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1. DCI: learning causal differences between gene regulatory networks

   https://doi.org/10.1093/bioinformatics/btab167  

   Belyaeva, Anastasiya ; Squires, Chandler ; Uhler, Caroline ( March 2021 , Bioinformatics)

   Cowen, Lenore (Ed.)

   Abstract Summary Designing interventions to control gene regulation necessitates modeling a gene regulatory network by a causal graph. Currently, large-scale gene expression datasets from different conditions, cell types, disease states, and developmental time points are being collected. However, application of classical causal inference algorithms to infer gene regulatory networks based on such data is still challenging, requiring high sample sizes and computational resources. Here, we describe an algorithm that efficiently learns the differences in gene regulatory mechanisms between different conditions. Our difference causal inference (DCI) algorithm infers changes (i.e. edges that appeared, disappeared, or changed weight) between two causal graphs given gene expression data from the two conditions. This algorithm is efficient in its use of samples and computation since it infers the differences between causal graphs directly without estimating each possibly large causal graph separately. We provide a user-friendly Python implementation of DCI and also enable the user to learn the most robust difference causal graph across different tuning parameters via stability selection. Finally, we show how to apply DCI to single-cell RNA-seq data from different conditions and cell states, and we also validate our algorithm by predicting the effects of interventions. Availability and implementation Python package freely available at http://uhlerlab.github.io/causaldag/dci. Supplementary information Supplementary data are available at Bioinformatics online. 

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2. JRmGRN: joint reconstruction of multiple gene regulatory networks with common hub genes using data from multiple tissues or conditions

   https://doi.org/10.1093/bioinformatics/bty354  

   Deng, Wenping ; Zhang, Kui ; Liu, Sanzhen ; Zhao, Patrick X. ; Xu, Shizhong ; Wei, Hairong ; Birol, ed., Inanc ( April 2018 , Bioinformatics)

   Joint reconstruction of multiple gene regulatory networks (GRNs) using gene expression data from multiple tissues/conditions is very important for understanding common and tissue/condition-specific regulation. However, there are currently no computational models and methods available for directly constructing such multiple GRNs that not only share some common hub genes but also possess tissue/condition-specific regulatory edges.

   In this paper, we proposed a new graphic Gaussian model for joint reconstruction of multiple gene regulatory networks (JRmGRN), which highlighted hub genes, using gene expression data from several tissues/conditions. Under the framework of Gaussian graphical model, JRmGRN method constructs the GRNs through maximizing a penalized log likelihood function. We formulated it as a convex optimization problem, and then solved it with an alternating direction method of multipliers (ADMM) algorithm. The performance of JRmGRN was first evaluated with synthetic data and the results showed that JRmGRN outperformed several other methods for reconstruction of GRNs. We also applied our method to real Arabidopsis thaliana RNA-seq data from two light regime conditions in comparison with other methods, and both common hub genes and some conditions-specific hub genes were identified with higher accuracy and precision.

   JRmGRN is available as a R program from: https://github.com/wenpingd.

   Supplementary data are available at Bioinformatics online.

    

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3. SpaceX: gene co-expression network estimation for spatial transcriptomics

   https://doi.org/10.1093/bioinformatics/btac645  

   Acharyya, Satwik ; Zhou, Xiang ; Baladandayuthapani, Veerabhadran ; Kendziorski, ed., Christina ( September 2022 , Bioinformatics)

   The analysis of spatially resolved transcriptome enables the understanding of the spatial interactions between the cellular environment and transcriptional regulation. In particular, the characterization of the gene–gene co-expression at distinct spatial locations or cell types in the tissue enables delineation of spatial co-regulatory patterns as opposed to standard differential single gene analyses. To enhance the ability and potential of spatial transcriptomics technologies to drive biological discovery, we develop a statistical framework to detect gene co-expression patterns in a spatially structured tissue consisting of different clusters in the form of cell classes or tissue domains.

