From a discrete to a continuum model of cell dynamics in one dimension

Multiscale modeling is emerging as one of the key challenges in mathematical biology. However, the recent rapid increase in the number of modeling methodologies being used to describe cell populations has raised a number of interesting questions. For example, at the cellular scale, how can the appropriate discrete cell-level model be identified in a given context? Additionally, how can the many phenomenological assumptions used in the derivation of models at the continuum scale be related to individual cell behavior? In order to begin to address such questions, we consider a discrete one-dimensional cell-based model in which cells are assumed to interact via linear springs. From the discrete equations of motion, the continuous Rouse [P. E. Rouse, J. Chem. Phys. 21, 1272 (1953)] model is obtained. This formalism readily allows the definition of a cell number density for which a nonlinear "fast" diffusion equation is derived. Excellent agreement is demonstrated between the continuum and discrete models. Subsequently, via the incorporation of cell division, we demonstrate that the derived nonlinear diffusion model is robust to the inclusion of more realistic biological detail. In the limit of stiff springs, where cells can be considered to be incompressible, we show that cell velocity can be directly related to cell production. This assumption is frequently made in the literature but our derivation places limits on its validity. Finally, the model is compared with a model of a similar form recently derived for a different discrete cell-based model and it is shown how the different diffusion coefficients can be understood in terms of the underlying assumptions about cell behavior in the respective discrete models.

Classifying general nonlinear force laws in cell-based models via the continuum limit

though discrete cell-based frameworks are now commonly used to simulate a whole range of biological phenomena, it is typically not obvious how the numerous different types of model are related to one another, nor which one is most appropriate in a given context. Here we demonstrate how individual cell movement on the discrete scale modeled using nonlinear force laws can be described by nonlinear diffusion coefficients on the continuum scale. A general relationship between nonlinear force laws and their respective diffusion coefficients is derived in one spatial dimension and, subsequently, a range of particular examples is considered. For each case excellent agreement is observed between numerical solutions of the discrete and corresponding continuum models. Three case studies are considered in which we demonstrate how the derived nonlinear diffusion coefficients can be used to (a) relate different discrete models of cell behavior; (b) derive discrete, intercell force laws from previously posed diffusion coefficients, and (c) describe aggregative behavior in discrete simulations.

Mathematical modelling for the digital society

We argue the case for a new branch of mathematics and its applications: Mathematics for the Digital Society. There is a challenge for mathematics, a strong “pull” from new and emerging commercial and public activities; and a need to train and inspire a generation of quantitative scientists who will seek careers within the associated sectors. Although now going through an early phase of boiling up, prior to scholarly distillation, we discuss how data rich activities and applications may benefit from a wide range of continuous and discrete models, methods, analysis and inference. In ten years time such applications will be common place and associated courses may be embedded within the undergraduate curriculum.

Stable reduced-order models for discrete-time systems

The Routh-stability method is employed to reduce the order of discrete-time system transfer functions. It is shown that the Routh approximant is well suited to reduce both the denominator and the numerator polynomials, although alternative methods, such as PadÃ�Â(c)-Markov approximation, are also used to fit the model numerator coefficients.

Bayesian analysis of correlated evolution of discrete characters by reversible-jump Markov chain Monte Carlo

We describe a Bayesian method for investigating correlated evolution of discrete binary traits on phylogenetic trees. The method fits a continuous-time Markov model to a pair of traits, seeking the best fitting models that describe their joint evolution on a phylogeny. We employ the methodology of reversible-jump ( RJ) Markov chain Monte Carlo to search among the large number of possible models, some of which conform to independent evolution of the two traits, others to correlated evolution. The RJ Markov chain visits these models in proportion to their posterior probabilities, thereby directly estimating the support for the hypothesis of correlated evolution. In addition, the RJ Markov chain simultaneously estimates the posterior distributions of the rate parameters of the model of trait evolution. These posterior distributions can be used to test among alternative evolutionary scenarios to explain the observed data. All results are integrated over a sample of phylogenetic trees to account for phylogenetic uncertainty. We implement the method in a program called RJ Discrete and illustrate it by analyzing the question of whether mating system and advertisement of estrus by females have coevolved in the Old World monkeys and great apes.

