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.

Despite improvements in therapy, the prognosis for non-small cell lung cancer (NSCLC) patients remains poor, and cure is only possible in localized tumors after surgical resection. A new generation of targeted cancer drugs has led to the expectation that lung cancer therapy can be significantly improved, but these drugs are today only an option in a small subset of NSCLC patients, and their effect is temporary. Therefore, the aim of this thesis was to characterize NSCLC in order to find new treatment targets and to evaluate biomarkers that further optimize therapy selection. In Paper I, the expression of the potential treatment targets claudin 6 and claudin 18.2 were evaluated based on immunohistochemical- and gene expression analysis. High ectopic protein and gene expression were demonstrated for both claudins in small subgroups of NSCLC. Clinical trials using humanized monoclonal antibodies against both proteins are ongoing in other cancer forms and may be extended to NSCLC. In Paper II, the prognostic impact of the inflammatory mediator cyclooxygenase 2 (COX-2) was evaluated. No prognostic significance was found in a meta-analysis incorporating gene expression data of 1337 NSCLC patients. Likewise, COX-2 protein expression in tumor cells was not associated with survival in two independent NSCLC cohorts. However, in one of the analyzed cohorts, higher COX-2 expression in the tumor stroma was associated with longer survival and may therefore be a subject for further investigation. In Paper III, tumor and stromal COX-2 protein expression was examined in patients treated with the COX-2 inhibitor celecoxib in order to evaluate if COX-2 expression is a predictive biomarker for benefit of celecoxib therapy. Celecoxib did not prolong overall survival neither in the whole cohort nor in patients stratified according to COX-2 expression in tumor or stromal cells. Noteworthy, a tendency towards longer survival was again demonstrated in patients with high COX-2 stromal expression. In Paper IV, the diagnostic methods for identification of ALK rearrangements were assessed in a large representative Swedish NSCLC population. Fluorescence in situ hybridization (FISH), as the diagnostic standard, was compared to two immunohistochemical assays. ALK gene expression levels were incorporated to supplement the molecular data. The frequency of ALK rearrangements was lower than previously reported. The different methods to detect the ALK fusion demonstrated overlapping results. However, the overlap was poor, so the methods cannot be regarded as interchangeable and should thereby be interpreted with caution when used in clinical diagnostics. In summary, this thesis applied an integrative translational approach to characterize potential new treatment targets and to evaluate the detection of existing predictive biomarkers in NSCLC.

With the growth of Pentecostalism over the last few decades, conservative values and punitive sanctions related to the sexual behavior of adolescents and unmarried youth began to play an important and systematic role in Pentecostal and renewed Protestant churches as well as in charismatic Catholic communities. Simultaneously, religion has become an important and highly present factor in the lives of many adolescents and youth in Brazil. In terms of attempting to attract this age group, these churches and communities, stand out, as they have used their resources to create a space for this segment of the population to participate in a religious environment. Youth groups, dating groups, trade courses, lectures, aid work in poor communities, confirmation and other activities such as retreats and religious trips, have been frequently observed in these churches and charismatic communities. In this dissertation, I examine the associations between religious involvement and sexual initiation in Brazil. More specifically, I investigate (1) whether religious denomination and religiosity are associated with age at premarital first sexual intercourse, (2) whether these associations have changed over the last three decades, (3) how different churches and religious leaders address sexual behavior issues, and (4) the mechanisms through which religion can influence adolescents’ sexual behavior in Brazil. These research questions are assessed by employing multiple data sources and methodologies including three Demographic and Health Surveys carried out in Brazil in 1986, 1996, and 2006 and event history analysis, as well as in-depth interview data and participant observation among different religious groups and affiliations by attending several Catholic masses, Protestant religious services, youth groups, Sunday schools, and religious talks/lectures. Quantitative and qualitative findings of this dissertation show that adolescents and youth from Pentecostal churches and communities seem more likely to delay or abstain from premarital sexual initiation when compared to traditional Catholics. I conclude by suggesting that the dissemination of conservative norms and sanctions as well as the availability of greater space for youth to maintain close relationships with these churches have helped create mechanisms through which religion can directly and indirectly influence the lives and sexual behavior of young people in Brazil. / text

