Dissertations / Theses on the topic 'Survival curves'

Estimating parameters in a mixture of normal distributions dates back to the 19th century when Pearson originally considered data of crabs from the Bay of Naples. Since then, many real world applications of mixtures have led to various proposed methods for studying similar problems. Among them, maximum likelihood estimation (MLE) and the continuous empirical characteristic function (CECF) methods have drawn the most attention. However, the performance of these competing estimation methods has not been thoroughly studied in the literature and conclusions have not been consistent in published research. In this article, we review this classical problem with a focus on estimation bias. An extensive simulation study is conducted to compare the estimation bias between the MLE and CECF methods over a wide range of disparity values. We use the overlapping coefficient (OVL) to measure the amount of disparity, and provide a practical guideline for estimation quality in mixtures of normal distributions. Application to an ongoing multi-site Huntington disease study is illustrated for ascertaining cognitive biomarkers of disease progression. We also study joint modeling of longitudinal and time-to-event data and discuss pattern-mixture and selection models, but focus on shared parameter models, which utilize unobserved random effects in order to "join" a marginal longitudinal data model and marginal survival model in order to assess an internal time-dependent covariate's effect on time-to-event. The marginal models used in the analysis are the Cox Proportional Hazards model and the Linear Mixed model, and both of these models are covered in some detail before defining joints models and describing the estimation process. Joint modeling provides a modeling framework which accounts for correlation between the longitudinal data and the time-to-event data, while also accounting for measurement error in the longitudinal process, which previous methods failed to do. Since it has been shown that bias is incurred, and this bias is proportional to the amount of measurement error, utilizing a joint modeling approach is preferred. Our setting is also complicated by monotone degeneration of the internal covariate considered, and so a joint model which utilizes monotone B-Splines to recover the longitudinal trajectory and a Cox Proportional Hazards (CPH) model for the time-to-event data is proposed. The monotonicity constraints are satisfied via the Projected Newton Raphson Algorithm as described by Cheng et al., 2012, with the baseline hazard profiled out of the $Q$ function in each M-step of the Expectation Maximization (EM) algorithm used for optimizing the observed likelihood. This method is applied to assess Total Motor Score's (TMS) ability to predict Huntington Disease motor diagnosis in the Biological Predictors of Huntington's Disease study (PREDICT-HD) data.

Thesis (Ph. D.)--Mechanical Engineering, Georgia Institute of Technology, 2007.<br>Rahnema, Farzad, Committee Member ; Hertel, Nolan, Committee Member ; Wang, Chris, Committee Chair ; Radhakrishna, Harish, Committee Member ; Al-Sheikhly, Mohamad, Committee Member.

Grandes avanços tem sido feitos para melhorar a produção de leite, mas estes avanços têm resultado numa queda geral da eficiência reprodutiva. Para se combater esta queda, tem sido seguidos principalmente três caminhos: um relacionado com a vaca, outro com as gametas e outro com o ambiente. Os problemas associados à vaca compreendem os problemas relacionados com a detecção de cio e os problemas hormonais que resultam em baixas taxas de concepção e aumento das mortes embrionárias precoces. Alternativas para melhorar a detecção de cio tem sido procuradas, dentre estas, os medidores de atividade são uma alternativa promissória, porém ainda em desenvolvimento. Com o fim de avaliar a eficiência do uso de medidor de atividade na detecção de cio de vacas leiteiras de alta produção, foram desenvolvidos três experimentos. O primeiro avaliou a eficiência do uso de medidor de atividade na detecção de cio após o período de espera voluntario (PEV), o segundo avaliou a eficiência do uso de medidor de atividade na detecção do cio de retorno após o uso de um protocolo de inseminação artificial a tempo fixo (IATF), o terceiro avaliou a relação custo-benefício da aquisição do aparelho. Na detecção do primeiro cio efetivo após o PEV o medidor de atividade apresentou maior taxa de detecção de cio, comparado com a observação visual de cio. O aparelho mostrou especial avantaja sobre a observação visual de cio na detecção de vacas multíparas de alta produção. No experimento de detecção de cio de retorno após o uso de IATF, o medidor de atividade detectou maior número de animais em menor tempo, porém, as mudanças no padrão de comportamento animal causadas pelos hormônios próprios da sincronização de cio, diminuíram a confiabilidade do sistema automatizado de detecção, ainda assim o numero de animais detectados em cio verdadeiro do sistema automatizado foi superior. Na análise de custo-benefício, a taxa interna de retorno obtida, demonstrou que o medidor de atividade é um investimento rentável o que possibilita sua aquisição. Enquanto aos falsos positivos gerados pelo sistema, sugere-se integrar as indicações feitas pelo sistema automatizado com a experiência dos funcionários das fazendas.