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Description
Dopamine (DA) is a neurotransmitter involved in attention, goal oriented behavior, movement, reward learning, and short term and working memory. For the past four decades, mathematical and computational modeling approaches have been useful in DA research, and although every modeling approach has limitations, a model is an efficient way to generate and explore hypotheses. This work develops a model of DA dynamics in a representative, single DA neuron by integrating previous experimental, theoretical and computational research. The model consists of three compartments: the cytosol, the vesicles, and the extracellular space and forms the basis of a new mathematical paradigm for examining the dynamics of DA synthesis, storage, release and reuptake. The model can be driven by action potentials generated by any model of excitable membrane potential or even from experimentally induced depolarization voltage recordings. Here the model is forced by a previously published model of the excitable membrane of a mesencephalic DA neuron in order to study the biochemical processes involved in extracellular DA production. After demonstrating that the model exhibits realistic dynamics resembling those observed experimentally, the model is used to examine the functional changes in presynaptic mechanisms due to application of cocaine. Sensitivity analysis and numerical studies that focus on various possible mechanisms for the inhibition of DAT by cocaine provide insight for the complex interactions involved in DA dynamics. In particular, comparing numerical results for a mixed inhibition mechanism to those for competitive, non-competitive and uncompetitive inhibition mechanisms reveals many behavioral similarities for these different types of inhibition that depend on inhibition parameters and levels of cocaine. Placing experimental results within this context of mixed inhibition provides a possible explanation for the conflicting views of uptake inhibition mechanisms found in experimental neuroscience literature.
ContributorsTello-Bravo, David (Author) / Crook, Sharon M (Thesis advisor) / Greenwood, Priscilla E (Thesis advisor) / Baer, Steven M. (Committee member) / Castaneda, Edward (Committee member) / Castillo-Chavez, Carlos (Committee member) / Arizona State University (Publisher)
Created2012
Description
This dissertation explores the impact of environmental dependent risk on disease dynamics within a Lagrangian modeling perspective; where the identity (defined by place of residency) of individuals is preserved throughout the epidemic process. In Chapter Three, the impact of individuals who refuse to be vaccinated is explored. MMR vaccination and birth rate data from the State of California are used to determine the impact of the anti-vaccine movement on the dynamics of growth of the anti-vaccine sub-population. Dissertation results suggest that under realistic California social dynamics scenarios, it is not possible to revert the influence of anti-vaccine
contagion. In Chapter Four, the dynamics of Zika virus are explored in two highly distinct idealized environments defined by a parameter that models highly distinctive levels of risk, the result of vector and host density and vector control measures. The underlying assumption is that these two communities are intimately connected due to economics with the impact of various patterns of mobility being incorporated via
the use of residency times. In short, a highly heterogeneous community is defined by its risk of acquiring a Zika infection within one of two "spaces," one lacking access to health services or effective vector control policies (lack of resources or ignored due to high levels of crime, or poverty, or both). Low risk regions are defined as those with access to solid health facilities and where vector control measures are implemented routinely. It was found that the better connected these communities are, the existence of communities where mobility between risk regions is not hampered, lower the overall, two patch Zika prevalence. Chapter Five focuses on the dynamics of tuberculosis (TB), a communicable disease, also on an idealized high-low risk set up. The impact of mobility within these two highly distinct TB-risk environments on the dynamics and control of this disease is systematically explored. It is found that collaboration and mobility, under some circumstances, can reduce the overall TB burden.
contagion. In Chapter Four, the dynamics of Zika virus are explored in two highly distinct idealized environments defined by a parameter that models highly distinctive levels of risk, the result of vector and host density and vector control measures. The underlying assumption is that these two communities are intimately connected due to economics with the impact of various patterns of mobility being incorporated via
the use of residency times. In short, a highly heterogeneous community is defined by its risk of acquiring a Zika infection within one of two "spaces," one lacking access to health services or effective vector control policies (lack of resources or ignored due to high levels of crime, or poverty, or both). Low risk regions are defined as those with access to solid health facilities and where vector control measures are implemented routinely. It was found that the better connected these communities are, the existence of communities where mobility between risk regions is not hampered, lower the overall, two patch Zika prevalence. Chapter Five focuses on the dynamics of tuberculosis (TB), a communicable disease, also on an idealized high-low risk set up. The impact of mobility within these two highly distinct TB-risk environments on the dynamics and control of this disease is systematically explored. It is found that collaboration and mobility, under some circumstances, can reduce the overall TB burden.
ContributorsMoreno Martínez, Victor Manuel (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Kang, Yun (Committee member) / Mubayi, Anuj (Committee member) / Arizona State University (Publisher)
Created2018
Description
Statistical Methods have been widely used in understanding factors for clinical and public health data. Statistical hypotheses are procedures for testing pre-stated hypotheses. The development and properties of these procedures as well as their performance are based upon certain assumptions. Desirable properties of statistical tests are to maintain validity and to perform well even if these assumptions are not met. A statistical test that maintains such desirable properties is called robust. Mathematical models are typically mechanistic framework, used to study dynamic interactions between components (mechanisms) of a system, and how these interactions give rise to the changes in behavior (patterns) of the system as a whole over time.
