Network Reconstruction Approach Research Articles

Inference of human contact networks based on epidemic data

A key challenge in epidemic modeling is the lack of adequate data on population interactions (such as traffic flow or mobility patterns) which result in the spread of infectious diseases. Knowledge of social contact patterns is crucial for public health professionals to devise effective non-pharmaceutical interventions to control epidemics. This paper focuses on inferring social contact rates from reported infection counts during the spread of an infectious disease, addressing the increased difficulty that arises when dealing with “sparse” contact networks where only a small subset of the edges have non-zero weights. Specifically, a new geographically constrained lasso approach for network reconstruction for non-homogeneous mixing Susceptible-Infected-Removed (SIR) disease spread models is presented. The new network reconstruction method can explicitly account for the spatial proximity of network nodes in estimating the disease transmission rates and predicting the future evolution of the epidemic dynamics. Extensive numerical experiments are presented to show the proposed method outperforms existing approaches in terms of accuracy of contact identification under various graph topologies. A case study based on real data from the COVID-19 pandemic is presented to demonstrate the application of the approach for inferring contact structures and a counterfactual scenario analysis to assess effectiveness of containment strategies.

Computing the Bounds of the Number of Reticulations in a Tree-Child Network That Displays a Set of Trees.

Phylogenetic network is an evolutionary model that uses a rooted directed acyclic graph (instead of a tree) to model an evolutionary history of species in which reticulate events (e.g., hybrid speciation or horizontal gene transfer) occurred. Tree-child network is a kind of phylogenetic network with structural constraints. Existing approaches for tree-child network reconstruction can be slow for large data. In this study, we present several computational approaches for bounding from below the number of reticulations in a tree-child network that displays a given set of rooted binary phylogenetic trees. In addition, we also present some theoretical results on bounding from above the number of reticulations. Through simulation, we demonstrate that the new lower bounds on the reticulation number for tree-child networks can practically be computed for large tree data. The bounds can provide estimates of reticulation for relatively large data.

Causal connectivity measures for pulse-output network reconstruction: Analysis and applications

The causal connectivity of a network is often inferred to understand network function. It is arguably acknowledged that the inferred causal connectivity relies on the causality measure one applies, and it may differ from the network's underlying structural connectivity. However, the interpretation of causal connectivity remains to be fully clarified, in particular, how causal connectivity depends on causality measures and how causal connectivity relates to structural connectivity. Here, we focus on nonlinear networks with pulse signals as measured output, e.g., neural networks with spike output, and address the above issues based on four commonly utilized causality measures, i.e., time-delayed correlation coefficient, time-delayed mutual information, Granger causality, and transfer entropy. We theoretically show how these causality measures are related to one another when applied to pulse signals. Taking a simulated Hodgkin-Huxley network and a real mouse brain network as two illustrative examples, we further verify the quantitative relations among the four causality measures and demonstrate that the causal connectivity inferred by any of the four well coincides with the underlying network structural connectivity, therefore illustrating a direct link between the causal and structural connectivity. We stress that the structural connectivity of pulse-output networks can be reconstructed pairwise without conditioning on the global information of all other nodes in a network, thus circumventing the curse of dimensionality. Our framework provides a practical and effective approach for pulse-output network reconstruction.

Reliable network inference from unreliable data: A tutorial on latent network modeling using STRAND.

