The Vestibulo-Ocular Reflex (VOR) produces compensatory eye movements in response to head and body rotations movements, over a wide range of frequencies and in a variety of dimensions. The individual components of the VOR are separated into parallel pathways, each dealing with rotations or movements in individual planes or axes. The Horizontal VOR (hVOR) compensates for eye movements in the Horizontal plane, and comprises a linear and non-linear pathway. The linear pathway of the hVOR provides fast and accurate compensation for rotations, the response being produced through 3-neuron arc, producing a direct translation of detected head velocity to compensatory eye velocity. However, single neurons involved in the middle stage of this 3-neuron arc cannot account for the wide frequency over which the reflex compensates, and the response is produced through the population response of the Medial Vestibular Nucleus (MVN) neurons involved. Population Heterogeneity likely plays a role in the production of high fidelity population response, especially for high frequency rotations. Here we present evidence that, in populations of bio-physical compartmental models of the MVN neurons involved, Heterogeneity across the population, in the form of diverse spontaneous firing rates, improves the response fidelity of the population over Homogeneous populations. Further, we show that the specific intrinsic membrane properties that give rise to this Heterogeneity may be the diversity of certain slow voltage activated Potassium conductances of the neurons. We show that Heterogeneous populations perform significantly better than Homogeneous populations, for a wide range of input amplitudes and frequencies, producing a much higher fidelity response. We propose that variance of Potassium conductances provides a plausible biological means by which Heterogeneity arises, and that the Heterogeneity plays an important functional role in MVN neuron population responses. We discuss our findings in relation to the specific mechanism of Desynchronisation through which the benfits of Heterogeneity may arise, and place those findings in the context of previous work on Heterogeneity both in general neural processing, and the VOR in particular. Interesting findings regarding the emergence of phase leads are also discussed, as well as suggestions for future work, looking further at Heterogeneity of MVN neuron populations.

L'objectif de ce travail est de comparer les approches systémique, mécanique des fluides numérique (MFN) et compartimentale, une approche de modélisation en émergence basée sur l'exploitation quantitative de simulations de MFN pour construire le modèle. Une méthodologie de construction d'un tel modèle à compartiments est explicitée. Ces différentes approches de modélisation ont été appliquées au cas d'un réacteur pilote de traitement des eaux usées à boues activées : un réacteur triphasique (gaz/liquide/flocs), siège de réactions biologiques complexes. Le modèle hydrodynamique MFN a été validé par des mesures de champs de vitesse et de turbulence, réalisées par Vélocimétrie Laser Doppler ainsi que par des mesures de taux de vide réalisées à l'aide d'une sonde optique. L'hydrodynamique globale du réacteur est bien modélisée par un modèle piston à dispersion axiale et la MFN représente bien le comportement du réacteur. Des expériences sur réacteur pilote chargé en biomasse et alimenté par un substrat synthétique à base de Viandox ont été menées. La modélisation des réactions biologiques a été faite par le modèle ASM1 développé par l'IWA. Les modèles systémique et MFN permettent d'estimer l'évolution de la plupart des concentrations dans le réacteur avec moins de 25 % d'erreur. Des différences entre les deux modèles sont néanmoins observées. Il s'avère que le modèle à compartiment donne des résultats très similaires au modèle MFN pour un temps de calcul de 10 à 20 fois moindre. De plus ce modèle est presque aussi facile à manipuler qu'un modèle systémique et permet une meilleure compréhension des phénomènes mis en jeu dans le réacteur qu'avec un modèle MFN / The purpose of this work is the comparison of the systemic, computational fluid dynamics (CFD) and compartmental approaches. This last approach is a new method of model construction based on the quantitative results of a CFD simulation. A methodology to build such a model is described. These three modelisation approaches have been used to model a bench scale activated sludge wastewater treatment reactor : a complex biological tree-phase reactor (gas/liquid/floc). The CFD modelling has been validated with velocity and turbulence