Made available in DSpace on 2018-08-02T00:03:01Z (GMT). No. of bitstreams: 1 tese_11469_ADRIANA MACHADO MALAFAIA DA MATA.pdf: 525854 bytes, checksum: 6cb593fee29b00aa8d38d9498f996ea0 (MD5) Previous issue date: 2017-07-21 / O câncer é uma doença decorrente do crescimento desordenado de células. Comumente, a quimioterapia antineoplásica é utilizada no tratamento dos cânceres mais comuns. Nesse contexto, as pesquisas têm se voltado para modelos matemáticos que descrevem o crescimento de células tumorais com a ação de um fármaco quimioterápico. Diante de uma variedade de modelos existentes na literatura para tal fim, um método para selecionar o modelo mais adequado faz-se necessário. Esta dissertação estuda modelos matemáticos de tratamento de tumores e aplica Approximate Bayesian Computation (ABC) para seleção do modelo que melhor representa os dados observados. O algoritmo ABC utilizado foi determinístico, priorizando a seleção do modelo. Ao modelo selecionado, foi aplicado o filtro de partículas SIR que permitiu aprimorar as estimativas de parâmetros. Foram estudados modelos de crescimento tumoral via equações diferenciais ordinárias e os parâmetros foram assumidos como constantes. Os modelos foram estruturados a partir de farmacocinética Bicompartimental, que permite o estudo de drogas antineoplásicas administradas por via oral. Além disso, foram utilizadas formulações de crescimento de tumores conhecidas adicionando-se o fator de influência de uma dose única de droga quimioterápica.

The thesis begins with a general introduction to population genetics in chapter 1. I review the fundamental processes of evolution - mutation, recombination, selection, gene flow and genetic drift - and give an overview of Bayesian inference in statistical population genetics. Later, I introduce the studied species, Alpine ibex (Capra ibex ), and its recent history. This history is intimately linked to the structured population in the Swiss Alps that provides the source of genetic data for this thesis. A particular focus is devoted to approximate Bayesian computation (ABC) in chapter 2, a method of inference that has become important over the last 15 years and is convenient for complex problems of inference. In chapter 3, the biological focus is on estimating the distribution of mutation rates across neutral genetic variation (microsatellites), and on inferring the proportion of male ibex that obtain access to matings each breeding season. The latter is an important determinant of genetic drift. Methodologically, I compare different methods for the choice of summary statistics in ABC. One of the approaches proposed by collaborators and me and based on boosting (a technique developed in machine learning) is found to perform best in this case. Applying that method to microsatellite data from Alpine ibex, I estimate the scaled ancestral mutation rate (THETA anc = 4Neu) to about 1:288, and find that most of the variation across loci of the ancestral mutation rate u is between 7.7*10 -4 and 3.5*10 -3. The proportion of males with access to matings per breeding season is estimated to about 21%. Chapter 4 is devoted to the estimation of migration rates between a large number of pairs of populations. Again, I use ABC for inference. Estimating all rates jointly comes with substantial methodological problems. Therefore, I assess if, by dividing the whole problem into smaller ones and assuming that those are approximately independent, more accuracy may be achieved overall. The net accuracy of the second approach increases with the number of migration rates. Applying that approach to microsatellite data from Alpine ibex, and accounting for the possibility that a model without migration could also explain the data, I find no evidence for substantial gene flow via migration, except for one pair of demes in one direction. While chapters 3 and 4 deal with neutral variation, in chapter 5 I investigate if an allele of the Major Histocompatibility Complex (MHC) has been under selection over the last ten generations. Short- and medium-term methods for detecting signals of selection are combined. For the medium-term analysis, I adapt a matrix iteration approach that allows for joint estimation of the initial allele frequency, the dominance coefficient, and the strength of selection. The focal MHC allele is shared with domestic goat, and an interesting side issue is if this reflects an ancestral polymorphism or is due to recent introgression via hybridization. I find most evidence for asymmetric overdominance (selection coefficient s: 0.974; equilibrium frequency: 0.125) or directional selection against the `goat' allele (s: 0.5) with partial recessivity. Both scenarios suggest a disadvantage of the `goat' homozygote, but differ in the relative fitness of the heterozygotes. Overall, two aspects play a dominating role in this thesis: the biological questions and the process of inference. They are linked, yet while the proximate motivation for the biological component is given by a specific system - the structured population of Alpine ibex in the Swiss Alps - the methods used and advanced here are fairly general and may well be applied in different contexts.

