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- All Subjects: Applied Mathematics
- Creators: Nagy, John
Description
The phycologist, M. R. Droop, studied vitamin B12 limitation in the flagellate Monochrysis lutheri and concluded that its specific growth rate depended on the concentration of the vitamin within the cell; i.e. the cell quota of the vitamin B12. The Droop model provides a mathematical expression to link growth rate to the intracellular concentration of a limiting nutrient. Although the Droop model has been an important modeling tool in ecology, it has only recently been applied to study cancer biology. Cancer cells live in an ecological setting, interacting and competing with normal and other cancerous cells for nutrients and space, and evolving and adapting to their environment. Here, the Droop equation is used to model three cancers.
First, prostate cancer is modeled, where androgen is considered the limiting nutrient since most tumors depend on androgen for proliferation and survival. The model's accuracy for predicting the biomarker for patients on intermittent androgen deprivation therapy is tested by comparing the simulation results to clinical data as well as to an existing simpler model. The results suggest that a simpler model may be more beneficial for a predictive use, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting.
Next, two chronic myeloid leukemia models are compared that consider Imatinib treatment, a drug that inhibits the constitutively active tyrosine kinase BCR-ABL. Both models describe the competition of leukemic and normal cells, however the first model also describes intracellular dynamics by considering BCR-ABL as the limiting nutrient. Using clinical data, the differences in estimated parameters between the models and the capacity for each model to predict drug resistance are analyzed.
Last, a simple model is presented that considers ovarian tumor growth and tumor induced angiogenesis, subject to on and off anti-angiogenesis treatment. In this environment, the cell quota represents the intracellular concentration of necessary nutrients provided through blood supply. Mathematical analysis of the model is presented and model simulation results are compared to pre-clinical data. This simple model is able to fit both on- and off-treatment data using the same biologically relevant parameters.
First, prostate cancer is modeled, where androgen is considered the limiting nutrient since most tumors depend on androgen for proliferation and survival. The model's accuracy for predicting the biomarker for patients on intermittent androgen deprivation therapy is tested by comparing the simulation results to clinical data as well as to an existing simpler model. The results suggest that a simpler model may be more beneficial for a predictive use, although further research is needed in this field prior to implementing mathematical models as a predictive method in a clinical setting.
Next, two chronic myeloid leukemia models are compared that consider Imatinib treatment, a drug that inhibits the constitutively active tyrosine kinase BCR-ABL. Both models describe the competition of leukemic and normal cells, however the first model also describes intracellular dynamics by considering BCR-ABL as the limiting nutrient. Using clinical data, the differences in estimated parameters between the models and the capacity for each model to predict drug resistance are analyzed.
Last, a simple model is presented that considers ovarian tumor growth and tumor induced angiogenesis, subject to on and off anti-angiogenesis treatment. In this environment, the cell quota represents the intracellular concentration of necessary nutrients provided through blood supply. Mathematical analysis of the model is presented and model simulation results are compared to pre-clinical data. This simple model is able to fit both on- and off-treatment data using the same biologically relevant parameters.
ContributorsEverett, Rebecca Anne (Author) / Kuang, Yang (Thesis advisor) / Nagy, John (Committee member) / Milner, Fabio (Committee member) / Crook, Sharon (Committee member) / Jackiewicz, Zdzislaw (Committee member) / Arizona State University (Publisher)
Created2015
Description
In 1968, phycologist M.R. Droop published his famous discovery on the functional relationship between growth rate and internal nutrient status of algae in chemostat culture. The simple notion that growth is directly dependent on intracellular nutrient concentration is useful for understanding the dynamics in many ecological systems. The cell quota in particular lends itself to ecological stoichiometry, which is a powerful framework for mathematical ecology. Three models are developed based on the cell quota principal in order to demonstrate its applications beyond chemostat culture.
First, a data-driven model is derived for neutral lipid synthesis in green microalgae with respect to nitrogen limitation. This model synthesizes several established frameworks in phycology and ecological stoichiometry. The model demonstrates how the cell quota is a useful abstraction for understanding the metabolic shift to neutral lipid production that is observed in certain oleaginous species.