fields, obtained with laser doppler velocimétry and with void fraction measurements obtained with an optical probe. The global hydrodynamics of the reactor is well represented by a plug flow model with axial dispersion. This behaviour is well represented by CFD simulation of residence time distribution. Experiments on the bench scale activated sludge reactor fed with a synthetic substrate primarily composed of Viandox have been carried out. Biological reactions have been modelled by the ASM1 model developped by IWA. Evolution of almost all the concentrations along the reactor are simulated with a maximum error of 25 \% with systemic and CFD models. Some differences are highlighted between these two models. The compartmental model gives almost the same results as the CFD model with a calculation time from 10 to 20 times shorter. Moreover this compartment model is as easy to handle as the sytemic model and allows a better understanding of the phenomena which take place in the reactor than the CFD model

A dose resultante da contaminação interna pode ser estimada por meio de modelos biocinéticos em conjunto com os resultados experimentais obtidos de medidas de bioanálise e do conhecimento do momento da incorporação. Os modelos biocinéticos são representados por um conjunto de compartimentos que expressam o transporte, a retenção e a eliminação dos radionuclídeos do organismo. As publicações 66, 78 e 100 da ICRP apresentam modelos compartimentais para o trato respiratório, trato gastrointestinal e de distribuição sistêmica para diversos radionuclídeos de interesse para a proteção radiológica. O objetivo deste trabalho é desenvolver um código computacional para utilização em Dosimetria Interna considerando os principais radionuclídeos de interesse do IPEN do ponto de vista das exposições ocupacionais, tanto em situações rotineiras como também em casos acidentais, de modo a servir de ferramenta ágil e eficiente na construção, visualização e resolução de modelos compartimentais de qualquer natureza. A arquitetura do sistema foi concebida contendo dois programas independentes: CBT - responsável pela criação e manipulação dos modelos, e SSID - responsável pela resolução matemática dos mesmos. São oferecidas quatro técnicas diferentes para a resolução do sistema de equações incluindo métodos semi-analíticos e numéricos, onde se pode comparar a precisão e o desempenho destas. O desenvolvimento foi feito na linguagem de programação C#, utilizando um banco de dados Microsoft Access e o padrão XML para a troca de arquivos com outros aplicativos. Para a validação do programa CBT foram construídos os modelos de compartimentos para os radionuclídeos urânio, tório e iodo. Com o programa SSID os modelos foram resolvidos e os resultados comparados com os valores publicados pela ICRP 78. Em todos os casos, o sistema desenvolvido conseguiu reproduzir os valores publicados pela ICRP. / The dose resulting from internal contamination can be estimated with the use of biokinetic models combined with experimental results obtained from bioanalysis and assessment of the time of incorporation. The biokinetics models are represented by a set of compartments expressing the transportation, retention and elimination of radionuclides from the body. The ICRP publications, number 66, 78 and 100, present compartmental models for the respiratory tract, gastrointestinal tract and for systemic distribution for an array of radionuclides of interest for the radiological protection. The objective of this work is to develop a computational code for the internal doses assessment of the main radionuclides of occupational exposure at IPEN. Consequently serving as a agile and efficient tool for the designing, visualization and resolution of compartmental models of any nature. The architecture of the system was conceived containing two independent software: CBT responsible for the setup and manipulation of models and SSID responsible for the mathematical solution of the models. Four different techniques are offered for the resolution of system of equations, including semi-analytical and numerical methods, allowing for comparison of precision and performance of both. The software was developed in C# programming, using a Microsoft Access database and XML standards for file exchange with other applications. Compartmental models for uranium, thorium and iodine radionuclides were generated for the validation of the CBT software. The models were subsequently solved via SSID software and the results compared with the values published in the issue 78 of ICRP. In all cases the system replicated the values published by ICRP.

