Les essais cliniques de phase I en cancérologie permettent d’identifier la dose optimale (DO), définie comme la dose maximale tolérée (DMT). Les approches conventionnelles de recherche de dose reposent uniquement sur les événements de toxicité observés au cours du premier cycle de traitement. Le développement des thérapies moléculaires ciblées (TMC), habituellement administrées sur de longues périodes, a remis en question cet objectif. Considérer uniquement le premier cycle de traitement n’est pas suffisant. De plus, comme l'activité n'augmente pas nécessairement de façon monotone avec la dose, la toxicité et l'activité doivent être prises en compte pour identifier la DO. Récemment, les biomarqueurs continus sont de plus en plus utilisés pour mesurer l'activité.L’objectif de cette thèse était de proposer et d'évaluer des designs adaptatifs pour identifier la DO. Nous avons développé deux designs de recherche de dose, basés sur une modélisation conjointe des mesures longitudinales de l'activité des biomarqueurs et de la première toxicité dose-limitante (DLT), avec un effet aléatoire partagé. En utilisant des propriétés de distribution normales asymétriques, l'estimation reposait sur la vraisemblance sans approximation ce qui est une propriété importante dans le cas de petits échantillons qui sont souvent disponibles dans ces essais. La DMT est associée à un certain risque cumulé de DLT sur un nombre prédéfini de cycles de traitement. La DO a été définie comme la dose la moins toxique parmi les doses actives, sous la contrainte de ne pas dépasser la DMT. Le second design étendait cette approche pour les cas d’une relation dose-activité qui pouvait atteindre un plateau. Un modèle à changement de pente a été implémenté. Nous avons évalué les performances des designs avec des études de simulations en étudiant plusieurs scénarios et divers degrés d'erreur de spécification des modèles.Finalement, nous avons effectué une analyse de 27 études des TMCs de phase I, en tant que monothérapie. Les études ont été réalisées par l'Institut National du Cancer. L'objectif principal était d'estimer le risque par cycle et l’incidence cumulative de la toxicité sévère, jusqu’à six cycles. Les analyses ont été effectuées séparément pour différents sous-groupes de doses, ainsi que pour les toxicités hématologiques et non-hématologiques. / Conventional dose-finding approaches in oncology of phase I clinical trials aim to identify the optimal dose (OD) defined as the maximum tolerated dose (MTD), based on the toxicity events observed during the first treatment cycle. The constant development of molecularly targeted agents (MTAs), usually administered in chronic schedules, has challenged this objective. Not only, the outcomes after the first cycle are of importance, but also activity does not necessarily increase monotonically with dose. Therefore, both toxicity and activity should be considered for the identification of the OD. Lately, continuous biomarkers are used more and more to monitor activity. The aim of this thesis was to propose and evaluate adaptive designs for the identification of the OD. We developed two dose-finding designs, based on a joint modeling of longitudinal continuous biomarker activity measurements and time to first dose limiting toxicity (DLT), with a shared random effect, using skewed normal distribution properties. Estimation relied on likelihood that did not require approximation, an important property in the context of small sample sizes, typical of phase I/II trials. We addressed the important case of missing at random data that stem from unacceptable toxicity, lack of activity and rapid deterioration of phase I patients. The MTD was associated to some cumulative risk of DLT over a predefined number of treatment cycles. The OD was defined as the lowest dose within a range of active doses, under the constraint of not exceeding the MTD. The second design extended this approach for cases of a dose-activity relationship that could reach a plateau. A change point model was implemented. The performance of the approaches was evaluated through simulation studies, investigating a wide range of scenarios and various degrees of data misspecification. As a last part, we performed an analysis of 27 phase I studies of MTAs, as monotherapy, conducted by the National Cancer Institut. The primary focus was to estimate the per-cycle risk and the cumulative incidence function of severe toxicity, over up to six cycles. Analyses were performed separately for different dose subgroups, as well as for hematologic and non-hematologic toxicities.

In this thesis, two methods for assessing the functional form of covariates in the Cox proportional hazards model are evaluated. The methods include one graphical check based on martingale residuals and one graphical check, together with a Kolmogorov-type supremum test, based on cumulative sums of martingale residuals. The methods are evaluated in a simulation study under five different covariate misspecifications with varying sample sizes and censoring degrees. The results from both methods indicate that the type of covariate misspecification, sample size and censoring degree affect the ability to detect and identify the misspecification. The procedure based on smoothed scatterplots of martingale residuals reveals difficulties with assessing whether the behaviour of the smoothed curve in the plot is an indication of a misspecification or a phenomenon that can occur in a correctly specified model. The graphical check together with the test procedure based on cumulative sums of martingale residuals is shown to successfully detect and identify three out of five covariate misspecifications for large sample sizes. For small sample sizes, especially combined with a high censoring degree, the power of the supremum test is low for all covariate misspecifications.