Next a producer-grazer model is developed based on the cell quota model and nutrient recycling. The model incorporates a novel feedback loop to account for animal toxicity due to accumulation of nitrogen waste. The model exhibits rich, complex dynamics which leave several open mathematical questions.
Lastly, disease dynamics in vivo are in many ways analogous to those of an ecosystem, giving natural extensions of the cell quota concept to disease modeling. Prostate cancer can be modeled within this framework, with androgen the limiting nutrient and the prostate and cancer cells as competing species. Here the cell quota model provides a useful abstraction for the dependence of cellular proliferation and apoptosis on androgen and the androgen receptor. Androgen ablation therapy is often used for patients in biochemical recurrence or late-stage disease progression and is in general initially effective. However, for many patients the cancer eventually develops resistance months to years after treatment begins. Understanding how and predicting when hormone therapy facilitates evolution of resistant phenotypes has immediate implications for treatment. Cell quota models for prostate cancer can be useful tools for this purpose and motivate applications to other diseases.
First, a data-driven model is derived for neutral lipid synthesis in green microalgae with respect to nitrogen limitation. This model synthesizes several established frameworks in phycology and ecological stoichiometry. The model demonstrates how the cell quota is a useful abstraction for understanding the metabolic shift to neutral lipid production that is observed in certain oleaginous species.
Next a producer-grazer model is developed based on the cell quota model and nutrient recycling. The model incorporates a novel feedback loop to account for animal toxicity due to accumulation of nitrogen waste. The model exhibits rich, complex dynamics which leave several open mathematical questions.
Lastly, disease dynamics in vivo are in many ways analogous to those of an ecosystem, giving natural extensions of the cell quota concept to disease modeling. Prostate cancer can be modeled within this framework, with androgen the limiting nutrient and the prostate and cancer cells as competing species. Here the cell quota model provides a useful abstraction for the dependence of cellular proliferation and apoptosis on androgen and the androgen receptor. Androgen ablation therapy is often used for patients in biochemical recurrence or late-stage disease progression and is in general initially effective. However, for many patients the cancer eventually develops resistance months to years after treatment begins. Understanding how and predicting when hormone therapy facilitates evolution of resistant phenotypes has immediate implications for treatment. Cell quota models for prostate cancer can be useful tools for this purpose and motivate applications to other diseases.
ContributorsPacker, Aaron (Author) / Kuang, Yang (Thesis advisor) / Nagy, John (Committee member) / Smith, Hal (Committee member) / Kostelich, Eric (Committee member) / Kang, Yun (Committee member) / Arizona State University (Publisher)
Created2014
Description
In complex consumer-resource type systems, where diverse individuals are interconnected and interdependent, one can often anticipate what has become known as the tragedy of the commons, i.e., a situation, when overly efficient consumers exhaust the common resource, causing collapse of the entire population. In this dissertation I use mathematical modeling to explore different variations on the consumer-resource type systems, identifying some possible transitional regimes that can precede the tragedy of the commons. I then reformulate it as a game of a multi-player prisoner's dilemma and study two possible approaches for preventing it, namely direct modification of players' payoffs through punishment/reward and modification of the environment in which the interactions occur. I also investigate the questions of whether the strategy of resource allocation for reproduction or competition would yield higher fitness in an evolving consumer-resource type system and demonstrate that the direction in which the system will evolve will depend not only on the state of the environment but largely on the initial composition of the population. I then apply the developed framework to modeling cancer as an evolving ecological system and draw conclusions about some alternative approaches to cancer treatment.