<br>Huge progress has been made to improve the milk yield, but these advances have resulted in a general decrease of reproductive efficiency. Three main ways have been taken to combat this decrease: one related to the cow, another with the gametes and the lasts related with the environment. The problems associated with cow comprehend the estrous detection problems and the hormonal disorders that results in low conception rates and increases the early embryonic deaths. Alternatives to improve the heat detection has been developed. Among them, the activity meters are a promissory alternative, but still in development. Three experiments were developed in order to assess the efficiency of use of an activity meter in the estrous detection of high producing dairy cows. The first assessed the efficiency of the use of activity meter detecting estrous after the voluntary waiting period (VWP), the second assessed the efficiency of use of activity meter in the detection of the return estrous after use of a fixed-time artificial insemination (TAI) protocol, the third assessed the cost-benefit of acquisition of the system. In the first estrous after the VWP, the activity meter presented higher estrous detection rate, compared with the visual observation. The system has special vantage in the detection of multiparous high producing cows, if compared with visual observation. In the experiment of detecting return estrous after use of TAI, the activity meter detected greater number of animals in less time, however, changes in the pattern of animal behavior caused by hormones during the synchronization, decreased the accuracy of the automated system. On the other hand, the number of animals detected in real estrous of the automated system was superior than in visual observation. In the cost-benefit analysis, the internal rate of return obtained, showed that the activity meter is a profitable investment. Referent to the false positives generated by the system, it is suggested to integrate the indications made by the automated system with the experience of the functionaries of the dairy farms.

Em um contexto de analise de dados de sobrevivência univariados ou multivariados, dados de tempos de falha caracterizam-se pela possibilidade de poderem ser censurados. Embora comum na pratica, a censura impede o uso de alguns procedimentos estatisticos covencionais o que vem motivando, em especial apos a publicacao do artigo de Cox (1972), o desenvolvimento de metodos estatisticos nessa area. Uma linha de estudo recente e a de que, em algumas situacoes, a variavel resposta esteja sendo inuenciada por variaveis latentes, variaveis estas que sao usadas, em um sentido estatistico, para descreverem efeitos geneticos ou ambientais compartilhados pelos indivduos ou, ainda, covariaveis nao consideradas no estudo. Nesse trabalho, enfase e dada aos modelos de sobrevivencia que consideram tempos de falha multivariados e variaveis latentes. Esses tempos aparecem quando, por exemplo, cada individuo em estudo esta sujeito a diversos eventos ou, quando existe um agrupamento natural ou artificial o qual induz dependencia entre os tempos dos individuos do mesmo grupo. Modelos com variaveis latentes em que tais tempos de falha ocorrem em intervalos de tempo, ou seja, em um contexto de censura intervalar sao especialmente considerados nesse trabalho. O modelo de fragilidade gama para dados de sobrevivencia com censura intervalar e proposto, nesse trabalho, como um criterio para a selecao de bovinos. Como uma alternativa para esta selecao, o modelo de curvas de crescimento com efeitos aleatorios e tambem considerado. Para a estimacao dos parametros envolvidos em ambos os modelos propostos, programas computacionais sao apresentados. Uma abordagem Bayesiana e considerada no processo de estimação sendo, o metodo de Markov chain Monte Carlo (MCMC) utilizado e as distribuicoes a posteriori obtidas, usando-se o amostrador de Gibbs. O modelo de fragilidade gama com censura intervalar e o de curvas de crescimento com efeitos aleatorios sao comparados por meio de um estudo de simulação. Para ilustrar ambos os modelos propostos, estudos com bovinos das racas Nelore e Canchim são utilizados.<br>In a context of univariate or multivariate survival data analysis, failure times data are characterized by the possibility to be censored. Although common in practice, censoring precludes the use of some conventional statistical procedures and it has been motivating, specially after the publication of the Cox's paper (1972), the development of statistical methods in this area. A recent topic of study is concerned with some situations where the response variable is in uenced by latent variables which are used in a statistical sense to describe genetic or environmental efects shared by individuals or also covariates not considered in the study. In this work emphasis is given to survival models which consider multivariate failure times and latent variables. Such times occur when, for instance, each individual under study is exposed to several events or when there is a natural or artificial clustering that causes dependence among times of those individuals at the same cluster. Models with latent variables where such failure times lie in intervals of time, i.e. in an interval censored context are specially considered in this work. The gamma frailty interval censored survival model is proposed in this work as a selection criterion for cattle. As an alternative selection criterion the growth curves model with random efects is also considered. To estimate the involved parameters in both proposed models, computational programs are presented. A Bayesian approach is considered in the estimation process so that the Markov chain Monte Carlo (MCMC) method is used and the posterior distributions are obtained using Gibbs sampling. The gamma frailty interval-censored survival model and the growth curves model with random efects are compared using a simulation study. To illustrate both proposed models studies with Nelore and Canchim cattle are used.

