Aims: To investigate the natural history of CHC, estimate the disease burden of CHC, and assess the cost-effectiveness of screening for CHC among immigrants living in Canada. Methods: A retrospective cohort study compared the prognosis of CHC between immigrant patients and native-born patients who had advanced fibrosis. A cross-sectional study assessed the association between obesity and hepatitis C viremia. The disease burden of CHC among immigrants was estimated through Markov cohort model. The cost-effectiveness of screening for CHC was assessed among immigrants. Results: The retrospective cohort study including 318 patients demonstrated that immigrant patients had significantly higher risk of hepatocellular carcinoma than Canadian-born patients (p=0.005). The hazard ratio associated with ‘immigrant’ for hepatocellular carcinoma in multivariate Cox proportional-hazards analyses reduced to the least and non-significant (p=0.318) after adjusting age and type 2 diabetes. The prevalence of obesity in 1118 individuals tested positive for hepatitis C antibody was 28.8%. Multiple regression analyses and propensity score methods suggested a significant association between obesity and hepatitis C viremia. The disease burden study estimated that immigrants with CHC had much shorter average life years (26.9 years vs. 39.1 years) and quality adjusted life years (20.6 years vs. 32.4 years) than the age matched immigrants without CHC. The cost-effectiveness study indicated that screening for CHC among immigrants from 183 countries (72.1% of immigrant population in Canada) had an incremental cost-effectiveness ratio less than $50,000 per quality adjusted life year gained. Conclusion: Immigrant patients with CHC could have a higher risk of HCC than native-born patients. The significant association between obesity and hepatitis C viremia could explain the observed high prevalence of type 2 diabetes in patients with CHC. CHC reduces the average life expectancy of immigrants with CHC more than 10 years. Screening for CHC is cost-effective among over 70% of immigrants living in Canada.

Optokinetic nystagmus (OKN) is a fundamental gaze-stabilising response in which eye movements attempt to compensate for the retinal slip caused by self-motion. The OKN response consists of a slow following movement made in the direction of stimulus motion interrupted by fast eye movements that are primarily made in the opposite direction. The timing and amplitude of these slow phases and quick phases are notably variable, but this variability is poorly understood. In this study I performed principal component analysis on OKN parameters in order to investigate how the eigenvectors and eigenvalues of the underlying components contribute to the correlation between OKN parameters over time. I found three categories of principal components that could explain the variance within each cycle of OKN, and only parameters from within a single cycle contributed highly to any given component. Differences found in the correlation matrices of OKN parameters appear to reflect changes in the eigenvalues of components, while eigenvectors remain predominantly similar across participants, and trials. I have developed a linear and stochastic model of OKN based on these results and demonstrated that OKN can be described as a 1st order Markov process, with three sources of noise affecting SP velocity, QP triggering, and QP amplitude. I have used this model to make some important predictions about the optokinetic reflex: the transient response of SP velocity, the existence of signal dependent noise in the system, the target position of QPs, and the threshold at which QPs are generated. Finally, I investigate whether the significant variability within OKN may represent adaptive control of explicit and implicit parameters. iii

DNA sequence alignments are usually not homogeneous. Mosaic structures may result as a consequence of recombination or rate heterogeneity. Interspecific recombination, in which DNA subsequences are transferred between different (typically viral or bacterial) strains may result in a change of the topology of the underlying phylogenetic tree. Rate heterogeneity corresponds to a change of the nucleotide substitution rate. Various methods for simultaneously detecting recombination and rate heterogeneity in DNA sequence alignments have recently been proposed, based on complex probabilistic models that combine phylogenetic trees with factorial hidden Markov models or multiple changepoint processes. The objective of my thesis is to identify potential shortcomings of these models and explore ways of how to improve them. One shortcoming that I have identified is related to an approximation made in various recently proposed Bayesian models. The Bayesian paradigm requires the solution of an integral over the space of parameters. To render this integration analytically tractable, these models assume that the vectors of branch lengths of the phylogenetic tree are independent among sites. While this approximation reduces the computational complexity considerably, I show that it leads to the systematic prediction of spurious topology changes in the Felsenstein zone, that is, the area in the branch lengths configuration