ContributorsKareva, Irina (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Collins, James (Committee member) / Nagy, John (Committee member) / Smith, Hal (Committee member) / Arizona State University (Publisher)
Created2012
Description
Predicting resistant prostate cancer is critical for lowering medical costs and improving the quality of life of advanced prostate cancer patients. I formulate, compare, and analyze two mathematical models that aim to forecast future levels of prostate-specific antigen (PSA). I accomplish these tasks by employing clinical data of locally advanced prostate cancer patients undergoing androgen deprivation therapy (ADT). I demonstrate that the inverse problem of parameter estimation might be too complicated and simply relying on data fitting can give incorrect conclusions, since there is a large error in parameter values estimated and parameters might be unidentifiable. I provide confidence intervals to give estimate forecasts using data assimilation via an ensemble Kalman Filter. Using the ensemble Kalman Filter, I perform dual estimation of parameters and state variables to test the prediction accuracy of the models. Finally, I present a novel model with time delay and a delay-dependent parameter. I provide a geometric stability result to study the behavior of this model and show that the inclusion of time delay may improve the accuracy of predictions. Also, I demonstrate with clinical data that the inclusion of the delay-dependent parameter facilitates the identification and estimation of parameters.
ContributorsBaez, Javier (Author) / Kuang, Yang (Thesis advisor) / Kostelich, Eric (Committee member) / Crook, Sharon (Committee member) / Gardner, Carl (Committee member) / Nagy, John (Committee member) / Arizona State University (Publisher)
Created2017
Description
The role of climate change, as measured in terms of changes in the climatology of geophysical variables (such as temperature and rainfall), on the global distribution and burden of vector-borne diseases (VBDs) remains a subject of considerable debate. This dissertation attempts to contribute to this debate via the use of mathematical (compartmental) modeling and statistical data analysis. In particular, the objective is to find suitable values and/or ranges of the climate variables considered (typically temperature and rainfall) for maximum vector abundance and consequently, maximum transmission intensity of the disease(s) they cause.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
ContributorsOkuneye, Kamaldeen O (Author) / Gumel, Abba B (Thesis advisor) / Kuang, Yang (Committee member) / Smith, Hal (Committee member) / Thieme, Horst (Committee member) / Nagy, John (Committee member) / Arizona State University (Publisher)
Created2018
Description
The retina is the lining in the back of the eye responsible for vision. When light photons hits the retina, the photoreceptors within the retina respond by sending impulses to the optic nerve, which connects to the brain. If there is injury to the eye or heredity retinal problems, this part can become detached. Detachment leads to loss of nutrients, such as oxygen and glucose, to the cells in the eye and causes cell death. Sometimes the retina is able to be surgically reattached. If the photoreceptor cells have not died and the reattachment is successful, then these cells are able to regenerate their outer segments (OS) which are essential for their functionality and vitality. In this work we will explore how the regrowth of the photoreceptor cells in a healthy eye after retinal detachment can lead to a deeper understanding of how eye cells take up nutrients and regenerate. This work uses a mathematical model for a healthy eye in conjunction with data for photoreceptors' regrowth and decay. The parameters for the healthy eye model are estimated from the data and the ranges of these parameter values are centered +/- 10\% away from these values are used for sensitivity analysis. Using parameter estimation and sensitivity analysis we can better understand how certain processes represented by these parameters change within the model as a result of retinal detachment. Having a deeper understanding for any sort of photoreceptor death and growth can be used by the greater scientific community to help with these currently irreversible conditions that lead to blindness, such as retinal detachment. The analysis in this work shows that maximizing the carrying capacity of the trophic pool and the rate of RDCVF, as well as minimizing nutrient withdrawal of the rods and the cones from the trophic pool results in both the most regrowth and least cell death in retinal detachment.