Este trabalho apresenta dois modelos baseados em análise compartimental: modelo Animal e modelo Humano, usando imagens obtidas com mini gama câmera e dados de pacientes (obtidos da literatura) para a determinação das constantes cinéticas na biodistribuição do 177Lu-DOTATATO para três espécies animais (rato Wistar, hamster armênio e hamster sírio) e para o Humano. Os estudos de biodistribuição consideraram duas fases: a Fase 1, governada pela transferência do sangue para os órgãos e a Fase 2 governada pela excreção renal. As constantes cinéticas calculadas a partir dos dados obtidos com os animais foram usadas para a construção de escalas alométricas para prever a biodistribuição do radiofármaco 177Lu-DOTATATO empregando relações de massa, metabolismo, longevidade e parâmetros fisiológicos. Os resultados de extrapolação foram comparados com resultados calculados diretamente para os pacientes de PRRT (Peptide Receptor Radiotherapy) usando o modelo Humano. As constantes cinéticas calculadas a partir dos dados obtidos com humanos foram usadas para estimativa de dose em pacientes de PRRT considerando 26 órgãos e tecidos considerados pelo método MIRD. Os resultados de dosimetria foram concordantes com aqueles disponíveis na literatura. Para a Fase 1, as relações alométricas para as constantes cinéticas dos principais órgãos envolvidos no metabolismo e excreção do 177Lu-DOTATATO - fígado, rins e bexiga - mostraram boa correlação na projeção por massa, por metabolismo e por parâmetros fisiológicos. Para a Fase 2, apenas as constantes do sangue para os rins e do sangue para o fígado apresentaram boa correlação. Considerando o efeito de bloqueio da excreção renal pelo uso de anestésico, não se justificam tempos de medição maiores que 40 minutos para estudos in vivo, em pequenos animais. Dessa maneira, os resultados obtidos com as medições da Fase 1 da biodistribuição do 177Lu-DOTATATO em animais se apresentam como suficientes para estabelecer relações alométricas para estimativa de dose em pacientes submetidos à PRRT. / This work proposes two models based in compartimental analyses: Animal model and Human model, using images from gamma camera measurements to determinate the kinetic constants of the 177Lu-DOTATATE to three animal species (rat Wistar, Armenian hamster and Syrian hamster) and to the human in biodistridution studies split in two phases: Phase 1 governed by uptake from the blood and Phase 2 governed by the real excretion. The kinetic constants obtained from the animals data were used to build allometric scaling to predict radiopharmaceutical biodistribution in the human employing relations by mass, metabolism, by life span and by physiological parameters. These extrapolation results were compared with the PRRT (Peptide receptor radiotherapy) patients kinetic data calculated using the Human model. The kinetic constants obtained from humans were used in dose assessment to PRRT patients considering MIRD 26 organs and tissues. Dosimetry results were in agreement with available results from literature. For the Phase 1 allometric scaling from kinetic data from the blood to the organs straight responsible for the 177Lu-DOTATATO metabolism and excretion - liver, kidneys and urinary bladder -show good correlation in the scaling by mass, metabolism and physiological and parameters. For the Phase 2, only the kinetic data from blood to the liver and to the kidneys show good correlation. Based in the anaesthetics inhibitory action over the renal excretion, there is not empirical basis to allow measurement times over 40 minutes in in vivo studies with small animals. Consequently, the Phase 1 results seem enough to make allometric scaling to assessment dose in PRRT.

"Magnetic resonance imaging (MRI) has increasingly become the preferred imaging modality in modern day research to study disease. MRI presents an imaging technique that is practically non-invasive and without any ionizing radiation. This dissertation presents the use of contrast agents in MRI studies to differentiate compartments, to study dose dependence of relaxation times, and to characterize tumors using signal amplifying enzymes in the brain. Differentiating compartments in the brain can be useful in diffusion studies to detect stroke at an early stage. Diffusion-weighted NMR techniques have established that the apparent diffusion coefficient (ADC) of cerebral tissue water decreases during ischemia. However, it is unclear whether the ADC change occurs due to changes in the intracellular (IC) space, extracellular (EC) space, or both. To better understand the mechanism of water ADC changes in response to ischemic injury, making IC and EC compartment specific measurements of water diffusion is essential. The first study was done where manganese (Mn2+) was used as an IC contrast agent. Mn2+ uptake by cells causes shortening of the T1 relaxation time of IC water. The relative difference in T1 relaxation times between the IC and EC compartments can be used to discriminate between the MR signals arising from water in the respective compartments. Mn2+ is also widely used in manganese-enhanced MRI (MEMRI) studies to visualize functional neural tracts and anatomy in the brain in vivo. In animal studies, the goal is to use a dose of Mn2+ that will maximize the contrast while minimizing its toxic effects. The goal of dose study was to investigate the MRI dose response of Mn2+ in rat brain following SC administration of Mn2+. The dose dependence and temporal dynamics of Mn2+ after SC injection can prove useful for longitudinal in vivo studies that require brain enhancement to persist for a long period of time to visualize neuroarchitecture like in neurodegenerative disease studies. Contrast agents, in addition to their use in compartmental differentiation and dose studies, can be used for imaging tumors. The last study in this dissertation focuses on imaging EGF receptors in brain tumors. We tested a novel pretargeting imaging approach that includes the administration of humanized monoclonal antibody (anti-EGFR mAb, EMD72000) linked to enzymes with complementing activities that use a low-molecular weight paramagnetic molecule (diTyr-GdDTPA) as a reducing substrate administered following the mAb conjugates. We analyzed the differential MR tumor signal decay in vivo using orthotopic models of human glioma. The patterns of MR signal change following substrate administration revealed differences in elimination patterns that allowed distinguishing between non-specific and specific modes of MR signal decay. "

Este trabalho apresenta dois modelos baseados em análise compartimental: modelo Animal e modelo Humano, usando imagens obtidas com mini gama câmera e dados de pacientes (obtidos da literatura) para a determinação das constantes cinéticas na biodistribuição do 177Lu-DOTATATO para três espécies animais (rato Wistar, hamster armênio e hamster sírio) e para o Humano. Os estudos de biodistribuição consideraram duas fases: a Fase 1, governada pela transferência do sangue para os órgãos e a Fase 2 governada pela excreção renal. As constantes cinéticas calculadas a partir dos dados obtidos com os animais foram usadas para a construção de escalas alométricas para prever a biodistribuição do radiofármaco 177Lu-DOTATATO empregando relações de massa, metabolismo, longevidade e parâmetros fisiológicos. Os resultados de extrapolação foram comparados com resultados calculados diretamente para os pacientes de PRRT (Peptide Receptor Radiotherapy) usando o modelo Humano. As constantes cinéticas calculadas a partir dos dados obtidos com humanos foram usadas para estimativa de dose em pacientes de PRRT considerando 26 órgãos e tecidos considerados pelo método MIRD. Os resultados de dosimetria foram concordantes com aqueles disponíveis na literatura. Para a Fase 1, as relações alométricas para as constantes cinéticas dos principais órgãos envolvidos no metabolismo e excreção do 177Lu-DOTATATO - fígado, rins e bexiga - mostraram boa correlação na projeção por massa, por metabolismo e por parâmetros fisiológicos. Para a Fase 2, apenas as constantes do sangue para os rins e do sangue para o fígado apresentaram boa correlação. Considerando o efeito de bloqueio da excreção renal pelo uso de anestésico, não se justificam tempos de medição maiores que 40 minutos para estudos in vivo, em pequenos animais. Dessa maneira, os resultados obtidos com as medições da Fase 1 da biodistribuição do 177Lu-DOTATATO em animais se apresentam como suficientes para estabelecer relações alométricas para estimativa de dose em pacientes submetidos à PRRT. / This work proposes two models based in compartimental analyses: Animal model and Human model, using images from gamma camera measurements to determinate the kinetic constants of the 177Lu-DOTATATE to three animal species (rat Wistar, Armenian hamster and Syrian hamster) and to the human in biodistridution studies split in two phases: Phase 1 governed by uptake from the blood and Phase 2 governed by the real excretion. The kinetic constants obtained from the animals data were used to build allometric scaling to predict radiopharmaceutical biodistribution in the human employing relations by mass, metabolism, by life span and by physiological parameters. These extrapolation results were compared with the PRRT (Peptide receptor radiotherapy) patients kinetic data calculated using the Human model. The kinetic constants obtained from humans were used in dose assessment to PRRT patients considering MIRD 26 organs and tissues. Dosimetry results were in agreement with available results from literature. For the Phase 1 allometric scaling from kinetic data from the blood to the organs straight responsible for the 177Lu-DOTATATO metabolism and excretion - liver, kidneys and urinary bladder -show good correlation in the scaling by mass, metabolism and physiological and parameters. For the Phase 2, only the kinetic data from blood to the liver and to the kidneys show good correlation. Based in the anaesthetics inhibitory action over the renal excretion, there is not empirical basis to allow measurement times over 40 minutes in in vivo studies with small animals. Consequently, the Phase 1 results seem enough to make allometric scaling to assessment dose in PRRT.

