Data-driven modelling of biological multi-scale processes

Biological processes involve a variety of spatial and temporal scales. A holistic understanding of many biological processes therefore requires multi-scale models which capture the relevant properties on all these scales. In this manuscript we review mathematical modelling approaches used to describe the individual spatial scales and how they are integrated into holistic models. We discuss the relation between spatial and temporal scales and the implication of that on multi-scale modelling. Based upon this overview over state-of-the-art modelling approaches, we formulate key challenges in mathematical and computational modelling of biological multi-scale and multi-physics processes. In particular, we considered the availability of analysis tools for multi-scale models and model-based multi-scale data integration. We provide a compact review of methods for model-based data integration and model-based hypothesis testing. Furthermore, novel approaches and recent trends are discussed, including computation time reduction using reduced order and surrogate models, which contribute to the solution of inference problems. We conclude the manuscript by providing a few ideas for the development of tailored multi-scale inference methods.Comment: This manuscript will appear in the Journal of Coupled Systems and Multiscale Dynamics (American Scientific Publishers

A modular hybrid simulation framework for complex manufacturing system design

For complex manufacturing systems, the current hybrid Agent-Based Modelling and Discrete Event Simulation (ABM–DES) frameworks are limited to component and system levels of representation and present a degree of static complexity to study optimal resource planning. To address these limitations, a modular hybrid simulation framework for complex manufacturing system design is presented. A manufacturing system with highly regulated and manual handling processes, composed of multiple repeating modules, is considered. In this framework, the concept of modular hybrid ABM–DES technique is introduced to demonstrate a novel simulation method using a dynamic system of parallel multi-agent discrete events. In this context, to create a modular model, the stochastic finite dynamical system is extended to allow the description of discrete event states inside the agent for manufacturing repeating modules (meso level). Moreover, dynamic complexity regarding uncertain processing time and resources is considered. This framework guides the user step-by-step through the system design and modular hybrid model. A real case study in the cell and gene therapy industry is conducted to test the validity of the framework. The simulation results are compared against the data from the studied case; excellent agreement with 1.038% error margin is found in terms of the company performance. The optimal resource planning and the uncertainty of the processing time for manufacturing phases (exo level), in the presence of dynamic complexity is calculated

Feedback methods for inverse simulation of dynamic models for engineering systems applications

Inverse simulation is a form of inverse modelling in which computer simulation methods are used to find the time histories of input variables that, for a given model, match a set of required output responses. Conventional inverse simulation methods for dynamic models are computationally intensive and can present difficulties for high-speed applications. This paper includes a review of established methods of inverse simulation,giving some emphasis to iterative techniques that were first developed for aeronautical applications. It goes on to discuss the application of a different approach which is based on feedback principles. This feedback method is suitable for a wide range of linear and nonlinear dynamic models and involves two distinct stages. The first stage involves design of a feedback loop around the given simulation model and, in the second stage, that closed-loop system is used for inversion of the model. Issues of robustness within closed-loop systems used in inverse simulation are not significant as there are no plant uncertainties or external disturbances. Thus the process is simpler than that required for the development of a control system of equivalent complexity. Engineering applications of this feedback approach to inverse simulation are described through case studies that put particular emphasis on nonlinear and multi-input multi-output models

Reduction of dynamical biochemical reaction networks in computational biology

Biochemical networks are used in computational biology, to model the static and dynamical details of systems involved in cell signaling, metabolism, and regulation of gene expression. Parametric and structural uncertainty, as well as combinatorial explosion are strong obstacles against analyzing the dynamics of large models of this type. Multi-scaleness is another property of these networks, that can be used to get past some of these obstacles. Networks with many well separated time scales, can be reduced to simpler networks, in a way that depends only on the orders of magnitude and not on the exact values of the kinetic parameters. The main idea used for such robust simplifications of networks is the concept of dominance among model elements, allowing hierarchical organization of these elements according to their effects on the network dynamics. This concept finds a natural formulation in tropical geometry. We revisit, in the light of these new ideas, the main approaches to model reduction of reaction networks, such as quasi-steady state and quasi-equilibrium approximations, and provide practical recipes for model reduction of linear and nonlinear networks. We also discuss the application of model reduction to backward pruning machine learning techniques

GPU-powered Simulation Methodologies for Biological Systems

The study of biological systems witnessed a pervasive cross-fertilization between experimental investigation and computational methods. This gave rise to the development of new methodologies, able to tackle the complexity of biological systems in a quantitative manner. Computer algorithms allow to faithfully reproduce the dynamics of the corresponding biological system, and, at the price of a large number of simulations, it is possible to extensively investigate the system functioning across a wide spectrum of natural conditions. To enable multiple analysis in parallel, using cheap, diffused and highly efficient multi-core devices we developed GPU-powered simulation algorithms for stochastic, deterministic and hybrid modeling approaches, so that also users with no knowledge of GPUs hardware and programming can easily access the computing power of graphics engines.Comment: In Proceedings Wivace 2013, arXiv:1309.712

StocHy: automated verification and synthesis of stochastic processes

StocHy is a software tool for the quantitative analysis of discrete-time stochastic hybrid systems (SHS). StocHy accepts a high-level description of stochastic models and constructs an equivalent SHS model. The tool allows to (i) simulate the SHS evolution over a given time horizon; and to automatically construct formal abstractions of the SHS. Abstractions are then employed for (ii) formal verification or (iii) control (policy, strategy) synthesis. StocHy allows for modular modelling, and has separate simulation, verification and synthesis engines, which are implemented as independent libraries. This allows for libraries to be easily used and for extensions to be easily built. The tool is implemented in C++ and employs manipulations based on vector calculus, the use of sparse matrices, the symbolic construction of probabilistic kernels, and multi-threading. Experiments show StocHy's markedly improved performance when compared to existing abstraction-based approaches: in particular, StocHy beats state-of-the-art tools in terms of precision (abstraction error) and computational effort, and finally attains scalability to large-sized models (12 continuous dimensions). StocHy is available at www.gitlab.com/natchi92/StocHy

A 4D-Var Method with Flow-Dependent Background Covariances for the Shallow-Water Equations

The 4D-Var method for filtering partially observed nonlinear chaotic dynamical systems consists of finding the maximum a-posteriori (MAP) estimator of the initial condition of the system given observations over a time window, and propagating it forward to the current time via the model dynamics. This method forms the basis of most currently operational weather forecasting systems. In practice the optimization becomes infeasible if the time window is too long due to the non-convexity of the cost function, the effect of model errors, and the limited precision of the ODE solvers. Hence the window has to be kept sufficiently short, and the observations in the previous windows can be taken into account via a Gaussian background (prior) distribution. The choice of the background covariance matrix is an important question that has received much attention in the literature. In this paper, we define the background covariances in a principled manner, based on observations in the previous $b$ assimilation windows, for a parameter $b\ge 1$. The method is at most $b$ times more computationally expensive than using fixed background covariances, requires little tuning, and greatly improves the accuracy of 4D-Var. As a concrete example, we focus on the shallow-water equations. The proposed method is compared against state-of-the-art approaches in data assimilation and is shown to perform favourably on simulated data. We also illustrate our approach on data from the recent tsunami of 2011 in Fukushima, Japan.Comment: 32 pages, 5 figure