ContributorsGoldman, Miriam Ayla (Author) / Camacho, Erikia (Thesis director) / Wirkus, Stephen (Committee member) / School of Mathematical and Natural Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2017-05
Description
Combination therapy has shown to improve success for cancer treatment. Oncolytic virotherapy is cancer treatment that uses engineered viruses to specifically infect and kill cancer cells, without harming healthy cells. Immunotherapy boosts the body's natural defenses towards cancer. The combination of oncolytic virotherapy and immunotherapy is explored through deterministic systems of nonlinear differential equations, constructed to match experimental data for murine melanoma. Mathematical analysis was done in order to gain insight on the relationship between cancer, viruses and immune response. One extension of the model focuses on clinical needs, with the underlying goal to seek optimal treatment regimens; for both frequency and dose quantity. The models in this work were first used to estimate parameters from preclinical experimental data, to identify biologically realistic parameter values. Insight gained from the mathematical analysis in the first model, allowed for numerical analysis to explore optimal treatment regimens of combination oncolytic virotherapy and dendritic vaccinations. Permutations accounting for treatment scheduled were done to find regimens that reduce tumor size. Observations from the produced data lead to in silico exploration of immune-viral interactions. Results suggest under optimal settings, combination treatment works better than monotherapy of either type. The most optimal result suggests treatment over a longer period of time, with fractioned doses, while reducing the total dendritic vaccination quantity, and maintaining the maximum virotherapy used in the experimental work.
ContributorsSummer, Ilyssa Aimee (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Nagy, John (Thesis advisor) / Mubayi, Anuj (Committee member) / Kang, Yun (Committee member) / Arizona State University (Publisher)
Created2016
Description
The increased number of novel pathogens that potentially threaten the human population has motivated the development of mathematical and computational modeling approaches for forecasting epidemic impact and understanding key environmental characteristics that influence the spread of diseases. Yet, in the case that substantial uncertainty surrounds the transmission process during a rapidly developing infectious disease outbreak, complex mechanistic models may be too difficult to be calibrated quick enough for policy makers to make informed decisions. Simple phenomenological models that rely on a small number of parameters can provide an initial platform for assessing the epidemic trajectory, estimating the reproduction number and quantifying the disease burden from the early epidemic phase.
Chapter 1 provides background information and motivation for infectious disease forecasting and outlines the rest of the thesis.
In chapter 2, logistic patch models are used to assess and forecast the 2013-2015 West Africa Zaire ebolavirus epidemic. In particular, this chapter is concerned with comparing and contrasting the effects that spatial heterogeneity has on the forecasting performance of the cumulative infected case counts reported during the epidemic.
In chapter 3, two simple phenomenological models inspired from population biology are used to assess the Research and Policy for Infectious Disease Dynamics (RAPIDD) Ebola Challenge; a simulated epidemic that generated 4 infectious disease scenarios. Because of the nature of the synthetically generated data, model predictions are compared to exact epidemiological quantities used in the simulation.
In chapter 4, these models are applied to the 1904 Plague epidemic that occurred in Bombay. This chapter provides evidence that these simple models may be applicable to infectious diseases no matter the disease transmission mechanism.
Chapter 5, uses the patch models from chapter 2 to explore how migration in the 1904 Plague epidemic changes the final epidemic size.
The final chapter is an interdisciplinary project concerning within-host dynamics of cereal yellow dwarf virus-RPV, a plant pathogen from a virus group that infects over 150 grass species. Motivated by environmental nutrient enrichment due to anthropological activities, mathematical models are employed to investigate the relevance of resource competition to pathogen and host dynamics.
Chapter 1 provides background information and motivation for infectious disease forecasting and outlines the rest of the thesis.
In chapter 2, logistic patch models are used to assess and forecast the 2013-2015 West Africa Zaire ebolavirus epidemic. In particular, this chapter is concerned with comparing and contrasting the effects that spatial heterogeneity has on the forecasting performance of the cumulative infected case counts reported during the epidemic.
In chapter 3, two simple phenomenological models inspired from population biology are used to assess the Research and Policy for Infectious Disease Dynamics (RAPIDD) Ebola Challenge; a simulated epidemic that generated 4 infectious disease scenarios. Because of the nature of the synthetically generated data, model predictions are compared to exact epidemiological quantities used in the simulation.
In chapter 4, these models are applied to the 1904 Plague epidemic that occurred in Bombay. This chapter provides evidence that these simple models may be applicable to infectious diseases no matter the disease transmission mechanism.