Optimal observers for ARMA models

A polynomial-based ARMA model, when posed in a state-space framework can be regarded in many different ways. In this paper two particular state-space forms of the ARMA model are considered, and although both are canonical in structure they differ in respect of the mode in which disturbances are fed into the state and output equations. For both forms a solution is found to the optimal discrete-time observer problem and algebraic connections between the two optimal observers are shown. The purpose of the paper is to highlight the fact that the optimal observer obtained from the first state-space form, commonly known as the innovations form, is not that employed in an optimal controller, in the minimum-output variance sense, whereas the optimal observer obtained from the second form is. Hence the second form is a much more appropriate state-space description to use for controller design, particularly when employed in self-tuning control schemes.

Comparing a discrete and continuum model of the intestinal crypt

The integration of processes at different scales is a key problem in the modelling of cell populations. Owing to increased computational resources and the accumulation of data at the cellular and subcellular scales, the use of discrete, cell-level models, which are typically solved using numerical simulations, has become prominent. One of the merits of this approach is that important biological factors, such as cell heterogeneity and noise, can be easily incorporated. However, it can be difficult to efficiently draw generalizations from the simulation results, as, often, many simulation runs are required to investigate model behaviour in typically large parameter spaces. In some cases, discrete cell-level models can be coarse-grained, yielding continuum models whose analysis can lead to the development of insight into the underlying simulations. In this paper we apply such an approach to the case of a discrete model of cell dynamics in the intestinal crypt. An analysis of the resulting continuum model demonstrates that there is a limited region of parameter space within which steady-state (and hence biologically realistic) solutions exist. Continuum model predictions show good agreement with corresponding results from the underlying simulations and experimental data taken from murine intestinal crypts.

Discrete time representation of continuous time ARMA processes

This paper derives exact discrete time representations for data generated by a continuous time autoregressive moving average (ARMA) system with mixed stock and flow data. The representations for systems comprised entirely of stocks or of flows are also given. In each case the discrete time representations are shown to be of ARMA form, the orders depending on those of the continuous time system. Three examples and applications are also provided, two of which concern the stationary ARMA(2, 1) model with stock variables (with applications to sunspot data and a short-term interest rate) and one concerning the nonstationary ARMA(2, 1) model with a flow variable (with an application to U.S. nondurable consumers’ expenditure). In all three examples the presence of an MA(1) component in the continuous time system has a dramatic impact on eradicating unaccounted-for serial correlation that is present in the discrete time version of the ARMA(2, 0) specification, even though the form of the discrete time model is ARMA(2, 1) for both models.

On a stochastic Trotter formula with application to spontaneous localization models

We consider the relation between so called continuous localization models—i.e. non-linear stochastic Schrödinger evolutions—and the discrete GRW-model of wave function collapse. The former can be understood as scaling limit of the GRW process. The proof relies on a stochastic Trotter formula, which is of interest in its own right. Our Trotter formula also allows to complement results on existence theory of stochastic Schrödinger evolutions by Holevo and Mora/Rebolledo.

Rheology of discrete failure regimes of anisotropic sea ice

A rheological model of sea ice is presented that incorporates the orientational distribution of ice thickness in leads embedded in isotropic floe ice. Sea ice internal stress is determined by coulombic, ridging and tensile failure at orientations where corresponding failure criteria are satisfied at minimum stresses. Because sea ice traction increases in thinner leads and cohesion is finite, such failure line angles are determined by the orientational distribution of sea ice thickness relative to the imposed stresses. In contrast to the isotropic case, sea ice thickness anisotropy results in these failure lines becoming dependent on the stress magnitude. Although generally a given failure criteria type can be satisfied at many directions, only two at most are considered. The strain rate is determined by shearing along slip lines accompanied by dilatancy and closing or opening across orientations affected by ridging or tensile failure. The rheology is illustrated by a yield curve determined by combining coulombic and ridging failure for the case of two pairs of isotropically formed leads of different thicknesses rotated with regard to each other, which models two events of coulombic failure followed by dilatancy and refreezing. The yield curve consists of linear segments describing coulombic and ridging yield as failure switches from one lead to another as the stress grows. Because sliding along slip lines is accompanied by dilatancy, at typical Arctic sea ice deformation rates a one-day-long deformation event produces enough open water that these freshly formed slip lines are preferential places of ridging failure.