Stochastic effects in cellular systems are usually modeled and simulated with Gillespie's stochastic simulation algorithm (SSA), which follows the same theoretical derivation as the chemical master equation (CME), but the low efficiency of SSA limits its application to large chemical networks. To improve efficiency of stochastic simulations, Haseltine and Rawlings proposed a hybrid of ODE and SSA algorithm, which combines ordinary differential equations (ODEs) for traditional deterministic models and SSA for stochastic models. In this dissertation, accuracy analysis, efficient implementation strategies, and application of of Haseltine and Rawlings's hybrid method (HR) to a budding yeast cell cycle model are discussed. Accuracy of the hybrid method HR is studied based on a linear chain reaction system, motivated from the modeling practice used for the budding yeast cell cycle control mechanism. Mathematical analysis and numerical results both show that the hybrid method HR is accurate if either numbers of molecules of reactants in fast reactions are above certain thresholds, or rate constants of fast reactions are much larger than rate constants of slow reactions. Our analysis also shows that the hybrid method HR allows for a much greater region in system parameter space than those for the slow scale SSA (ssSSA) and the stochastic quasi steady state assumption (SQSSA) method. Implementation of the hybrid method HR requires a stiff ODE solver for numerical integration and an efficient event-handling strategy for slow reaction firings. In this dissertation, an event-handling strategy is developed based on inverse interpolation. Performances of five wildly used stiff ODE solvers are measured in three numerical experiments. Furthermore, inspired by the strategy of the hybrid method HR, a hybrid of ODE and SSA stochastic models for the budding yeast cell cycle is developed, based on a deterministic model in the literature. Simulation results of this hybrid model match very well with biological experimental data, and this model is the first to do so with these recently available experimental data. This study demonstrates that the hybrid method HR has great potential for stochastic modeling and simulation of large biochemical networks. / Ph. D.

The cell cycle of eukaryotes consists of alternation between growth and DNA replication (interphase), and DNA distribution and cell-division (mitosis or M-phase). This process is regulated by a complex network of biochemical reactions. A core part of this network, called the "Cell Cycle engine" is evolutionarily conserved. The dimer of CDK1 (a protein kinase) and Cyclin proteins (the regulatory components), called M-phase Promoting Factor (MPF), and its key regulatory proteins Cdc25 and Wee1, are central parts of this cell cycle engine. Maintaining the fidelity of the DNA during the cell cycle is critical for successful propagation of the cell lineage. In the presence of unreplicated DNA, the cell cycle engine''s progress into mitosis is slowed down (or halted) by regulation of MPF activity through Cdc25 and Wee1. This regulatory event, called the unreplicated DNA checkpoint, was modeled in a rudimentary fashion in the Novak and Tyson (1993) model of frog eggs. Since then, many new experiments have uncovered relevant parts of this network. Here, we include these parts into a detailed model of the unreplicated DNA checkpoint in the cell cycle of frog-egg extracts. This work and future studies of the unreplicated DNA checkpoint will lead to its better understanding and hopefully to some strategies for tackling cancer. / Master of Science

No / Sulfate causes various health issues for human if on average daily intake of sulfate is more than 500 mg from drinking-water, air, and food. Moreover, the presence of sulfate in rainwater causes acid rains which has harmful effects on animals and plants. Food is the major source of sulfate intake; however, in areas of South-Punjab, Pakistan, the drinking-water containing high levels of sulfate may constitute the principal source of intake. The spatial behavior of sulfate in groundwater is recorded for South-Punjab province, Pakistan. The spatial dependence of the response variable (sulfate) is modeled by using various variograms models that are estimated by maximum likelihood method, restricted maximum likelihood method, ordinary least squares, and weighted least squares. The parameters of estimated variogram models are utilized in ordinary kriging, universal kriging, Bayesian kriging with constant trend, and varying trend and the above methods are used for interpolation of sulfate concentration. The K-fold cross validation is used to measure the performances of variogram models and interpolation methods. Bayesian kriging with a constant trend produces minimum root mean square prediction error than other interpolation methods. Concentration of sulfate in drinking water within the study area is increasing to the Northern part, and health risks are really high due to poor quality of water.