A análise de dados de sobrevivência tem sido tradicionalmente baseada no modelo de regressão de Cox (COX, 1972). No entanto, a suposição de taxas de falha proporcionais assumida para esse modelo pode não ser atendida em diversas situações práticas. Essa restrição do modelo de Cox tem gerado interesse em abordagens alternativas, dentre elas os modelos dinâmicos que permitem efeito das covariáveis variando no tempo. Neste trabalho, foram revisados os principais modelos de sobrevivência dinâmicos com estrutura aditiva e multiplicativa nos contextos não paramétrico e semiparamétrico. Métodos gráficos baseados em resíduos foram apresentados com a finalidade de avaliar a qualidade de ajuste desses modelos. Uma versão tempo-dependente da área sob a curva ROC, denotada por AUC(t), foi proposta com a finalidade de avaliar e comparar a qualidade de predição entre modelos de sobrevivência com estruturas aditiva e multiplicativa. O desempenho da AUC(t) foi avaliado por meio de um estudo de simulação. Dados de três estudos descritos na literatura foram também analisados para ilustrar ou complementar os cenários que foram considerados no estudo de simulação. De modo geral, os resultados obtidos indicaram que os métodos gráficos apresentados para avaliar a adequação dos modelos em conjunto com a AUC(t) se constituem em um conjunto de ferramentas estatísticas úteis para o próposito de avaliar modelos de sobrevivência dinâmicos nos contextos não paramétrico e semiparamétrico. Além disso, a aplicação desse conjunto de ferramentas em alguns conjuntos de dados evidenciou que se, por um lado, os modelos dinâmicos são atrativos por permitirem covariáveis tempo-dependentes, por outro lado podem não ser apropriados para todos os conjuntos de dados, tendo em vista que estimação pode apresentar restrições para alguns deles.<br>Analysis of survival data has been traditionally based on the Cox regression model (COX, 1972). However, the proportionality of the hazards required by this model may not be attended for many practical situations. This restriction of the Cox model has generated interest in alternative approaches, among them dynamic models that allow covariates with time-varying effect. In this work, the main dynamic survival models with additive and multiplicative structures were revised under the nonparametric and semiparametric settings. Graphical methods based on residuals were presented in order to evaluate the goodness-of-fit of these models. A time-dependent version of the area under the ROC curve, denoted by AUC(t), was proposed to evaluate and compare the predictive accuracy of additive and multiplicative survival models. The performance of the AUC(t) was evaluated by means of a simulation study. Data from three studies described in the literature were also analyzed to illustrate or complement the scenarios that were considered in the simulation study. Overall, the results indicate that the graphical methods presented to assess the goodness-of-fit of the models together with the AUC(t) provide a useful set of statistics tools for the purpose of evaluating dynamic survival models in the nonparametric and semiparametric settings. Moreover, applying this set of tools in some data sets showed that on the one hand dynamic models are attractive because they allow time-dependent covariates, but on the other hand they may not be appropriate for all data sets since estimation may present restrictions for some of them.

