Differential Network Testing Reveals Diverging Dynamics of Organ System Interactions for Survivors and Non-survivors in Intensive Care Medicine

Statistical network analyses have become popular in many scientific disciplines, where an important task is to test for differences between two networks. We describe an overall framework for differential network testing procedures that vary regarding (1) the network estimation method, typically based on specific concepts of association, and (2) the network characteristic employed to measure the difference. Using permutation-based tests, our approach is general and applicable to various overall, node-specific or edge-specific network difference characteristics. The methods are implemented in our freely available R software package DNT, along with an R Shiny application. In a study in intensive care medicine, we compare networks based on parameters representing main organ systems to evaluate the prognosis of critically ill patients in the intensive care unit (ICU), using data from the surgical ICU of the University Medical Centre Mannheim, Germany. We specifically consider both cross-sectional comparisons between a non-survivor and a survivor group and longitudinal comparisons at two clinically relevant time points during the ICU stay: first, at admission, and second, at an event stage prior to death in non-survivors or a matching time point in survivors. The non-survivor and the survivor networks do not significantly differ at the admission stage. However, the organ system interactions of the survivors then stabilize at the event stage, revealing significantly more network edges, whereas those of the non-survivors do not. In particular, the liver appears to play a central role for the observed increased connectivity in the survivor network at the event stage.

Disparity-filtered differential correlation network analysis: a case study on CRC metabolomics

Differential network analysis has become a widely used technique to investigate changes of interactions among different conditions. Although the relationship between observed interactions and biochemical mechanisms is hard to establish, differential network analysis can provide useful insights about dysregulated pathways and candidate biomarkers. The available methods to detect differential interactions are heterogeneous and often rely on assumptions that are unrealistic in many applications. To address these issues, we develop a novel method for differential network analysis, using the so-called disparity filter as network reduction technique. In addition, we propose a classification model based on the inferred network interactions. The main novelty of this work lies in its ability to preserve connections that are statistically significant with respect to a null model without favouring any resolution scale, as a hard threshold would do, and without Gaussian assumptions. The method was tested using a published metabolomic dataset on colorectal cancer (CRC). Detected hub metabolites were consistent with recent literature and the classifier was able to distinguish CRC from polyp and healthy subjects with great accuracy. In conclusion, the proposed method provides a new simple and effective framework for the identification of differential interaction patterns and improves the biological interpretation of metabolomics data.

Differential Network Analysis of Longitudinal Gene Expression in Response to Perturbations

Understanding changes in gene expression under the effects of a perturbation is a key goal of systems biology. A powerful approach to address this goal uses gene networks and describes the perturbation’s effects as a rewiring of each gene’s connections. This approach is known as differential network (DN) analysis. Here, we used DNs to analyze RNA-sequencing time series datasets, focusing on expression changes: (i) In the saliva of a human subject after vaccination with a pneumococcal vaccine (PPSV23), and (ii) in B cells treated ex vivo with a monoclonal antibody drug (Rituximab). Using network community detection, we revealed the collective behavior of clusters of genes, and detected communities of genes based on their longitudinal behavior, and corresponding pathway activations. We identified biological pathways consistent with the mechanism of action of the vaccine and with Rituximab’s targets. The approach may be useful in drug development by providing an effective analysis of expressing changes in response to a drug.

Identifying Network Biomarkers of Cancer By Sample-Specific Differential Network

Abundant datasets generated from various big science projects on diseases have presented great challenges and opportunities, which are contributed to unfold the complexity of diseases. The discovery of disease- associated molecular networks for each individual plays an important role in personalized therapy and precision treatment of cancer based on the reference networks. However, there are no effective ways to distinguish the consistency of different reference networks. In this study, we developed a statistical method, i.e. a sample-specific differential network (SSDN), to construct and analyze such networks based on gene expression of a single sample against a reference dataset. We proved that the SSDN is structurally consistent even with different reference datasets if the reference dataset can follow certain conditions. The SSDN also can be used to identify patient-specific disease modules or network biomarkers as well as predict the potential driver genes of a tumor sample.

