Infection dynamics: from organ to host population

A symposium discussing collaborative research work on infectious diseases dynamics was held at Queens' College, University of Cambridge on 25 October 2006

Efficient History Matching of a High Dimensional Individual-Based HIV Transmission Model

History matching is a model (pre-)calibration method that has been applied to computer models from a wide range of scientific disciplines. In this work we apply history matching to an individual-based epidemiological model of HIV that has 96 input and 50 output parameters, a model of much larger scale than others that have been calibrated before using this or similar methods. Apart from demonstrating that history matching can analyze models of this complexity, a central contribution of this work is that the history match is carried out using linear regression, a statistical tool that is elementary and easier to implement than the Gaussian process--based emulators that have previously been used. Furthermore, we address a practical difficulty with history matching, namely, the sampling of tiny, nonimplausible spaces, by introducing a sampling algorithm adjusted to the specific needs of this method. The effectiveness and simplicity of the history matching method presented here shows that it is a useful tool for the calibration of computationally expensive, high dimensional, individual-based models

Bayesian history matching of complex infectious disease models using emulation: A tutorial and a case study on HIV in Uganda

Advances in scientific computing have allowed the development of complex models that are being routinely applied to problems in disease epidemiology, public health and decision making. The utility of these models depends in part on how well they can reproduce empirical data. However, fitting such models to real world data is greatly hindered both by large numbers of input and output parameters, and by long run times, such that many modelling studies lack a formal calibration methodology. We present a novel method that has the potential to improve the calibration of complex infectious disease models (hereafter called simulators). We present this in the form of a tutorial and a case study where we history match a dynamic, event-driven, individual-based stochastic HIV simulator, using extensive demographic, behavioural and epidemiological data available from Uganda. The tutorial describes history matching and emulation. History matching is an iterative procedure that reduces the simulator's input space by identifying and discarding areas that are unlikely to provide a good match to the empirical data. History matching relies on the computational efficiency of a Bayesian representation of the simulator, known as an emulator. Emulators mimic the simulator's behaviour, but are often several orders of magnitude faster to evaluate. In the case study, we use a 22 input simulator, fitting its 18 outputs simultaneously. After 9 iterations of history matching, a non-implausible region of the simulator input space was identified that was times smaller than the original input space. Simulator evaluations made within this region were found to have a 65% probability of fitting all 18 outputs. History matching and emulation are useful additions to the toolbox of infectious disease modellers. Further research is required to explicitly address the stochastic nature of the simulator as well as to account for correlations between outputs

Choice of time horizon critical in estimating costs and effects of changes to HIV programmes

Background: Uganda changed its antiretroviral therapy guidelines in 2014, increasing the CD4 threshold for antiretroviral therapy initiation from 350 cells/µl to 500 cells/µl. We investigate what effect this change in policy is likely to have on HIV incidence, morbidity, and programme costs, and estimate the cost-effectiveness of the change over different time horizons. Methods: We used a complex individual-based model of HIV transmission and antiretroviral therapy scale-up in Uganda. 100 model fits were generated by fitting the model to 51 demographic, sexual behaviour, and epidemiological calibration targets, varying 96 input parameters, using history matching with model emulation. An additional 19 cost and disability weight parameters were varied during the analysis of the model results. For each model fit, the model was run to 2030, with and without the change in threshold to 500 cells/µl. Results: The change in threshold led to a 9.7% (90% plausible range: 4.3%-15.0%) reduction in incidence in 2030, and averted 278,944 (118,452-502,790) DALYs, at a total cost of $28M (-$142M to +$195M). The cost per disability adjusted life year (DALY) averted fell over time, from$3238 (-$125 to +$29,969) in 2014 to $100 (-$499 to +$785) in 2030. The change in threshold was cost-effective (cost <3×Uganda's per capita GDP per DALY averted) by 2018, and highly cost-effective (cost <Uganda's per capita GDP per DALY averted) by 2022, for more than 50% of parameter sets. Conclusions: Model results suggest that the change in threshold is unlikely to have been cost-effective to date, but is likely to be highly cost-effective in Uganda by 2030. The time horizon needs to be chosen carefully when projecting intervention effects. Large amounts of uncertainty in our results demonstrates the need to comprehensively incorporate uncertainties in model parameterisation

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

From firm to fluid – Structure-texture relations of filled gels probed under Large Amplitude Oscillatory Shear

