Estimation of constant and time-varying dynamic parameters of HIV infection in a nonlinear differential equation model

Modeling viral dynamics in HIV/AIDS studies has resulted in a deep understanding of pathogenesis of HIV infection from which novel antiviral treatment guidance and strategies have been derived. Viral dynamics models based on nonlinear differential equations have been proposed and well developed over the past few decades. However, it is quite challenging to use experimental or clinical data to estimate the unknown parameters (both constant and time-varying parameters) in complex nonlinear differential equation models. Therefore, investigators usually fix some parameter values, from the literature or by experience, to obtain only parameter estimates of interest from clinical or experimental data. However, when such prior information is not available, it is desirable to determine all the parameter estimates from data. In this paper we intend to combine the newly developed approaches, a multi-stage smoothing-based (MSSB) method and the spline-enhanced nonlinear least squares (SNLS) approach, to estimate all HIV viral dynamic parameters in a nonlinear differential equation model. In particular, to the best of our knowledge, this is the first attempt to propose a comparatively thorough procedure, accounting for both efficiency and accuracy, to rigorously estimate all key kinetic parameters in a nonlinear differential equation model of HIV dynamics from clinical data. These parameters include the proliferation rate and death rate of uninfected HIV-targeted cells, the average number of virions produced by an infected cell, and the infection rate which is related to the antiviral treatment effect and is time-varying. To validate the estimation methods, we verified the identifiability of the HIV viral dynamic model and performed simulation studies.Comment: Published in at http://dx.doi.org/10.1214/09-AOAS290 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

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

Grey-box model identification via evolutionary computing

This paper presents an evolutionary grey-box model identification methodology that makes the best use of a priori knowledge on a clear-box model with a global structural representation of the physical system under study, whilst incorporating accurate blackbox models for immeasurable and local nonlinearities of a practical system. The evolutionary technique is applied to building dominant structural identification with local parametric tuning without the need of a differentiable performance index in the presence of noisy data. It is shown that the evolutionary technique provides an excellent fitting performance and is capable of accommodating multiple objectives such as to examine the relationships between model complexity and fitting accuracy during the model building process. Validation results show that the proposed method offers robust, uncluttered and accurate models for two practical systems. It is expected that this type of grey-box models will accommodate many practical engineering systems for a better modelling accuracy

Investigating biocomplexity through the agent-based paradigm.

Capturing the dynamism that pervades biological systems requires a computational approach that can accommodate both the continuous features of the system environment as well as the flexible and heterogeneous nature of component interactions. This presents a serious challenge for the more traditional mathematical approaches that assume component homogeneity to relate system observables using mathematical equations. While the homogeneity condition does not lead to loss of accuracy while simulating various continua, it fails to offer detailed solutions when applied to systems with dynamically interacting heterogeneous components. As the functionality and architecture of most biological systems is a product of multi-faceted individual interactions at the sub-system level, continuum models rarely offer much beyond qualitative similarity. Agent-based modelling is a class of algorithmic computational approaches that rely on interactions between Turing-complete finite-state machines--or agents--to simulate, from the bottom-up, macroscopic properties of a system. In recognizing the heterogeneity condition, they offer suitable ontologies to the system components being modelled, thereby succeeding where their continuum counterparts tend to struggle. Furthermore, being inherently hierarchical, they are quite amenable to coupling with other computational paradigms. The integration of any agent-based framework with continuum models is arguably the most elegant and precise way of representing biological systems. Although in its nascence, agent-based modelling has been utilized to model biological complexity across a broad range of biological scales (from cells to societies). In this article, we explore the reasons that make agent-based modelling the most precise approach to model biological systems that tend to be non-linear and complex

Ascent trajectory optimisation for a single-stage-to-orbit vehicle with hybrid propulsion

This paper addresses the design of ascent trajectories for a hybrid-engine, high performance, unmanned, single-stage-to-orbit vehicle for payload deployment into low Earth orbit. A hybrid optimisation technique that couples a population-based, stochastic algorithm with a deterministic, gradient-based technique is used to maximize the nal vehicle mass in low Earth orbit after accounting for operational constraints on the dynamic pressure, Mach number and maximum axial and normal accelerations. The control search space is first explored by the population-based algorithm, which uses a single shooting method to evaluate the performance of candidate solutions. The resultant optimal control law and corresponding trajectory are then further refined by a direct collocation method based on finite elements in time. Two distinct operational phases, one using an air-breathing propulsion mode and the second using rocket propulsion, are considered. The presence of uncertainties in the atmospheric and vehicle aerodynamic models are considered in order to quantify their effect on the performance of the vehicle. Firstly, the deterministic optimal control law is re-integrated after introducing uncertainties into the models. The proximity of the final solutions to the target states are analysed statistically. A second analysis is then performed, aimed at determining the best performance of the vehicle when these uncertainties are included directly in the optimisation. The statistical analysis of the results obtained are summarized by an expectancy curve which represents the probable vehicle performance as a function of the uncertain system parameters. This analysis can be used during the preliminary phase of design to yield valuable insights into the robustness of the performance of the vehicle to uncertainties in the specification of its parameters

Improved gene expression programming to solve the inverse problem for ordinary differential equations

Many complex systems in the real world evolve with time. These dynamic systems are often modeled by ordinary differential equations in mathematics. The inverse problem of ordinary differential equations is to convert the observed data of a physical system into a mathematical model in terms of ordinary differential equations. Then the modelay be used to predict the future behavior of the physical system being modeled. Genetic programming has been taken as a solver of this inverse problem. Similar to genetic programming, gene expression programming could do the same job since it has a similar ability of establishing the model of ordinary differential systems. Nevertheless, such research is seldom studied before. This paper is one of the first attempts to apply gene expression programming for solving the inverse problem of ordinary differential equations. Based on a statistic observation of traditional gene expression programming, an improvement is made in our algorithm, that is, genetic operators should act more often on the dominant part of genes than on the recessive part. This may help maintain population diversity and also speed up the convergence of the algorithm. Experiments show that this improved algorithm performs much better than genetic programming and traditional gene expression programming in terms of running time and prediction precisio