Social network analysis provides an important framework for studying the causes, consequences, and structure of social ties. However, standard self-report measures-for example, as collected through the popular "name-generator" method-do not provide an impartial representation of such ties, be they transfers, interactions, or social relationships. At best, they represent perceptions filtered through the cognitive biases of respondents. Individuals may, for example, report transfers that did not really occur, or forget to mention transfers that really did. The propensity to make such reporting inaccuracies is both an individual-level and item-level characteristic-variable across members of any given group. Past research has highlighted that many network-level properties are highly sensitive to such reporting inaccuracies. However, there remains a dearth of easily deployed statistical tools that account for such biases. To address this issue, we provide a latent network model that allows researchers to jointly estimate parameters measuring both reporting biases and a latent, underlying social network. Building upon past research, we conduct several simulation experiments in which network data are subject to various reporting biases, and find that these reporting biases strongly impact fundamental network properties. These impacts are not adequately remedied using the most frequently deployed approaches for network reconstruction in the social sciences (i.e., treating either the union or the intersection of double-sampled data as the true network), but are appropriately resolved through the use of our latent network models. To make implementation of our models easier for end-users, we provide a fully documented R package, STRAND, and include a tutorial illustrating its functionality when applied to empirical food/money sharing data from a rural Colombian population. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Constructing gene regulatory networks using epigenetic data

The biological processes that drive cellular function can be represented by a complex network of interactions between regulators (transcription factors) and their targets (genes). A cell’s epigenetic state plays an important role in mediating these interactions, primarily by influencing chromatin accessibility. However, how to effectively use epigenetic data when constructing a gene regulatory network remains an open question. Almost all existing network reconstruction approaches focus on estimating transcription factor to gene connections using transcriptomic data. In contrast, computational approaches for analyzing epigenetic data generally focus on improving transcription factor binding site predictions rather than deducing regulatory network relationships. We bridged this gap by developing SPIDER, a network reconstruction approach that incorporates epigenetic data into a message-passing framework to estimate gene regulatory networks. We validated SPIDER’s predictions using ChIP-seq data from ENCODE and found that SPIDER networks are both highly accurate and include cell-line-specific regulatory interactions. Notably, SPIDER can recover ChIP-seq verified transcription factor binding events in the regulatory regions of genes that do not have a corresponding sequence motif. The networks estimated by SPIDER have the potential to identify novel hypotheses that will allow us to better characterize cell-type and phenotype specific regulatory mechanisms.

Performance Assessment of the Network Reconstruction Approaches on Various Interactomes.

Beyond the list of molecules, there is a necessity to collectively consider multiple sets of omic data and to reconstruct the connections between the molecules. Especially, pathway reconstruction is crucial to understanding disease biology because abnormal cellular signaling may be pathological. The main challenge is how to integrate the data together in an accurate way. In this study, we aim to comparatively analyze the performance of a set of network reconstruction algorithms on multiple reference interactomes. We first explored several human protein interactomes, including PathwayCommons, OmniPath, HIPPIE, iRefWeb, STRING, and ConsensusPathDB. The comparison is based on the coverage of each interactome in terms of cancer driver proteins, structural information of protein interactions, and the bias toward well-studied proteins. We next used these interactomes to evaluate the performance of network reconstruction algorithms including all-pair shortest path, heat diffusion with flux, personalized PageRank with flux, and prize-collecting Steiner forest (PCSF) approaches. Each approach has its own merits and weaknesses. Among them, PCSF had the most balanced performance in terms of precision and recall scores when 28 pathways from NetPath were reconstructed using the listed algorithms. Additionally, the reference interactome affects the performance of the network reconstruction approaches. The coverage and disease- or tissue-specificity of each interactome may vary, which may result in differences in the reconstructed networks.

A strategy to incorporate prior knowledge into correlation network cutoff selection

Correlation networks are frequently used to statistically extract biological interactions between omics markers. Network edge selection is typically based on the statistical significance of the correlation coefficients. This procedure, however, is not guaranteed to capture biological mechanisms. We here propose an alternative approach for network reconstruction: a cutoff selection algorithm that maximizes the overlap of the inferred network with available prior knowledge. We first evaluate the approach on IgG glycomics data, for which the biochemical pathway is known and well-characterized. Importantly, even in the case of incomplete or incorrect prior knowledge, the optimal network is close to the true optimum. We then demonstrate the generalizability of the approach with applications to untargeted metabolomics and transcriptomics data. For the transcriptomics case, we demonstrate that the optimized network is superior to statistical networks in systematically retrieving interactions that were not included in the biological reference used for optimization.