Soft-solid foods show a progressive transition from a viscoelastic solid state to a flowing fluid state when subjected to a large load. The engineering properties and sensory texture of soft-solid foods depend strongly on the rheological properties that characterize this fluidization. In this paper we use Large Amplitude Oscillatory Shear (LAOS) rheometry to quantify the texture of emulsion-filled food gels in terms of measurable material properties. We provide unambiguous rheological definitions for the firmness, rubberiness, softening and fluidization of soft-solid food gels. We propose a new measure for the load-induced solid-fluid transition, the fluidizing ratio, which quantifies the progression of damage and the degree of plastic flow in the soft-solid gel. We use another dimensionless measure, the thickening ratio, to reveal and characterize the resulting sequence of flow regimes. We use our rheological definitions to quantify the texture of zero-fat, low-fat and full-fat semi-hard cheese respectively. Our data provides evidence that the rate of two physical processes, microcrack nucleation and microcrack propagation, are controlled by the amount of fat emulsion in the gel and govern the rubberiness and brittleness of semi-hard cheese. By translating texture terminology into quantitative material properties measured using Large Amplitude Oscillatory Shear, we augment the capabilities of LAOS as an analytical tool for structure-texture engineering of soft-solid food gels

Describing the firmness, springiness and rubberiness of food gels using fractional calculus. Part II: Measurements on semi-hard cheese

We use the framework of fractional calculus to quantify the linear viscoelastic properties of full-fat, low-fat, and zero-fat, semi-hard cheeses over a range of temperatures and water/protein ratios. These fractional constitutive models correctly predict the time-dependence and interrelation of the firmness, springiness, and rubberiness of these emulsion-filled hydrocolloidal gels. Our equations for the firmness F, springiness S, and rubberiness R, also correctly predict the effect of changing the magnitude or time-scale of the stress loading on the material even in the case of irreversible flow events, when cheese progressively transitions from a solid to a liquid. Finally we show how our FSR-equations can be used in a texture engineering context; they provide rational guidance to product reformulation studies and allow for extrapolation of a firmness measurement to practical situations in which the gel is subjected to prolonged creep loading. Keywords Rational reformulation Food gels Structure-texture engineering Constitutive model Fractional calculus Scott Blai

Describing the firmness, springiness and rubberiness of food gels using fractional calculus. Part I: Theoretical framework

Constitutive models for soft solids that quantitatively relate the state of the stress in the material to the deformation history have the potential to be used in a structure-texture engineering context, but successful examples are scarce. In the present work we define equations for the firmness F, springiness S, and rubberiness R, of semi-soft food gels such as cheeses that exhibit broad power-law stress relaxation over a wide range of timescales. The equations contain only two material properties, which have their origin in the food microstructure: a fractional exponent, which quantifies the frequency and temporal response and secondly a scale factor or “quasi-property”, which sets the magnitude of the stress in the material. Together they form a constitutive element, known as the ‘springpot’ or Scott Blair element which can accurately capture the viscoelastic properties of food gels such as semi-hard cheeses. Using this model it becomes possible to provide clear and unambiguous definitions of textural parameters such as firmness, springiness and rubberiness, and to quantify their time-dependence and interrelationship. The magnitude of the firmness and springiness are inversely related through the fractional constitutive model. Our FSR-equations can be used in a texture engineering context to guide effective product reformulation of soft-solid, hydrocolloidal gels. Keywords Rational reformulation Food gels Structure-texture engineering Constitutive model Fractional calculus Scott Blai

From firm to fluid – Structure-texture relations of filled gels probed under Large Amplitude Oscillatory Shear

Soft-solid foods show a progressive transition from a viscoelastic solid state to a flowing fluid state when subjected to a large load. The engineering properties and sensory texture of soft-solid foods depend strongly on the rheological properties that characterize this fluidization. In this paper we use Large Amplitude Oscillatory Shear (LAOS) rheometry to quantify the texture of emulsion-filled food gels in terms of measurable material properties. We provide unambiguous rheological definitions for the firmness, rubberiness, softening and fluidization of soft-solid food gels. We propose a new measure for the load-induced solid-fluid transition, the fluidizing ratio, which quantifies the progression of damage and the degree of plastic flow in the soft-solid gel. We use another dimensionless measure, the thickening ratio, to reveal and characterize the resulting sequence of flow regimes. We use our rheological definitions to quantify the texture of zero-fat, low-fat and full-fat semi-hard cheese respectively. Our data provides evidence that the rate of two physical processes, microcrack nucleation and microcrack propagation, are controlled by the amount of fat emulsion in the gel and govern the rubberiness and brittleness of semi-hard cheese. By translating texture terminology into quantitative material properties measured using Large Amplitude Oscillatory Shear, we augment the capabilities of LAOS as an analytical tool for structure-texture engineering of soft-solid food gels. Keywords: Emulsion-filled gels, Fluidization, Food texture engineering, Microstructure, LAO