Orientador: Vera Lúcia Gil da Silva Lopes / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T00:02:24Z (GMT). No. of bitstreams: 1 Araujo_TaniaKawasakide_D.pdf: 3447671 bytes, checksum: 97911848c6334882843e4b270b9c6771 (MD5) Previous issue date: 2015 / Resumo: A fenda de labiopalatal (FLP) isolada é o defeito craniofacial mais comum em humanos. O objetivo deste estudo foi avaliar associações entre 39 genes e a etiologia de FLP isolada em uma amostra da população brasileira. Este estudo de associação do tipo caso-controle foi desenhado com um poder estatístico de 81,29% por meio de regressão logística. O grupo de casos foi composto por 182 pacientes com FLP isolada registrados na Base Brasileira de Dados Clínicos e Familiais de Fendas Orofaciais Típicas. O grupo controle foi formado por 355 indivíduos saudáveis, sem história de fendas orais em três gerações. Toda a amostra foi genotipada por meio do sistema OpenArray®TaqManTM para 253 polimorfismos de nucleotídeo único (SNPs) em 39 genes, incluindo dois genes que, recentemente, haviam sido descritos por este grupo de pesquisa. A seleção de SNPs foi feita com o programa SNPbrowser 4.0 (Applied Biosystems) para verificar o número e a localização dos SNPs apropriados para explorar a associação de cada gene com FLP isolada. A análise de associação foi realizada por meio de regressão logística e regressão stepwise. Os resultados foram corrigidos para múltiplos testes (correção de Bonferroni). Vinte e quatro SNPs em 16 genes foram significativamente associados com a etiologia da FLP isolada, incluindo MSX1, SPRY1, MSX2, PRSS35, TFAP2A, SHH, VAX1, TBX10, WNT11, PAX9, BMP4, JAG2, AXIN2, DVL2, KIF7 e TCBE3. A análise de regressão stepwise revelou que 11 genes contribuiram em 15,5% do fenótipo de FLP isolada nessa amostra. Este é o primeiro estudo a associar os genes KIF7 e TCEB3 à FLP isolada / Abstract: Nonsyndromic cleft lip and palate (NSCLP) is the most common craniofacial birth defect. The aim of this study was to evaluate associations between 39 genes and the etiology of NSCLP in a Brazilian population. This case-control association study was designed with 81.29% statistical power according to logistic regression. The case group was composed of 182 patients with NSCLP enrolled in the Brazilian Database on Orofacial Clefts. The controls included 355 healthy individuals with no history of oral clefting in the past three generations. All samples were genotyped by TaqMan®OpenArrayTM system for 253 single nucleotide polymorphisms (SNPs) in 39 genes, including two that had recently been associated with this process. The SNPs selection was made by SNPbrowser 4.0 (Applied Biosystems) in order to establish the best SNPs to explor the association between each gene and NSCLP. The association analysis was performed using logistic regression and stepwise regression. The results were corrected for multiple testing (Bonferroni correction). Twenty-four SNPs in 16 genes were significantly associated with the etiology of NSCLP, including MSX1, SPRY1, MSX2, PRSS35, TFAP2A, SHH, VAX1, TBX10, WNT11, PAX9, BMP4, JAG2, AXIN2, DVL2, KIF7 and TCBE3. Stepwise regression analysis revealed that 11 genes contributed to 15.5% of the phenotype of NSCLP in the sample. This is the first study to associate KIF7 and TCEB3 with NSCLP / Doutorado / Ciencias Biomedicas / Doutora em Ciências Médicas

Foram selecionados 231 indivíduos, no período de abril de 1997 a janeiro de 1998, divididos em dois grupos controle com 88 indivíduos e 143 pacientes com doença arterial coronária. Os pacientes foram subdivididos em dois grupos: 59 com angina estável e 84 com IAM. Foram analisadas as características clínicas, fatores de risco, pressão arterial sistólica e diastólica, perfil lipídico, glicemia, tabagismo, apoliproteína Al, apoliproteína B, lipoproteína (a), fibrinogênio, ácido úrico e hemograma completo. Análise multivariada mostrou que a idade, o HDL-colesterol, leucócitos e monócitos foram fatores de risco independentes para doença arterial coronária. / Between april 1997 and january 1998, 231 patients were selected and divided into two groups: control group with 88 patients and 143 patients with coronary artery disease. The latter group was then divided into two subgroups: 59 patients with stable angina and 84 patients with AMI. Clinical characteristics, risk factors, systolic and diastolic blood pressure, lipid profile, glycemia, smoking, apoliprotein Al, apoliprotein B, lipoprotein(a), fibrinogen, uric acid and total blood cell count were analyzed. Multivariate analysis showed age, HDL-cholesterol, leukocytes and monocytes as independent risk factors for coronay heart disease.