Neste trabalho estudamos o efeito da exposição de células humanas à radiação ionizante e em associação a campos elétricos exógenos estáticos. A linhagem T47D de células de carcinoma ductal mamário foi irradiada com gamas no intervalo 0 8 Gy. A viabilidade celular da linhagem T47D exposta à radiação gama e campo elétrico estático (CEE) de 1.250 V/cm foi cerca de 12% inferior à viabilidade observada apenas com irradiação. Quando aplicado isoladamente por 24 e 72 horas o CEE não induziu toxicidade. A imunofluorescência realizada na linhagem normal MRC5 (fibroblasto de pulmão humano normal) quantificou a expressão da histona -H2AX. A quantidade de histonas fosforiladas foi cerca de 40% maior após irradiação com 2 Gy mais CEE aplicado por 1h, indicando que o campo elétrico interferiu negativamente no processo de reparo das quebras duplas de DNA. A análise de citometria de fluxo (FACS) mostrou que em células T47D tratadas com 1 e 2 Gy por 24 horas o CEE também interferiu negativamente no processo de reparo do DNA, notadamente pelo maior acúmulo de células na fase S.<br>Our goal is the study in human cells of the effect resulting from the association of irradiation with exposure to exogenous static electric fields. The T47D cell line of breast cancer cells was irradiated with gammas in the 0 8 Gy doses range. The viability of this T47D cells exposed to both gamma radiation and 1.250 V/cm static electric field (SEF) was about 12% lower than when only irradiated. The sole exposure of the cells to SEF by 24 and 72 hours didnt induce toxicity. Immunofluorescence runs carried out in irradiated normal MRC5 cell line of human lung fibroblast have quantified the expression of the g-H2AX histone. The amount of phosphorylated histones was approximately 40% higher after irradiation with 2 Gy plus exposure to a SEF by 1 hour, showing that the electric field negatively interfered in the repairing process of the DNA double strand breaks. The flow cytometry analysis with FACS showed that in T47D cells treated with 1 and 2 Gy by 24 hours the SEF also negatively interfered in the DNA repairing process, as evidenced by the higher accumulation of cells in the S phase.

A principal motivação desta dissertação é um estudo realizado pelo Instituto do Câncer do Estado de São Paulo (ICESP), envolvendo oitocentos e oito pacientes com câncer em estado avançado. Cada paciente foi acompanhado a partir da primeira admissão em uma unidade de terapia intensiva (UTI) pelo motivo de câncer, por um período de no máximo dois anos. O principal objetivo do estudo é avaliar o tempo de sobrevivência e a qualidade de vida desses pacientes através do uso de um tempo ajustado pela qualidade de vida (TAQV). Segundo Gelber et al. (1989), a combinação dessas duas informações, denominada TAQV, induz a um esquema de censura informativa; consequentemente, os métodos tradicionais de análise para dados censurados, tais como o estimador de Kaplan-Meier (Kaplan e Meier, 1958) e o teste de log-rank (Peto e Peto, 1972), tornam-se inapropriados. Visando sanar essa deficiência, Zhao e Tsiatis (1997) e Zhao e Tsiatis (1999) propuseram novos estimadores para a função de sobrevivência e, em Zhao e Tsiatis (2001), foi desenvolvido um teste análogo ao teste log-rank para comparar duas funções de sobrevivência. Todos os métodos considerados levam em conta a ocorrência de censura informativa. Neste trabalho avaliamos criticamente esses métodos, aplicando-os para estimar e testar curvas de sobrevivência associadas ao TAQV no estudo do ICESP. Por fim, utilizamos um método empírico, baseado na técnica de reamostragem bootstrap, a m de propor uma generalização do teste de Zhao e Tsiatis para mais do que dois grupos.<br>The motivation for this research is related to a study undertaken at the Cancer Institute at São Paulo (ICESP), which comprises the follow up of eight hundred and eight patients with advanced cancer. The patients are followed up from the first admission to the intensive care unit (ICU) for a period up to two years. The main objective is to evaluate the quality-adjusted lifetime (QAL). According to Gelber et al. (1989), the combination of both this information leads to informative censoring; therefore, traditional methods of survival analisys, such as the Kaplan-Meier estimator (Kaplan and Meier, 1958) and log-rank test (Peto and Peto, 1972) become inappropriate. For these reasons, Zhao and Tsiatis (1997) and Zhao and Tsiatis (1999) proposed new estimators for the survival function, and Zhao and Tsiatis (2001) developed a test similar to the log-rank test to compare two survival functions. In this dissertation we critically evaluate and summarize these methods, and employ then in the estimation and hypotheses testing to compare survival curves derived for QAL, the proposed methods to estimate and test survival functions under informative censoring. We also propose a empirical method, based on the bootstrap resampling method, to compare more than two groups, extending the proposed test by Zhao and Tsiatis.