Pedestrian Behavior Recognition Based on Improved Dual-stream Network with Differential Feature in Surveillance Video

In order to improve the pedestrian behavior recognition accuracy of video sequences in complex background, an improved spatial-temporal two-stream network is proposed in this paper. Firstly, the deep differential network is used to replace the temporal-stream network so as to improve the representation ability and extraction efficiency of spatiotemporal features. Then, the improved Softmax loss function based on decision-making level feature fusion mechanism is used to train the model, which can retain the spatiotemporal characteristics of images between different network frames to a greater extent and reflect the action category of pedestrians more realistically. Simulation results show that the proposed improved network achieves 87% recognition accuracy on the self-built infrared dataset, and the computational efficiency is improved by 15.1%.

The Analysis of Gene Expression Data Incorporating Tumor Purity Information

The tumor microenvironment is composed of tumor cells, stroma cells, immune cells, blood vessels, and other associated non-cancerous cells. Gene expression measurements on tumor samples are an average over cells in the microenvironment. However, research questions often seek answers about tumor cells rather than the surrounding non-tumor tissue. Previous studies have suggested that the tumor purity (TP)—the proportion of tumor cells in a solid tumor sample—has a confounding effect on differential expression (DE) analysis of high vs. low survival groups. We investigate three ways incorporating the TP information in the two statistical methods used for analyzing gene expression data, namely, differential network (DN) analysis and DE analysis. Analysis 1 ignores the TP information completely, Analysis 2 uses a truncated sample by removing the low TP samples, and Analysis 3 uses TP as a covariate in the underlying statistical models. We use three gene expression data sets related to three different cancers from the Cancer Genome Atlas (TCGA) for our investigation. The networks from Analysis 2 have greater amount of differential connectivity in the two networks than that from Analysis 1 in all three cancer datasets. Similarly, Analysis 1 identified more differentially expressed genes than Analysis 2. Results of DN and DE analyses using Analysis 3 were mostly consistent with those of Analysis 1 across three cancers. However, Analysis 3 identified additional cancer-related genes in both DN and DE analyses. Our findings suggest that using TP as a covariate in a linear model is appropriate for DE analysis, but a more robust model is needed for DN analysis. However, because true DN or DE patterns are not known for the empirical datasets, simulated datasets can be used to study the statistical properties of these methods in future studies.

Gene regulatory networks analysis of muscle-invasive bladder cancer subtypes using differential graphical model

Background Recently, erdafitinib (Balversa), the first targeted therapy drug for genetic alteration, was approved to metastatic urothelial carcinoma. Cancer genomics research has been greatly encouraged. Currently, a large number of gene regulatory networks between different states have been constructed, which can reveal the difference states of genes. However, they have not been applied to the subtypes of Muscle-invasive bladder cancer (MIBC). Results In this paper, we propose a method that construct gene regulatory networks under different molecular subtypes of MIBC, and analyse the regulatory differences between different molecular subtypes. Through differential expression analysis and the differential network analysis of the top 100 differential genes in the network, we find that SERPINI1, NOTUM, FGFR1 and other genes have significant differences in expression and regulatory relationship between MIBC subtypes. Conclusions Furthermore, pathway enrichment analysis and differential network analysis demonstrate that Neuroactive ligand-receptor interaction and Cytokine-cytokine receptor interaction are significantly enriched pathways, and the genes contained in them are significant diversity in the subtypes of bladder cancer.

Comparing Statistical Tests for Differential Network Analysis of Gene Modules

Genes often work together to perform complex biological processes, and “networks” provide a versatile framework for representing the interactions between multiple genes. Differential network analysis (DiNA) quantifies how this network structure differs between two or more groups/phenotypes (e.g., disease subjects and healthy controls), with the goal of determining whether differences in network structure can help explain differences between phenotypes. In this paper, we focus on gene co-expression networks, although in principle, the methods studied can be used for DiNA for other types of features (e.g., metabolome, epigenome, microbiome, proteome, etc.). Three common applications of DiNA involve (1) testing whether the connections to a single gene differ between groups, (2) testing whether the connection between a pair of genes differs between groups, or (3) testing whether the connections within a “module” (a subset of 3 or more genes) differs between groups. This article focuses on the latter, as there is a lack of studies comparing statistical methods for identifying differentially co-expressed modules (DCMs). Through extensive simulations, we compare several previously proposed test statistics and a new p-norm difference test (PND). We demonstrate that the true positive rate of the proposed PND test is competitive with and often higher than the other methods, while controlling the false positive rate. The R package discoMod (differentially co-expressed modules) implements the proposed method and provides a full pipeline for identifying DCMs: clustering tools to derive gene modules, tests to identify DCMs, and methods for visualizing the results.