A modelagem em radiobiologia possibilita prever a eficácia de tratamentos radioterápicos, especificando protocolos e estratégias para se tratar pacientes com câncer. Muitos modelos matemáticos têm sido propostos para a avaliação da Probabilidade de Controle Tumoral (TCP). Nesta tese, inicialmente apresenta-se um estudo desenvolvido em colaboração com pesquisadores da Universidade de Alberta, no Canadá, em que são comparadas as TCP\'s obtidas através de simulações Monte Carlo e dos modelos Poissoniano, de Zaider-Minerbo (ZM) e de Dawson-Hillen (DH). Os resultados mostram que, para tumores de baixa proliferação celular, o uso do modelo Poissoniano para indicação de protocolos de tratamento é tão eficaz quanto o método Monte Carlo ou o uso de modelos mais sofisticados (ZM e DH). Na segunda parte da tese, propõe-se um teste estatístico, baseado em simulações Monte Carlo do modelo de TCP de DH, para se determinar a capacidade de previsão de erradicação de tumor (cura). Obtem-se a curva ROC do teste a partir das distribuições de probabilidade da fração de células tumorais remanescentes, nas condições de cura ou não-cura. Os resultados mostram que o método pode ser também aplicado a dados clínicos, sugerindo que a avaliação do tamanho do tumor no início da radioterapia permite a prognose do tratamento a curto prazo. Na terceira parte da tese, aborda-se o estudo da fração de sobrevivência (FS) de células tumorais em função da dose de radiação a que são submetidas. Na literatura, esta fração de sobrevivência tem sido formulada através do modelo Linear-Quadrático (LQ) e, mais recentemente, da estatística não-extensiva de Tsallis. Avalia-se o comportamento dessas duas formulações em termos dos ajustes da FS a dados experimentais da literatura (referentes a células cultivadas in vitro para vários tecidos tumorais) estendendo-se assim estudos prévios da literatura. Os parâmetros da FS para ambas formulações são obtidos e a qualidade dos ajustes da FS a dados experimentais é comparada utilizando-se o qui-quadrado reduzido. Os resultados mostram que, em geral, as duas formulações permitem bons ajustes das curvas de FS. Além deste estudo, utilizamos a estatística não-extensiva de Tsallis para obtenção da TCP de ZM em função da dose, expressando-a analiticamente em termos da função Gama (para um perfil de dose típico de radiação de feixe externo) e da função Hipergeométrica (para um perfil de dose típico de braquiterapia). Finalmente, as curvas das correspondentes TCP\'s são levantadas com o uso de dados experimentais e comparadas com a TCP\'s obtidas através do modelo LQ. / Radiobiological modeling allows one to predict the efficacy of radiotherapeutic treatments, specifying protocols and strategies to treat patients with cancer. Many mathematical models have been proposed to evaluate the Tumor Control Probability (TCP). In this thesis we first present a study in colaboration with researchers at the University of Alberta, Canada, in which we compare the TCPs obtained by Monte Carlo simulations and from the Poissonian, Zaider-Minerbo (ZM) and Dawson-Hillen (DH) models. Results show that, for low proliferation tumors, the use of the Poissonian model for indicating the treatment protocol is as effective as the Monte Carlo method or more sofisticated models (ZM and DH). in the second part of the thesis, we propose a statistical test based on Monte Carlo simulations of the DH TCP model to determine the prediction capacity of tumor eradication (cure). We obtain the ROC curve of the test from the probability distributions of the remaining tumor cells for conditions of cure and non-cure. Results show that the method can also be applied to clinical data suggesting that the evaluation of the tumor size at the beginning of the radiotherapy leads to a short-term prognosis of the treatment. In the third part of the thesis, we study the surviving fraction (FS) of tumor cells as function of the radiation dose to which they are subjected. In the literature, this surviving fraction has been formulated by the Linear-Quadratic (LQ) model and, more recently, from the Tsallis non-extensive statistics. We evaluate the behaviour of both formulations in terms of the FS fittings to experimental data in the literature (related to cells cultivated for several tumoral tissues) so that we extend previous studies in the literature. The FS parameters for both formulations are obtained and the quality of the FS fittings to experimental data is compared using the reduced chi-square. Results show that in general both formulations lead to very good FS-curve fittings. Furthermore, we use the Tsallis non-extensive statistics to obtain the ZM TCP as function of the dose, expressing it analitically in terms of the Gamma function (for a dose profile typical of external beam radiation) and the Hipergeometric function (for a dose profile typical of brachitherapy). Finally, the curves of the corresponding TCPs are plotted using experimental data and then compared with TCPs obtained from the LQ model.