Dendrocolaptes platyrostris é uma espécie de ave florestal associada às matas de galeria do corredor de vegetação aberta da América do sul (D. p. intermedius) e à Floresta Atlântica (D. p. platyrostris). Em um trabalho anterior, foi observada estrutura genética populacional associada às subespécies, além de dois clados dentro da Floresta Atlântica e evidências de expansão na população do sul, o que é compatível com o modelo Carnaval-Moritz. Utilizando approximate Bayesian computation, o presente trabalho avaliou a diversidade genética de dois marcadores nucleares e um marcador mitocondrial dessa espécie com o objetivo de comparar os resultados obtidos anteriormente com os obtidos utilizando uma estratégia multi-locus e considerando variação coalescente. Os resultados obtidos sugerem uma relação de politomia entre as populações que se separaram durante o último período interglacial, mas expandiram após o último máximo glacial. Este resultado é consistente com o modelo de Carnaval-Moritz, o qual sugere que as populações sofreram alterações demográficas devido às alterações climáticas ocorridas nestes períodos. Trabalhos futuros incluindo outros marcadores e modelos que incluam estabilidade em algumas populações e expansão em outras são necessários para avaliar o presente resultado / Dendrocolaptes platyrostris is a forest specialist bird associated to gallery forests of the open vegetation corridor of South America (D. p. intermedius) and to the Atlantic forest (D. p. platyrostris). A previous study showed a population genetic structure associated with the subspecies, two clades within the Atlantic forest, and evidence of population expansion in the south, which is compatible with Carnaval- Moritz\'s model. The present study evaluated the genetic diversity of two nuclear and one mitochondrial markers of this species using approximate Bayesian computation, in order to compare the results previously obtained with those based on a multi-locus strategy and considering the coalescent variation. The results suggest a polytomic relationship among the populations that split during the last interglacial period and expanded after the last glacial maximum. This result is consistent with the model of Carnaval-Moritz, which suggests that populations have undergone demographic changes due to climatic changes that occurred in these periods. Future studies including other markers and models that include stability in some populations and expansion in others are needed to evaluate the present result

Neste trabalho apresentaremos dois problemas do contexto de controle estatístico da qualidade: monitoramento \"on-line\'\' de qualidade e environmental stress screening, analisados pela óptica bayesiana. Apresentaremos os problemas dos modelos bayesianos relativos a sua aplicação e, os reanalisamos com o auxílio do ABC o que nos fornece resultados de uma maneira mais rápida, e assim possibilita análises diferenciadas e a previsão novas observações. / In this work we will present two problems in the context of statistical quality control: on line quality monitoring and environmental stress screening, analyzed from the Bayesian perspective. We will present problems of the Bayesian models related to their application, and also we reanalyze the problems with the assistance of ABC methods which provides results in a faster way, and so enabling differentiated analyzes and new observations forecast.

Neste trabalho apresentaremos dois problemas do contexto de controle estatístico da qualidade: monitoramento \"on-line\'\' de qualidade e environmental stress screening, analisados pela óptica bayesiana. Apresentaremos os problemas dos modelos bayesianos relativos a sua aplicação e, os reanalisamos com o auxílio do ABC o que nos fornece resultados de uma maneira mais rápida, e assim possibilita análises diferenciadas e a previsão novas observações. / In this work we will present two problems in the context of statistical quality control: on line quality monitoring and environmental stress screening, analyzed from the Bayesian perspective. We will present problems of the Bayesian models related to their application, and also we reanalyze the problems with the assistance of ABC methods which provides results in a faster way, and so enabling differentiated analyzes and new observations forecast.

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.

Dendrocolaptes platyrostris é uma espécie de ave florestal associada às matas de galeria do corredor de vegetação aberta da América do sul (D. p. intermedius) e à Floresta Atlântica (D. p. platyrostris). Em um trabalho anterior, foi observada estrutura genética populacional associada às subespécies, além de dois clados dentro da Floresta Atlântica e evidências de expansão na população do sul, o que é compatível com o modelo Carnaval-Moritz. Utilizando approximate Bayesian computation, o presente trabalho avaliou a diversidade genética de dois marcadores nucleares e um marcador mitocondrial dessa espécie com o objetivo de comparar os resultados obtidos anteriormente com os obtidos utilizando uma estratégia multi-locus e considerando variação coalescente. Os resultados obtidos sugerem uma relação de politomia entre as populações que se separaram durante o último período interglacial, mas expandiram após o último máximo glacial. Este resultado é consistente com o modelo de Carnaval-Moritz, o qual sugere que as populações sofreram alterações demográficas devido às alterações climáticas ocorridas nestes períodos. Trabalhos futuros incluindo outros marcadores e modelos que incluam estabilidade em algumas populações e expansão em outras são necessários para avaliar o presente resultado / Dendrocolaptes platyrostris is a forest specialist bird associated to gallery forests of the open vegetation corridor of South America (D. p. intermedius) and to the Atlantic forest (D. p. platyrostris). A previous study showed a population genetic structure associated with the subspecies, two clades within the Atlantic forest, and evidence of population expansion in the south, which is compatible with Carnaval- Moritz\'s model. The present study evaluated the genetic diversity of two nuclear and one mitochondrial markers of this species using approximate Bayesian computation, in order to compare the results previously obtained with those based on a multi-locus strategy and considering the coalescent variation. The results suggest a polytomic relationship among the populations that split during the last interglacial period and expanded after the last glacial maximum. This result is consistent with the model of Carnaval-Moritz, which suggests that populations have undergone demographic changes due to climatic changes that occurred in these periods. Future studies including other markers and models that include stability in some populations and expansion in others are needed to evaluate the present result