Personalized whole-body models integrate metabolism, physiology, and the gut microbiome.

Comprehensive molecular‐level models of human metabolism have been generated on a cellular level. However, models of whole‐body metabolism have not been established as they require new methodological approaches to integrate molecular and physiological data. We developed a new metabolic network reconstruction approach that used organ‐specific information from literature and omics data to generate two sex‐specific whole‐body metabolic (WBM) reconstructions. These reconstructions capture the metabolism of 26 organs and six blood cell types. Each WBM reconstruction represents whole‐body organ‐resolved metabolism with over 80,000 biochemical reactions in an anatomically and physiologically consistent manner. We parameterized the WBM reconstructions with physiological, dietary, and metabolomic data. The resulting WBM models could recapitulate known inter‐organ metabolic cycles and energy use. We also illustrate that the WBM models can predict known biomarkers of inherited metabolic diseases in different biofluids. Predictions of basal metabolic rates, by WBM models personalized with physiological data, outperformed current phenomenological models. Finally, integrating microbiome data allowed the exploration of host–microbiome co‐metabolism. Overall, the WBM reconstructions, and their derived computational models, represent an important step toward virtual physiological humans.

Unraveling the metabolic and machinery constraints on protein secretion through a novel systems biology framework

In mammalian cells, metabolism is a core process driving homeostasis, but variations in other cell processes largely define cell type identity and cell‐type specific functions. The profile of secreted and membrane proteins show substantial cell‐type specificity and drive many tissue specific functions. These proteins, encoded by up to 1/3 of mammalian protein‐coding genes, include hormones, membrane proteins, and extracellular enzymes, and these are synthesized and trafficked through the secretory pathway. The pathway complexity, however, obfuscates its impact on the secretion of different proteins. Unraveling its impact on diverse proteins is particularly important since the pathway is implicated in many diseases and harnessed for biopharmaceutical production. Through the use of network reconstruction approaches and protein interaction assays, we have mapped out the core secretory pathway and integrated it with our genome‐scale metabolic models of human, mouse, and Chinese hamster ovary cells. We first deploy graph‐based approaches to evaluate the dependency of protein secretion on diverse human secreted proteins. We then deployed constraint‐based modeling to quantify the bioenergetic demands for the synthesis and secretion of these proteins. Finally, we deployed these models to engineer mammalian cells for enhanced secretion of high‐value biologic drugs. Thus, we present a platform that enables the study and engineering of the mammalian secretory pathway and metabolism for systems biotechnology.Support or Funding InformationNIGMS R35 GM119850 and the Novo Nordisk Foundation Center for Biosustainability NNF10CC1016517

Inferring Causal Gene Regulatory Networks from Coupled Single-Cell Expression Dynamics Using Scribe.

Here, we present Scribe (https://github.com/aristoteleo/Scribe-py), a toolkit for detecting and visualizing causal regulatory interactions between genes and explore the potential for single-cell experiments to power network reconstruction. Scribe employs restricted directed information to determine causality by estimating the strength of information transferred from a potential regulator to its downstream target. We apply Scribe and other leading approaches for causal network reconstruction to several types of single-cell measurements and show that there is a dramatic drop in performance for "pseudotime"-ordered single-cell data compared with true time-series data. We demonstrate that performing causal inference requires temporal coupling between measurements. We show that methods such as "RNA velocity" restore some degree of coupling through an analysis of chromaffin cell fate commitment. These analyses highlight a shortcoming in experimental and computational methods for analyzing gene regulation at single-cell resolution and suggest ways of overcoming it.

