The target of the work is to apply mathematical and statistical methods in the analysis of the Lithuanian language by identifying and taking into account peculiarities of the Lithuanian language, its heterogeneity, complexity and variability. / Pagrindinis darbo tikslas – pritaikyti matematinius ir statistinius metodus lietuvių kalbos analizėje, identifikuojant ir atsižvelgiant į lietuvių kalbos ypatumus, jos heterogeniškumą, sudėtingumą ir variabilumą.

Neste trabalho apresenta-se uma revisão da metodologia de experimentos de microarray relativas a sua instalação e análise estatística dos dados obtidos. A seguir, aplica-se essa metodologia na análise de dados de expressão gênica em citros, gerados por um experimento de macroarray, utilizando modelos lineares de efeitos fixos considerando a inclusão ou não de diferentes efeitos e considerando ajustes de modelos para cada gene separadamente e para todos os genes simultaneamente. Os experimentos de macroarray são similares aos experimentos de microarray, porém utilizam um menor número de genes. Em geral, são utilizados devido a restrições econômicas. Devido ao fato de terem sido utilizados poucos arrays no experimento analisado neste trabalho foi utilizada uma abordagem bayesiana empírica que utiliza estimativas de variância mais estáveis e que leva em consideração a correlação entre as repetições do gene dentro do array. Também foi utilizado um método de análise não paramétrico para contornar o problema da falta de normalidade para alguns genes. Os resultados obtidos em cada um dos métodos de análise descritos foram então comparados. / This paper presents a review of the methodology of microarray experiments for its installation and statistical analysis of data obtained. Then this methodology is applied in data analysis of gene expression in citrus, generated by a macroarray experiment, using linear models with fixed effects considering the inclusion or exclusion of different effects and considering adjustments of models for each gene separately and for all genes simultaneously. The macroarray experiments are similar to the microarray experiments, but use a smaller number of genes. In general, are used due to economic restrictions. Because they have been used a few arrays in the experiment analyzed in this study it was used a empirical Bayes approach that uses estimates of variance more stable and that takes into account the correlation among replicates of the gene within array. A non parametric analysis method was also used to outline the problem of the non normality for some genes. The results obtained in each of the described methods of analysis were then compared.

<p>cDNA microarrays is one of the first high-throughput gene expression technologies that has emerged within molecular biology for the purpose of functional genomics. cDNA microarrays compare the gene expression levels between cell samples, for thousands of genes simultaneously. </p><p>The microarray technology offers new challenges when it comes to data analysis, since the thousands of genes are examined in parallel, but with very few replicates, yielding noisy estimation of gene effects and variances. Although careful image analyses and normalisation of the data is applied, traditional methods for inference like the Student <i>t</i> or Fisher’s <i>F</i>-statistic fail to work.</p><p>In this thesis, four papers on the topics of empirical Bayes and full Bayesian methods for two-channel microarray data (as e.g. cDNA) are presented. These contribute to proving that empirical Bayes methods are useful to overcome the specific data problems. The sample distributions of all the genes involved in a microarray experiment are summarized into prior distributions and improves the inference of each single gene.</p><p>The first part of the thesis includes biological and statistical background of cDNA microarrays, with an overview of the different steps of two-channel microarray analysis, including experimental design, image analysis, normalisation, cluster analysis, discrimination and hypothesis testing. The second part of the thesis consists of the four papers. Paper I presents the empirical Bayes statistic <i>B</i>, which corresponds to a <i>t</i>-statistic. Paper II is based on a version of <i>B</i> that is extended for linear model effects. Paper III assesses the performance of empirical Bayes models by comparisons with full Bayes methods. Paper IV provides extensions of <i>B</i> to what corresponds to <i>F</i>-statistics.</p>