Diferentes métodos geoestatísticos são apresentados como a melhor solução para diferentes contextos de acordo com a natureza dos dados a serem analisados. Alguns dos métodos de estimativa mais populares incluem a krigagem ordinária e a krigagem ordinária lognormal, esta ultima requerendo a transformação dos dados originais para uma distribuição gaussiana. No entanto, esses métodos apresentam limitações, sendo uma das mais discutidas o efeito de suavização apresentado pelas estimativas obtidas. Alguns algoritmos recentes foram propostos como meios de se corrigir este efeito, e são avaliados neste trabalho para a sua eficiência, assim como alguns algoritmos para a transformada reversa dos valores convertidos na krigagem ordinária lognormal. Outra abordagem para o problema é por meio do grupo de métodos denominado de simulação estocástica, alguns dos mais populares sendo a simulação gaussiana seqüencial e a simulação por bandas rotativas, que apesar de não apresentar o efeito de suavização da krigagem, não possuem a precisão local característica dos métodos de estimativa. Este trabalho busca avaliar a eficiência dos diferentes métodos de estimativa (krigagem ordinária, krigagem ordinária lognormal, assim como suas estimativas corrigidas) e simulação (simulação seqüencial gaussiana e simulação por bandas rotativas) para diferentes cenários de dados. Vinte e sete conjuntos de dados exaustivos (em grid 50x50) foram amostrados em 90 pontos por meio da amostragem aleatória simples. Estes conjuntos de dados partiam de uma distribuição gaussiana (Log1) e tinham seus coeficientes de variação progressivamente aumentados até se chegar a uma distribuição altamente assimétrica (Log27). Semivariogramas amostrais foram computados e modelados para os processos geoestatísticos de estimativa e simulação. As estimativas ou realizações resultantes foram então comparadas com os dados exaustivos originais de maneira a se avaliar quão bem esses dados originais eram reproduzidos. Isto foi feito pela comparação de parâmetros estatísticos dos dados originais com os dos dados reconstruídos, assim como por meio de análise gráfica. Resultados demonstraram que o método que apresentou melhores resultados foi a krigagem ordinária lognormal, estes ainda melhores quando aplicada a transformação reversa de Yamamoto, com grande melhora principalmente nos resultados para os dados altamente assimétricos. A krigagem ordinária apresentou sérias limitações na reprodução da cauda inferior dos conjuntos de dados mais assimétricos, apresentando para estes resultados piores que as estimativas não corrigidas. Ambos os métodos de simulação utilizados apresentaram uma baixa correlação como os dados exaustivos, seus resultados também cada vez menos representativos de acordo com o aumento do coeficiente de variação, apesar de apresentar a vantagem de fornecer diferentes cenários para tomada de decisões. / Different geostatistical methods present themselves as the optimal solution to different realities according to the characteristics displayed by the data in analysis. Some of the most popular estimation methods include ordinary kriging and lognormal ordinary kriging, this last one involving the transformation of data from their original space to a Gaussian distribution. However, these methods present some limitations, one of the most prominent ones being the smoothing effect observed in the resulting estimates. Some recent algorithms have been proposed as a way to correct this effect, and are tested in this work for their effectiveness, as well as some methods for the backtransformation of the lognormal converted values. Another approach to the problem is by means of the group of methods known as stochastic simulation, some of the most popular ones being the sequential Gaussian simulation and turning bands simulation, which although do not present the smoothing effect, lack the local accuracy characteristic of the estimation methods. This work seeks to assess the effectiveness of the different estimation (ordinary kriging, lognormal ordinary kriging, and their corrected estimates) and simulation (sequential Gaussian simulation and turning bands simulation) methods for different scenarios. Twenty seven exhaustive data sets (in a 50x50 grid) have been sampled at 90 points based on simple random sampling. These data sets started from a Gaussian distribution (Log1) and had their variation coefficients increased progressively, up to a highly asymmetrical distribution (Log27). Experimental semivariograms have been computed and modeled for geostatistical estimation and simulation processes. The resulting estimates or realizations were then compared to the original exhaustive data in order to assess how well these reproduced the original data. This was done by comparing statistical parameters of the original data and the ones of the reconstructed data, as well as graphically. Results showed that the method that presented the best correlation with the exhaustive data was lognormal ordinary kriging, even better when the backtransformation technique by Yamamoto is applied, which much improved the results for the more asymmetrical data sets. Ordinary kriging and its correction had some severe limitations in reproducing the lower tail of the more asymmetrical data sets, with worst results than those for the uncorrected estimates. Both simulation methods used presented a very small degree of correlation to the exhaustive data, their results also progressively less representative as the variation coefficient grew, even though it has the advantage of presenting several scenarios for decision making.