A dose resultante da contaminação interna pode ser estimada por meio de modelos biocinéticos em conjunto com os resultados experimentais obtidos de medidas de bioanálise e do conhecimento do momento da incorporação. Os modelos biocinéticos são representados por um conjunto de compartimentos que expressam o transporte, a retenção e a eliminação dos radionuclídeos do organismo. As publicações 66, 78 e 100 da ICRP apresentam modelos compartimentais para o trato respiratório, trato gastrointestinal e de distribuição sistêmica para diversos radionuclídeos de interesse para a proteção radiológica. O objetivo deste trabalho é desenvolver um código computacional para utilização em Dosimetria Interna considerando os principais radionuclídeos de interesse do IPEN do ponto de vista das exposições ocupacionais, tanto em situações rotineiras como também em casos acidentais, de modo a servir de ferramenta ágil e eficiente na construção, visualização e resolução de modelos compartimentais de qualquer natureza. A arquitetura do sistema foi concebida contendo dois programas independentes: CBT - responsável pela criação e manipulação dos modelos, e SSID - responsável pela resolução matemática dos mesmos. São oferecidas quatro técnicas diferentes para a resolução do sistema de equações incluindo métodos semi-analíticos e numéricos, onde se pode comparar a precisão e o desempenho destas. O desenvolvimento foi feito na linguagem de programação C#, utilizando um banco de dados Microsoft Access e o padrão XML para a troca de arquivos com outros aplicativos. Para a validação do programa CBT foram construídos os modelos de compartimentos para os radionuclídeos urânio, tório e iodo. Com o programa SSID os modelos foram resolvidos e os resultados comparados com os valores publicados pela ICRP 78. Em todos os casos, o sistema desenvolvido conseguiu reproduzir os valores publicados pela ICRP. / The dose resulting from internal contamination can be estimated with the use of biokinetic models combined with experimental results obtained from bioanalysis and assessment of the time of incorporation. The biokinetics models are represented by a set of compartments expressing the transportation, retention and elimination of radionuclides from the body. The ICRP publications, number 66, 78 and 100, present compartmental models for the respiratory tract, gastrointestinal tract and for systemic distribution for an array of radionuclides of interest for the radiological protection. The objective of this work is to develop a computational code for the internal doses assessment of the main radionuclides of occupational exposure at IPEN. Consequently serving as a agile and efficient tool for the designing, visualization and resolution of compartmental models of any nature. The architecture of the system was conceived containing two independent software: CBT responsible for the setup and manipulation of models and SSID responsible for the mathematical solution of the models. Four different techniques are offered for the resolution of system of equations, including semi-analytical and numerical methods, allowing for comparison of precision and performance of both. The software was developed in C# programming, using a Microsoft Access database and XML standards for file exchange with other applications. Compartmental models for uranium, thorium and iodine radionuclides were generated for the validation of the CBT software. The models were subsequently solved via SSID software and the results compared with the values published in the issue 78 of ICRP. In all cases the system replicated the values published by ICRP.

The abuse of and dependence on opioids are major public health problems, and have been the focus of intense media coverage and scholarly inquiry. This research explores the problem in Iowa through the lens of infectious disease modeling. We wanted to identify the current state of the crisis, factors affecting the progression of the addiction process, and evaluate interventions as data becomes available. We introduced a novel sequential Approximate Bayesian Computation technique to address shortcomings of existing methods in this complex problem space, after surveying the literature for available Bayesian computation techniques. A spatial compartmental model was used which allowed forward and backward progression through susceptible, exposed, addicted, and removed disease states. Data for this model were compiled over the years 2006-2016 for Iowa counties, from a variety of sources. Prescription overdose deaths and treatment data were obtained from the Iowa Department of Public Health, possession and distribution arrest data were acquired from the Iowa Department of Public Safety, a measure of total available pain reliever prescriptions was derived from private health insurance claims data, and population totals were obtained from the US Census Bureau. Inference was conducted in a Bayesian framework. A measure called the empirically adjusted reproductive number which estimates the expected number of new users generated from a single user was used to examine the growth of the crisis. Results expose the trend in recruitment of new users, and peak recruitment times. While we identify an overall decrease in the rate of spread during the study period, the scope of the problem remains severe, and interesting outlying trends require further investigation. In addition, an examination of the reproductive numbers estimated for contact within and between counties indicates that medical exposure, rather than spread through social networks, may be the key driver of this crisis.

Threshold dynamics used to control the spread of the disease in infectious disease phenomena has an overwhelming importance and interest in mathematical epidemiology. One of the famous threshold quantity is known to be the basic reproduction ratio. Its formulation as well as computation is the main concern of infectious diseases. The aim of this thesis is to analyze the basic reproduction ratio in both autonomous and periodic systems via defining R0 as the spectral radius of the next generation operator. This thesis presents the vector host model for the diseases Dengue fever and avian influenza. As emerging of the diseases shows periodicity, systems of periodic ordinary differential equations are considered for both types of diseases. Simple implementation of the time-averaged systems gives rise to the comparison of these with the periodic systems. Thus, we investigate the occurence of the existence of underestimation or overestimation of the basic reproduction ratio in timeaveraged systems.

