This report proposes a novel framework for a rigorous robustness analysis of stochastic biochemical systems. The technique is based on probabilistic model checking. We adapt the general definition of robustness introduced by Kitano to the class of stochastic systems modelled as continuous time Markov Chains in order to extensively analyse and compare robustness of biological models with uncertain parameters. The framework utilises novel computational methods that enable to effectively evaluate the robustness of models with respect to quantitative temporal properties and parameters such as reaction rate constants and initial conditions. The framework is applied to gene regulation as an example of a central biological mechanism where intrinsic and extrinsic stochasticity plays crucial role due to low numbers of DNA and RNA molecules. Using our methods we have obtained a comprehensive and precise analysis of stochastic dynamics under parameter uncertainty. Furthermore, we apply our framework to compare several variants of two-component signalling networks from the perspective of robustness with respect to intrinsic noise caused by low populations of signalling components. We succeeded to extend previous studies performed on deterministic models (ODE) and show that stochasticity may significantly affect obtained predictions. Our case studies demonstrate that the framework can provide deeper insight into the role of key parameters in maintaining the system functionality and thus it significantly contributes to formal methods in computational systems biology.
In the domain of ODE models, there exist several analytic methods for effective analysis under parameter uncertainty. They build on static analysis (stoichiometric analysis, flux balance analysis) as well as dynamic numerical methods (simulation, monitoring by temporal formulae, sensitivity analysis) implemented in tools (e.g. @cite_20 @cite_30 @cite_7 ). Robustness analysis with respect to functionality specified in terms of temporal formulae has been introduced recently @cite_40 @cite_12 . There exist two major approaches how to define and analyse robustness. If only parameters of the model are perturbed, we speak of a to robustness. This approach has been explored by Fainekos & Pappas @cite_40 , further extended by A. Donz ' e et al @cite_10 and implemented in the toolbox Breach @cite_32 . Another option could be to perturb the model structure i.e. the reaction topology, as this is done in many gene knock-out biological experiments. Such changes are in principle discrete and the problem of robustness computation for such perturbations would reduce to solving many individual instances of the same problem for each discrete topology. However identifying model behaviour shared among individual perturbations can lead to more efficient analysis @cite_22 .
@cite_30 @cite_22 @cite_7 @cite_32 @cite_40 @cite_20 @cite_10 @cite_12
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Abstract Stochastic models such as Continuous-Time Markov Chains (CTMC) and Stochastic Hybrid Automata (SHA) are powerful formalisms to model and to reason about the dynamics of biological systems, due to their ability to capture the stochasticity inherent in biological processes. A classical question in formal modelling with clear relevance to biological modelling is the model checking problem, i.e. calculate the probability that a behaviour, expressed for instance in terms of a certain temporal logic formula, may occur in a given stochastic process. However, one may not only be interested in the notion of satisfiability, but also in the capacity of a system to maintain a particular emergent behaviour unaffected by the perturbations, caused e.g. from extrinsic noise, or by possible small changes in the model parameters. To address this issue, researchers from the verification community have recently proposed several notions of robustness for temporal logic providing suitable definitions of distance between a trajectory of a (deterministic) dynamical system and the boundaries of the set of trajectories satisfying the property of interest. The contributions of this paper are twofold. First, we extend the notion of robustness to stochastic systems, showing that this naturally leads to a distribution of robustness degrees. By discussing three examples, we show how to approximate the distribution of the robustness degree and the average robustness . Secondly, we show how to exploit this notion to address the system design problem , where the goal is to optimise some control parameters of a stochastic model in order to maximise robustness of the desired specifications. Abstract This paper describes a new approach for ascertaining the stability of stochastic dynamical systems in their parameter space by examining their time series using topological data analysis (TDA). We illustrate the approach using a nonlinear delayed model that describes the tool oscillations due to self-excited vibrations in turning. Each time series is generated using the Euler-Maruyama method and a corresponding point cloud is obtained using the Takens embedding. The point cloud can then be