cDNA microarrays is one of the first high-throughput gene expression technologies that has emerged within molecular biology for the purpose of functional genomics. cDNA microarrays compare the gene expression levels between cell samples, for thousands of genes simultaneously. The microarray technology offers new challenges when it comes to data analysis, since the thousands of genes are examined in parallel, but with very few replicates, yielding noisy estimation of gene effects and variances. Although careful image analyses and normalisation of the data is applied, traditional methods for inference like the Student t or Fisher’s F-statistic fail to work. In this thesis, four papers on the topics of empirical Bayes and full Bayesian methods for two-channel microarray data (as e.g. cDNA) are presented. These contribute to proving that empirical Bayes methods are useful to overcome the specific data problems. The sample distributions of all the genes involved in a microarray experiment are summarized into prior distributions and improves the inference of each single gene. The first part of the thesis includes biological and statistical background of cDNA microarrays, with an overview of the different steps of two-channel microarray analysis, including experimental design, image analysis, normalisation, cluster analysis, discrimination and hypothesis testing. The second part of the thesis consists of the four papers. Paper I presents the empirical Bayes statistic B, which corresponds to a t-statistic. Paper II is based on a version of B that is extended for linear model effects. Paper III assesses the performance of empirical Bayes models by comparisons with full Bayes methods. Paper IV provides extensions of B to what corresponds to F-statistics.

There is high variability in response to cancer chemotherapies among patients. Its sources are diverse: genetic, physiologic, comorbidities, concomitant medications, environment, compliance, etc. As the therapeutic window of anticancer drugs is usually narrow, such variability may have serious consequences: severe (even life-threatening) toxicities or lack of therapeutic effect. Therefore, various approaches to individually tailor treatments and dosing regimens have been developed: a priori (based on genetic information, body size, drug elimination functions, etc.) and a posteriori (that is using information of measurements of drug exposure and/or effects). Mixed-effects modelling of pharmacokinetics and pharmacodynamics (PK-PD), combined with Bayesian maximum a posteriori probability estimation of individual effects, is the method of choice for a posteriori adjustments of dosing regimens. In this thesis, a novel approach to adjust the doses on the basis of predictions, given by a model for ordered categorical observations of toxicity, was developed and investigated by computer simulations. More technical aspects concerning the estimation of individual parameters were analysed to determine the factors of good performance of the method. These works were based on the example of capecitabine-induced hand-and-foot syndrome in the treatment of colorectal cancer. Moreover, a review of pharmacodynamic models for discrete data (categorical, count, time-to-event) was performed. Finally, PK-PD analyses of hydroxyurea in the treatment of sickle cell anemia were performed and used to compare different dosing regimens and determine the optimal measures for monitoring the treatment

Neste trabalho apresenta-se uma revisão da metodologia de experimentos de microarray relativas a sua instalação e análise estatística dos dados obtidos. A seguir, aplica-se essa metodologia na análise de dados de expressão gênica em citros, gerados por um experimento de macroarray, utilizando modelos lineares de efeitos fixos considerando a inclusão ou não de diferentes efeitos e considerando ajustes de modelos para cada gene separadamente e para todos os genes simultaneamente. Os experimentos de macroarray são similares aos experimentos de microarray, porém utilizam um menor número de genes. Em geral, são utilizados devido a restrições econômicas. Devido ao fato de terem sido utilizados poucos arrays no experimento analisado neste trabalho foi utilizada uma abordagem bayesiana empírica que utiliza estimativas de variância mais estáveis e que leva em consideração a correlação entre as repetições do gene dentro do array. Também foi utilizado um método de análise não paramétrico para contornar o problema da falta de normalidade para alguns genes. Os resultados obtidos em cada um dos métodos de análise descritos foram então comparados. / This paper presents a review of the methodology of microarray experiments for its installation and statistical analysis of data obtained. Then this methodology is applied in data analysis of gene expression in citrus, generated by a macroarray experiment, using linear models with fixed effects considering the inclusion or exclusion of different effects and considering adjustments of models for each gene separately and for all genes simultaneously. The macroarray experiments are similar to the microarray experiments, but use a smaller number of genes. In general, are used due to economic restrictions. Because they have been used a few arrays in the experiment analyzed in this study it was used a empirical Bayes approach that uses estimates of variance more stable and that takes into account the correlation among replicates of the gene within array. A non parametric analysis method was also used to outline the problem of the non normality for some genes. The results obtained in each of the described methods of analysis were then compared.