space where maximum parsimony consistently infers the wrong topology due to long-branch attraction. I demonstrate these failures by using two Bayesian hypothesis tests, based on an inter- and an intra-model approach to estimating the marginal likelihood. I then propose a revised model that addresses these shortcomings, and demonstrate its improved performance on a set of synthetic DNA sequence alignments systematically generated around the Felsenstein zone. The core model explored in my thesis is a phylogenetic factorial hidden Markov model (FHMM) for detecting two types of mosaic structures in DNA sequence alignments, related to recombination and rate heterogeneity. The focus of my work is on improving the modelling of the latter aspect. Earlier research efforts by other authors have modelled different degrees of rate heterogeneity with separate hidden states of the FHMM. Their work fails to appreciate the intrinsic difference between two types of rate heterogeneity: long-range regional effects, which are potentially related to differences in the selective pressure, and the short-term periodic patterns within the codons, which merely capture the signature of the genetic code. I have improved these earlier phylogenetic FHMMs in two respects. Firstly, by sampling the rate vector from the posterior distribution with RJMCMC I have made the modelling of regional rate heterogeneity more flexible, and I infer the number of different degrees of divergence directly from the DNA sequence alignment, thereby dispensing with the need to arbitrarily select this quantity in advance. Secondly, I explicitly model within-codon rate heterogeneity via a separate rate modification vector. In this way, the within-codon effect of rate heterogeneity is imposed on the model a priori, which facilitates the learning of the biologically more interesting effect of regional rate heterogeneity a posteriori. I have carried out simulations on synthetic DNA sequence alignments, which have borne out my conjecture. The existing model, which does not explicitly include the within-codon rate variation, has to model both effects with the same modelling mechanism. As expected, it was found to fail to disentangle these two effects. On the contrary, I have found that my new model clearly separates within-codon rate variation from regional rate heterogeneity, resulting in more accurate predictions.

Approved for public release, distribution is unlimited / A Markov Model was used to determine the number of nurses the Navy must gain each year in order to maintain desired end strength. Significant characteristics affecting career progression of individuals in the Navy Nurse Corps were identified. The characteristic of primary concern, accession source, was determined to be significant. Markov models were created to identify personnel flow from ENS through LCDR. The models end-strength projections for 2006-2009 were then compared to Nurse Corps targeted end-strengths for this same period. Several scenarios were run to minimize overages and underages in rank distribution. Optimization was achieved by changing both the distribution of accession sources and the distribution of recruited ranks. Optimal distribution of accession source and rank are dependant upon the degree of accepTable deviation from these targets. As stated above we were not able to acquire this information limiting our ability to accurately forecast optimized distribution of accession source or rank. The Markov Model demonstrated that the Nurse Corps current business practices optimize accessions for two year projections. Increasing variation between the current force structure plan and our models projections suggest that greater efficiency could be obtained in the out-years. This Markov Model provides a tool for improving extended forecasts. / Lieutenant Commander, United States Navy

La reconnaissance de mouvements naturels est de toute première importance dans la mise en oeuvre d’Interfaces Homme-Machine intelligentes et efficaces, utilisables de manière intuitive en environnement virtuel. En effet, elle permet à l’utilisateur d’agir de manière naturelle et au système de reconnaitre les mouvements corporel effectués tels qu’ils seraient perçu par un humain. Cette tâche est complexe, car elle demande de relever plusieurs défis : prendre en compte les spécificités du dispositif d’acquisition des données de mouvement, gérer la variabilité cinématique dans l’exécution du mouvement, et enfin gérer les différences morphologiques inter-individuelles, de sorte que les mouvements de tout nouvel utilisateur puissent être reconnus. De plus, de part la nature interactive des environnements virtuels, cette reconnaissancedoit pouvoir se faire en temps-réel, sans devoir attendre la fin du mouvement. La littérature scientifique propose de nombreuses méthodes pour répondre aux deux premiers défis mais la gestion de la variabilité morphologique est peu abordée. Dans cette thèse, nous proposons une description du mouvement permettant de répondre à cette problématique et évaluons sa capacité à reconnaitre les mouvements naturels d’un utilisateur inconnu. Enfin, nous proposons unenouvelle méthode permettant de tirer partie de cette représentation dans une reconnaissance