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1. GLIDER: function prediction from GLIDE-based neighborhoods

   https://doi.org/10.1093/bioinformatics/btac322  

   Devkota, Kapil ; Schmidt, Henri ; Werenski, Matt ; Murphy, James M. ; Erden, Mert ; Arsenescu, Victor ; Cowen, Lenore J. ; Valencia, ed., Alfonso ( May 2022 , Bioinformatics)

   Protein function prediction, based on the patterns of connection in a protein–protein interaction (or association) network, is perhaps the most studied of the classical, fundamental inference problems for biological networks. A highly successful set of recent approaches use random walk-based low-dimensional embeddings that tend to place functionally similar proteins into coherent spatial regions. However, these approaches lose valuable local graph structure from the network when considering only the embedding. We introduce GLIDER, a method that replaces a protein–protein interaction or association network with a new graph-based similarity network. GLIDER is based on a variant of our previous GLIDE method, which was designed to predict missing links in protein–protein association networks, capturing implicit local and global (i.e. embedding-based) graph properties.

   GLIDER outperforms competing methods on the task of predicting GO functional labels in cross-validation on a heterogeneous collection of four human protein–protein association networks derived from the 2016 DREAM Disease Module Identification Challenge, and also on three different protein–protein association networks built from the STRING database. We show that this is due to the strong functional enrichment that is present in the local GLIDER neighborhood in multiple different types of protein–protein association networks. Furthermore, we introduce the GLIDER graph neighborhood as a way for biologists to visualize the local neighborhood of a disease gene. As an application, we look at the local GLIDER neighborhoods of a set of known Parkinson’s Disease GWAS genes, rediscover many genes which have known involvement in Parkinson’s disease pathways, plus suggest some new genes to study.

   All code is publicly available and can be accessed here: https://github.com/kap-devkota/GLIDER.

   Supplementary data are available at Bioinformatics online.

    

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2. EnGRaiN : a supervised ensemble learning method for recovery of large-scale gene regulatory networks

   https://doi.org/10.1093/bioinformatics/btab829  

   Aluru, Maneesha ; Shrivastava, Harsh ; Chockalingam, Sriram P. ; Shivakumar, Shruti ; Aluru, Srinivas ; Martelli, ed., Pier Luigi ( December 2021 , Bioinformatics)

   Reconstruction of genome-scale networks from gene expression data is an actively studied problem. A wide range of methods that differ between the types of interactions they uncover with varying trade-offs between sensitivity and specificity have been proposed. To leverage benefits of multiple such methods, ensemble network methods that combine predictions from resulting networks have been developed, promising results better than or as good as the individual networks. Perhaps owing to the difficulty in obtaining accurate training examples, these ensemble methods hitherto are unsupervised.

   In this article, we introduce EnGRaiN, the first supervised ensemble learning method to construct gene networks. The supervision for training is provided by small training datasets of true edge connections (positives) and edges known to be absent (negatives) among gene pairs. We demonstrate the effectiveness of EnGRaiN using simulated datasets as well as a curated collection of Arabidopsis thaliana datasets we created from microarray datasets available from public repositories. EnGRaiN shows better results not only in terms of receiver operating characteristic and PR characteristics for both real and simulated datasets compared with unsupervised methods for ensemble network construction, but also generates networks that can be mined for elucidating complex biological interactions.

   EnGRaiN software and the datasets used in the study are publicly available at the github repository: https://github.com/AluruLab/EnGRaiN.

   Supplementary data are available at Bioinformatics online.

    

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3. Towards future directions in data-integrative supervised prediction of human aging-related genes

   https://doi.org/10.1093/bioadv/vbac081  

   Li, Qi ; Newaz, Khalique ; Milenković, Tijana ; Kuijjer, ed., Marieke Lydia ( November 2022 , Bioinformatics Advances)

   Identification of human genes involved in the aging process is critical due to the incidence of many diseases with age. A state-of-the-art approach for this purpose infers a weighted dynamic aging-specific subnetwork by mapping gene expression (GE) levels at different ages onto the protein–protein interaction network (PPIN). Then, it analyzes this subnetwork in a supervised manner by training a predictive model to learn how network topologies of known aging- versus non-aging-related genes change across ages. Finally, it uses the trained model to predict novel aging-related gene candidates. However, the best current subnetwork resulting from this approach still yields suboptimal prediction accuracy. This could be because it was inferred using outdated GE and PPIN data. Here, we evaluate whether analyzing a weighted dynamic aging-specific subnetwork inferred from newer GE and PPIN data improves prediction accuracy upon analyzing the best current subnetwork inferred from outdated data.