Diferentes métodos geoestatísticos são apresentados como a melhor solução para diferentes contextos de acordo com a natureza dos dados a serem analisados. Alguns dos métodos de estimativa mais populares incluem a krigagem ordinária e a krigagem ordinária lognormal, esta ultima requerendo a transformação dos dados originais para uma distribuição gaussiana. No entanto, esses métodos apresentam limitações, sendo uma das mais discutidas o efeito de suavização apresentado pelas estimativas obtidas. Alguns algoritmos recentes foram propostos como meios de se corrigir este efeito, e são avaliados neste trabalho para a sua eficiência, assim como alguns algoritmos para a transformada reversa dos valores convertidos na krigagem ordinária lognormal. Outra abordagem para o problema é por meio do grupo de métodos denominado de simulação estocástica, alguns dos mais populares sendo a simulação gaussiana seqüencial e a simulação por bandas rotativas, que apesar de não apresentar o efeito de suavização da krigagem, não possuem a precisão local característica dos métodos de estimativa. Este trabalho busca avaliar a eficiência dos diferentes métodos de estimativa (krigagem ordinária, krigagem ordinária lognormal, assim como suas estimativas corrigidas) e simulação (simulação seqüencial gaussiana e simulação por bandas rotativas) para diferentes cenários de dados. Vinte e sete conjuntos de dados exaustivos (em grid 50x50) foram amostrados em 90 pontos por meio da amostragem aleatória simples. Estes conjuntos de dados partiam de uma distribuição gaussiana (Log1) e tinham seus coeficientes de variação progressivamente aumentados até se chegar a uma distribuição altamente assimétrica (Log27). Semivariogramas amostrais foram computados e modelados para os processos geoestatísticos de estimativa e simulação. As estimativas ou realizações resultantes foram então comparadas com os dados exaustivos originais de maneira a se avaliar quão bem esses dados originais eram reproduzidos. Isto foi feito pela comparação de parâmetros estatísticos dos dados originais com os dos dados reconstruídos, assim como por meio de análise gráfica. Resultados demonstraram que o método que apresentou melhores resultados foi a krigagem ordinária lognormal, estes ainda melhores quando aplicada a transformação reversa de Yamamoto, com grande melhora principalmente nos resultados para os dados altamente assimétricos. A krigagem ordinária apresentou sérias limitações na reprodução da cauda inferior dos conjuntos de dados mais assimétricos, apresentando para estes resultados piores que as estimativas não corrigidas. Ambos os métodos de simulação utilizados apresentaram uma baixa correlação como os dados exaustivos, seus resultados também cada vez menos representativos de acordo com o aumento do coeficiente de variação, apesar de apresentar a vantagem de fornecer diferentes cenários para tomada de decisões. / Different geostatistical methods present themselves as the optimal solution to different realities according to the characteristics displayed by the data in analysis. Some of the most popular estimation methods include ordinary kriging and lognormal ordinary kriging, this last one involving the transformation of data from their original space to a Gaussian distribution. However, these methods present some limitations, one of the most prominent ones being the smoothing effect observed in the resulting estimates. Some recent algorithms have been proposed as a way to correct this effect, and are tested in this work for their effectiveness, as well as some methods for the backtransformation of the lognormal converted values. Another approach to the problem is by means of the group of methods known as stochastic simulation, some of the most popular ones being the sequential Gaussian simulation and turning bands simulation, which although do not present the smoothing effect, lack the local accuracy characteristic of the estimation methods. This work seeks to assess the effectiveness of the different estimation (ordinary kriging, lognormal ordinary kriging, and their corrected estimates) and simulation (sequential Gaussian simulation and turning bands simulation) methods for different scenarios. Twenty seven exhaustive data sets (in a 50x50 grid) have been sampled at 90 points based on simple random sampling. These data sets started from a Gaussian distribution (Log1) and had their variation coefficients increased progressively, up to a highly asymmetrical distribution (Log27). Experimental semivariograms have been computed and modeled for geostatistical estimation and simulation processes. The resulting estimates or realizations were then compared to the original exhaustive data in order to assess how well these reproduced the original data. This was done by comparing statistical parameters of the original data and the ones of the reconstructed data, as well as graphically. Results showed that the method that presented the best correlation with the exhaustive data was lognormal ordinary kriging, even better when the backtransformation technique by Yamamoto is applied, which much improved the results for the more asymmetrical data sets. Ordinary kriging and its correction had some severe limitations in reproducing the lower tail of the more asymmetrical data sets, with worst results than those for the uncorrected estimates. Both simulation methods used presented a very small degree of correlation to the exhaustive data, their results also progressively less representative as the variation coefficient grew, even though it has the advantage of presenting several scenarios for decision making.