précoce du mouvement / Recognition of natural movements is of utmost importance in the implementation of intelligent and effective Human-Machine Interfaces for virtual environments. It allows the user to behave naturally and the system to recognize its body movements in the same way a human might perceive it. This task is complex, because it addresses several challenges : take account of the specificities of the motion capture system, manage kinematic variability in motion performance, and finally take account of the morphological differences between individuals, so that actions of any new user can be recognized. Moreover, due to the interactive nature of virtual environments, this recognition must be achieved in real-time without waiting for the motion end. The literature offers many methods to meet the first two challenges. But the management of the morphological variability is not dealt. In this thesis, we propose a description of the movement to address this issue and we evaluate its ability to recognize the movements of an unknown user. Finally, we propose a new method to take advantage of this representation in early motion recognition

Thesis advisor: Gabor T. Marth / Background: Due to the rapid development and application of next generation sequencing (NGS) techniques, large amounts of NGS data have become available for genome-related biological research, such as population genetics, evolutionary research, and genome wide association studies. A crucial step of these genome-related studies is the detection of genomic variation between different species and individuals. Current approaches for the detection of genomic variation can be classified into alignment-based variation detection and assembly-based variation detection. Due to the limitation of current NGS read length, alignment-based variation detection remains the mainstream approach. The Smith-Waterman algorithm, which produces the optimal pairwise alignment between two sequences, is frequently used as a key component of fast heuristic read mapping and variation detection tools for next-generation sequencing data. Though various fast Smith-Waterman implementations are developed, they are either designed as monolithic protein database searching tools, which do not return detailed alignment, or they are embedded into other tools. These issues make reusing these efficient Smith-Waterman implementations impractical. After the alignment step in the traditional variation detection pipeline, the afterward variation detection using pileup data and the Bayesian model is also facing great challenges especially from low-complexity genomic regions. Sequencing errors and misalignment problems still influence variation detection (especially INDEL detection) a lot. The accuracy of genomic variation detection still needs to be improved, especially when we work on low- complexity genomic regions and low-quality sequencing data. Results: To facilitate easy integration of the fast Single-Instruction-Multiple-Data Smith-Waterman algorithm into third-party software, we wrote a C/C++ library, which extends Farrar's Striped Smith-Waterman (SSW) to return alignment information in addition to the optimal Smith-Waterman score. In this library we developed a new method to generate the full optimal alignment results and a suboptimal score in linear space at little cost of efficiency. This improvement makes the fast Single-Instruction-Multiple-Data Smith-Waterman become really useful in genomic applications. SSW is available both as a C/C++ software library, as well as a stand-alone alignment tool at: https://github.com/mengyao/Complete- Striped-Smith-Waterman-Library. The SSW library has been used in the primary read mapping tool MOSAIK, the split-read mapping program SCISSORS, the MEI detector TAN- GRAM, and the read-overlap graph generation program RZMBLR. The speeds of the mentioned software are improved significantly by replacing their ordinary Smith-Waterman or banded Smith-Waterman module with the SSW Library. To improve the accuracy of genomic variation detection, especially in low-complexity genomic regions and on low-quality sequencing data, we developed PHV, a genomic variation detection tool based on the profile hidden Markov model. PHV also demonstrates a novel PHMM application in the genomic research field. The banded PHMM algorithms used in PHV make it a very fast whole-genome variation detection tool based on the HMM method. The comparison of PHV to GATK, Samtools and Freebayes for detecting variation from both simulated data and real data shows PHV has good potential for dealing with sequencing errors and misalignments. PHV also successfully detects a 49 bp long deletion that is totally misaligned by the mapping tool, and neglected by GATK and Samtools. Conclusion: The efforts made in this thesis are very meaningful for methodology development in studies of genomic variation detection. The two novel algorithms stated here will also inspire future work in NGS data analysis. / Thesis (PhD) — Boston College, 2014. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