Non-oxidative dehydrogenation of hydrocarbons is an attractive alternative route for the production of CO- and CO2-free hydrogen. It will satisfy a major requirement for successful utilization of polymer electrolyte membrane (PEM) fuel cells (< 10 ppm CO) and sequestering carbon as a potentially valuable by-product, carbon nanotubes (CNTs). Due to the deposition of carbon on the surface of catalyst particles during the reaction, catalyst performance, life-time, and purification of the generated carbon product, are significant issues to solve in order to make the process practically feasible. The scope of this thesis includes: the development of novel Fe, Ni, and Fe-Ni catalysts supported on a Mg(Al)O support to achieve improved catalytic performance with easily-purified CNTs; evaluation of catalysts for ethane/methane dehydrogenation at moderate reaction temperatures; and study of activation and deactivation mechanisms by a variety of characterization techniques including TEM, HRTEM, XRD, Mössbauer spectroscopy, and x-ray absorption fine structure (XAFS) spectroscopy. The Mg(Al)O support was prepared by calcination of synthetic MgAl-hydrotalcite with a Mg to Al ratio of 5. The catalysts were prepared either by conventional incipient wetness method or by a novel nanoparticle impregnation method, where the monodisperse catalyst nanoparticles were prepared in advance by thermal decomposition of a metal-organic complex in an organic-phase solution and then dispersed onto the Mg(Al)O support. Dehydrogenation of undiluted methane was conducted in a fix-bed plug-flow reactor. Before reaction, the catalysts were activated by reduction in hydrogen. Fe-based catalysts exhibit a higher hydrogen yield at temperature above 600ºC compared with monometallic Ni catalyst. FeNi-9 nm/Mg(Al)O, Fe-10 nm/Mg(Al)O and Fe-5 nm/ Mg(Al)O nanoparticle catalysts show much improved performance and longer life-times compared with the corresponding FeNi IW/Mg(Al)O and Fe IW/Mg(Al)O catalysts prepared by incipient wetness. 10 nm is the optimum particle size for methane dehydrogenation. Addition of Ni to Fe forming a bimetallic FeNi alloy catalyst enhances the catalytic performance at the temperatures below 650ºC. Metallic Fe, Ni, FeNi alloy and Fe-Ni-C alloy, unstable iron carbide are all catalytically active components. Catalysts deactivation is due to the carbon encapsulation. The carbon products are in the form of stack-cone CNTs (SCNTs) and multi-walled CNTs (MWNTs), depending on the reaction temperature and catalyst composition. The growth of CNTs follows a tip growth mechanism and the purity of cleaned CNTs is more than 99.5%.

全文一冊，共五章，前四章各二小節，後一章不分節，約二萬字。 內容大致為，不完整樣本的適應檢定中，若在ARMITAGE-COX模型下，可求出生存函數 的最概估計量，本文討論在一般的情形下的PRODUCT-LIMIT 估計量以及ARMITAGE-COX 模型下的最概估計量，它們在指數分配的CORRELATION 適合度檢定及NEW BETTER THA N USED檢定的表現，並以模擬作數值上的討論。 本文第一章入整體的簡單介紹，第二章介紹不完整樣本的模型，第三章適合度檢定， 第四章指出數值模擬的結果及分析，第五章結論。

以往重複事件分析法主要用於醫學與科學領域，近來學者逐漸將其應用至經濟、商學、社會科學等領域，本篇論文採用重複事件分析法，分析S&P 500公司股票回購的行為，回顧過去學者對股票回購之研究，我們檢視公司執行股票回購的三大原因，根據我們的實證結果發現公司可能會以股票回購作為影響公司資本結構的工具，再者亦可能用以減低剩餘資金，然而，本篇論文的實證結果較不支持訊號發射理論。 / In this study, we apply Cox proportional hazard model in recurrent event analysis, which usually used in medical and science studies, to analyze the determinants of the stock repurchase events of S&P 500 companies. We investigate three main incentives that companies conduct stock repurchase. The empirical results show that companies employ repurchase as a technique to alter capital structure. In addition, companies conduct stock repurchase to distribute excess capital. In contrast, there are little evidences to support signaling undervaluation.