   Unexpectedly, we find that not to be the case. To understand this, we perform aging-related pathway and Gene Ontology term enrichment analyses. We find that the suboptimal prediction accuracy, regardless of which GE or PPIN data is used, may be caused by the current knowledge about which genes are aging-related being incomplete, or by the current methods for inferring or analyzing an aging-specific subnetwork being unable to capture all of the aging-related knowledge. These findings can potentially guide future directions towards improving supervised prediction of aging-related genes via -omics data integration.

   All data and code are available at zenodo, DOI: 10.5281/zenodo.6995045.

   Supplementary data are available at Bioinformatics Advances online.

    

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4. MCPNet: a parallel maximum capacity-based genome-scale gene network construction framework

   https://doi.org/10.1093/bioinformatics/btad373  

   Pan, Tony C. ; Chockalingam, Sriram P. ; Aluru, Maneesha ; Aluru, Srinivas ; Cowen, ed., Lenore ( June 2023 , Bioinformatics)

   Gene network reconstruction from gene expression profiles is a compute- and data-intensive problem. Numerous methods based on diverse approaches including mutual information, random forests, Bayesian networks, correlation measures, as well as their transforms and filters such as data processing inequality, have been proposed. However, an effective gene network reconstruction method that performs well in all three aspects of computational efficiency, data size scalability, and output quality remains elusive. Simple techniques such as Pearson correlation are fast to compute but ignore indirect interactions, while more robust methods such as Bayesian networks are prohibitively time consuming to apply to tens of thousands of genes.

   We developed maximum capacity path (MCP) score, a novel maximum-capacity-path-based metric to quantify the relative strengths of direct and indirect gene–gene interactions. We further present MCPNet, an efficient, parallelized gene network reconstruction software based on MCP score, to reverse engineer networks in unsupervised and ensemble manners. Using synthetic and real Saccharomyces cervisiae datasets as well as real Arabidopsis thaliana datasets, we demonstrate that MCPNet produces better quality networks as measured by AUPRC, is significantly faster than all other gene network reconstruction software, and also scales well to tens of thousands of genes and hundreds of CPU cores. Thus, MCPNet represents a new gene network reconstruction tool that simultaneously achieves quality, performance, and scalability requirements.

   Source code freely available for download at https://doi.org/10.5281/zenodo.6499747 and https://github.com/AluruLab/MCPNet, implemented in C++ and supported on Linux.

    

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5. WMGCN: Weighted Meta-Graph Based Graph Convolutional Networks for Representation Learning in Heterogeneous Networks

   JINLI ZHANG, ZONGLI JIANG ( April 2020 , IEEE access)

   Network embedding has been an effective tool to analyze heterogeneous networks (HNs) by representing nodes in a low-dimensional space. Although many recent methods have been proposed for representation learning of HNs, there is still much room for improvement. Random walks based methods are currently popular methods to learn network embedding; however, they are random and limited by the length of sampled walks, and have difculty capturing network structural information. Some recent researches proposed using meta paths to express the sample relationship in HNs. Another popular graph learning model, the graph convolutional network (GCN) is known to be capable of better exploitation of network topology, but the current design of GCN is intended for homogenous networks. This paper proposes a novel combination of meta-graph and graph convolution, the meta-graph based graph convolutional networks (MGCN). To fully capture the complex long semantic information, MGCN utilizes different meta-graphs in HNs. As different meta-graphs express different semantic relationships, MGCN learns the weights of different meta-graphs to make up for the loss of semantics when applying GCN. In addition, we improve the current convolution design by adding node self-signicance. To validate our model in learning feature representation, we present comprehensive experiments on four real-world datasets and two representation tasks: classication and link prediction. WMGCN's representations can improve accuracy scores by up to around 10% in comparison to other popular representation learning models. What's more, WMGCN'feature learning outperforms other popular baselines. The experimental results clearly show our model is superior over other state-of-the-art representation learning algorithms. 

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