Le vieillissement de la population est un enjeu majeur pour les prochaines années en raison, notamment, de l'augmentation du nombre de personnes dépendantes. La question du maintien à domicile de ces personnes se pose alors, du fait de l'impossibilité pour les instituts spécialisés de les accueillir toutes et, surtout, de la volonté des personnes âgées de rester chez elles le plus longtemps possible. Or, le développement de systèmes technologiques peut aider à résoudre certains problèmes comme celui de la sécurisation en détectant les chutes, et de l'évaluation du degré d'autonomie pour prévenir les accidents. Plus particulièrement, nous nous intéressons au développement des systèmes ambiants, peu coûteux, pour l'équipement du domicile. Les caméras de profondeur permettent d'analyser en temps réel les déplacements de la personne. Nous montrons dans cette thèse qu'il est possible de reconnaître l'activité de la personne et de mesurer des paramètres de sa marche à partir de l'analyse de caractéristiques simples extraites des images de profondeur. La reconnaissance d'activité est réalisée à partir des modèles de Markov cachés, et permet en particulier de détecter les chutes et des activités à risque. Lorsque la personne marche, l'analyse de la trajectoire du centre de masse nous permet de mesurer les paramètres spatio-temporels pertinents pour l'évaluation de la fragilité de la personne. Ce travail a été réalisé sur la base d'expérimentations menées en laboratoire, d'une part, pour la construction des modèles par apprentissage automatique et, d'autre part, pour évaluer la validité des résultats. Les expérimentations ont montré que certains modèles de Markov cachés, développés pour ce travail, sont assez robustes pour classifier les différentes activités. Nous donnons, également dans cette thèse, la précision, obtenue avec notre système, des paramètres de la marche en comparaison avec un tapis actimètrique. Nous pensons qu'un tel système pourrait facilement être installé au domicile de personnes âgées, car il repose sur un traitement local des images. Il fournit, au quotidien, des informations sur l'analyse de l'activité et sur l'évolution des paramètres de la marche qui sont utiles pour sécuriser et évaluer le degré de fragilité de la personne. / Population ageing is a major issue for society in the next years, especially because of the increase of dependent people. The limits in specialized institutes capacity and the wish of the elderly to stay at home as long as possible explain a growing need for new specific at home services. Technologies can help securing the person at home by detecting falls. They can also help in the evaluation of the frailty for preventing future accidents. This work concerns the development of low cost ambient systems for helping the stay at home of elderly. Depth cameras allow analysing in real time the displacement of the person. We show that it is possible to recognize the activity of the person and to measure gait parameters from the analysis of simple feature extracted from depth images. Activity recognition is based on Hidden Markov Models and allows detecting at risk behaviours and falls. When the person is walking, the analysis of the trajectory of her centre of mass allows measuring gait parameters that can be used for frailty evaluation. This work is based on laboratory experimentations for the acquisition of data used for models training and for the evaluation of the results. We show that some of the developed Hidden Markov Models are robust enough for classifying the activities. We also evaluate de precision of the gait parameters measurement in comparison to the measures provided by an actimetric carpet. We believe that such a system could be installed in the home of the elderly because it relies on a local processing of the depth images. It would be able to provide daily information on the person activity and on the evolution of her gait parameters that are useful for securing her and evaluating her frailty

O câncer é atualmente a segunda maior causa de mortalidade no mundo, depois das doenças cardiovasculares. A prevalência de câncer em países em desenvolvimento tem alcançado patamares próximos à registrada em países desenvolvidos. No caso do câncer de mama, há evidências crescentes quanto à influência de inovações em tratamentos oncológicos na chance de sobrevivência de pacientes após diagnóstico e tratamento, assim como em termos de redução do risco de reincidência e melhoria da qualidade de vida durante tratamento. A avaliação de tecnologias em saúde constitui importante instrumento para alocação racional dos recursos escassos em saúde, especialmente no apoio ao cumprimento dos princípios do Sistema Único de Saúde quanto à equidade, integralidade e universalidade no atendimento em saúde da população brasileira. O presente trabalho tem como objetivo geral efetuar uma análise de custo-efetividade no tratamento de pacientes com câncer de mama HER2 positivo inicial e localmente avançado no âmbito do Sistema Único de Saúde (SUS). Os resultados da simulação computacional apontam razão custo-efetividade favorável à quimioterapia adjuvante com trastuzumabe somente caso seja adotado limiar acima de três vezes valor do Produto Interno Bruto (PIB) per capita brasileiro por anos de vida ganhos ou anos de vida ganhos ajustados por qualidade de vida. O presente estudo encontrou resultados