Introdução: luto complicado é caracterizado pela procura persistente pelo falecido, tristeza e dor emocional intensos em resposta à morte de ente querido. Luto complicado é frequentemente pouco reconhecido e subtratado. O Texas Inventory Revised of Grief (TRIG) é um instrumento de alta confiabilidade e validade na medida de avaliação do luto. Nosso objetivo foi traduzir, adaptar e validar o TRIG para Português do Brasil e verificar se o mesmo, em uma população enlutada, é capaz de distinguir entre os que têm e os que não tem luto complicado assim como identificar quais elementos da escala contribuem para isso. Métodos: o trabalho foi realizado em duas etapas: a) tradução e adaptação transcultural do TRIG para o português do Brasil e b) estudo em corte transversal para análise da confiabilidade e validação desse instrumento. Participantes: 165 pacientes adultos foram recrutados de: a) Ambulatório de Luto do Departamento e Instituto de Psiquiatria - Universidade de São Paulo, b) Ambulatório de convênio e Particulares no mesmo departamento e, c) Colegas de trabalho que perderam um ente querido. Todos os pacientes foram entrevistados com o TRIG e de acordo com critérios clínicos, 69 dos 165 pacientes enlutados foram diagnosticados com luto complicado. Resultados: quanto à tradução e adaptação transcultural, o TRIG foi traduzido para o português, feito a retrotradução para o inglês e adaptado à cultura local. Esse processo foi realizado por dois psiquiatras bilíngues. A confiabilidade e consistência interna do instrumento foram medidos pelo coeficiente de Alpha de Cronbach que alcançou 0,735 para parte I e 0,896 para a parte II do instrumento. A sensibilidade, especificidade e ponto de corte para identificar enlutados com e sem luto complicado foram medidos pela Curva ROC. Viu-se que usando o ponto de corte encontrado de 104 (escore total das partes I, II, III + variáveis psicográficas), é possível classificar corretamente 71,3% dos indivíduos com e sem luto complicado. A validação do instrumento foi realizada pela análise fatorial exploratória e confirmatória. Pela regressão logística demonstrou-se que nível educacional, idade do falecido, idade do enlutado, perda de filho(a) e morte do tipo inesperada são fatores de risco para luto complicado. Nossos resultados também sugerem que religião pode influenciar luto complicado. Conclusões: a versão traduzida e adaptada do TRIG para o português é confiável e válida como medida do luto tanto quanto a versão original. O TRIG foi capaz de distinguir pacientes com e sem luto complicado. Nós sugerimos o uso do TRIG com ponto de corte igual a 104 para identificar enlutados com luto complicado / Background: Complicated grief is characterized by persistent yearning for the deceased, intense sorrow and emotional pain in response to death causing significant distress. Complicated grief is often underrecognized and under treated. The Texas Revised Inventory of Grief (TRIG) is a questionnaire that has been demonstrated to have high validity and reliability in the assessment of complicated grief. Our objective was to translate, adapt, and validate the TRIG to Brazilian Portuguese and to verify whether the TRIG, in a bereaved population, is able to distinguish between those with and those without complicated grief and to identify which elements in the scale contribute to this. Methods: Two stages: a) cross-culture adaptation of a questionnaire, and b) crosssectional study of reliability and validity. Setting and Participants: 165 adult patients were recruited from a) the Grief Outpatient Clinic at the Department and Institute of Psychiatry - University of São Paulo, b) private practice at the same department, and c) co-workers who have lost a loved one. All the patients were interviewed with the TRIG. According to clinical criteria 69 of 165 bereaved patients were presenting complicated grief. Results: Cross-culture adaptation: the TRIG was translated from American English, then back-translated and finally compared with the Brazilian Portuguese version by two bilingual psychiatrists. Reliability: the Cronbach\'s alpha coefficients (internal consistency) of the TRIG scales were 0,735 (part I) and 0,896 (part II). Sensitivity, specificity as well as cutoff points to identify complicated and non-complicated grief, were measured using the ROC curve Using the total score of 104 (part I + part