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Pedestrian countdown signals (PCSs) are viable traffic control devices that assist pedestrians in crossing intersections safely. Despite the fact that PCSs are meant for pedestrians, they also have an impact on drivers’ behavior at intersections. This study focuses on the evaluation of the safety effectiveness of PCSs to drivers in the cities of Jacksonville and Gainesville, Florida. The study employs two Bayesian approaches, before-and-after empirical Bayes (EB) and full Bayes (FB) with a comparison group, to quantify the safety impacts of PCSs to drivers. Specifically, crash modification factors (CMFs), which are estimated using the aforementioned two methods, were used to evaluate the safety effects of PCSs to drivers. Apart from establishing CMFs, crash modification functions (CMFunctions) were also developed to observe the relationship between CMFs and traffic volume. The CMFs were established for distinctive categories of crashes based on crash type (rear-end and angle collisions) and severity level (total, fatal and injury (FI), and property damage only (PDO) collisions). The CMFs findings, using the EB approach indicated that installing PCSs result in a significant improvement of driver’s safety, at a 95% confidence interval (CI), by a 8.8% reduction in total crashes, a 8.0% reduction in rear-end crashes, and a 7.1% reduction in PDO crashes. In addition, FI crashes and angle crashes were observed to be reduced by 4.8%, whereas a 4.6% reduction in angle crashes was observed. In the case of the FB approach, PCSs were observed to be effective and significant, at a 95% Bayesian credible interval (BCI), for a total (Mean = 0.894, 95% BCI (0.828, 0.911)), PDO (Mean = 0.908, 95% BCI (0.838, 0.953)), and rear-end (Mean = 0.920, 95% BCI (0.842, 0.942)) crashes. The results of two crash categories such as FI (Mean = 0.957, 95% BCI (0.886, 1. 020)) and angle (Mean = 0.969, 95% BCI (0.931, 1.022)) crashes are less than one but are not significant at the 95 % BCI. Also, discussed in this study are the CMFunctions, showing the relationship between the developed CMFs and total entering traffic volume, obtained by combining the total traffic on the major and the minor approaches. In addition, the CMFunctions developed using the FB indicated the relationship between the estimated CMFs with the post-treatment year. The CMFunctions developed in this study clearly show that the treatment effectiveness varies considerably with post-treatment time and traffic volume. Moreover, using the FB methodology, the results suggest the treatment effectiveness increased over time in the post-treatment years for the crash categories with two important indicators of effectiveness, i.e., total and PDO, and rear-end crashes. Nevertheless, the treatment effectiveness on rear-end crashes is observed to decline with post-treatment time, although the base value is still less than one for all the three years. In summary, the results suggest the usefulness of PCSs for drivers.

The local false discovery rate (LFDR) is one of many existing statistical methods that analyze multiple hypothesis testing. As a Bayesian quantity, the LFDR is based on the prior probability of the null hypothesis and a mixture distribution of null and non-null hypothesis. In practice, the LFDR is unknown and needs to be estimated. The empirical Bayes approach can be used to estimate that mixture distribution. Empirical Bayes does not require complete information about the prior and hyper prior distributions as in hierarchical Bayes. When we do not have enough information at the prior level, and instead of placing a distribution at the hyper prior level in the hierarchical Bayes model, empirical Bayes estimates the prior parameters using the data via, often, the marginal distribution. In this research, we developed new Bayesian methods under unknown prior distribution. A set of adequate prior distributions maybe defined using Bayesian model checking by setting a threshold on the posterior predictive p-value, prior predictive p-value, calibrated p-value, Bayes factor, or integrated likelihood. We derive a set of adequate posterior distributions from that set. In order to obtain a single posterior distribution instead of a set of adequate posterior distributions, we used a blended distribution, which minimizes the relative entropy of a set of adequate prior (or posterior) distributions to a "benchmark" prior (or posterior) distribution. We present two approaches to generate a blended posterior distribution, namely, updating-before-blending and blending-before-updating. The blended posterior distribution can be used to estimate the LFDR by considering the nonlocal false discovery rate as a benchmark and the different LFDR estimators as an adequate set. The likelihood ratio can often be misleading in multiple testing, unless it is supplemented by adjusted p-values or posterior probabilities based on sufficiently strong prior distributions. In case of unknown prior distributions, they can be estimated by empirical Bayes methods or blended distributions. We propose a general framework for applying the laws of likelihood to problems involving multiple hypotheses by bringing together multiple statistical models. We have applied the proposed framework to data sets from genomics, COVID-19 and other data.