Avaliar por ressonância magnética (IRM), placa e remodelamento coronários, comparar estenose por IRM e cinecoronariografia (CINE) e correlacionar achados de US de carótidas em pacientes (pts) com DAC. Avaliamos 10 controles(ctls) e 26 pts (lesão > 50% à CINE). Realizamos cortes transversais em artérias DA e CD (2Dblack-blood). Calculamos espessamento parietal (EP), área luminal (AL), área da parede (AP) e área total do vaso (ATV). Detectamos significantes aumentos em EP, AP e ATV nos pts vs. ctls, sem diferenças quanto a AL. Ajustando AL pela ATV, houve redução desta relação nos pts vs. ctls (remodelamento positivo). Em conclusão, a IRM identifica a parede e remodelamento de coronárias em pts com DAC, não houve correlação entre IRM e CINE quanto à estenose e placa em carótidas foi mais prevalente nos pts / To test magnetic resonance imaging (MRI) in detecting atherosclerotic plaque and coronary remodeling in patients (pts) with CAD, to compare stenosis grade (MRI vs. angiography), and to correlate carotid plaque by US and CAD. Cross-sectional slices (2D black-blood) was performed in LAD and RCA in 10 controls (ctls) and 26 pts ( > 50% stenosis) by MRI. Maximum wall thickness (WT), vessel wall area (VWA), luminal area (LA) and total vessel area (TVA) were analyzed. MRI detected increases in WT, VWA and TVA in pts vs. ctls, but not for LA. Adjusting LA for TVA, reduction was found in pts (positive remodeling). In conclusion, MRI allowed vessel abnormalities and coronary remodeling in pts with CAD, there was no correlation between stenosis grade (MRI vs. angiography) and carotid plaque was more prevalent in pts

BACKGROUND: The Problematic Internet use among adolescents is an increasingly discussed topic in connection with the continuous development of technologies. If it enters to the period of adolescent age factor of hematoncological disease, which requires long term tratment and isolation for a long time, the risk of growth of non-substance addictive behavior is likely to increase in this context. AIM: The main aim of the research was to find out the prevalence of Problematic Internet use in a group of adolescent patients after the intensive cancer treatment within the Department of Pediatric Hematology and Oncology of the University Hospital in Motol (KDHO). Another aim was to map specific characteristics that may be a predictor of later risk behavior and to find out possible correlation between these characteristics and problematic Internet use. METHODS: The concept of the research is based on quantitative methods of epidemiological cases and controls study. The data were collected through a screening questionnaire survey using a compilation of a short version of the Problematic Internet Use Questionnaire (PIU Q- SF 6) and Substance Use Risk Profile (SURPS) personality traits). Data were evaluated using descriptive statistics and the χ2 test. The p value p < 0,05 was determined as statistically...