Chapter 5, uses the patch models from chapter 2 to explore how migration in the 1904 Plague epidemic changes the final epidemic size.
The final chapter is an interdisciplinary project concerning within-host dynamics of cereal yellow dwarf virus-RPV, a plant pathogen from a virus group that infects over 150 grass species. Motivated by environmental nutrient enrichment due to anthropological activities, mathematical models are employed to investigate the relevance of resource competition to pathogen and host dynamics.
ContributorsPell, Bruce (Author) / Kuang, Yang (Thesis advisor) / Chowell-Puente, Gerardo (Committee member) / Nagy, John (Committee member) / Kostelich, Eric (Committee member) / Gardner, Carl (Committee member) / Arizona State University (Publisher)
Created2016
Description
\begin{abstract}The human immunodeficiency virus (HIV) pandemic, which causes the syndrome of opportunistic infections that characterize the late stage HIV disease, known as the acquired immunodeficiency syndrome (AIDS), remains a major public health challenge to many parts of the world. This dissertation contributes in providing deeper qualitative insights into the transmission dynamics and control of the HIV/AIDS disease in Men who have Sex with Men (MSM) community. A new mathematical model (which is relatively basic), which incorporates some of the pertinent aspects of HIV epidemiology and immunology and fitted using the yearly new case data of the MSM population from the State of Arizona, was designed and used to assess the population-level impact of awareness of HIV infection status and condom-based intervention, on the transmission dynamics and control of HIV/AIDS in an MSM community. Conditions for the existence and asymptotic stability of the various equilibria ofthe model were derived. The numerical simulations showed that the prospects for the effective control and/or elimination of HIV/AIDS in the MSM community in the United States are very promising using a condom-based intervention, provided the condom efficacy is high and the compliance is moderate enough. The model was extended in Chapter 3 to account for the effect of risk-structure, staged-progression property of HIV disease, and the use of pre-exposure prophylaxis (PrEP) on the spread and control of the disease. The model was shown to undergo a PrEP-induced \textit{backward bifurcation} when the associated control reproduction number is less than one. It was shown that when the compliance in PrEP usage is $50%(80%)$ then about $19.1%(34.2%)$ of the yearly new HIV/AIDS cases recorded at the peak will have been prevented, in comparison to the worst-case scenario where PrEP-based intervention is not implemented in the MSM community. It was also shown that the HIV pandemic elimination is possible from the MSM community even for the scenario when the effective contact rate is increased by 5-fold from its baseline value, if low-risk individuals take at least 15 years before they change their risky behavior and transition to the high-risk group (regardless of the value of the transition rate from high-risk to low-risk susceptible population).
ContributorsTollett, Queen Wiggs (Author) / Gumel, Abba (Thesis advisor) / Crook, Sharon (Committee member) / Fricks, John (Committee member) / Gardner, Carl (Committee member) / Nagy, John (Committee member) / Arizona State University (Publisher)
Created2023
Description
Signaling cascades transduce signals received on the cell membrane to the nucleus. While noise filtering, ultra-sensitive switches, and signal amplification have all been shown to be features of such signaling cascades, it is not understood why cascades typically show three or four layers. Using singular perturbation theory, Michaelis-Menten type equations are derived for open enzymatic systems. When these equations are organized into a cascade, it is demonstrated that the output signal as a function of time becomes sigmoidal with the addition of more layers. Furthermore, it is shown that the activation time will speed up to a point, after which more layers become superfluous. It is shown that three layers create a reliable sigmoidal response progress curve from a wide variety of time-dependent signaling inputs arriving at the cell membrane, suggesting that natural selection may have favored signaling cascades as a parsimonious solution to the problem of generating switch-like behavior in a noisy environment.
ContributorsYoung, Jonathan Trinity (Author) / Armbruster, Dieter (Thesis advisor) / Platte, Rodrigo (Committee member) / Nagy, John (Committee member) / Baer, Steven (Committee member) / Taylor, Jesse (Committee member) / Arizona State University (Publisher)
Created2013