O objetivo deste trabalho e estudar algumas propriedades de soluções de equações diferenciais ordinárias generalizadas e aplicar tais resultados a algumas equações diferenciais clássicas (equações diferenciais ordinárias abstratas e equações diferenciais funcionais em medida). Os principais resultados tratam de existência-unicidade de soluções para uma classe de equações diferenciais ordinárias generalizadas, dependência contnua de soluções com respeito as condições iniciais e bacia de atração. Estes resultados são transferidos para uma classe de equações diferencias ordinárias abstratas. Também obtemos resultados sobre estabilidade da solução trivial de equações diferenciais ordinárias generalizadas e transferimos estes resultados para uma classe de equações diferenciais funcionais em medida / The purpose of this work is to study some properties of solutions of generalized ordinary dierential equations and apply these results to some classical dierential equations (abstract ordinary dierential equations and measure functional dierential equations). The main results concern existence-uniqueness of a solution for a class of generalized ordinary dierential equations, continuous dependence of solutions with respect to initial conditions and basin of attraction. These results are transfered to a class of abstract ordinary dierential equations. We also obtain some results on the stability of the trivial solution of generalized ordinary dierential equations and we transfer these results to a class of measure functional dierential equations

O objetivo deste trabalho e estudar algumas propriedades de soluções de equações diferenciais ordinárias generalizadas e aplicar tais resultados a algumas equações diferenciais clássicas (equações diferenciais ordinárias abstratas e equações diferenciais funcionais em medida). Os principais resultados tratam de existência-unicidade de soluções para uma classe de equações diferenciais ordinárias generalizadas, dependência contnua de soluções com respeito as condições iniciais e bacia de atração. Estes resultados são transferidos para uma classe de equações diferencias ordinárias abstratas. Também obtemos resultados sobre estabilidade da solução trivial de equações diferenciais ordinárias generalizadas e transferimos estes resultados para uma classe de equações diferenciais funcionais em medida / The purpose of this work is to study some properties of solutions of generalized ordinary dierential equations and apply these results to some classical dierential equations (abstract ordinary dierential equations and measure functional dierential equations). The main results concern existence-uniqueness of a solution for a class of generalized ordinary dierential equations, continuous dependence of solutions with respect to initial conditions and basin of attraction. These results are transfered to a class of abstract ordinary dierential equations. We also obtain some results on the stability of the trivial solution of generalized ordinary dierential equations and we transfer these results to a class of measure functional dierential equations

