reduce the number of relevant biological pathways with respect to a non-specific list of genes. CONCLUSION: The proposed method provides two-fold enhancements. Network analysis reveals fewer DEGs, by selecting only relevant DEGs and the detected DEGs improve the enriched pathways' statistical significance, rather than simply using a general list of genes.

Design and Implementation of a New Local Alignment Algorithm for Multilayer Networks.

Network alignment (NA) is a popular research field that aims to develop algorithms for comparing networks. Applications of network alignment span many fields, from biology to social network analysis. NA comes in two forms: global network alignment (GNA), which aims to find a global similarity, and LNA, which aims to find local regions of similarity. Recently, there has been an increasing interest in introducing complex network models such as multilayer networks. Multilayer networks are common in many application scenarios, such as modelling of relations among people in a social network or representing the interplay of different molecules in a cell or different cells in the brain. Consequently, the need to introduce algorithms for the comparison of such multilayer networks, i.e., local network alignment, arises. Existing algorithms for LNA do not perform well on multilayer networks since they cannot consider inter-layer edges. Thus, we propose local alignment of multilayer networks (MultiLoAl), a novel algorithm for the local alignment of multilayer networks. We define the local alignment of multilayer networks and propose a heuristic for solving it. We present an extensive assessment indicating the strength of the algorithm. Furthermore, we implemented a synthetic multilayer network generator to build the data for the algorithm's evaluation.

Application of CCTV Methodology to Analyze COVID-19 Evolution in Italy.

Italy was one of the European countries most afflicted by the COVID-19 pandemic. From 2020 to 2022, Italy adopted strong containment measures against the COVID-19 epidemic and then started an important vaccination campaign. Here, we extended previous work by applying the COVID-19 Community Temporal Visualizer (CCTV) methodology to Italian COVID-19 data related to 2020, 2021, and five months of 2022. The aim of this work was to evaluate how Italy reacted to the pandemic in the first two waves of COVID-19, in which only containment measures such as the lockdown had been adopted, in the months following the start of the vaccination campaign, the months with the mildest weather, and the months affected by the new COVID-19 variants. This assessment was conducted by observing the behavior of single regions. CCTV methodology allows us to map the similarities in the behavior of Italian regions on a graph and use a community detection algorithm to visualize and analyze the spatio-temporal evolution of data. The results depict that the communities formed by Italian regions change with respect to the ten data measures and time.

Challenges and Limitations of Biological Network Analysis.

High-Throughput technologies are producing an increasing volume of data that needs large amounts of data storage, effective data models and efficient, possibly parallel analysis algorithms. Pathway and interactomics data are represented as graphs and add a new dimension of analysis, allowing, among other features, graph-based comparison of organisms' properties. For instance, in biological pathway representation, the nodes can represent proteins, RNA and fat molecules, while the edges represent the interaction between molecules. Otherwise, biological networks such as Protein-Protein Interaction (PPI) Networks, represent the biochemical interactions among proteins by using nodes that model the proteins from a given organism, and edges that model the protein-protein interactions, whereas pathway networks enable the representation of biochemical-reaction cascades that happen within the cells or tissues. In this paper, we discuss the main models for standard representation of pathways and PPI networks, the data models for the representation and exchange of pathway and protein interaction data, the main databases in which they are stored and the alignment algorithms for the comparison of pathways and PPI networks of different organisms. Finally, we discuss the challenges and the limitations of pathways and PPI network representation and analysis. We have identified that network alignment presents a lot of open problems worthy of further investigation, especially concerning pathway alignment.

An Extensive Assessment of Network Embedding in PPI Network Alignment.

Network alignment is a fundamental task in network analysis. In the biological field, where the protein-protein interaction (PPI) is represented as a graph, network alignment allowed the discovery of underlying biological knowledge such as conserved evolutionary pathways and functionally conserved proteins throughout different species. A recent trend in network science concerns network embedding, i.e., the modelling of nodes in a network as a low-dimensional feature vector. In this survey, we present an overview of current PPI network embedding alignment methods, a comparison among them, and a comparison to classical PPI network alignment algorithms. The results of this comparison highlight that: (i) only five network embeddings for network alignment algorithms have been applied in the biological context, whereas the literature presents several classical network alignment algorithms; (ii) there is a need for developing an evaluation framework that may enable a unified comparison between different algorithms; (iii) the majority of the proposed algorithms perform network embedding through matrix factorization-based techniques; (iv) three out of five algorithms leverage external biological resources, while the remaining two are designed for domain agnostic network alignment and tested on PPI networks; (v) two algorithms out of three are stated to perform multi-network alignment, while the remaining perform pairwise network alignment.

Using Gene Ontology to Annotate and Prioritize Microarray Data.