En 2007, le Centre International de Recherche sur le Cancer (CIRC) a classé le “travail de nuit entrainant une perturbation du rythme circadien” comme probablement cancérogène pour l'homme (groupe 2A) sur la base de preuves suffisantes chez l’animal mais limitées chez l'Homme. A ce jour, peu d’études se sont intéressées au rôle du travail de nuit et des gènes de l’horloge dans la survenue du cancer de la prostate. Dans ce contexte, nous avons étudié le rôle du travail de nuit, des gènes circadiens ainsi que leurs interactions dans le risque de cancer de la prostate, à partir des données d’EPICAP, étude cas-témoins réalisée en population générale), incluant 819 cas et 879 témoins. Un questionnaire standardisé a permis de recueillir des informations détaillées sur le travail de nuit, qu’il soit fixe ou rotatif. La réalisation d’un prélèvement biologique a permis un génotypage de l’ADN pour l’étude des gènes de l’horloge. Globalement, nous n’avons pas mis en évidence d’association entre le travail de nuit et le cancer de la prostate quelle que soit l'agressivité du cancer de la prostate, alors que nous avons observé une augmentation du risque chez les hommes ayant un chronotype du soir. Une durée d’exposition d’au moins 20 ans au travail de nuit fixe associée au cancer de la prostate agressif et de manière plus prononcée en combinaison avec des nuits de longue durée (en moyenne de plus de 10 heures par nuit) ou avec un nombre maximal de nuits consécutives supérieur à 6. Nous avons observé une association significative avec le cancer de la prostate pour les gènes NPAS2 et PER1, alors que seul le gène RORA était significatif pour les cancers agressifs. L’analyse de l’interaction entre les gènes de l’horloge et le travail de nuit dans le risque de survenue de cancer de la prostate a révélé des interactions significatives avec les gènes RBX1, CRY1, NPAS2 et PRKAG2. Les résultats de notre étude renforcent l'hypothèse d'un lien entre le travail de nuit en tant que facteur de perturbation du rythme circadien et le risque de cancer de la prostate et fournissent également de nouvelles preuves d'un lien potentiel avec les variants des gènes de l’horloge. Ces résultats, pourraient contribuer à l’identification de nouveaux facteurs de risque modifiables pour le cancer de la prostate pouvant être accessibles à la prévention. Des recherches plus approfondies aideront à mieux cerner les mécanismes biologiques impliquant les gènes circadiens dans le développement du cancer de la prostate ainsi que leurs interactions avec le travail de nuit. / In 2007, the International Agency for Research on Cancer (IARC) classified "shift work leading to a disruption of circadian rhythm» as probably carcinogenic to humans (Group 2A) on the basis of sufficient evidence in animals but limited evidence in humans. To date, few studies have focused on the role of night work and clock genes in prostate cancer occurrence. In this context, we studied the role of night work, circadian genes and their interactions in prostate cancer risk, using data from EPICAP, a population-based case-control study, including 819 cases and 879 controls. A standardized questionnaire was used to collect detailed information on both fixed and rotating night work. Biological samples were also collected for DNA genotyping and for prostate cancer-clock genes association study. Overall, we did not find an association between night work and prostate cancer whatever the disease aggressiveness, while we observed an increased risk in men with an evening chronotype. At least 20 years of exposure to fixed night work was associated with aggressive prostate cancer and this was more stricken in combination with long nights (on average more than 10 hours per night shift) or more than 6 consecutive night shifts. We observed a significant association with prostate cancer for the clock genes NPAS2 and PER1, while only RORA was significant for aggressive cancers. We found significant interaction between clock genes and night work in the risk of prostate cancer for RBX1, CRY1, NPAS2 and PRKAG2. Our results provide support for the hypothesis that night work disrupting circadian rhythm could be associated with prostate cancer and they also provide new evidence of a potential link between clock genes variants and prostate cancer. These results may particularly contribute to the identification of new prostate cancer risk factors that could be modifiable and available for prevention. Further studies are warranted to better understand the biological mechanisms involving circadian genes in the development of prostate cancer and their interactions with night work.

