•INDEED integrates differential expression & network analyses for biomarker discovery.•INDEED builds sparse network based on partial correlation for better visualization.•INDEED’s performance in ...solving classification and regression problems is evaluated.
Differential expression (DE) analysis is commonly used to identify biomarker candidates that have significant changes in their expression levels between distinct biological groups. One drawback of DE analysis is that it only considers the changes on single biomolecule level. Recently, differential network (DN) analysis has become popular due to its capability to measure the changes on biomolecular pair level. In DN analysis, network is typically built based on correlation and biomarker candidates are selected by investigating the network topology. However, correlation tends to generate over-complicated networks and the selection of biomarker candidates purely based on network topology ignores the changes on single biomolecule level. In this paper, we propose a novel approach, INDEED, that builds sparse differential network based on partial correlation and integrates DE and DN analyses for biomarker discovery. We applied this approach on real proteomic and glycomic data generated by liquid chromatography coupled with mass spectrometry for hepatocellular carcinoma (HCC) biomarker discovery study. For each omic data, we used one dataset to select biomarker candidates, built a disease classifier and evaluated the performance of the classifier on an independent dataset. The biomarker candidates, selected by INDEED, were more reproducible across independent datasets, and led to a higher classification accuracy in predicting HCC cases and cirrhotic controls compared with those selected by separate DE and DN analyses. INDEED also identified some candidates previously reported to be relevant to HCC, such as intercellular adhesion molecule 2 (ICAM2) and c4b-binding protein alpha chain (C4BPA), which were missed by both DE and DN analyses. In addition, we applied INDEED for survival time prediction based on transcriptomic data acquired by analysis of samples from breast cancer patients. We selected biomarker candidates and built a regression model for survival time prediction based on a gene expression dataset and patients’ survival records. We evaluated the performance of the regression model on an independent dataset. Compared with the biomarker candidates selected by DE and DN analyses, those selected through INDEED led to more accurate survival time prediction.
The differential network (DN) analysis identifies changes in measures of association among genes under two or more experimental conditions. In this article, we introduce a pseudo-value regression ...approach for network analysis (PRANA). This is a novel method of differential network analysis that also adjusts for additional clinical covariates. We start from mutual information criteria, followed by pseudo-value calculations, which are then entered into a robust regression model.
This article assesses the model performances of PRANA in a multivariable setting, followed by a comparison to dnapath and DINGO in both univariable and multivariable settings through variety of simulations. Performance in terms of precision, recall, and F1 score of differentially connected (DC) genes is assessed. By and large, PRANA outperformed dnapath and DINGO, neither of which is equipped to adjust for available covariates such as patient-age. Lastly, we employ PRANA in a real data application from the Gene Expression Omnibus database to identify DC genes that are associated with chronic obstructive pulmonary disease to demonstrate its utility.
To the best of our knowledge, this is the first attempt of utilizing a regression modeling for DN analysis by collective gene expression levels between two or more groups with the inclusion of additional clinical covariates. By and large, adjusting for available covariates improves accuracy of a DN analysis.
Abstract
Differential network analysis (DiNA) denotes a recent class of network-based Bioinformatics algorithms which focus on the differences in network topologies between two states of a cell, such ...as healthy and disease, to identify key players in the discriminating biological processes. In contrast to conventional differential analysis, DiNA identifies changes in the interplay between molecules, rather than changes in single molecules. This ability is especially important in cases where effectors are changed, e.g. mutated, but their expression is not. A number of different DiNA approaches have been proposed, yet a comparative assessment of their performance in different settings is still lacking. In this paper, we evaluate 10 different DiNA algorithms regarding their ability to recover genetic key players from transcriptome data. We construct high-quality regulatory networks and enrich them with co-expression data from four different types of cancer. Next, we assess the results of applying DiNA algorithms on these data sets using a gold standard list (GSL). We find that local DiNA algorithms are generally superior to global algorithms, and that all DiNA algorithms outperform conventional differential expression analysis. We also assess the ability of DiNA methods to exploit additional knowledge in the underlying cellular networks. To this end, we enrich the cancer-type specific networks with known regulatory miRNAs and compare the algorithms performance in networks with and without miRNA. We find that including miRNAs consistently and considerably improves the performance of almost all tested algorithms. Our results underline the advantages of comprehensive cell models for the analysis of -omics data.