Population genetic analyses can provide information about both neutral and selective evolutionary processes shaping genetic variation. In this thesis, extensive population genetic methods were used to make inferences about genetic drift and selection in spruce species. In paper I we studied four species from the Qinghai-Tibetan Plateau (QTP): Picea likiangensis, P. purpurea, P. wilsonii and P. schrenkiana. Big differences in estimates of genetic diversity and Ne were observed in the more restricted species, P. schrenkiana, and the other more widely distributed species. Furthermore, P. purpurea appears to be a hybrid between P. likiangensis and P. wilsonii. In paper II we used Approximate Bayesian Computation (ABC) to find that the data support a drastic reduction of Ne in Taiwan spruce around 300-500 kya, in line with evidence from the pollen records. The split from P. wilsonii was dated to between 4-8 mya, around the time that Taiwan was formed. These analyses relied on a small sample size, and so in Paper III we investigated the impact of small datasets on the power to distinguish between models in ABC. We found that when genetic diversity is low there is little power to distinguish between simple coalescent models and this can determine the number of samples and loci required. In paper IV we studied the relative importance of genetic drift and selection in four spruce species with differing Ne: P. abies, P. glauca, P. jezoensis and P. breweriana. P. breweriana, which has a low Ne, exhibits a low fraction of adaptive substitutions, while P. abies has high Ne and a high fraction of adaptive substitutions. The other two spruce, however, do not support this suggesting other factors a more important. In paper V we find that several SNPs correlate with both a key adaptive trait (budset) and latitude. The expression of one in particular (PoFTL2) correlates with budset and was previously indentified in P. abies. These studies have helped characterise the importance of different population genetic processes in shaping genetic variation in spruce species and has laid some solid groundwork for future studies of spruce.

<p>Agent-based models (ABMs) are computational models used to simulate the behaviors, </p><p>actionsand interactions of agents within a system. The individual agents </p><p>each have their own set of assigned attributes and rules, which determine</p><p>their behavior within the ABM system. These rules can be</p><p>deterministic or probabilistic, allowing for a great deal of</p><p>flexibility. ABMs allow us to</p><p>observe how the behaviors of the individual agents affect the system</p><p>as a whole and if any emergent structure develops within the</p><p>system. Examining rule sets in conjunction with corresponding emergent</p><p>structure shows how small-scale changes can</p><p>affect large-scale outcomes within the system. Thus, we can better</p><p>understand and predict the development and evolution of systems of</p><p>interest. </p><p>ABMs have become ubiquitous---they used in business</p><p>(virtual auctions to select electronic ads for display), atomospheric</p><p>science (weather forecasting), and public health (to model epidemics).</p><p>But there is limited understanding of the statistical properties of</p><p>ABMs. Specifically, there are no formal procedures</p><p>for calculating confidence intervals on predictions, nor for</p><p>assessing goodness-of-fit, nor for testing whether a specific</p><p>parameter (rule) is needed in an ABM.</p><p>Motivated by important challenges of this sort, </p><p>this dissertation focuses on developing methodology for uncertainty</p><p>quantification and statistical inference in a likelihood-free context</p><p>for ABMs. </p><p>Chapter 2 of the thesis develops theory related to ABMs, </p><p>including procedures for model validation, assessing model </p><p>equivalence and measuring model complexity. </p><p>Chapters 3 and 4 of the thesis focuses on two approaches </p><p>for performing likelihood-free inference involving ABMs, </p><p>which is necessary because of the intractability of the </p><p>likelihood function due to the variety of input rules and </p><p>the complexity of outputs.</p><p>Chapter 3 explores the use of </p><p>Gaussian Process emulators in conjunction with ABMs to perform </p><p>statistical inference. This draws upon a wealth of research on emulators, </p><p>which find smooth functions on lower-dimensional Euclidean spaces that approximate</p><p>the ABM. Emulator methods combine observed data with output from ABM</p><p>simulations, using these</p><p>to fit and calibrate Gaussian-process approximations. </p><p>Chapter 4 discusses Approximate Bayesian Computation for ABM inference, </p><p>the goal of which is to obtain approximation of the posterior distribution </p><p>of some set of parameters given some observed data. </p><p>The final chapters of the thesis demonstrates the approaches </p><p>for inference in two applications. Chapter 5 presents application models the spread </p><p>of HIV based on detailed data on a social network of men who have sex with</p><p>men (MSM) in southern India. Use of an ABM</p><p>will allow us to determine which social/economic/policy </p><p>factors contribute to thetransmission of the disease. </p><p>We aim to estimate the effect that proposed medical interventions will</p><p>have on the spread of HIV in this community. </p><p>Chapter 6 examines the function of a heroin market </p><p>in the Denver, Colorado metropolitan area. Extending an ABM </p><p>developed from ethnographic research, we explore a procedure </p><p>for reducing the model, as well as estimating posterior </p><p>distributions of important quantities based on simulations.</p> / Dissertation

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