Cette thèse porte sur les déterminants de la migration des compétences au Liban, dont l'objet principal est l'identification des facteurs et des risques associés à la migration chez les individus hautement qualifiés. La problématique se résume par la question suivante : À formation universitaire égale, quel diplômé devient-il migrant ? Afin de combler le manque de données sur le sujet, nous avons réalisé une enquête (en ligne) auprès des diplômés de la Lebanese American University et de l'Université Saint-Esprit de Kaslik, au Liban. Ces diplômés forment une pluralité et une mixité culturelle, linguistique et socio-économique représentatives des étudiants du Liban. L'objectif de l'enquête était de comparer les similarités et de contraster les différences entre des diplômés migrants et non-migrants, afin de comprendre les logiques différenciées de leurs comportements migratoires. Au début, nous avons effectué une segmentation des diplômés pour les répartir en sous-groupes en fonction de leur statut migratoire, ce qui nous a permis d'identifier et de comprendre les logiques différenciées de leurs comportements migratoires. L'analyse descriptive des résultats de l'enquête révèle des différences en termes de caractéristiques démographiques, économiques et familiales entre diplômés migrants et non-migrants, mais un peu moins de divergences en ce qui concerne leurs parcours universitaires et le domaine des études. À partir de la modélisation, nous avons démontré comment le risque de migrer à l'étranger peut être déterminé par certains facteurs individuels et familiaux, mais surtout en fonction du temps, c'est-à-dire en fonction de la durée depuis l'obtention du diplôme universitaire le plus élevé. Nous démontrons ainsi que, même à formation universitaire égale, le capital humain et le capital social peuvent engendrer des migrations internationales parmi des diplômés ayant effectué un même parcours universitaire et ayant vécu les mêmes conditions socio-économiques au Liban. Nous examinons également des obstacles qui freinent la migration des compétences, pour finalement analyser brièvement les facteurs qui déterminent la migration de retour au Liban. Sur la base de ces conclusions, nous confirmons que nous avons vérifié nos hypothèses par les faits qui se basent sur les résultats de notre enquête. Malgré la difficulté relative à l'étude des migrations internationales en générale et à l'utilisation de la technique de l'enquête en ligne, nous avons réussi à obtenir des résultats très intéressants, que nous avons comparés à des données disponibles sur la migration des compétences au Liban et à l'échelle globale<br>This thesis focuses on the determinants of the highly skilled migration in Lebanon whose main purpose is to identify factors and risks associated with migration among highly skilled graduates. The research problem is summarized in the following main question: Given equal level of education, which graduate becomes a migrant? To address the lack of data on this particular topic, we conducted a (online) survey on graduates from the Lebanese American University and the Holy Spirit University of Kaslik in Lebanon. Graduates from both universities form diverse cultural, linguistic and socioeconomic characteristics that are representative of Lebanese graduates in general. The aim of the survey was to compare similarities and contrast differences between migrant and non-migrant graduates in order to understand their diverse behavior with regard to migration. Based on survey results, we carried out a segmentation of graduates and divided them into sub-groups based on their migration status allowing us to understand their behavior with regard to migration. The descriptive analysis of the survey results reveals differences in demographic, economic and family characteristics between migrant and non-migrant graduates, but little divergence were found regarding their university studies and the field of education. We also modeled a number of risks associated with migration and we demonstrated that the risk of migrating could be determined by a number of individual and family factors, but mainly over time, i.e. the time since graduation with the highest university degree. We also demonstrate that even at equal level of education, human capital and social capital can determine international migration among graduates who have obtained the same level of education and experienced the same socio-economic conditions in Lebanon. We have also explored barriers that hinder migration among skilled graduates and briefly analyzed the main factors determining their return migration to Lebanon. Based on these findings we confirm that we have validated our assumptions by facts based on survey results. Despite the relative difficulty in the study of international migration in general and the implementation of online surveys, we managed to obtain very interesting results which we also compared to available data on skilled migration in Lebanon and at the global level

