ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

Background: Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, with the goal to gain a better understanding of the system. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. Although there exist sophisticated algorithms to determine the dynamics of discrete models, their implementations usually require labor-intensive formatting of the model formulation, and they are oftentimes not accessible to users without programming skills. Efficient analysis methods are needed that are accessible to modelers and easy to use. Method: By converting discrete models into algebraic models, tools from computational algebra can be used to analyze their dynamics. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Results: A method for efficiently identifying attractors, and the web-based tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness, i.e., while the number of nodes in a biological network may be quite large, each node is affected only by a small number of other nodes, and robustness, i.e., small number of attractors

A structural analysis of the A5/1 state transition graph

We describe efficient algorithms to analyze the cycle structure of the graph induced by the state transition function of the A5/1 stream cipher used in GSM mobile phones and report on the results of the implementation. The analysis is performed in five steps utilizing HPC clusters, GPGPU and external memory computation. A great reduction of this huge state transition graph of 2^64 nodes is achieved by focusing on special nodes in the first step and removing leaf nodes that can be detected with limited effort in the second step. This step does not break the overall structure of the graph and keeps at least one node on every cycle. In the third step the nodes of the reduced graph are connected by weighted edges. Since the number of nodes is still huge an efficient bitslice approach is presented that is implemented with NVIDIA's CUDA framework and executed on several GPUs concurrently. An external memory algorithm based on the STXXL library and its parallel pipelining feature further reduces the graph in the fourth step. The result is a graph containing only cycles that can be further analyzed in internal memory to count the number and size of the cycles. This full analysis which previously would take months can now be completed within a few days and allows to present structural results for the full graph for the first time. The structure of the A5/1 graph deviates notably from the theoretical results for random mappings.Comment: In Proceedings GRAPHITE 2012, arXiv:1210.611

The inhomogeneous evolution of subgraphs and cycles in complex networks

Subgraphs and cycles are often used to characterize the local properties of complex networks. Here we show that the subgraph structure of real networks is highly time dependent: as the network grows, the density of some subgraphs remains unchanged, while the density of others increase at a rate that is determined by the network's degree distribution and clustering properties. This inhomogeneous evolution process, supported by direct measurements on several real networks, leads to systematic shifts in the overall subgraph spectrum and to an inevitable overrepresentation of some subgraphs and cycles.Comment: 4 pages, 4 figures, submitted to Phys. Rev.

Inferring Regulatory Networks by Combining Perturbation Screens and Steady State Gene Expression Profiles

Reconstructing transcriptional regulatory networks is an important task in functional genomics. Data obtained from experiments that perturb genes by knockouts or RNA interference contain useful information for addressing this reconstruction problem. However, such data can be limited in size and/or are expensive to acquire. On the other hand, observational data of the organism in steady state (e.g. wild-type) are more readily available, but their informational content is inadequate for the task at hand. We develop a computational approach to appropriately utilize both data sources for estimating a regulatory network. The proposed approach is based on a three-step algorithm to estimate the underlying directed but cyclic network, that uses as input both perturbation screens and steady state gene expression data. In the first step, the algorithm determines causal orderings of the genes that are consistent with the perturbation data, by combining an exhaustive search method with a fast heuristic that in turn couples a Monte Carlo technique with a fast search algorithm. In the second step, for each obtained causal ordering, a regulatory network is estimated using a penalized likelihood based method, while in the third step a consensus network is constructed from the highest scored ones. Extensive computational experiments show that the algorithm performs well in reconstructing the underlying network and clearly outperforms competing approaches that rely only on a single data source. Further, it is established that the algorithm produces a consistent estimate of the regulatory network.Comment: 24 pages, 4 figures, 6 table

Cycle-based Cluster Variational Method for Direct and Inverse Inference

We elaborate on the idea that loop corrections to belief propagation could be dealt with in a systematic way on pairwise Markov random fields, by using the elements of a cycle basis to define region in a generalized belief propagation setting. The region graph is specified in such a way as to avoid dual loops as much as possible, by discarding redundant Lagrange multipliers, in order to facilitate the convergence, while avoiding instabilities associated to minimal factor graph construction. We end up with a two-level algorithm, where a belief propagation algorithm is run alternatively at the level of each cycle and at the inter-region level. The inverse problem of finding the couplings of a Markov random field from empirical covariances can be addressed region wise. It turns out that this can be done efficiently in particular in the Ising context, where fixed point equations can be derived along with a one-parameter log likelihood function to minimize. Numerical experiments confirm the effectiveness of these considerations both for the direct and inverse MRF inference.Comment: 47 pages, 16 figure