Stabilized Reconstruction of Signaling Networks from Single-Cell Cue-Response Data

Inferring cell-signaling networks from high-throughput data is a challenging problem in systems biology. Recent advances in cytometric technology enable us to measure the abundance of a large number of proteins at the single-cell level across time. Traditional network reconstruction approaches usually consider each time point separately, resulting thus in inferred networks that strongly vary across time. To account for the possibly time-invariant physical couplings within the signaling network, we extend the traditional graphical lasso with an additional regularizer that penalizes network variations over time. ROC evaluation of the method on in silico data showed higher reconstruction accuracy than standard graphical lasso. We also tested our approach on single-cell mass cytometry data of IFNγ-stimulated THP1 cells with 26 phospho-proteins simultaneously measured. Our approach recapitulated known signaling relationships, such as connection within the JAK/STAT pathway, and was further validated in characterizing perturbed signaling network with PI3K, MEK1/2 and AMPK inhibitors.

A Bioinformatics Approach to Explore MicroRNAs as Tools to Bridge Pathways Between Plants and Animals. Is DNA Damage Response (DDR) a Potential Target Process?

MicroRNAs, highly-conserved small RNAs, act as key regulators of many biological functions in both plants and animals by post-transcriptionally regulating gene expression through interactions with their target mRNAs. The microRNA research is a dynamic field, in which new and unconventional aspects are emerging alongside well-established roles in development and stress adaptation. A recent hypothesis states that miRNAs can be transferred from one species to another and potentially target genes across distant species. Here, we propose to look into the trans-kingdom potential of miRNAs as a tool to bridge conserved pathways between plant and human cells. To this aim, a novel multi-faceted bioinformatic analysis pipeline was developed, enabling the investigation of common biological processes and genes targeted in plant and human transcriptome by a set of publicly available Medicago truncatula miRNAs. Multiple datasets, including miRNA, gene, transcript and protein sequences, expression profiles and genetic interactions, were used. Three different strategies were employed, namely a network-based pipeline, an alignment-based pipeline, and a M. truncatula network reconstruction approach, to study functional modules and to evaluate gene/protein similarities among miRNA targets. The results were compared in order to find common features, e.g., microRNAs targeting similar processes. Biological processes like exocytosis and response to viruses were common denominators in the investigated species. Since the involvement of miRNAs in the regulation of DNA damage response (DDR)-associated pathways is barely explored, especially in the plant kingdom, a special attention is given to this aspect. Hereby, miRNAs predicted to target genes involved in DNA repair, recombination and replication, chromatin remodeling, cell cycle and cell death were identified in both plants and humans, paving the way for future interdisciplinary advancements.

Network as a Biomarker: A Novel Network-Based Sparse Bayesian Machine for Pathway-Driven Drug Response Prediction.

With the advances in different biological networks including gene regulation, gene co-expression, protein–protein interaction networks, and advanced approaches for network reconstruction, analysis, and interpretation, it is possible to discover reliable and accurate molecular network-based biomarkers for monitoring cancer treatment. Such efforts will also pave the way toward the realization of biomarker-driven personalized medicine against cancer. Previously, we have reconstructed disease-specific driver signaling networks using multi-omics profiles and cancer signaling pathway data. In this study, we developed a network-based sparse Bayesian machine (NBSBM) approach, using previously derived disease-specific driver signaling networks to predict cancer cell responses to drugs. NBSBM made use of the information encoded in a disease-specific (differentially expressed) network to improve its prediction performance in problems with a reduced amount of training data and a very high-dimensional feature space. Sparsity in NBSBM is favored by a spike and slab prior distribution, which is combined with a Markov random field prior that encodes the network of feature dependencies. Gene features that are connected in the network are assumed to be both relevant and irrelevant to drug responses. We compared the proposed method with network-based support vector machine (NBSVM) approaches and found that the NBSBM approach could achieve much better accuracy than the other two NBSVM methods. The gene modules selected from the disease-specific driver networks for predicting drug sensitivity might be directly involved in drug sensitivity or resistance. This work provides a disease-specific network-based drug sensitivity prediction approach and can uncover the potential mechanisms of the action of drugs by selecting the most predictive sub-networks from the disease-specific network.

Decoding competing endogenous RNA networks for cancer biomarker discovery.