II + Part III + psychographics variables), we can correctly classify 71.3% of individuals with and without complicated grief. The construct validity was assessed by exploratory factor analysis and confirmatory analysis. Furthermore, by logistic regression, our study demonstrated that a low education level, age of the deceased and age of the bereaved, loss of a son or daughter, and unexpected death were all risk factors for complicated grief. Our results also suggest that religion may influence complicated grief. Conclusions: The TRIG adapted to Brazilian Portuguese is as reliable and valid as the original version. In the evaluation of Brazilian bereaved, it was able to distinguish individuals with and without complicated grief. And, we suggest a cut-off value of 104 for complicated grief

La narcolepsie est une maladie rare, touchant une personne sur 2000. Elle se caractérise par l'association d'une somnolence diurne excessive, d'épisodes de cataplexie, de paralysies du sommeil, d'hallucinations hypnagogiques. et d'une fragmentation du sommeil. La narcolepsie sans cataplexie constitue un sous-type hétérogène. Le diagnostic de narcolepsie peut être clinique, mais bien souvent un Test Itératif de Latence d'Endormissement (T1LE), précédé d'une polysomnographie nocturne (NPSG). sont utilisés pour porter le diagnostic.La cause de la plupart des cas de narcolepsie avec cataplexie a été découverte au début des années 2000: la destruction, probablement d'origine auto-immune. des neurones à hypocrétine de l'hypothalamus. Un déficit en hypocrétine à la ponction lombaire constitue désormais un test de référence pour établir le diagnostic, ce qui offre l'opportunité d'optimiser les critères actuels et de tester de nouvelles hypothèses diagnostiques en regard de ce test de référence. Peu d'études ont à ce jour spécifiquement porté sur la narcolepsie sans cataplexie et son diagnostic. Nous avons donc cherché à identifier les prédicteurs du déficit en hypocrétine dans la narcolepsie sans cataplexie. De plus, dans la narcolepsie-cataplexie, l'utilisation comme critère diagnostique d'une latence courte d'apparition du sommeil paradoxal à la NPSG n'a jamais été évaluée en utilisant comme test de référence le déficit en hypocrétine, et nous avons donc cherché à en déterminer l'utilité diagnostic et la valeur-seuil optimale.Afin de mener à bien ces projets de recherche, nous avons initié et participé au développement du logiciel d'analyse ROC (Receiver Operating Characteristic) SoftROC. Dans la narcolepsie sans cataplexie. nous avons montré que les paramètres électrophysiologiques, plus que cliniques, différaient entre les patients avec un taux bas d'hypocrétine et ceux avec un taux normal. Dans la narcolepsie avec cataplexie. nous avons établi qu'une latence courte (< 15 minutes) d'apparition du sommeil paradoxal à la NPSG était un test diagnostique spécifique, mais peu sensible, pour la narcolepsie avec déficit en hypocrétine. Nos résultats ont contribué à la révision des classifications internationales des troubles du sommeil. / Narcolepsy is characterised by excessive diurnal sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations andsleep fragmentation. Narcolepsy without cataplexy is a heterogeneous subtype. Diagnosis can be established clinically,but a Mulitple Sleep Latency Test (MSLT) following a Nocturnal PolySomnoGraphy (NPSG), is used most of the time.Auto-immune loss of hypocretin cells is responsible for narcolepsy with cataplexy. Hypocretin deficiency at lumbarpuncture is a gold standard for diagnosis.Few studies have focused specifically on narcolepsy without cataplexy. Our aim was to identify predictors of hypocretindeficiency in this condition. Moreover, in narcolepsy with cataplexy, a short REM sleep latency at NPSG has never beenevaluated as a diagnostic test using hypocretin deficiency as a gold standard, and we therefore have aimed at assessing itsdiagnostic utility and optimal cut-off.In order to conduct our research, we have contributed to developing a ROC analysis software (SoftROC).In narcolepsy without cataplexy- objective (NPSG and MSLT) more than clinical parameters were predictors ofhypocretin-deficiency. In narcolepsy-cataplexy, a short (< 15 mins) REM latency at NPSG was a specific, but notsensitive. diagnostic test. Our results contributed to the revision of international diagnostic classifications.