In this thesis, I have developed a study that uses novel techniques to link robust statistical tests and mathematical modeling methods guided by limited data from developed and developing regions in order to address pressing clinical and epidemiological questions of interest. The procedure in this study consists of three primary steps, namely, data collection, uncertainty quantification in data, and linking dynamic model to collected data.
The first part of the study focuses on designing, collecting, and summarizing empirical data from the only national survey of hospitals ever conducted regarding patient controlled analgesia (PCA) practices among 168 hospitals across 40 states, in order to assess risks before putting patients on PCA. I used statistical relational models and exploratory data analysis to address the question. Risk factors assessed indicate a great concern for the safety of patients from one healthcare institution to other.
In the second part, I quantify uncertainty associated with data obtained from James A Lovell Federal Healthcare Center to primarily study the effect of Benign Prostatic Hypertrophy (BPH) on sleep architecture in patients with Obstructive Sleep Apnea (OSA). Patients with OSA and BPH demonstrated significant difference in their sleep architecture in comparison to patients without BPH. One of the ways to validate these differences in sleep architecture between the two groups may be to carry out a similar study that evaluates the effect of some other chronic disease on sleep architecture in patients with OSA.
Additionally, I also address theoretical statistical questions such as (1) how to estimate the distribution of a variable in order to retest null hypothesis when the sample size is limited, and (2) how changes on assumptions (like monotonicity and nonlinearity) translate into the effect of the independent variable on the outcome variable. To address these questions we use multiple techniques such as Partial Rank Correlation Coefficients (PRCC) based sensitivity analysis, Fractional Polynomials, and statistical relational models.
In the third part, my goal was to identify socio-economic-environment-related risk factors for Visceral Leishmaniasis (VL) and use the identified critical factors to develop a mathematical model to understand VL transmission dynamics when data is highly underreported. I primarily studied the role of age-specific- susceptibility and epidemiological quantities on the dynamics of VL in the Indian state of Bihar. Statistical results provided ideas on the choice of the modeling framework and estimates of model parameters.
In the conclusion, this study addressed three primary theoretical modeling-related questions (1) how to analyze collected data when sample size limited, and how modeling assumptions varies results of data analysis? (2) Is it possible to identify hidden associations and nonlinearity of these associations using such underpowered data and (3) how statistical models provide more reasonable structure to mathematical modeling framework that can be used in turn to understand dynamics of the system.
In this thesis, I have developed a study that uses novel techniques to link robust statistical tests and mathematical modeling methods guided by limited data from developed and developing regions in order to address pressing clinical and epidemiological questions of interest. The procedure in this study consists of three primary steps, namely, data collection, uncertainty quantification in data, and linking dynamic model to collected data.
The first part of the study focuses on designing, collecting, and summarizing empirical data from the only national survey of hospitals ever conducted regarding patient controlled analgesia (PCA) practices among 168 hospitals across 40 states, in order to assess risks before putting patients on PCA. I used statistical relational models and exploratory data analysis to address the question. Risk factors assessed indicate a great concern for the safety of patients from one healthcare institution to other.
In the second part, I quantify uncertainty associated with data obtained from James A Lovell Federal Healthcare Center to primarily study the effect of Benign Prostatic Hypertrophy (BPH) on sleep architecture in patients with Obstructive Sleep Apnea (OSA). Patients with OSA and BPH demonstrated significant difference in their sleep architecture in comparison to patients without BPH. One of the ways to validate these differences in sleep architecture between the two groups may be to carry out a similar study that evaluates the effect of some other chronic disease on sleep architecture in patients with OSA.
Additionally, I also address theoretical statistical questions such as (1) how to estimate the distribution of a variable in order to retest null hypothesis when the sample size is limited, and (2) how changes on assumptions (like monotonicity and nonlinearity) translate into the effect of the independent variable on the outcome variable. To address these questions we use multiple techniques such as Partial Rank Correlation Coefficients (PRCC) based sensitivity analysis, Fractional Polynomials, and statistical relational models.
In the third part, my goal was to identify socio-economic-environment-related risk factors for Visceral Leishmaniasis (VL) and use the identified critical factors to develop a mathematical model to understand VL transmission dynamics when data is highly underreported. I primarily studied the role of age-specific- susceptibility and epidemiological quantities on the dynamics of VL in the Indian state of Bihar. Statistical results provided ideas on the choice of the modeling framework and estimates of model parameters.
In the conclusion, this study addressed three primary theoretical modeling-related questions (1) how to analyze collected data when sample size limited, and how modeling assumptions varies results of data analysis? (2) Is it possible to identify hidden associations and nonlinearity of these associations using such underpowered data and (3) how statistical models provide more reasonable structure to mathematical modeling framework that can be used in turn to understand dynamics of the system.
ContributorsGonzalez, Beverly, 1980- (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Mubayi, Anuj (Thesis advisor) / Nuno, Miriam (Committee member) / Arizona State University (Publisher)
Created2015