The study area for this dissertation is Hamilton, Ontario, Canada. / The general theme of this dissertation is understanding and enabling safe walking routes to school for children. We restrict our focus to safety issues related to the motorized-transportation environment, thereby defining safety as a function of factors that determine whether or not a child will be struck by a motor-vehicle on their journey to or from school. Our analysis is unique because it is at a small geographical scale but is representative of an entire urban environment. Working at a small geographic scale allows us to evaluate the variability in safe routes for children within our study area and apply our findings to develop a decision support tool that could be used to plan individualized routes for children in other similar urban environments. Our study area for this dissertation is Hamilton, Ontario, Canada. The findings in this dissertation contribute ideas about how features of the local road environment may and may not influence risk of collisions between child pedestrians and motor-vehicles. It also offers methodological insight for future research on pedestrian safety at small geographic scales. This dissertation demonstrates the potential reduction in the risk of child pedestrian injuries by planning safer routes to school and also introduces methods that can be used to plan safer routes for children. Our results are a reminder of the importance of understanding the interaction between environment and behaviour in research on traffic safety and offer some caution to the notion of a universal 'safe route' to school. Whether or not a particular route to school is safe will very likely be dependent both on the environment and the child's behaviour in that environment. / Dissertation / Doctor of Social Science

Thèse en cotutelle internationale (Université Paris-Saclay) / Thesis completed under international cotutelle (Université Paris-Saclay) / CONTEXTE : Des résultats issus d'études sur les migrants suggèrent que les facteurs de risque environnementaux peuvent jouer un rôle dans la pathogenèse du cancer du sein, de l'ovaire et du poumon. Néanmoins, le rôle de ces facteurs dans l’étiologie de ces cancers reste mal connu. Les facteurs de risque professionnels chez les femmes ont été relativement peu étudiés malgré la proportion importante de la main-d'œuvre féminine à travers le monde. Peu d'études ont en effet examiné les professions fréquentes chez les femmes et les risques professionnels liés aux cancers féminins. OBJECTIFS : Etudier les associations entre 1) la profession, les expositions professionnelles et le cancer de l'ovaire, 2) les expositions professionnelles et le cancer du sein, et 3) la profession, les expositions professionnelles et le cancer du poumon. METHODES : Les données de trois études cas-témoins réalisées en population générale chez des femmes au Canada et en France qui disposaient d’informations sur l'historique professionnel ont été utilisées : l'étude PROVAQ sur le cancer de l'ovaire (491 cas, 897 témoins), l'étude CECILE sur le cancer du sein (1 206 cas, 1 294 témoins) et l'étude WELCA sur le cancer du poumon (731 cas, 751 témoins). Dans ces trois études, un hygiéniste industriel a codé la profession de chaque emploi de chaque participante. Les codes de profession ont été croisés avec une matrice emplois-expositions canadienne afin d’estimer les expositions professionnelles aux agents les plus répandus. La relation entre l'exposition à chacun des agents et le risque de cancer a été évaluée : 29 agents pour le cancer de l'ovaire, 49 agents pour le cancer du sein et 41 agents pour le cancer du poumon. Pour les cancers de l'ovaire et du poumon, les risques associés aux professions les plus fréquemment rencontrées ont également été étudiés. Les associations avec le risque de cancer pour les professions et les expositions professionnelles ont été estimées par régression logistique et en ajustant pour des facteurs de confusion, identifiés à l'aide de graphes acycliques dirigés. RESULTATS : Des risques accrus de cancer de l'ovaire ont été suggérés pour les professions dans le domaine de la comptabilité, de la vente, de la coiffure et de la couture, ainsi que pour les expositions aux agents chimiques utilisés dans les métiers de la coiffure. Pour le cancer du sein, les expositions professionnelles aux poussières de fibres textiles, aux solvants organiques, aux hydrocarbures aromatiques polycycliques, aux poussières de plastique et aux fumées de pyrolyse, étaient associées à des augmentations du risque. Les odds ratios différaient selon les sous-types de cancer du sein et en fonction du statut ménopausique pour certains agents. Pour le cancer du