Environmental justice communities, those disproportionately affected by pollutants, are simultaneously exposed to multiple environmental stressors and also experience social and cultural factors that may heighten their health risks in comparison to other communities. In addition to being more susceptible to toxic exposures and being exposed to more toxins, such communities may have weakened abilities to combat or rebound from such exposures. Many communities that are overburdened by environmental exposures reject traditional risk assessment approaches that solely consider the effects of single chemicals or mixtures of like chemicals and instead have advocated for the use of place-based approaches and collaborative problem solving models that consider cumulative exposures and impacts. Cumulative risks are the combined risks from aggregate exposures to multiple agents or stressors, including chemical, biological or physical agents and psychosocial stressors. This dissertation adapts three research approaches that each use either publicly available data (“expert” data) or community-generated data about environmental and social factors in Northwest Atlanta’s Proctor Creek Watershed. Through this work, we were able to define cumulative environmental and social impacts experienced by watershed residents and to prioritize geographic areas and environmental challenges for investments in environmental monitoring and further research, community capacity-building, and policy change. A principal finding of the study is that local community knowledge is helpful to fill critical gaps about local conditions and pollution sources than a reliance on expert data alone.

As the U.S. population ages, there is a significant increase in functional impairment, chronic conditions and other age related health concerns. In later life, functional limitations and poor quality of health often lead to the utilization of skilled nursing care in institutional settings. However, older adults often report the desire to age in place even when experiencing health challenges. Therefore, identifying ways to promote aging in place at home as a long-term care option could enhance quality of life. The objective of the study is to examine the impact of home modification and other home and community-based services on the ability of Black older adults to age in place in comparison to Whites. The study utilizes administrative data from the Georgia Money Follows the Person program. The results indicate that race, the use of financial support and the utilization of many services were significant in attaining success in the MFP program.

The focus of this research is on hypotheses testing involving inequality constraints. In the first chapter of this dissertation, we propose Kolmogorov-Smirnov type tests for stochastic dominance relations between the potential outcomes of a binary treatment under the unconfoundedness assumption. Our stochastic dominance tests compare every point of the cumulative distribution functions (CDF), so they can fully utilize all information in the distributions. For first order stochastic dominance, the test statistic is defined as the supremum of the difference of two inverse-probability-weighting estimators for the CDFs of the potential outcomes. The critical values are approximated based on a simulation method. We show that our test has good size properties and is consistent in the sense that it can detect any violation of the null hypothesis asymptotically. First order stochastic dominance tests in the treated subpopulation, and higher order stochastic dominance tests in the whole population and among the treated are shown to share the same properties. The tests are applied to evaluate the effect of a job training program on incomes, and we find that job training has a positive effect on real earnings. Finally, we extend our tests to cases in which the unconfoundedness assumption does not hold. On the other hand, there has been a considerable amount of attention paid to testing inequality restrictions using Wald type tests. As noted by Wolak (1991), there are certain situations where it is difficult to obtain tests with correct size even asymptotically. These situations occur when the variance-covariance matrix of the functions in the constraints depends on the unknown parameters as would be the case in nonlinear models. This dependence on the unknown parameters makes it computationally difficult to find the least favorable configuration (LFC) which can be used to bound the size of the test. In the second chapter of this dissertation, we extend Hansen's (2005) superior predictive ability (SPA) test to testing hypotheses involving general inequality constraints in which the variance-covariance matrix can be dependent on the unknown parameters. For our test we are able to obtain correct size asymptotically plus test consistency without requiring knowledge of the LFC. Also the test can be applied to a wider class of problems than considered in Wolak (1991). In the last chapter, we construct new Kolmogorov-Smirnov tests for stochastic dominance of any pre-specified order without resorting to the LFC to improve the power of Barrett and Donald's (2003) tests. To do this, we first show that under the null hypothesis if the objects being compared at a given income level are not equal, then the objects at this given income level will have no effect on the null distribution. Second, we extend Hansen's (2005) recentering method to a continuum of inequality constraints and construct a recentering function that will converge to the underlying parameter function uniformly asymptotically under the null hypothesis. We treat the recentering function as a true underlying parameter function and add it to the simulated Brownian bridge processes to simulate the critical values. We show that our tests can control the size asymptotically and are consistent. We also show that by avoiding the LFC, our tests are less conservative and more powerful than Barrett and Donald's (2003). Monte Carlo simulations support our results. We also examine the performances of our tests in an empirical example. / text