Modelos estatísticos com objetivos preditivos são frequentemente aplicados como ferramentas no processo de tomadas de decisão em diversas áreas. Uma classe importante de modelos estatísticos é composta por modelos de análise de sobrevivência. Duas quantidades são de interesse nessa classe: o tempo até o instante do evento de interesse ou o status para um determinado instante de tempo fixado. Aplicações importantes desses modelos incluem a identificação de novos marcadores para certas doenças e definição de qual terapia será mais adequada de acordo com o paciente. Os marcadores utilizados podem ser dados por biomarcadores, assim como por marcadores baseados em modelos de regressão. Um exemplo de marcador baseado em modelos de regressão é dado pelo preditor linear. Ainda que a utilização de modelos de sobrevivência com objetivos preditivos seja de suma importância, a literatura nesse assunto é muito esparsa e não há consenso na forma de se avaliar o desempenho preditivo desses. Esse trabalho pretende reunir e comparar diferentes abordagens de se avaliar o desempenho preditivo de modelos de sobrevivência. Essa avaliação é feita principalmente utilizando-se funções de perda para o tempo de sobrevivência e quantidades associadas a diferentes definições de curva ROC para o status. Para a comparação dessas diferentes metodologias foi feito um estudo de simulação e no final aplicou-se essas técnicas em um conjunto de dados de um estudo do Instituto do Câncer de São Paulo.<br>In many fields, predictive models are often applied as a helpful tool in the decision making process. An important class of predictive models is composed by survival models. Two quantities of special interest in these class are: time until the occurrence of a specified event and survival status for a fixed moment of time. Important applications of these models include new markers identification for certain diseases, as well as defining which therapy is the most appropriated for a patient. Markers can be given by biomarkers, but they can also be derived from regression models. An example of regression models based markers is the linear predictor. Despite the importance of survival models applications with predictive goals, literature is this subject is very sparse and there is no agreement on the best methodology to evaluate predictive performance of these models. In this work we intend to assemble and to compare different methodologies for assessing the predictive performance of survival models. This assessment is made mainly with loss functions for the survival time and ROC curve associated quantities for status. An simulation study was done in order to compare these different methodologies, which were also applied to a study about survival of patients at ICU of ICESP (Instituto do Câncer de São Paulo)

Hot peppers are gaining popularity in the United States as both a vegetable and a spice. In 2008, jalapeño peppers were involved in a multistate outbreak of Salmonella Saintpaul. This is the first outbreak implicating jalapeño as a vehicle for foodborne illness. Hot peppers contain many compounds thought to possess antimicrobial characteristics. This research was conducted to provide more information on the interactions of pathogenic bacteria and jalapeño peppers, as well as to identify properties of Capsicum annuum that affect bacterial survival, growth, and inhibition. Behavior of pathogens associated with jalapeños was investigated by inoculating jalapeño fruits with a cocktail of Listeria monocytogenes, Salmonella enterica, or Escherichia coli O157:H7 on the intact external surface, injured external surface, or intact internal cavity and storing the jalapeños at 7°C or 12°C. Intact external jalapeñosurfaces did not support the growth of the bacteria tested under storage conditions of 7°C. However, L. monocytogenes populations remained detectable throughout the 2 week study. At 7°C, pathogenic bacteria were able to survive but not grow on injured and internally inoculated jalapeño, but populations increased at 12°C (p=0.05). The most supportive growth environment for the pathogenic bacteria was the internal cavity of jalapeño held at 12°C. This study demonstrated the importance of intact uninjured produce and proper storage temperatures for food microbial safety. Inhibitory properties of jalapeños were studied by making extracts from fresh jalapeño peppers to test for antimicrobial activity. A disk diffusion assay determined that the extracts were capable of inhibiting the growth of the pathogenic bacteria tested. Listeria monocytogenes was especially sensitive to the extracts. jalapeño extracts were fractionated using HPLC and used for inhibition assays using disk diffusion and growth curve generation. Two fractions stimulated bacterial growth (p=0.05), while two other fractions inhibited bacterial growth. The inhibitory fractions were separated further using HPLC and tested for antimicrobial activity. Fraction E1 suppressed the growth of L. monocytogenes. HPLC-MS analysis revealed that Fraction E1 contained compounds known as capsianosides. To prove that inhibition is caused by capsianoside(s) and determine minimum inhibitory concentrations, a method to isolate the pure compound should be developed.<br>Ph. D.