poumon, des odds ratios élevés ont été observés dans les métiers de l'enseignement, les professions libérales, chez les cols-blancs, la vente et les services. Des associations étaient également observées avec de nombreuses expositions professionnelles, en cohérence avec des études antérieures chez les femmes, telles que les fumées de cuisson, le formaldéhyde, les solvants organiques, les hydrocarbures aromatiques polycycliques, les métaux et les peintures/vernis. Les risques de cancer du poumon pour certains agents semblaient différer selon le statut tabagique. CONCLUSIONS : Certaines professions et expositions professionnelles peuvent être associées à des risques accrus de cancer de l'ovaire, du sein et du poumon chez les femmes. Du fait de la nature exploratoire du travail, d'autres recherches chez des femmes en population générale doivent être menées afin de confirmer ces résultats. Des études portant sur des échantillons plus importants et l’évaluation des expositions par experts, permettant d’utiliser des méthodes statiques avancées, pourraient être utiles pour identifier le rôle spécifique de certaines expositions professionnelles dans le risque de cancer. / BACKGROUND: Evidence from migrant studies suggests that environmental risk factors may play a role in the pathogenesis of breast, ovarian, and lung cancers, yet the etiology of these cancers remains poorly understood. Women account for a significant proportion of the labour force worldwide, yet research on occupational hazards of female workers is limited. Few studies have examined occupations common to women and occupational risks in relation to female cancers. OBJECTIVES: The specific objectives of the thesis were: 1) to study the association between occupation, occupational exposures and ovarian cancer, 2) to study the association between occupational exposures and breast cancer, and 3) to study the association between occupation, occupational exposures and lung cancer in women. METHODS: Data from three population-based case-control studies on women in Canada and France that collected occupational history information was used to achieve the objectives: the PROVAQ study on ovarian cancer (491 cases, 897 controls), the CECILE study on breast cancer (1,206 cases, 1,294 controls), and the WELCA study on lung cancer (731 cases, 751 controls). In all three studies, an industrial hygienist coded the occupation of each participant’s job. Job codes were linked to the Canadian job-exposure matrix, thereby generating exposure estimates for many agents. The relationship between exposure to each of the most prevalent agents and cancer risk was assessed, specifically 29 agents for ovarian cancer, 49 agents for breast cancer, and 41 agents for lung cancer. For ovarian and lung cancers, prevalent occupations were additionally examined by comparing participants employed in an occupation for <10 years and ≥10 years vs. never employed in the occupation. Associations with cancer risk for occupations and occupational exposures were estimated using logistic regression and adjusting for minimally sufficient confounder sets, identified using directed acyclic graphs. RESULTS: Excess ovarian cancer risks were suggested for accountancy, sales, hairdressing, and sewing occupations, and for occupational exposure to agents linked to hairdressing-related occupations. Interpretations of results for single agents were limited due to multiple correlated exposures. For breast cancer, occupational exposure to agents, particularly textile fibre dusts, organic solvents, polycyclic aromatic hydrocarbons, plastic dusts and pyrolysis fumes, were potentially associated with increased risks. Relative risks were suggested to differ among breast cancer subtypes and according to menopausal status for some agents. For lung cancer, elevated odds ratios were observed for teaching, professional, white-collar, sales, and service occupations, and for numerous occupational exposures, some of which were consistent with previous studies in women, such as cooking fumes, formaldehyde, organic solvents, polycyclic aromatic hydrocarbons, metals, and paints/varnishes. Lung cancer risks for some agents were suggested to differ by smoking status. CONCLUSIONS: Certain occupations and occupational exposures may be associated with excess ovarian, breast, and lung cancer risks in women. As many odds ratios observed were imprecise, further population-based research on women is warranted to replicate findings. Studies with larger sample sizes and expert assessment information that can perform more advanced statistical methods accounting for multiple exposures may be useful in disentangling the effects of correlated agents in the estimation of cancer risk.

