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Abstract BackgroundCharacterizing the topology of gene regulatory networks (GRNs) is a fundamental problem in systems biology. The advent of single cell technologies has made it possible to construct GRNs at finer resolutions than bulk and microarray datasets. However, cellular heterogeneity and sparsity of the single cell datasets render void the application of regular Gaussian assumptions for constructing GRNs. Additionally, most GRN reconstruction approaches estimate a single network for the entire data. This could cause potential loss of information when single cell datasets are generated from multiple treatment conditions/disease states. ResultsTo better characterize single cell GRNs under different but related conditions, we propose the joint estimation of multiple networks using multiple signed graph learning (scMSGL). The proposed method is based on recently developed graph signal processing (GSP) based graph learning, where GRNs and gene expressions are modeled as signed graphs and graph signals, respectively. scMSGL learns multiple GRNs by optimizing the total variation of gene expressions with respect to GRNs while ensuring that the learned GRNs are similar to each other through regularization with respect to a learned signed consensus graph. We further kernelize scMSGL with the kernel selected to suit the structure of single cell data. ConclusionsscMSGL is shown to have superior performance over existing state of the art methods in GRN recovery on simulated datasets. Furthermore, scMSGL successfully identifies well-established regulators in a mouse embryonic stem cell differentiation study and a cancer clinical study of medulloblastoma. 

For many decades now, Bayesian Model Averaging (BMA) has been a popular framework to systematically account for model uncertainty that arises in situations when multiple competing models are available to describe the same or similar physical process. The implementation of this framework, however, comes with a multitude of practical challenges including posterior approximation via Markov chain Monte Carlo and numerical integration. We present a Variational Bayesian Inference approach to BMA as a viable alternative to the standard solutions which avoids many of the aforementioned pitfalls. The proposed method is “black box” in the sense that it can be readily applied to many models with little to no model-specific derivation. We illustrate the utility of our variational approach on a suite of examples and discuss all the necessary implementation details. Fully documented Python code with all the examples is provided as well.