The results of high-throughput experiments consist of numerous candidate genes, proteins, or other molecules potentially associated with diseases. A challenge for omics science is the knowledge extraction from the results and the filtering of promising gene or protein candidates. Especially, the hot topic in clinical scenarios consists of highlighting the behavior of few molecules related to some specific disease. In this contest, different computational approaches, also referred Gene prioritization methods, ensure to identify the most related genes to a disease among a larger set of candidate genes. The identification requires the use of domain-specific knowledge that is often encoded into ontologies.

COVID-19 Community Temporal Visualizer: a new methodology for the network-based analysis and visualization of COVID-19 data.

Understanding the evolution of the spread of the COVID-19 pandemic requires the analysis of several data at the spatial and temporal levels. Here, we present a new network-based methodology to analyze COVID-19 data measures containing spatial and temporal features and its application on a real dataset. The goal of the methodology is to analyze sets of homogeneous datasets (i.e. COVID-19 data taken in different periods and in several regions) using a statistical test to find similar/dissimilar datasets, mapping such similarity information on a graph and then using a community detection algorithm to visualize and analyze the spatio-temporal evolution of data. We evaluated diverse Italian COVID-19 data made publicly available by the Italian Protezione Civile Department at https://github.com/pcm-dpc/COVID-19/. Furthermore, we considered the climate data related to two periods and we integrated them with COVID-19 data measures to detect new communities related to climate changes. In conclusion, the application of the proposed methodology provides a network-based representation of the COVID-19 measures by highlighting the different behaviour of regions with respect to pandemics data released by Protezione Civile and climate data. The methodology and its implementation as R function are publicly available at https://github.com/mmilano87/analyzeC19D.

Statistical and Network-Based Analysis of Italian COVID-19 Data: Communities Detection and Temporal Evolution.

The coronavirus disease (COVID-19) outbreak started in Wuhan, China, and it has rapidly spread across the world. Italy is one of the European countries most affected by COVID-19, and it has registered high COVID-19 death rates and the death toll. In this article, we analyzed different Italian COVID-19 data at the regional level for the period 24 February to 29 March 2020. The analysis pipeline includes the following steps. After individuating groups of similar or dissimilar regions with respect to the ten types of available COVID-19 data using statistical test, we built several similarity matrices. Then, we mapped those similarity matrices into networks where nodes represent Italian regions and edges represent similarity relationships (edge length is inversely proportional to similarity). Then, network-based analysis was performed mainly discovering communities of regions that show similar behavior. In particular, network-based analysis was performed by running several community detection algorithms on those networks and by underlying communities of regions that show similar behavior. The network-based analysis of Italian COVID-19 data is able to elegantly show how regions form communities, i.e., how they join and leave them, along time and how community consistency changes along time and with respect to the different available data.

L-HetNetAligner: A novel algorithm for Local Alignment of Heterogeneous Biological Networks.

Networks are largely used for modelling and analysing a wide range of biological data. As a consequence, many different research efforts have resulted in the introduction of a large number of algorithms for analysis and comparison of networks. Many of these algorithms can deal with networks with a single class of nodes and edges, also referred to as homogeneous networks. Recently, many different approaches tried to integrate into a single model the interplay of different molecules. A possible formalism to model such a scenario comes from node/edge coloured networks (also known as heterogeneous networks) implemented as node/ edge-coloured graphs. Therefore, the need for the introduction of algorithms able to compare heterogeneous networks arises. We here focus on the local comparison of heterogeneous networks, and we formulate it as a network alignment problem. To the best of our knowledge, the local alignment of heterogeneous networks has not been explored in the past. We here propose L-HetNetAligner a novel algorithm that receives as input two heterogeneous networks (node-coloured graphs) and builds a local alignment of them. We also implemented and tested our algorithm. Our results confirm that our method builds high-quality alignments. The following website *contains Supplementary File 1 material and the code.

GLAlign: A Novel Algorithm for Local Network Alignment.

Networks are successfully used as a modelling framework in many application domains. For instance, Protein-Protein Interaction Networks (PPINs) model the set of interactions among proteins in a cell. A critical application of network analysis is the comparison among PPINs of different organisms to reveal similarities among the underlying biological processes. Algorithms for comparing networks (also referred to as network aligners) fall into two main classes: global aligners, which aim to compare two networks on a global scale, and local aligners that evidence single sub-regions of similarity among networks. The possibility to improve the performance of the aligners by mixing the two approaches is a growing research area. In our previous work, we started to explore the possibility to use global alignment to improve the local one. We here examine further this possibility by using topological information extracted from global alignment to guide the steps of the local alignment. Therefore, we present GLAlign (Global Local Aligner), a methodology that improves the performances of local network aligners by exploiting a preliminary global alignment. Furthermore, we provide an implementation of GLAlign. As a proof-of-principle, we evaluated the performance of the GLAlign prototype. Results show that GLAlign methodology outperforms the state-of-the-art local alignment algorithms. GLAlign is publicly available for academic use and can be downloaded here: https://sites.google.com/site/globallocalalignment/.

An extensive assessment of network alignment algorithms for comparison of brain connectomes.