We first discuss some fundamental results such as equilibria, linearization, and stability of nonlinear dynamical systems arising in mathematical modeling. Next we study the dynamics in planar systems such as limit cycles, the Poincaré-Bendixson theorem, and some of its useful consequences. We then study the interaction between two and three different cell populations, and perform stability and bifurcation analysis on the systems. We also analyze the impact of immunotherapy on the tumor cell population numerically.

<p>Efficient global dynamic optimization (GDO) using spatial branch-and-bound (SBB) requires the ability to construct tight bounds for the dynamic model. This thesis works toward efficient GDO by developing effective convex relaxation techniques for models with ordinary differential equations (ODEs). In particular, a novel algorithm, based upon a verified interval ODE method and the McCormick relaxation technique, is developed for constructing convex and concave relaxations of solutions of nonlinear parametric ODEs. In addition to better convergence properties, the relaxations so obtained are guaranteed to be no looser than their underlying interval bounds, and are typically tighter in practice. Moreover, they are rigorous in the sense of accounting for truncation errors. Nonetheless, the tightness of the relaxations is affected by the overestimation from the dependency problem of interval arithmetic that is not addressed systematically in the underlying interval ODE method. To handle this issue, the relaxation algorithm is extended to a Taylor model ODE method, which can provide generally tighter enclosures with better convergence properties than the interval ODE method. This way, an improved version of the algorithm is achieved where the relaxations are generally tighter than those computed with the interval ODE method, and offer better convergence. Moreover, they are guaranteed to be no looser than the interval bounds obtained from Taylor models, and are usually tighter in practice. However, the nonlinearity and (potentially) nonsmoothness of the relaxations impedes their fast and reliable solution. Therefore, the algorithm is finally modified by incorporating polyhedral relaxations in order to generate relatively tight and computationally cheap linear relaxations for the dynamic model. The resulting relaxation algorithm along with a SBB procedure is implemented in the MC++ software package. GDO utilizing the proposed relaxation algorithm is demonstrated to have significantly reduced computational expense, up to orders of magnitude, compared to existing GDO methods.</p> / Doctor of Philosophy (PhD)

Magnetic resonance imaging (MRI) of the liver is an important non-invasive tool for diagnosing liver disease. A key application is dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). With the use of the hepatocyte specific contrast agent (CA) Gd-EOB-DTPA it is now possible to evaluate the liver function. Beyond traditional qualitative evaluation of the DCE-MRI images, parametric quantitative techniques are on the rise which yields more objective evaluations. Systems biology is a gradually expanding field using mathematical modeling to gain deeper mechanistic understanding in complex biological systems. The aim of this thesis to combine these two fields in order to derive a physiologically accurate minimal whole body model that can be used to quantitatively evaluate liver function using clinical DCE-MRI examinations.  The work is based on two previously published sources of data using Gd-EOB-DTPA in healthy humans; i) a region of interest analysis of the liver using DCE-MRI ii) a pre-clinical evaluation of the contrast agent using blood sampling.  The modeling framework consists of a system of ordinary differential equations for the contrast agent dynamics and non-linear models for conversion of contrast agent concentrations to relaxivity values in the DCE-MRI image volumes. Using a χ2-test I have shown that the model, with high probability, can fit the experimental data for doses up to twenty times the clinically used one, using the same parameters for all doses. The results also show that some of the parameters governing the hepatocyte flux of CA can be numerically identifiable. Future applications with the model might be as a basis for regional liver function assessment. This can lead to disease diagnosis and progression evaluation for physicians as well as support for surgeons planning liver resection.