The objective of this study was to evaluate the survival of non-O157:H7 STEC, Salmonella spp., and S. aureus in dry fermented sausages. Chorizo and Landjager sausages were inoculated with individual bacterial cocktails and stuffed into natural casings. Temperature, relative humidity, pH, and water activity were monitored through fermentation, drying, and storage. Bacterial counts were determined by serial dilution and plated in triplicates on selective media. Plates were incubated at 37°C for 24 hours and colony forming units per gram (CFU/g) were observed. Results of the first study validate that contaminated raw materials contribute to pathogen survival and background bacteria outcompeted the starter culture. The pH critical limit of < 5.3 was met but there was no pathogen inhibition. Results from the second study confirm that pH and water activity are not enough to eliminate pathogens when post processing interventions are not used. Critical pH (< 5.3) and water activity (< 0.85) limits were met, but pathogens still survived. In chorizo, non-O157:H7 was recovered through enrichments until the end of the study. In landjager, non-O157:H7 STEC and Salmonella were recovered through enrichments until the end of the study.The studies suggest that sausages produced without post processing interventions are a health risk to consumers.

Piglet death during the perinatal and lactation periods is one of the most detectable causes of reduced production efficiency in swine herds. and it has also been identified as an important welfare issue. Piglet mortality within the first three days of life is still a problem in intensive farms. Mortality rates vary between 10 and 20% depending on the housing system. Data used in this study were collected in the nucleus and sib testing program of the C21 Large White boar line (Gorzagri, Fonzaso, Italy) from 2000 to 2006. In the selection nucleus farm (Riese Pio X, Italy) the pure C21 boars are produced and mated to pure C21 sows, while in a sib testing program farm (Todi, Italy), the same C21 boars are mated to crossbred sows to produce crossbred piglets. The general aim of this thesis was to explore the genetic aspects of piglet survival in the aforementioned dry-cured ham-producing crossbred line. In chapter 2 the piglet pre-weaning survival and its relationship with a total merit index (TMI) used for selection of Large White terminal boars for dry-cured ham production was investigated. Piglet pre-weaning survival was analyzed under a frailty proportional hazards model, assuming different baseline hazard functions and including sire and nursed litter as random effects. Estimated hazard ratios (HR) indicated that sex, cross-fostering, year month of birth, parity of the nurse sow, size of the nursed litter and class of TMI were significant effects for piglet pre weaning survival. Female piglets had less risk of dying than males (HR = 0.81) as well as cross-fostered piglets (HR = 0.60). Survival increased when piglets were nursed by sows of third (HR = 0.85), fourth (HR = 0.76) and fifth (HR = 0.79) parity. Piglets of small (HR = 3.90) or very large litters (HR > 1.60) had less chances of surviving in comparison with litters of intermediate size. Class of TMI exhibited an unfavorable relationship with survival (HR = 1.20 for the TMI top class). The modal estimates of sire variance under different baseline hazard functions were 0.06 whereas the variance for the nursed litter was close to 0.7. The estimate of the nursed litter effect variance was higher than the sire, underlying the importance of the common environmental generated by the nurse sow. The relationships between sire ranking obtained from different survival models highly agreed each others. The heritability estimate in equivalent scale was low (0.03). Nevertheless, the exploitable genetic variation for this trait justifies the inclusion of piglet pre-weaning survival in the current breeding program for selection of Large White terminal boars for dry-cured ham-production. In order to evaluate the opportunity of including the survival trait in such breeding programme, the relevance of purebred information for predicting genetic merit of survival at birth of crossbred piglets was assessed (chapter 3). A question is whether purebred performance (in the nucleus) predicts accurately outcomes in crossbreds (commercial tier). This was investigated by considering the two performances as different traits in a model and by estimating the genetic correlation. The objective of chapter 3 was to infer (co)variance components for farrowing survival in purebred (P) and crossbred (C) pigs; the latter were from crosses between P boars and Large White-derived crossbred sows. If the genetic correlation between C and P traits is large enough, selection in