Crosstalk between competing endogenous RNAs (ceRNAs) is mediated by shared microRNAs (miRNAs) and plays important roles both in normal physiology and tumorigenesis; thus, it is attractive for systems-level decoding of gene regulation. As ceRNA networks link the function of miRNAs with that of transcripts sharing the same miRNA response elements (MREs), e.g. pseudogenes, competing mRNAs, long non-coding RNAs, and circular RNAs, the perturbation of crucial interactions in ceRNA networks may contribute to carcinogenesis by affecting the balance of cellular regulatory system. Therefore, discovering biomarkers that indicate cancer initiation, development, and/or therapeutic responses via reconstructing and analyzing ceRNA networks is of clinical significance. In this review, the regulatory function of ceRNAs in cancer and crucial determinants of ceRNA crosstalk are firstly discussed to gain a global understanding of ceRNA-mediated carcinogenesis. Then, computational and experimental approaches for ceRNA network reconstruction and ceRNA validation, respectively, are described from a systems biology perspective. We focus on strategies for biomarker identification based on analyzing ceRNA networks and highlight the translational applications of ceRNA biomarkers for cancer management. This article will shed light on the significance of miRNA-mediated ceRNA interactions and provide important clues for discovering ceRNA network-based biomarker in cancer biology, thereby accelerating the pace of precision medicine and healthcare for cancer patients.

Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation.

Being able to explore the metabolism of broad metabolizing cells is of critical importance in many research fields. This article presents an original modeling solution combining metabolic network and omics data to identify modulated metabolic pathways and changes in metabolic functions occurring during differentiation of a human hepatic cell line (HepaRG). Our results confirm the activation of hepato-specific functionalities and newly evidence modulation of other metabolic pathways, which could not be evidenced from transcriptomic data alone. Our method takes advantage of the network structure to detect changes in metabolic pathways that do not have gene annotations and exploits flux analyses techniques to identify activated metabolic functions. Compared to the usual cell-specific metabolic network reconstruction approaches, it limits false predictions by considering several possible network configurations to represent one phenotype rather than one arbitrarily selected network. Our approach significantly enhances the comprehensive and functional assessment of cell metabolism, opening further perspectives to investigate metabolic shifts occurring within various biological contexts.

Reconstructing Networks with Unknown and Heterogeneous Errors

The vast majority of network datasets contains errors and omissions, although this is rarely incorporated in traditional network analysis. Recently, an increasing effort has been made to fill this methodological gap by developing network reconstruction approaches based on Bayesian inference. These approaches, however, rely on assumptions of uniform error rates and on direct estimations of the existence of each edge via repeated measurements, something that is currently unavailable for the majority of network data. Here we develop a Bayesian reconstruction approach that lifts these limitations by not only allowing for heterogeneous errors, but also for single edge measurements without direct error estimates. Our approach works by coupling the inference approach with structured generative network models, which enable the correlations between edges to be used as reliable uncertainty estimates. Although our approach is general, we focus on the stochastic block model as the basic generative process, from which efficient nonparametric inference can be performed, and yields a principled method to infer hierarchical community structure from noisy data. We demonstrate the efficacy of our approach with a variety of empirical and artificial networks.

Inferring gene expression networks with hubs using a degree weighted Lasso approach.