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A variety of complex data has broadened in many research fields such as epidemiology, genomics, and analytical chemistry with the development of science, technologies, and design scheme over the past few decades. For example, in epidemiology, the matched case-crossover study design is used to investigate the association between the clustered binary outcomes of disease and a measurement error in covariate within a certain period by stratifying subjects' conditions. In genomics, high-correlated and high-dimensional(HCHD) data are required to identify important genes and their interaction effect over diseases. In analytical chemistry, multiple time series data are generated to recognize the complex patterns among multiple classes. Due to the great diversity, we encounter three problems in analyzing those complex data in this dissertation. We have then provided several contributions to semiparametric and nonparametric methods for dealing with the following problems: the first is to propose a method for testing the significance of a functional association under the matched study; the second is to develop a method to simultaneously identify important variables and build a network in HDHC data; the third is to propose a multi-class dynamic model for recognizing a pattern in the time-trend analysis. For the first topic, we propose a semiparametric omnibus test for testing the significance of a functional association between the clustered binary outcomes and covariates with measurement error by taking into account the effect modification of matching covariates. We develop a flexible omnibus test for testing purposes without a specific alternative form of a hypothesis. The advantages of our omnibus test are demonstrated through simulation studies and 1-4 bidirectional matched data analyses from an epidemiology study. For the second topic, we propose a joint semiparametric kernel machine network approach to provide a connection between variable selection and network estimation. Our approach is a unified and integrated method that can simultaneously identify important variables and build a network among them. We develop our approach under a semiparametric kernel machine regression framework, which can allow for the possibility that each variable might be nonlinear and is likely to interact with each other in a complicated way. We demonstrate our approach using simulation studies and real application on genetic pathway analysis. Lastly, for the third project, we propose a Bayesian focal-area detection method for a multi-class dynamic model under a Bayesian hierarchical framework. Two-step Bayesian sequential procedures are developed to estimate patterns and detect focal intervals, which can be used for gas chromatography. We demonstrate the performance of our proposed method using a simulation study and real application on gas chromatography on Fast Odor Chromatographic Sniffer (FOX) system. / Doctor of Philosophy / A variety of complex data has broadened in many research fields such as epidemiology, genomics, and analytical chemistry with the development of science, technologies, and design scheme over the past few decades. For example, in epidemiology, the matched case-crossover study design is used to investigate the association between the clustered binary outcomes of disease and a measurement error in covariate within a certain period by stratifying subjects' conditions. In genomics, high-correlated and high-dimensional(HCHD) data are required to identify important genes and their interaction effect over diseases. In analytical chemistry, multiple time series data are generated to recognize the complex patterns among multiple classes. Due to the great diversity, we encounter three problems in analyzing the following three types of data: (1) matched case-crossover data, (2) HCHD data, and (3) Time-series data. We contribute to the development of statistical methods to deal with such complex data. First, under the matched study, we discuss an idea about hypothesis testing to effectively determine the association between observed factors and risk of interested disease. Because, in practice, we do not know the specific form of the association, it might be challenging to set a specific alternative hypothesis. By reflecting the reality, we consider the possibility that some observations are measured with errors. By considering these measurement errors, we develop a testing procedure under the matched case-crossover framework. This testing procedure has the flexibility to make inferences on various hypothesis settings. Second, we consider the data where the number of variables is very large compared to the sample size, and the variables are correlated to each other. In this case, our goal is to identify important variables for outcome among a large amount of the variables and build their network. For example, identifying few genes among whole genomics associated with diabetes can be used to develop biomarkers. By our proposed approach in the second project, we can identify differentially expressed and important genes and their network structure with consideration for the outcome. Lastly, we consider the scenario of changing patterns of interest over time with application to gas chromatography. We propose an efficient detection method to effectively distinguish the patterns of multi-level subjects in time-trend analysis. We suggest that our proposed method can give precious information on efficient search for the distinguishable patterns so as to reduce the burden of examining all observations in the data.