analyzed using a tool from TDA known as persistent homology. The results of this study show that the described approach can be used for analyzing datasets of delay dynamical systems generated both from numerical simulation and experimental data. The contributions of this paper include presenting for the first time a topological approach for investigating the stability of a class of nonlinear stochastic delay equations, and introducing a new application of TDA to machining processes. Traditionally, traffic assignment models, both for within-day static and dynamic demand, have been formulated following an equilibrium approach in which a state ensuring internal consistency between demand (flows) and costs is sought. However, equilibrium analysis is significant under some assumptions on its “representativeness” (coincidence or closeness with the actual attractor of the system) and analytical properties, such as existence, uniqueness, and stability. Moreover, transients due to modifications of demand and or supply cannot be simulated through equilibrium models, nor can a statistical description of the state of the system, i.e. means, modes, moments and, more generally, frequency distributions of flows over time be obtained. In this paper, interperiodic (day-to-day) dynamic modeling of transportation networks is addressed following two different approaches, namely deterministic and stochastic processes. In both cases several theoretical results are shown by making use of a formal framework covering most models discussed in the literature as well as some possible extensions. Most of the results reported can be extended to cover within-day dynamic models but these models are not explicitly dealt with. Within the framework of deterministic processes the relevance of day-to-day dynamic models for demand supply interaction in comparison with the traditional user equilibrium approach is discussed, and conditions for coincidence of fixed-point attractors and equilibrium states are stated. Conditions for existence and uniqueness of fixed-point attractors are proposed, generalizing and extending those presented in the literature for user equilibrium. Conditions for stability of both fixed-points and equilibrium states were formulated by making use of results from non-linear dynamic system theory. Moreover, it is possible to devise a new family of “dynamic” algorithms which simulate the system convergence to a fixed-point in order to obtain an equivalent equilibrium state, as opposed to conventional “optimisation” algorithms. In this case the fixed-point stability analysis can be viewed as a convergence analysis for the algorithms specified this way. Conditions for stochastic process regularity are proposed ensuring, among other things, existence and uniqueness of a stationary probability distribution of system states. These conditions generalize and extend results presented in the literature to a wider class of possible dynamic models. Relationships between a deterministic process, together with corresponding fixed-points or equilibrium states, and stochastic probability distribution are also briefly addressed. Finally, some numerical examples confirming theoretical results are reported for a small test network. We consider temporal logic formulae specifying constraints in continuous time and space on the behaviors of continuous and hybrid dynamical system admitting uncertain parameters. We present several variants of robustness measures that indicate how far a given trajectory stands, in space and time, from satisfying or violating a property. We present a method to compute these robustness measures as well as their sensitivity to the parameters of the system or parameters appearing in the formula. Combined with an appropriate strategy for exploring the parameter space, this technique can be used to guide simulation-based verification of complex nonlinear and hybrid systems against temporal properties. Our methodology can be used for other non-traditional applications of temporal logic such as characterizing subsets of the parameter space for which a system is guaranteed to satisfy a formula with a desired robustness degree. In robust biological systems, wide deviations from highly controlled normal behavior may be rare, yet they may result in catastrophic complications. While in silico analysis has gained an appreciation as a tool to offer insights into system-level properties of biological systems, analysis of such rare events provides a particularly challenging computational problem. This paper proposes an efficient stochastic simulation method to analyze rare events in biochemical systems. Our new approach can substantially increase the frequency of the rare events of interest by appropriately manipulating the underlying probability measure of the system, allowing high-precision results to be obtained with substantially fewer simulation runs than the conventional direct Monte Carlo simulation. Here, we show the algorithm of our new approach, and we apply it to the analysis of rare deviant transitions of two systems, resulting in several orders of magnitude speedup in generating high-precision estimates compared with the c... 1 Model Problem and Its Discretization.