De nos jours, la quantité de données génétiques séquencées augmente de manière exponentielle sous l'impulsion d'outils de séquençage de plus en plus performants, tels que les outils de séquençage haut débit en particulier. De plus, ces données sont de plus en plus facilement accessibles grâce aux bases de données en ligne. Cette plus grande disponibilité des données ouvre de nouveaux sujets d'étude qui nécessitent de la part des statisticiens et bio-informaticiens de développer des outils adaptés. Par ailleurs, les progrès constants de la statistique, dans des domaines tels que le clustering, la réduction de dimension, ou les régressions entre autres, nécessitent d'être régulièrement adaptés au contexte de la bio-informatique. L’objectif de cette thèse est l’application de techniques avancées de statistiques à des problématiques de bio-informatique. Dans ce manuscrit, nous présentons les résultats de nos travaux concernant le clustering de séquences génétiques via Laplacian eigenmaps et modèle de mélange gaussien, l'étude de la propagation des éléments transposables dans le génome via un processus de branchement, l'analyse de données métagénomiques en écologie via des courbes ROC ou encore la régression polytomique ordonnée pénalisée par la norme l1. / Nowadays, the quantity of sequenced genetic data is increasing exponentially under the impetus of increasingly powerful sequencing tools, such as high-throughput sequencing tools in particular. In addition, these data are increasingly accessible through online databases. This greater availability of data opens up new areas of study that require statisticians and bioinformaticians to develop appropriate tools. In addition, constant statistical progress in areas such as clustering, dimensionality reduction, regressions and others needs to be regularly adapted to the context of bioinformatics. The objective of this thesis is the application of advanced statistical techniques to bioinformatics issues. In this manuscript we present the results of our works concerning the clustering of genetic sequences via Laplacian eigenmaps and Gaussian mixture model, the study of the propagation of transposable elements in the genome via a branching process, the analysis of metagenomic data in ecology via ROC curves or the ordinal polytomous regression penalized by the l1-norm.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Background: To compare the clinical value of the measurement of complex and total PSA in the discrimination between benign prostatic hyperplasia (BPH) and prostate cancer. Methods: In serum samples collected from 166 men with histopathologically proven clinically localized prostate cancer and of 97 men with BPH, total prostate-specific antigen (PSA), complexed PSA and the free to total PSA ratio were determined. The statistical analysis was done by the comparison of the receiver operator characteristic (ROC) curves. Results: The areas under the ROC curves were 0.776 for total PSA, 0.799 for complexed PSA (total PSA vs. cPSA: p < 0.0001) and 0.812 for the free to total PSA ratio. With a cut-off of 3.0 ng/ml for complexed PSA, the sensitivity was 90%, the specificity 58%, the positive and the negative predictive values 79 and 78%, respectively. With a cut-off of 4.0 ng/ml for total PSA, the sensitivity was 87%, the specificity 59%, the positive and the negative predictive values were 78 and 72%, respectively. Conclusions: There was a statistically significant advantage for complexed PSA compared to total PSA in the discrimination between BPH and prostate cancer. The difference was, however, small and its clinical relevance is questionable. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Typ- 1 diabetes (T1D) är en autoimmun sjukdom med insulinbrist orsakad av nedbrytning av insulinproducerande betaceller i pankreas. Fyra olika antikroppar har identifierats som är riktade mot betacellsspecifika antigen; insulinautoantikroppar (IAA), glutamic acid decarboxylase antibodies (GADA), islet antigen2-antikroppar (IA-2A) och antikroppar riktade mot zinktransportören 8 (ZnT8A). I denna studie gjordes en jämförelse av metoderna 2screen islet cell autoantibody ELISA-kit (RSR, Cardiff, UK) och 3screen islet cell autoantibody ELISA- kit (RSR, Cardiff, UK), vars brunnar är coatade med GAD65/IA-2 antigen respektive GAD65/IA-2/ZnT8 antigen, för att undersöka ifall dessa båda kit ger jämförbar sensitivitet och specificitet i en adult population av nydebuterade patienter med T1D och friska vuxna blodgivare. RSR 2screen erhöll 1 % högre specificitet (98 %) jämfört med RSR 3screen (97 %) vid samma sensitivitet (92 %) och rekommenderas i första hand för screening av autoantikroppar i en population av vuxna patienter med ökad risk för T1D och friska vuxna blodgivare. / Type- 1 diabetes (T1D) is an autoimmune disease with insulin deficiency caused by degradation of insulin- producing betacells in pancreas. Four different autoantibodies that target beta- cell specific antigenes have been identified: insulinautoantibodies (IAA), glutamic acid decarboxylase antibodies (GADA), islet antigen2-antibodies (IA-2A) and antibodies against zinktransporter 8 (ZnT8A). In this study, a comparison between 2screen islet cell autoantibody ELISA-kit (RSR, Cardiff, UK) coated with GAD65/IA-2 and 3screen islet cell autoantibody ELISA- kit (RSR, Cardiff, UK) coated with GAD65/IA-2/ZnT8, was performed to investigate whether results from these two kits provide comparable sensitivity and specificity in an adult population of new onset patients with T1D and healthy adults. RSR 2screen obtained 1 % higher specificity (98 %) in comparison to RSR 3screen (97 %) on the same sensitivity (92 %) and is recommended primarily for screening of autoantibodies in a population of adult patients at increased risk for T1D and healthy adults blood donors.