BACKGROUND: Recently the study of the complex system of connections in neural systems, i.e. the connectome, has gained a central role in neurosciences. The modeling and analysis of connectomes are therefore a growing area. Here we focus on the representation of connectomes by using graph theory formalisms. Macroscopic human brain connectomes are usually derived from neuroimages; the analyzed brains are co-registered in the image domain and brought to a common anatomical space. An atlas is then applied in order to define anatomically meaningful regions that will serve as the nodes of the network - this process is referred to as parcellation. The atlas-based parcellations present some known limitations in cases of early brain development and abnormal anatomy. Consequently, it has been recently proposed to perform atlas-free random brain parcellation into nodes and align brains in the network space instead of the anatomical image space, as a way to deal with the unknown correspondences of the parcels. Such process requires modeling of the brain using graph theory and the subsequent comparison of the structure of graphs. The latter step may be modeled as a network alignment (NA) problem. RESULTS: In this work, we first define the problem formally, then we test six existing state of the art of network aligners on diffusion MRI-derived brain networks. We compare the performances of algorithms by assessing six topological measures. We also evaluated the robustness of algorithms to alterations of the dataset. CONCLUSION: The results confirm that NA algorithms may be applied in cases of atlas-free parcellation for a fully network-driven comparison of connectomes. The analysis shows MAGNA++ is the best global alignment algorithm. The paper presented a new analysis methodology that uses network alignment for validating atlas-free parcellation brain connectomes. The methodology has been experimented on several brain datasets.

Extracting Cross-Ontology Weighted Association Rules from Gene Ontology Annotations.

Gene Ontology (GO) is a structured repository of concepts (GO Terms) that are associated to one or more gene products through a process referred to as annotation. The analysis of annotated data is an important opportunity for bioinformatics. There are different approaches of analysis, among those, the use of association rules (AR) which provides useful knowledge, discovering biologically relevant associations between terms of GO, not previously known. In a previous work, we introduced GO-WAR (Gene Ontology-based Weighted Association Rules), a methodology for extracting weighted association rules from ontology-based annotated datasets. We here adapt the GO-WAR algorithm to mine cross-ontology association rules, i.e., rules that involve GO terms present in the three sub-ontologies of GO. We conduct a deep performance evaluation of GO-WAR by mining publicly available GO annotated datasets, showing how GO-WAR outperforms current state of the art approaches.

Methodologies and experimental platforms for generating and analysing microarray and mass spectrometry-based omics data to support P4 medicine.

Predictive, preventive, personalized and participatory (P4) medicine is an emerging medical model that is based on the customization of all medical aspects (i.e. practices, drugs, decisions) of the individual patient. P4 medicine presupposes the elucidation of the so-called omic world, under the assumption that this knowledge may explain differences of patients with respect to disease prevention, diagnosis and therapies. Here, we elucidate the role of some selected omics sciences for different aspects of disease management, such as early diagnosis of diseases, prevention of diseases, selection of personalized appropriate and optimal therapies based on molecular profiling of patients. After introducing basic concepts of P4 medicine and omics sciences, we review some computational tools and approaches for analysing selected omics data, with a special focus on microarray and mass spectrometry data, which may be used to support P4 medicine. Some applications of biomarker discovery and pharmacogenomics and some experiences on the study of drug reactions are also described.

Ontology-Based Analysis of Microarray Data.

The importance of semantic-based methods and algorithms for the analysis and management of biological data is growing for two main reasons. From a biological side, knowledge contained in ontologies is more and more accurate and complete, from a computational side, recent algorithms are using in a valuable way such knowledge. Here we focus on semantic-based management and analysis of protein interaction networks referring to all the approaches of analysis of protein-protein interaction data that uses knowledge encoded into biological ontologies. Semantic approaches for studying high-throughput data have been largely used in the past to mine genomic and expression data. Recently, the emergence of network approaches for investigating molecular machineries has stimulated in a parallel way the introduction of semantic-based techniques for analysis and management of network data. The application of these computational approaches to the study of microarray data can broad the application scenario of them and simultaneously can help the understanding of disease development and progress.

Using GO-WAR for mining cross-ontology weighted association rules.

The Gene Ontology (GO) is a structured repository of concepts (GO terms) that are associated to one or more gene products. The process of association is referred to as annotation. The relevance and the specificity of both GO terms and annotations are evaluated by a measure defined as information content (IC). The analysis of annotated data is thus an important challenge for bioinformatics. There exist different approaches of analysis. From those, the use of association rules (AR) may provide useful knowledge, and it has been used in some applications, e.g. improving the quality of annotations. Nevertheless classical association rules algorithms do not take into account the source of annotation nor the importance yielding to the generation of candidate rules with low IC. This paper presents GO-WAR (Gene Ontology-based Weighted Association Rules) a methodology for extracting weighted association rules. GO-WAR can extract association rules with a high level of IC without loss of support and confidence from a dataset of annotated data. A case study on using of GO-WAR on publicly available GO annotation datasets is used to demonstrate that our method outperforms current state of the art approaches.