The incidence of Type 1 diabetes is growing yearly. Worryingly, the aetiology of the disease is inconclusive. What is known is that the total number of affected individuals, as well as the severity and number of associated complications are growing for this chronic disease. With increasing complications due to severity, length of exposure, and poor control, the disease is beginning to consume an increasingly major portion of healthcare costs to the extent that it poses major economic risks in several nations. Research has shown that intensive insulin therapy aimed at certain minimum glycosylated haemoglobin threshold levels reduces the incidence of complications by up to 76% compared to conventional insulin therapy. Moreover, the effects of such intensive therapy regimes over a 6.5y duration persists for at least 10y after, a so called metabolic memory. Thus, early intervention can slow the momentum of complications far more easily than later intervention. Early, safe, intensive therapy protocols offer potential solutions to the growing social and economic effects of diabetes. Since the 1970s, the artificial endocrine pancreas has been heralded as just this type of solution. However, no commercial product currently exists, and ongoing limitations in sensors and pumps have resulted in, at best, modest clinical advantages over conventional methods of insulin administration or multiple daily injection. With high upfront costs, high costs of consumables, significant complexity, and the extensive infrastructure and support required, these systems and devices are only used by 2-15% of individuals with Type 1 diabetes. Clearly, there is an urgent need to address the large majority of the Type 1 diabetes population using conventional glucose measurement and insulin administration. For these individuals, current conventional or intensive therapies are failing to deliver recommended levels of glycaemic control. This research develops an understanding of clinical glycaemic control using conventional insulin administration and glucose measurement techniques in Type 1 diabetes based on a clinically validated in silico virtual patient simulation. Based on this understanding, a control protocol for Type 1 diabetes that is relatively simple and clinically practical is developed. The protocol design incorporates physiological modelling and engineering techniques to adapt to individual patient clinical requirements. By doing so, it produces accurate, patient-specific recommendations for insulin interventions. Initially, a simple, physiological compartmental model for the pharmacokinetics of subcutaneously injected insulin is developed. While the absorption process itself is subject to significant potential variability, such models enable a real-time estimation of plasma insulin concentration. This information would otherwise be lacking in the clinical environment of outpatient Type 1 diabetes treatment due to the inconvenience, cost, and laboratory turnaround for plasma insulin measurements. Hence, this validated model offers significant opportunity to optimise therapy selection. An in silico virtual patient simulation tool is also developed. A virtual patient cohort is developed on patient data from a representative cohort of the broad diabetes population. The simulation tool is used to develop a robust, adaptive protocol for prandial insulin dosing against a conventional intensive insulin therapy, as well as a controls group representative of the general diabetes population. The effect on glycaemic control of suboptimal and optimal, prandial and basal insulin therapies is also investigated, with results matching clinical expectations. To gauge the robustness of the developed adaptive protocol, a Monte Carlo analysis is performed, incorporating realistic and physiological errors and variability. Due to the relatively infrequent glucose measurement in outpatient Type 1 diabetes, a method for identifying the diurnal cycle in effective insulin sensitivity and modelling it in retrospective patient data is also presented. The method consists of identifying deterministic and stochastic components in the patient effective insulin sensitivity profile. Circadian rhythmicity and sleep-wake phases have profound effects on effective insulin sensitivity. Identification and prediction of this rhythm is of utmost clinical relevance, with the potential for safer and more effective glycaemic control, with less frequent measurement. It is thus a means of further enhancing any robust protocol and making it more clinically practical to implement. Finally, this research presents an entire framework for the realistic, and rapid development and testing of clinical glycaemic control protocols for outpatient Type 1 diabetes. The models and methods developed within this framework allow rapid and physiological identification of time-variant, patient-specific, effective insulin sensitivity profiles. These profiles form the responses of the virtual patient and can be used to develop and robustly test clinical glycaemic control protocols in a broad range of patients. These effective insulin sensitivity profiles are also rich in dynamics, specifically those circadian in nature which can be identified, and used to provide more accurate glycaemic prediction with the potential for safer and more effective control.