Dataset Information

A novel probabilistic generator for large-scale gene association networks

ABSTRACT:

Motivation

Gene expression data provide an opportunity for reverse-engineering gene-gene associations using network inference methods. However, it is difficult to assess the performance of these methods because the true underlying network is unknown in real data. Current benchmarks address this problem by subsampling a known regulatory network to conduct simulations. But the topology of regulatory networks can vary greatly across organisms or tissues, and reference-based generators—such as GeneNetWeaver—are not designed to capture this heterogeneity. This means, for example, benchmark results from the E. coli regulatory network will not carry over to other organisms or tissues. In contrast, probabilistic generators do not require a reference network, and they have the potential to capture a rich distribution of topologies. This makes probabilistic generators an ideal approach for obtaining a robust benchmarking of network inference methods.

Results

We propose a novel probabilistic network generator that (1) provides an alternative to address the inherent limitation of reference-based generators and (2) is able to create realistic gene association networks, and (3) captures the heterogeneity found across gold-standard networks better than existing generators used in practice. Eight organism-specific and 12 human tissue-specific gold-standard association networks are considered. Several measures of global topology are used to determine the similarity of generated networks to the gold-standards. Along with demonstrating the variability of network structure across organisms and tissues, we show that the commonly used “scale-free” model is insufficient for replicating these structures.

Availability

This generator is implemented in the R package “SeqNet” and is available on CRAN (https://cran.r-project.org/web/packages/SeqNet/index.html).

SUBMITTER: Grimes T

PROVIDER: S-EPMC8589155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGraphical Gaussian models are popular tools for the estimation of (undirected) gene association networks from microarray data. A key issue when the number of variables greatly exceeds the number of samples is the estimation of the matrix of partial correlations. Since the (Moore-Penrose) inverse of the sample covariance matrix leads to poor estimates in this scenario, standard methods are inappropriate and adequate regularization techniques are needed. Popular approaches include biased estimates of the covariance matrix and high-dimensional regression schemes, such as the Lasso and Partial Least Squares.ResultsIn this article, we investigate a general framework for combining regularized regression methods with the estimation of Graphical Gaussian models. This framework includes various existing methods as well as two new approaches based on ridge regression and adaptive lasso, respectively. These methods are extensively compared both qualitatively and quantitatively within a simulation study and through an application to six diverse real data sets. In addition, all proposed algorithms are implemented in the R package "parcor", available from the R repository CRAN.ConclusionIn our simulation studies, the investigated non-sparse regression methods, i.e. Ridge Regression and Partial Least Squares, exhibit rather conservative behavior when combined with (local) false discovery rate multiple testing in order to decide whether or not an edge is present in the network. For networks with higher densities, the difference in performance of the methods decreases. For sparse networks, we confirm the Lasso's well known tendency towards selecting too many edges, whereas the two-stage adaptive Lasso is an interesting alternative that provides sparser solutions. In our simulations, both sparse and non-sparse methods are able to reconstruct networks with cluster structures. On six real data sets, we also clearly distinguish the results obtained using the non-sparse methods and those obtained using the sparse methods where specification of the regularization parameter automatically means model selection. In five out of six data sets, Partial Least Squares selects very dense networks. Furthermore, for data that violate the assumption of uncorrelated observations (due to replications), the Lasso and the adaptive Lasso yield very complex structures, indicating that they might not be suited under these conditions. The shrinkage approach is more stable than the regression based approaches when using subsampling.