similares ao Herceptin Adjuvant (HERA), em que quimioterapia adjuvante com trastuzumabe reduziu recorrência e, particularmente, recorrência à distância, porém a sobrevida global apresentou um acréscimo modesto. Contudo, ainda é necessária extensão da investigação proposta, preferencialmente por meio de avaliação de prontuários de pacientes na rotina em prática clínica que utilizam quimioterapia adjuvante com trastuzumabe / Cancer is currently the second leading cause of death worldwide, behind heart diseases only. The prevalence of cancer in developing countries has been reaching levels close to the ones recorded in developed countries. Regarding breast cancer, there are uprising evidences in terms of the influence on innovations of oncological treatments on the chances of patients to survive after diagnosis and treatment, as in terms of the fall in the risk of recurrence and the improvement on the quality of life during the treatment. The evaluation of health technologies represents an important instrument for the reasonable allocation of the scarce resources in the health system, especially in the endorsement of the compliance of the Unified Health System (UHS) in regards to the equity, integrality and universality of the health care service to the Brazilian people. The goal of this study has as a general objective to analyze the costs and outcomes for the treatment of patients with HER2-positive breast cancer in early and locally advanced stages in the scope of the Unified Health System (UHS). The computer simulation results reveal a favourable cost-effectiveness ratio to the adjuvant chemotherapy with trastuzumab only if the threshold above of three times the Brazilian Gross Domestic product (GDP) per capita is taken according to surviving years or surviving years adjusted by quality of life. This study reflected similar results to Herceptin Adjuvant (HERA), in which adjuvant chemotherapy with trastuzumab reduced recurrence and, particularly, distant recurrence, although global survival presented a modest increase. However, the strech on the proposed investigation is necessary, preferably via reviewing patients\' records in the routine of the clinical practice who are in the use of adjuvant chemotherapy with trastuzumab

O movimento dos lábios é um recurso visual relevante para a detecção da atividade de voz do locutor e para o reconhecimento da fala. Quando os lábios estão se movendo eles transmitem a idéia de ocorrências de diálogos (conversas ou períodos de fala) para o observador, enquanto que os períodos de silêncio podem ser representados pela ausência de movimentações dos lábios (boca fechada). Baseado nesta idéia, este trabalho foca esforços para detectar a movimentação de lábios e usá-la para realizar a detecção de atividade de voz. Primeiramente, é realizada a detecção de pele e a detecção de face para reduzir a área de extração dos lábios, sendo que as regiões mais prováveis de serem lábios são computadas usando a abordagem Bayesiana dentro da área delimitada. Então, a pré-segmentação dos lábios é obtida pela limiarização da região das probabilidades calculadas. A seguir, é localizada a região da boca pelo resultado obtido na pré-segmentação dos lábios, ou seja, alguns pixels que não são de lábios e foram detectados são eliminados, e em seguida são aplicados algumas operações morfológicas para incluir alguns pixels labiais e não labiais em torno da boca. Então, uma nova segmentação de lábios é realizada sobre a região da boca depois de aplicada uma transformação de cores para realçar a região a ser segmentada. Após a segmentação, é aplicado o fechamento das lacunas internas dos lábios segmentados. Finalmente, o movimento temporal dos lábios é explorado usando o modelo das cadeias ocultas de Markov (HMMs) para detectar as prováveis ocorrências de atividades de fala dentro de uma janela temporal. / Lips motion are relevant visual feature for detecting the voice active of speaker and speech recognition. When the lips are moving, they carries an idea of occurrence of dialogues (talk) or periods of speeches to the watcher, whereas the periods of silences may be represented by the absence of lips motion (mouth closed). Based on this idea, this work focus efforts to obtain the lips motion as features and to perform visual voice activity detection. First, the algorithm performs skin segmentation and face detection to reduce the search area for lip extraction, and the most likely lip regions are computed using a Bayesian approach within the delimited area. Then, the pre-segmentation of the lips is obtained by thresholding the calculated probability region. After, it is localized the mouth region by resulted obtained in pre-segmentation of the lips, i.e., some nonlips pixels detected are eliminated, and it are applied a simple morphological operators to include some lips pixels and non-lips around the mouth. Thus, a new segmentation of lips is performed over mouth region after transformation of color to enhance the region to be segmented. And, is applied the closing of gaps internal of lips segmented. Finally, the temporal motion of the lips is explored using Hidden Markov Models (HMMs) to detect the likely occurrence of active speech within a temporal window.