- 1.1 Conservation Laws.- 1.2 Finite Volume Methods.- 2 Multiscale Setting.- 2.1 Hierarchy of Meshes.- 2.2 Motivation.- 2.3 Box Wavelet.- 2.3.1 Box Wavelet on a Cartesian Grid Hierarchy.- 2.3.2 Box Wavelet on an Arbitrary Nested Grid Hierarchy.- 2.4 Change of Stable Completion.- 2.5 Box Wavelet with Higher Vanishing Moments.- 2.5.1 Definition and Construction.- 2.5.2 A Univariate Example.- 2.5.3 A Remark on Compression Rates.- 2.6 Multiscale Transformation.- 3 Locally Refined Spaces.- 3.1 Adaptive Grid and Significant Details.- 3.2 Grading.- 3.3 Local Multiscale Transformation.- 3.4 Grading Parameter.- 3.5 Locally Uniform Grids.- 3.6 Algorithms: Encoding, Thresholding, Grading, Decoding.- 3.7 Conservation Property.- 3.8 Application to Curvilinear Grids.- 4 Adaptive Finite Volume Scheme.- 4.1 Construction.- 4.1.1 Strategies for Local Flux Evaluation.- 4.1.2 Strategies for Prediction of Details.- 4.2 A gorithms: Initial data, Prediction, Fluxes and Evolution.- 5 Error Analysis.- 5.1 Perturbation Error.- 5.2 Stability of Approximation.- 5.3 Reliability of Prediction.- 6 Data Structures and Memory Management.- 6.1 Algorithmic Requirements and Design Criteria.- 6.2 Hashing.- 6.3 Data Structures.- 7 Numerical Experiments.- 7.1 Parameter Studies.- 7.1.1 Test Configurations.- 7.1.2 Discretization.- 7.1.3 Computational Complexity and Stability.- 7.1.4 Hash Parameters.- 7.2 Real World Application.- 7.2.1 Configurations.- 7.2.2 Discretization.- 7.2.3 Discussion of Results.- A Plots of Numerical Experiments.- B The Context of Biorthogonal Wavelets.- B.1 General Setting.- B.1.1 Multiscale Basis.- B.1.2 Stable Completion.- B.1.3 Multiscale Transformation.- B.2 Biorthogonal Wavelets of the Box Function.- B.2.1 Haar Wavelets.- B.2.2 Biorthogonal Wavelets on the Real Line.- References.- List of Figures.- List of Tables.- Notation. In this paper, we develop a rigorous, unified framework based on ordinary differential equations (ODEs) to study epidemic routing and its variations. These ODEs can be derived as limits of Markovian models under a natural scaling as the number of nodes increases. While an analytical study of Markovian models is quite complex and numerical solution impractical for large networks, the corresponding ODE models yield closed-form expressions for several performance metrics of interest, and a numerical solution complexity that does not increase with the number of nodes. Using this ODE approach, we investigate how resources such as buffer space and the number of copies made for a packet can be traded for faster delivery, illustrating the differences among various forwarding and recovery schemes considered. We perform model validations through simulation studies. Finally we consider the effect of buffer management by complementing the forwarding models with Markovian and fluid buffer models. In this paper, we propose three criteria for efficient sample selection in case of data stream regression problems within an online active learning context. The selection becomes important whenever the target values, which guide the update of the regressors as well as the implicit model structures, are costly or time-consuming to measure and also in case when very fast models updates are required to cope with stream mining real-time demands. Reducing the selected samples as much as possible while keeping the predictive accuracy of the models on a high level is, thus, a central challenge. This should be ideally achieved in unsupervised and single-pass manner. Our selection criteria rely on three aspects: 1) the extrapolation degree combined with the model's nonlinearity degree , which is measured in terms of a new specific homogeneity criterion among adjacent local approximators; 2) the uncertainty in model outputs, which can be measured in terms of confidence intervals using so-called adaptive local error bars — we integrate a weighted localization of an incremental noise level estimator and propose formulas for online merging of local error bars; 3) the uncertainty in model parameters, which is estimated by the so-called A-optimality criterion, which relies on the Fisher information matrix. The selection criteria are developed in combination with evolving generalized Takagi–Sugeno (TS) fuzzy models (containing rules in arbitrarily rotated position), as it could be shown in previous publications that these outperform conventional evolving TS models (containing axis-parallel rules). The results based on three high-dimensional real-world streaming problems show that a model update based on only 10 –20 selected samples can still achieve similar accumulated model errors over time to the case when performing a full model update on all samples. This can be achieved with a negligible sensitivity on the size of the active learning latency buffer. Random sampling with the same percentages of samples selected, however, achieved much higher error rates. Hence, the intelligence in our sample selection concept leads to an economic balance between model accuracy and measurement as well computational costs for model updates.