Genome-scale gene networks contain regulatory genes called hubs that have many interaction partners. These genes usually play an essential role in gene regulation and cellular processes. Despite recent advancements in high-throughput technology, inferring gene networks with hub genes from high-dimensional data still remains a challenging problem. Novel statistical network inference methods are needed for efficient and accurate reconstruction of hub networks from high-dimensional data. To address this challenge we propose DW-Lasso, a degree weighted Lasso (least absolute shrinkage and selection operator) method which infers gene networks with hubs efficiently under the low sample size setting. Our network reconstruction approach is formulated as a two stage procedure: first, the degree of networks is estimated iteratively, and second, the gene regulatory network is reconstructed using degree information. A useful property of the proposed method is that it naturally favors the accumulation of neighbors around hub genes and thereby helps in accurate modeling of the high-throughput data under the assumption that the underlying network exhibits hub structure. In a simulation study, we demonstrate good predictive performance of the proposed method in comparison to traditional Lasso type methods in inferring hub and scale-free graphs. We show the effectiveness of our method in an application to microarray data of Escherichia coli and RNA sequencing data of Kidney Clear Cell Carcinoma from The Cancer Genome Atlas datasets. Under the GNU General Public Licence at https://cran.r-project.org/package=DWLasso. Supplementary data are available at Bioinformatics online.

The Distance Precision Matrix: computing networks from non-linear relationships.

MotivationFull-order partial correlation, a fundamental approach for network reconstruction, e.g. in the context of gene regulation, relies on the precision matrix (the inverse of the covariance matrix) as an indicator of which variables are directly associated. The precision matrix assumes Gaussian linear data and its entries are zero for pairs of variables that are independent given all other variables. However, there is still very little theory on network reconstruction under the assumption of non-linear interactions among variables.ResultsWe propose Distance Precision Matrix, a network reconstruction method aimed at both linear and non-linear data. Like partial distance correlation, it builds on distance covariance, a measure of possibly non-linear association, and on the idea of full-order partial correlation, which allows to discard indirect associations. We provide evidence that the Distance Precision Matrix method can successfully compute networks from linear and non-linear data, and consistently so across different datasets, even if sample size is low. The method is fast enough to compute networks on hundreds of nodes.Availability and implementationAn R package DPM is available at https://github.molgen.mpg.de/ghanbari/DPM.Supplementary information Supplementary data are available at Bioinformatics online.

Application Research of Mathematical Economic Model in Terms of Gas Distribution and Reconstruction of Distribution Field in Coal Mine Stope

Research of the application on Mathematical Economic Model in Terms of Gas Distribution and Reconstruction of Distribution Field in Coal Mine Stope The research is divided into 2 sections, the first section is to analyze the application of mathematical economic model in coal mine stope gas distribution; The second section is to analyze the application of mathematic economic model in reconstruction of coal mine stope gas distribution field. From the perspective of mathematic economy, when there are a lot of data samples participating in distribution field reconstruction, the reconstruction based on neutral network algorithm is slightly superior to space information statistical approach. When there are a few data samples participating in reconstruction, the spatial system statistical approach is obviously superior to neutral network reconstruction approach in terms of reconstruction result. It is essential to choose coal mine stope gas distribution field reconstruction method scientifically so as to reduce occurrence of gas accident.

Functional brain networks reconstruction using group sparsity-regularized learning.

Investigating functional brain networks and patterns using sparse representation of fMRI data has received significant interests in the neuroimaging community. It has been reported that sparse representation is effective in reconstructing concurrent and interactive functional brain networks. To date, most of data-driven network reconstruction approaches rarely take consideration of anatomical structures, which are the substrate of brain function. Furthermore, it has been rarely explored whether structured sparse representation with anatomical guidance could facilitate functional networks reconstruction. To address this problem, in this paper, we propose to reconstruct brain networks utilizing the structure guided group sparse regression (S2GSR) in which 116 anatomical regions from the AAL template, as prior knowledge, are employed to guide the network reconstruction when performing sparse representation of whole-brain fMRI data. Specifically, we extract fMRI signals from standard space aligned with the AAL template. Then by learning a global over-complete dictionary, with the learned dictionary as a set of features (regressors), the group structured regression employs anatomical structures as group information to regress whole brain signals. Finally, the decomposition coefficients matrix is mapped back to the brain volume to represent functional brain networks and patterns. We use the publicly available Human Connectome Project (HCP) Q1 dataset as the test bed, and the experimental results indicate that the proposed anatomically guided structure sparse representation is effective in reconstructing concurrent functional brain networks.