O câncer é atualmente a segunda maior causa de mortalidade no mundo, depois das doenças cardiovasculares. A prevalência de câncer em países em desenvolvimento tem alcançado patamares próximos à registrada em países desenvolvidos. No caso do câncer de mama, há evidências crescentes quanto à influência de inovações em tratamentos oncológicos na chance de sobrevivência de pacientes após diagnóstico e tratamento, assim como em termos de redução do risco de reincidência e melhoria da qualidade de vida durante tratamento. A avaliação de tecnologias em saúde constitui importante instrumento para alocação racional dos recursos escassos em saúde, especialmente no apoio ao cumprimento dos princípios do Sistema Único de Saúde quanto à equidade, integralidade e universalidade no atendimento em saúde da população brasileira. O presente trabalho tem como objetivo geral efetuar uma análise de custo-efetividade no tratamento de pacientes com câncer de mama HER2 positivo inicial e localmente avançado no âmbito do Sistema Único de Saúde (SUS). Os resultados da simulação computacional apontam razão custo-efetividade favorável à quimioterapia adjuvante com trastuzumabe somente caso seja adotado limiar acima de três vezes valor do Produto Interno Bruto (PIB) per capita brasileiro por anos de vida ganhos ou anos de vida ganhos ajustados por qualidade de vida. O presente estudo encontrou resultados similares ao Herceptin Adjuvant (HERA), em que quimioterapia adjuvante com trastuzumabe reduziu recorrência e, particularmente, recorrência à distância, porém a sobrevida global apresentou um acréscimo modesto. Contudo, ainda é necessária extensão da investigação proposta, preferencialmente por meio de avaliação de prontuários de pacientes na rotina em prática clínica que utilizam quimioterapia adjuvante com trastuzumabe / Cancer is currently the second leading cause of death worldwide, behind heart diseases only. The prevalence of cancer in developing countries has been reaching levels close to the ones recorded in developed countries. Regarding breast cancer, there are uprising evidences in terms of the influence on innovations of oncological treatments on the chances of patients to survive after diagnosis and treatment, as in terms of the fall in the risk of recurrence and the improvement on the quality of life during the treatment. The evaluation of health technologies represents an important instrument for the reasonable allocation of the scarce resources in the health system, especially in the endorsement of the compliance of the Unified Health System (UHS) in regards to the equity, integrality and universality of the health care service to the Brazilian people. The goal of this study has as a general objective to analyze the costs and outcomes for the treatment of patients with HER2-positive breast cancer in early and locally advanced stages in the scope of the Unified Health System (UHS). The computer simulation results reveal a favourable cost-effectiveness ratio to the adjuvant chemotherapy with trastuzumab only if the threshold above of three times the Brazilian Gross Domestic product (GDP) per capita is taken according to surviving years or surviving years adjusted by quality of life. This study reflected similar results to Herceptin Adjuvant (HERA), in which adjuvant chemotherapy with trastuzumab reduced recurrence and, particularly, distant recurrence, although global survival presented a modest increase. However, the strech on the proposed investigation is necessary, preferably via reviewing patients\' records in the routine of the clinical practice who are in the use of adjuvant chemotherapy with trastuzumab