   We develop SpaceX (spatially dependent gene co-expression network), a Bayesian methodology to identify both shared and cluster-specific co-expression network across genes. SpaceX uses an over-dispersed spatial Poisson model coupled with a high-dimensional factor model which is based on a dimension reduction technique for computational efficiency. We show via simulations, accuracy gains in co-expression network estimation and structure by accounting for (increasing) spatial correlation and appropriate noise distributions. In-depth analysis of two spatial transcriptomics datasets in mouse hypothalamus and human breast cancer using SpaceX, detected multiple hub genes which are related to cognitive abilities for the hypothalamus data and multiple cancer genes (e.g. collagen family) from the tumor region for the breast cancer data.

   The SpaceX R-package is available at github.com/bayesrx/SpaceX.

   Supplementary data are available at Bioinformatics online.

    

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4. Hierarchical HotNet: identifying hierarchies of altered subnetworks

   https://doi.org/10.1093/bioinformatics/bty613  

   Reyna, Matthew A. ; Leiserson, Mark D. M. ; Raphael, Benjamin J. ( September 2018 , Bioinformatics)

   The analysis of high-dimensional ‘omics data is often informed by the use of biological interaction networks. For example, protein–protein interaction networks have been used to analyze gene expression data, to prioritize germline variants, and to identify somatic driver mutations in cancer. In these and other applications, the underlying computational problem is to identify altered subnetworks containing genes that are both highly altered in an ‘omics dataset and are topologically close (e.g. connected) on an interaction network.

   We introduce Hierarchical HotNet, an algorithm that finds a hierarchy of altered subnetworks. Hierarchical HotNet assesses the statistical significance of the resulting subnetworks over a range of biological scales and explicitly controls for ascertainment bias in the network. We evaluate the performance of Hierarchical HotNet and several other algorithms that identify altered subnetworks on the problem of predicting cancer genes and significantly mutated subnetworks. On somatic mutation data from The Cancer Genome Atlas, Hierarchical HotNet outperforms other methods and identifies significantly mutated subnetworks containing both well-known cancer genes and candidate cancer genes that are rarely mutated in the cohort. Hierarchical HotNet is a robust algorithm for identifying altered subnetworks across different ‘omics datasets.

   http://github.com/raphael-group/hierarchical-hotnet.

   Supplementary material are available at Bioinformatics online.

    

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5. tuxnet : a simple interface to process RNA sequencing data and infer gene regulatory networks

   https://doi.org/10.1111/tpj.14558  

   Spurney, Ryan J. ; Van den Broeck, Lisa ; Clark, Natalie M. ; Fisher, Adam P. ; de Luis Balaguer, Maria A. ; Sozzani, Rosangela ( November 2019 , The Plant Journal)

   Predicting gene regulatory networks (GRNs) from expression profiles is a common approach for identifying important biological regulators. Despite the increased use of inference methods, existing computational approaches often do not integrate RNA‐sequencing data analysis, are not automated or are restricted to users with bioinformatics backgrounds. To address these limitations, we developedtuxnet, a user‐friendly platform that can process raw RNA‐sequencing data from any organism with an existing reference genome using a modifiedtuxedopipeline (hisat 2 + cufflinkspackage) and infer GRNs from these processed data.tuxnetis implemented as a graphical user interface and can mine gene regulations, either by applying a dynamic Bayesian network (DBN) inference algorithm,genist, or a regression tree‐based pipeline,rtp‐star. We obtained time‐course expression data of aPERIANTHIA(PAN) inducible line and inferred a GRN usinggenistto illustrate the use oftuxnetwhile gaining insight into the regulations downstream of the Arabidopsis root stem cell regulatorPAN. Usingrtp‐star, we inferred the network ofATHB13, a downstream gene of PAN, for which we obtained wild‐type and mutant expression profiles. Additionally, we generated two networks using temporal data from developmental leaf data and spatial data from root cell‐type data to highlight the use oftuxnetto form new testable hypotheses from previously explored data. Our case studies feature the versatility oftuxnetwhen using different types of gene expression data to infer networks and its accessibility as a pipeline for non‐bioinformaticians to analyze transcriptome data, predict causal regulations, assess network topology and identify key regulators.

    

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