Inference of Sparse Networks with Unobserved Variables. Application to Gene Regulatory Networks

Networks are a unifying framework for modeling complex systems and network inference problems are frequently encountered in many fields. Here, I develop and apply a generative approach to network inference (RCweb) for the case when the network is sparse and the latent (not observed) variables affect the observed ones. From all possible factor analysis (FA) decompositions explaining the variance in the data, RCweb selects the FA decomposition that is consistent with a sparse underlying network. The sparsity constraint is imposed by a novel method that significantly outperforms (in terms of accuracy, robustness to noise, complexity scaling, and computational efficiency) Bayesian methods and MLE methods using l1 norm relaxation such as K-SVD and l1--based sparse principle component analysis (PCA). Results from simulated models demonstrate that RCweb recovers exactly the model structures for sparsity as low (as non-sparse) as 50% and with ratio of unobserved to observed variables as high as 2. RCweb is robust to noise, with gradual decrease in the parameter ranges as the noise level increases.Comment: 8 pages, 5 figure

Non-equilibrium phase transitions in biomolecular signal transduction

We study a mechanism for reliable switching in biomolecular signal-transduction cascades. Steady bistable states are created by system-size cooperative effects in populations of proteins, in spite of the fact that the phosphorylation-state transitions of any molecule, by means of which the switch is implemented, are highly stochastic. The emergence of switching is a nonequilibrium phase transition in an energetically driven, dissipative system described by a master equation. We use operator and functional integral methods from reaction-diffusion theory to solve for the phase structure, noise spectrum, and escape trajectories and first-passage times of a class of minimal models of switches, showing how all critical properties for switch behavior can be computed within a unified framework

An Introductory Guide to Aligning Networks Using SANA, the Simulated Annealing Network Aligner.

Sequence alignment has had an enormous impact on our understanding of biology, evolution, and disease. The alignment of biological networks holds similar promise. Biological networks generally model interactions between biomolecules such as proteins, genes, metabolites, or mRNAs. There is strong evidence that the network topology-the "structure" of the network-is correlated with the functions performed, so that network topology can be used to help predict or understand function. However, unlike sequence comparison and alignment-which is an essentially solved problem-network comparison and alignment is an NP-complete problem for which heuristic algorithms must be used.Here we introduce SANA, the Simulated Annealing Network Aligner. SANA is one of many algorithms proposed for the arena of biological network alignment. In the context of global network alignment, SANA stands out for its speed, memory efficiency, ease-of-use, and flexibility in the arena of producing alignments between two or more networks. SANA produces better alignments in minutes on a laptop than most other algorithms can produce in hours or days of CPU time on large server-class machines. We walk the user through how to use SANA for several types of biomolecular networks

Experimental design trade-offs for gene regulatory network inference: an in silico study of the yeast Saccharomyces cerevisiae cell cycle

Time-series of high throughput gene sequencing data intended for gene regulatory network (GRN) inference are often short due to the high costs of sampling cell systems. Moreover, experimentalists lack a set of quantitative guidelines that prescribe the minimal number of samples required to infer a reliable GRN model. We study the temporal resolution of data vs quality of GRN inference in order to ultimately overcome this deficit. The evolution of a Markovian jump process model for the Ras/cAMP/PKA pathway of proteins and metabolites in the G1 phase of the Saccharomyces cerevisiae cell cycle is sampled at a number of different rates. For each time-series we infer a linear regression model of the GRN using the LASSO method. The inferred network topology is evaluated in terms of the area under the precision-recall curve AUPR. By plotting the AUPR against the number of samples, we show that the trade-off has a, roughly speaking, sigmoid shape. An optimal number of samples corresponds to values on the ridge of the sigmoid

Spectral Alignment of Networks

Network alignment refers to the problem of finding a bijective mapping across vertices of two or more graphs to maximize the number of overlapping edges and/or to minimize the number of mismatched interactions across networks. This paper introduces a network alignment algorithm inspired by eigenvector analysis which creates a simple relaxation for the underlying quadratic assignment problem. Our method relaxes binary assignment constraints along the leading eigenvector of an alignment matrix which captures the structure of matched and mismatched interactions across networks. Our proposed algorithm denoted by EigeAlign has two steps. First, it computes the Perron-Frobenius eigenvector of the alignment matrix. Second, it uses this eigenvector in a linear optimization framework of maximum weight bipartite matching to infer bijective mappings across vertices of two graphs. Unlike existing network alignment methods, EigenAlign considers both matched and mismatched interactions in its optimization and therefore, it is effective in aligning networks even with low similarity. We show that, when certain technical conditions hold, the relaxation given by EigenAlign is asymptotically exact over Erdos-Renyi graphs with high probability. Moreover, for modular network structures, we show that EigenAlign can be used to split the large quadratic assignment optimization into small subproblems, enabling the use of computationally expensive, but tight semidefinite relaxations over each subproblem. Through simulations, we show the effectiveness of the EigenAlign algorithm in aligning various network structures including Erdos-Renyi, power law, and stochastic block models, under different noise models. Finally, we apply EigenAlign to compare gene regulatory networks across human, fly and worm species which we infer by integrating genome-wide functional and physical genomics datasets from ENCODE and modENCODE consortia. EigenAlign infers conserved regulatory interactions across these species despite large evolutionary distances spanned. We find strong conservation of centrally-connected genes and some biological pathways, especially for human-fly comparisons