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

Thèse diffusée initialement dans le cadre d'un projet pilote des Presses de l'Université de Montréal/Centre d'édition numérique UdeM (1997-2008) avec l'autorisation de l'auteur. / In spite of considerable research on Kenya’s fertility, questions remain. This dissertation examines three of these issues - the national and sub-national trend patterns in the country’s fertility and related proximate determinants, factors in the transitions to second and third conceptions, and the determinants of contraceptive use. Results, presented below, are based upon data which comprised five sample surveys conducted between 1977 and 2003 among women of reproductive age, as well as a community and health facility survey implemented in 1999. First, an exploratory analysis of trends in fertility and its proximate determinants shows that a pattern of later family formation and of a higher level of fertility control is associated with the more modernized and developed regions (urban areas and rural Central Province). Secondly, using survival analysis, the relative hazards of transition to the second and third conceptions for the 12-year periods during which fertility fell rapidly (1977-1989) and the pace of decline reduced (1991-2003) are compared. Among the findings, although child survival has significant effects during both periods, its influence is more pronounced during the recent period. Thirdly, multivariate analysis of the determinants of contraceptive use shows that motivation for fertility control is significant, while access to family planning services is not. That proximity to family planning services might nevertheless be important is shown by the significance of exposure to family planning messages, many of which are often communicated from the health facilities. This dissertation makes contributions in three areas. One, it confirms the dichotomy in the pattern of fertility change and its proximate determinants in the country, not so much along the usual rural-urban separation, but rather between urban areas and rural Central versus the rest of rural Kenya. Two, it shows that the decreased pace of the fertility transition in Kenya, including constant fertility over 1998-2003, might be associated with the rise in infant and child mortality since the 1990s. Three, it shows the significance of education, motivation for fertility control, and exposure to media messages about family planning in contraceptive use, thereby pointing out where policy and program effort should be directed in order to sustain the fertility transition. / Malgré de nombreuses études consacrées à la problématique de la transition de fécondité au Kenya, des questions subsistent. Cette thèse traite de trois d’entre elles : les tendances de la fécondité et ses déterminants proches, les facteurs liés au passage à la deuxième et à la troisième grossesse, et les déterminants de l’utilisation de la contraception. Les données proviennent de cinq enquêtes menées dans ce pays entre 1977 et 2003, auprès de femmes d’âge reproductif, ainsi que d’une étude, conduite en 1999, au niveau communautaire et de centres de santé. Les résultats montrent d’abord une tendance au mariage tardif et à un niveau plus élevé de contrôle de la fécondité dans les régions les plus modernisées et les plus développées (les villes et les zones rurales de la région de la Province Central). Deuxièmement, dans la comparaison des 12 années durant lesquelles la fécondité, mesurée par l’indice de fécondité, s’est réduite (1977- 1989) et celles où le pas de sa baisse a ralenti (1991-2003), on note une augmentation des effets relatifs de la mortalité infantile pendant la deuxième période. Troisièmement, la régression multi variée utilisée pour l’analyse des déterminants proches de l’utilisation de la contraception fait ressortir le rôle important de la motivation pour le contrôle de la fécondité. Bien que l’accès aux services de planification familiale ne constitue pas un facteur significatif en soi, il pourrait jouer néanmoins un rôle dans la mesure où les résultats montrent que l’exposition aux messages de planification familiale (généralement offerts dans les centres de santé) a un effet significatif. La contribution de cette thèse s’articule autour de trois aspects. Premièrement, elle montre une opposition dans les changements de la fécondité et de ses déterminants entre 1977 et 2003, non pas entre les zones urbaines et rurales comme d’habitude, mais plutôt entre zones urbaines et partie rurale de la Province Central d’une part et le reste du Kenya d’autre part. Deuxièmement, le ralentissement de la baisse de la fécondité, y compris le niveau stable observé entre 1998 et 2003, est probablement lié à la hausse, depuis les années quatre-vingt dix, de la mortalité infantile. Troisièmement, cette thèse confirme le rôle significatif de la scolarisation, de la motivation pour le contrôle des naissances, et de l’effet positif des messages sur l’usage des méthodes de planification familiale, montrant ainsi les domaines dans lesquels doivent intervenir les politiques et programmes afin de maintenir la transition de fécondité.

One situation in survival analysis is that the failure of an individual can happen because of one of multiple distinct causes. Survival data generated in this scenario are commonly referred to as competing risks data. One of the major tasks, when examining survival data, is to assess the dependence of survival time on explanatory variables. In competing risks, as with ordinary univariate survival data, there may be explanatory variables associated with the risks raised from the different causes being studied. The same variable might have different degrees of influence on the risks due to different causes. Given a set of explanatory variables, it is of interest to identify the subset of variables that are significantly associated with the risk corresponding to each failure cause. In this project, we develop a statistical methodology to achieve this purpose, that is, to perform variable selection in the presence of competing risks survival data. Asymptotic properties of the model and empirical simulation results for evaluation of the model performance are provided. One important feature of our method, which is based on the idea of the L1 penalized Cox model, is the ability to perform variable selection in situations where we have high-dimensional explanatory variables, i.e. the number of explanatory variables is larger than the number of observations. The method was applied on a real dataset originated from the National Institutes of Health funded project "Genes related to hepatocellular carcinoma progression in living donor and deceased donor liver transplant'' to identify genes that might be relevant to tumor progression in hepatitis C virus (HCV) infected patients diagnosed with hepatocellular carcinoma (HCC). The gene expression was measured on Affymetrix GeneChip microarrays. Based on the current available 46 samples, 42 genes show very strong association with tumor progression and deserve to be further investigated for their clinical implications in prognosis of progression on patients diagnosed with HCV and HCC.

Environmental events simultaneously transduced by more than one sensory modality underlie multisensory processing in the CNS. While most studies of multisensory processing examine functional effects, none have evaluated the influence of local or columnar circuitry. The goal of the present study is to examine of local features of the ferret lateral rostral suprasylvian sulcus (LRSS), a multisensory cortex. Immunostaining revealed the cytoarchitectonic features of the LRSS: thick supragranular layers, a narrow layer IV, and moderately stained but differentiated infragranular layers. Golgi-Cox techniques were used with light microscopy and digital reconstruction to document neuronal morphology. Among the 90 reconstructed neurons, 4 distinct forms or pyramidal and 2 types of non-pyramidal neurons were found. Measurement of maximal dendritic spread indicates that a cortical column in the LRSS was 250.9 um in diameter. These results describe local features of the LRSS upon which future experiments of intrinsic circuitry will be based.