Abstract
Identification of cancer-related genes is helpful for understanding the pathogenesis of cancer, developing targeted drugs and creating new diagnostic and therapeutic methods. Considering the ...complexity of the biological laboratory methods, many network-based methods have been proposed to identify cancer-related genes at the global perspective with the increasing availability of high-throughput data. Some studies have focused on the tissue-specific cancer networks. However, cancers from different tissues may share common features, and those methods may ignore the differences and similarities across cancers during the establishment of modeling. In this work, in order to make full use of global information of the network, we first establish the pan-cancer network via differential network algorithm, which not only contains heterogeneous data across multiple cancer types but also contains heterogeneous data between tumor samples and normal samples. Second, the node representation vectors are learned by network embedding. In contrast to ranking analysis-based methods, with the help of integrative network analysis, we transform the cancer-related gene identification problem into a binary classification problem. The final results are obtained via ensemble classification. We further applied these methods to the most commonly used gene expression data involving six tissue-specific cancer types. As a result, an integrative pan-cancer network and several biologically meaningful results were obtained. As examples, nine genes were ultimately identified as potential pan-cancer-related genes. Most of these genes have been reported in published studies, thus showing our method’s potential for application in identifying driver gene candidates for further biological experimental verification.
Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an ...array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA–MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some differences arise like in the case of amino acids.
Abundant datasets generated from various big science projects on diseases have presented great challenges and opportunities, which contributed to unfolding 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.
Differential network analysis is an important statistical problem with wide applications. Many statisticians focus on binary problems and propose to perform such analysis by obtaining sparse ...estimates of the difference between precision matrices. These methods are supported by excellent theoretical properties and practical performance. However, efficient computation for these methods remains a challenging problem. A novel algorithm referred to as the SMORE algorithm is proposed for differential network analysis. The SMORE algorithm has low storage cost and high computation speed, especially in the presence of strong sparsity. In the meantime, the SMORE algorithm provides a unified framework for binary and multiple network problems. In addition, the SMORE algorithm can be applied in high-dimensional quadratic discriminant analysis problems as well, leading to a new approach for multiclass high-dimensional quadratic discriminant analysis. Numerical studies confirm the stability and the efficiency of the proposed SMORE algorithm in both differential network analysis and quadratic discriminant analysis.
Advances in sequencing technology and cost reduction have enabled an emergence of various statistical methods used in RNA-sequencing data, including the differential co-expression network analysis ...(or differential network analysis). A key benefit of this method is that it takes into consideration the interactions between or among genes and do not require an established knowledge in biological pathways. As of now, none of existing softwares can incorporate covariates that should be adjusted if they are confounding factors while performing the differential network analysis.
We develop an R package PRANA which a user can easily include multiple covariates. The main R function in this package leverages a novel pseudo-value regression approach for a differential network analysis in RNA-sequencing data. This software is also enclosed with complementary R functions for extracting adjusted p-values and coefficient estimates of all or specific variable for each gene, as well as for identifying the names of genes that are differentially connected (DC, hereafter) between subjects under biologically different conditions from the output.
Herewith, we demonstrate the application of this package in a real data on chronic obstructive pulmonary disease. PRANA is available through the CRAN repositories under the GPL-3 license: https://cran.r-project.org/web/packages/PRANA/index.html .
Summary
Differential graphical models are designed to represent the difference between the conditional dependence structures of two groups, and thus are of particular interest for scientific ...investigations. Motivated by modern applications, this manuscript considers an extended setting where each group is generated by a latent variable Gaussian graphical model. Due to the existence of latent factors, the differential network is decomposed into sparse and low-rank components, both of which are symmetric indefinite matrices. We estimate these two components simultaneously using a two-stage procedure: (i) an initialization stage, which computes a simple, consistent estimator, and (ii) a convergence stage, implemented using a projected alternating gradient descent algorithm applied to a nonconvex objective, initialized using the output of the first stage. We prove that given the initialization, the estimator converges linearly with a nontrivial, minimax optimal statistical error. Experiments on synthetic and real data illustrate that the proposed nonconvex procedure outperforms existing methods.
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