When is a Network a Network? Multi-Order Graphical Model Selection in Pathways and Temporal Networks

We introduce a framework for the modeling of sequential data capturing pathways of varying lengths observed in a network. Such data are important, e.g., when studying click streams in information networks, travel patterns in transportation systems, information cascades in social networks, biological pathways or time-stamped social interactions. While it is common to apply graph analytics and network analysis to such data, recent works have shown that temporal correlations can invalidate the results of such methods. This raises a fundamental question: when is a network abstraction of sequential data justified? Addressing this open question, we propose a framework which combines Markov chains of multiple, higher orders into a multi-layer graphical model that captures temporal correlations in pathways at multiple length scales simultaneously. We develop a model selection technique to infer the optimal number of layers of such a model and show that it outperforms previously used Markov order detection techniques. An application to eight real-world data sets on pathways and temporal networks shows that it allows to infer graphical models which capture both topological and temporal characteristics of such data. Our work highlights fallacies of network abstractions and provides a principled answer to the open question when they are justified. Generalizing network representations to multi-order graphical models, it opens perspectives for new data mining and knowledge discovery algorithms.Comment: 10 pages, 4 figures, 1 table, companion python package pathpy available on gitHu

Short-term plasticity as cause-effect hypothesis testing in distal reward learning

Asynchrony, overlaps and delays in sensory-motor signals introduce ambiguity as to which stimuli, actions, and rewards are causally related. Only the repetition of reward episodes helps distinguish true cause-effect relationships from coincidental occurrences. In the model proposed here, a novel plasticity rule employs short and long-term changes to evaluate hypotheses on cause-effect relationships. Transient weights represent hypotheses that are consolidated in long-term memory only when they consistently predict or cause future rewards. The main objective of the model is to preserve existing network topologies when learning with ambiguous information flows. Learning is also improved by biasing the exploration of the stimulus-response space towards actions that in the past occurred before rewards. The model indicates under which conditions beliefs can be consolidated in long-term memory, it suggests a solution to the plasticity-stability dilemma, and proposes an interpretation of the role of short-term plasticity.Comment: Biological Cybernetics, September 201

Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Objective Bayesian Search of Gaussian DAG Models with Non-local Priors

Directed Acyclic Graphical (DAG) models are increasingly employed in the study of physical and biological systems, where directed edges between vertices are used to model direct influences between variables. Identifying the graph from data is a challenging endeavor, which can be more reasonably tackled if the variables are assumed to satisfy a given ordering; in this case, we simply have to estimate the presence or absence of each possible edge, whose direction is established by the ordering of the variables. We propose an objective Bayesian methodology for model search over the space of Gaussian DAG models, which only requires default non-local priors as inputs. Priors of this kind are especially suited to learn sparse graphs, because they allow a faster learning rate, relative to ordinary local priors, when the true unknown sampling distribution belongs to a simple model. We implement an efficient stochastic search algorithm, which deals effectively with data sets having sample size smaller than the number of variables. We apply our method to a variety of simulated and real data sets.Fractional Bayes factor; High-dimensional sparse graph; Moment prior; Non-local prior; Objective Bayes; Pathway based prior; Regulatory network; Stochastic search; Structural learning.

Dynamic Influence Networks for Rule-based Models

We introduce the Dynamic Influence Network (DIN), a novel visual analytics technique for representing and analyzing rule-based models of protein-protein interaction networks. Rule-based modeling has proved instrumental in developing biological models that are concise, comprehensible, easily extensible, and that mitigate the combinatorial complexity of multi-state and multi-component biological molecules. Our technique visualizes the dynamics of these rules as they evolve over time. Using the data produced by KaSim, an open source stochastic simulator of rule-based models written in the Kappa language, DINs provide a node-link diagram that represents the influence that each rule has on the other rules. That is, rather than representing individual biological components or types, we instead represent the rules about them (as nodes) and the current influence of these rules (as links). Using our interactive DIN-Viz software tool, researchers are able to query this dynamic network to find meaningful patterns about biological processes, and to identify salient aspects of complex rule-based models. To evaluate the effectiveness of our approach, we investigate a simulation of a circadian clock model that illustrates the oscillatory behavior of the KaiC protein phosphorylation cycle.Comment: Accepted to TVCG, in pres