As citizens of the Arabian Gulf states struggle to maintain identity and heritage in a swarm of economic boom and social modernization and mobilization, they are bombarded with media messages which conflict with the essential tenets of modernization and development: individualism, economic independence, freedom of expression, and elevated social status for women. The largely popular Gulf Arabic television miniseries genre is an important vehicle for those conflicting media messages, presenting stereotypical and simplistic representations of family life, the divide between good and evil, and prescribed gender dichotomies. Those messages which idealize traditionalism and conservative belief systems are crafted and informed by those who dominate the media apparatus in the Arabian Gulf: the ruling, male, Muslim, hegemonic elite. The miniseries genre keeps audiences glued to the television in the month of Ramadan, a time at which Muslims throughout the world are at a heightened sense of religiosity and devotion to family and are thus more susceptible to the persuasion of media messages related to religion, faith, virtues, and morals. This research examines the themes of patriarchy, gender dichotomies, family values, and the omnipresence of Islam in the genre and the relationship of all of these themes to the value and belief systems of the ruling hegemonic elite and audience members alike. The research is based on a data pool which includes 152 episodes, totaling roughly 101.5 televised hours. The data also include the results of a survey about audience interaction and interpretation of the genre. The survey is comprised of 35 questions to which 56 participants responded. It discusses the implications of the messages contained within the genre and communicated through the aforementioned themes, and examines the potential for them to influence audience members’ outlook on society as seen through the lens of relevant media theories. / text

A number of recent studies have found a strong link between peak global warming due to anthropogenic carbon dioxide and cumulative carbon emissions from the start of the industrial revolution. This thesis builds on this work by using a simple climate model to apply the concept of cumulative emissions to emission floors, by comparing cumulative emissions with other types of emissions target, and by extending the work to apply to noncarbon dioxide (CO₂) greenhouse gases and short-lived climate forcers (SLCFs). Though peak global warming correlates well with cumulative carbon emissions, the link to emissions over shorter periods or in the years 2020 or 2050 is shown to be weaker. It is also shown that the introduction of emissions floors does not reduce the importance of cumulative emissions, but may make some warming targets unachievable. For pathways that give a most likely warming up to about 4°C, cumulative emissions from pre-industrial times to year 2200 correlate strongly with most likely resultant peak warming in the simple model used, regardless of the type of emissions floor used. The maximum rate of CO2- induced warming is not determined by cumulative emissions but is shown to be limited by the peak rate of CO₂ emissions. A simple model of non-CO₂ greenhouse gases is also developed and used to investigate SLCFs. It is shown that emissions of SLCFs today have little impact on peak warming, and that delaying near-term reductions in SLCFs would not have a significant impact on peak warming. Only once CO₂ emissions are falling do SLCF emissions have a significant impact on peak warming. A global climate policy framework is presented as an example of how the work in this thesis could be used in policy. Future work is also discussed, particularly verification of these results in a more complex model.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

In an effort to apply Cumulative Risk Assessment (CRA) as developed by the U.S. EPA, the present study investigates the cumulative risks to Eastern oysters due to multiple stressors such as salinity, temperature and oxygen and carbon dioxide. I also compared the effectiveness of the Hazard Quotient Method (HQ) in CRA. Ambient conditions in the James River, VA were obtained from the Virginia DEQ database and respiratory responses were estimated using values from the literature. The multiple environmental stresses are evaluated using a probabilistic analysis that combines the environmental conditions. It was concluded that salinity was the most influential stressor in the model. Other risks were identified contributing to the vulnerability of the oysters. Crystal Ball simulations yielded that the oxygen uptake of oysters reduced by more than 29%. The HQ method was found to be inappropriate in analyzing cumulative risks for CRA. Oyster populations are dramatically declining in the James River and the Chesapeake Bay. Hence, effective oyster restoration activities are underway to rebuild oyster populations in the James River and throughout the Bay area.

Protection of minority shareholders after the recodification of Czech private law This thesis is concerned with the instruments designated for protection of minority shareholders, their reasons and aims. The thesis critically assesses Czech legislation concerning the protection of minority shareholders, with the focus on new instruments and interpretation ambiguities and having regard to the opinions of professional public. After assessing the opinions of professional public, the author presents his own view on interpretation ambiguities. The thesis is systematically divided into seven chapters. Chapter One includes general terminology definitions. Terms shareholder, Czech public limited company, minority shareholder and qualified shareholder are explained. The term of protection of minority shareholders is explained here as well. Chapter Two includes general summary of the legislation concerned with protection of minority shareholders. The chapter divided according to the individual legal areas containing the protection. It includes complex outline of minority shareholder rights, with regard to their reasons and aims. Chapter Three includes detailed view and justification of use of correspondence voting, the instrument of attendance of general meetings by technological means, and cumulative...