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Automatic Selection of Verification Tools for Efficient Analysis of Biochemical Models
YesMotivation: Formal verification is a computational approach that checks system correctness (in relation to a desired functionality). It has been widely used in engineering applications to verify that systems work correctly. Model checking, an algorithmic approach to verification, looks at whether a system model satisfies its requirements specification. This approach has been applied to a large number of models in systems and synthetic biology as well as in systems medicine. Model checking is, however, computationally very expensive, and is not scalable to large models and systems. Consequently, statistical model checking (SMC), which relaxes some of the constraints of model checking, has been introduced to address this drawback. Several SMC tools have been developed; however, the performance of each tool significantly varies according to the system model in question and the type of requirements being verified. This makes it hard to know, a priori, which one to use for a given model and requirement, as choosing the most efficient tool for any biological application requires a significant degree of computational expertise, not usually available in biology labs. The objective of this paper is to introduce a method and provide a tool leading to the automatic selection of the most appropriate model checker for the system of interest.
Results: We provide a system that can automatically predict the fastest model checking tool for a given biological model. Our results show that one can make predictions of high confidence, with over 90% accuracy. This implies significant performance gain in verification time and substantially reduces the “usability barrier” enabling biologists to have access to this powerful computational technology.EPSRC, Innovate U
Statistical Model Checking for Stochastic Hybrid Systems
This paper presents novel extensions and applications of the UPPAAL-SMC model
checker. The extensions allow for statistical model checking of stochastic
hybrid systems. We show how our race-based stochastic semantics extends to
networks of hybrid systems, and indicate the integration technique applied for
implementing this semantics in the UPPAAL-SMC simulation engine. We report on
two applications of the resulting tool-set coming from systems biology and
energy aware buildings.Comment: In Proceedings HSB 2012, arXiv:1208.315
Inferring Latent States and Refining Force Estimates via Hierarchical Dirichlet Process Modeling in Single Particle Tracking Experiments
Optical microscopy provides rich spatio-temporal information characterizing
in vivo molecular motion. However, effective forces and other parameters used
to summarize molecular motion change over time in live cells due to latent
state changes, e.g., changes induced by dynamic micro-environments,
photobleaching, and other heterogeneity inherent in biological processes. This
study focuses on techniques for analyzing Single Particle Tracking (SPT) data
experiencing abrupt state changes. We demonstrate the approach on GFP tagged
chromatids experiencing metaphase in yeast cells and probe the effective forces
resulting from dynamic interactions that reflect the sum of a number of
physical phenomena. State changes are induced by factors such as microtubule
dynamics exerting force through the centromere, thermal polymer fluctuations,
etc. Simulations are used to demonstrate the relevance of the approach in more
general SPT data analyses. Refined force estimates are obtained by adopting and
modifying a nonparametric Bayesian modeling technique, the Hierarchical
Dirichlet Process Switching Linear Dynamical System (HDP-SLDS), for SPT
applications. The HDP-SLDS method shows promise in systematically identifying
dynamical regime changes induced by unobserved state changes when the number of
underlying states is unknown in advance (a common problem in SPT applications).
We expand on the relevance of the HDP-SLDS approach, review the relevant
background of Hierarchical Dirichlet Processes, show how to map discrete time
HDP-SLDS models to classic SPT models, and discuss limitations of the approach.
In addition, we demonstrate new computational techniques for tuning
hyperparameters and for checking the statistical consistency of model
assumptions directly against individual experimental trajectories; the
techniques circumvent the need for "ground-truth" and subjective information.Comment: 25 pages, 6 figures. Differs only typographically from PLoS One
publication available freely as an open-access article at
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.013763
Efficient Parallel Statistical Model Checking of Biochemical Networks
We consider the problem of verifying stochastic models of biochemical
networks against behavioral properties expressed in temporal logic terms. Exact
probabilistic verification approaches such as, for example, CSL/PCTL model
checking, are undermined by a huge computational demand which rule them out for
most real case studies. Less demanding approaches, such as statistical model
checking, estimate the likelihood that a property is satisfied by sampling
executions out of the stochastic model. We propose a methodology for
efficiently estimating the likelihood that a LTL property P holds of a
stochastic model of a biochemical network. As with other statistical
verification techniques, the methodology we propose uses a stochastic
simulation algorithm for generating execution samples, however there are three
key aspects that improve the efficiency: first, the sample generation is driven
by on-the-fly verification of P which results in optimal overall simulation
time. Second, the confidence interval estimation for the probability of P to
hold is based on an efficient variant of the Wilson method which ensures a
faster convergence. Third, the whole methodology is designed according to a
parallel fashion and a prototype software tool has been implemented that
performs the sampling/verification process in parallel over an HPC
architecture
Cross-entropy optimisation of importance sampling parameters for statistical model checking
Statistical model checking avoids the exponential growth of states associated
with probabilistic model checking by estimating properties from multiple
executions of a system and by giving results within confidence bounds. Rare
properties are often very important but pose a particular challenge for
simulation-based approaches, hence a key objective under these circumstances is
to reduce the number and length of simulations necessary to produce a given
level of confidence. Importance sampling is a well-established technique that
achieves this, however to maintain the advantages of statistical model checking
it is necessary to find good importance sampling distributions without
considering the entire state space.
Motivated by the above, we present a simple algorithm that uses the notion of
cross-entropy to find the optimal parameters for an importance sampling
distribution. In contrast to previous work, our algorithm uses a low
dimensional vector of parameters to define this distribution and thus avoids
the often intractable explicit representation of a transition matrix. We show
that our parametrisation leads to a unique optimum and can produce many orders
of magnitude improvement in simulation efficiency. We demonstrate the efficacy
of our methodology by applying it to models from reliability engineering and
biochemistry.Comment: 16 pages, 8 figures, LNCS styl
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