P would produce a correlated response in C. Data were from 13,643 (1,213 litters) C and 30,919 (3,162 litters) P pigs, produced by mating the same 168 P boars to 319 Large White derived crossbred females and 1,413 P sows, respectively. The outcome variable was pig survival at birth as a binary trait. A Bayesian bivariate threshold model was implemented via Gibbs sampling. Effects of sex, parity of the dam, litter size and year-month of birth were assigned flat priors; those of litters, dams and sires were given Gaussian prior distributions. Marginal posterior means (SD) of the sire, dam and litter variances in P were 0.018 (0.008), 0.077 (0.020), 0.347 (0.025), respectively in the liability scale. For C, corresponding estimates were 0.030 (0.018), 0.120 (0.034), and 0.189 (0.032), respectively. The posterior means (SD) of heritability of survival in P and C, and of the genetic correlation between these traits were 0.049 (0.023), 0.091 (0.054) and 0.248 (0.336), respectively. Heritability estimates were low and in agreement with previous reports. The genetic correlation was also low, and a 95% Bayesian confidence region (-0.406, 0.821) included zero. Even though variation of estimates is large, results suggest that genetic progress expected in C when selection is based on P may be nil. In chapter 4 different methodologies (proportional hazard, threshold and sequential threshold model) for predicting genetic merit of piglet survival were compared in terms of predictive ability and goodness of fit. Data structure was the same used in chapter 3. A frailty proportional hazard model, assuming two different baseline hazard function (Cox and Weibull) and including sire and nursed litter as a random effects were fitted. The threshold and sequential threshold model considered the same effects. Model fitting was evaluated in terms of goodness-of-fit and predictive ability, using the mean square error as reference parameters. Estimated sire variances for piglet pre-weaning mortality were low, and heritability ranged from 0.04 to 0.06. All four models led to similar ranking for sires, with strong correlation between methods. The sequential threshold model had a better performance for predicting piglet survival but it had a lower performance in terms of goodness-of-fit than Cox model. Results from this study suggest that sequential threshold model may, globally, be better than other methods tested, both for its better predictive ability of piglet survival in genetic evaluations and for its easier interpretation. Further, sequential threshold model is computationally less demanding and can be extended to allow for different variance components by different period from birth to weaning.<br>Gli obiettivi del moderno allevamento suinicolo mirano principalmente a garantire buone performance in termini produttivi e costi di produzione contenuti. Il controllo della mortalità neonatale rappresenta una delle tematiche più attuali, proprio per gli importanti riflessi sul bilancio aziendale. Attualmente, il tasso di mortalità totale sino allo svezzamento può variare dal 18 al 20% sia per la realtà europea che statunitense. Il numero di suinetti annualmente partoriti da una scrofa è probabilmente considerato il carattere riproduttivo più importante, in grado di condizionare il management aziendale e spesso, per tali motivazioni, l’unico ad essere considerato nei programmi di miglioramento genetico di linee suine. In realtà, gli indubbi miglioramenti ottenuti relativamente a questo aspetto sono spesso vanificati da peggioramenti nella capacità di sopravvivenza del suinetto, sia al parto che durante la fase di allattamento. I dati utilizzati in questa tesi sono stati raccolti presso il nucleo di selezione Gorzagri, sito a Riese Pio X (TV, Italia) e il centro genetico, sito a Todi (PG, Italia) e dedicato al programma di sib-testing della linea verri C21. L’attività del centro è finalizzata alla produzione di famiglie di suinetti ibridi, originati dall’accoppiamento di verri C21 e scrofe ibride Goland. Questi suinetti, di costituzione genetica identica all’ibrido Gorzagri allevato negli allevamenti commerciali, producono le informazioni necessarie per la stima del valore genetico e successiva selezione dei verri e scrofe della linea C21. La linea verri C21 è oggetto di attività di selezione secondo obiettivi finalizzati al miglioramento delle performances di allevamento e dell’attitudine alla produzione del prosciutto crudo stagionato DOP. Obiettivi selettivi sono il miglioramento dell’attitudine alla trasformazione industriale della carcassa e della coscia, particolarmente in relazione alla copertura di grasso della coscia e alla sua qualità (numero di iodio e acido linoleico) e alla presenza di difetti della stessa quali la globosità ed il grado di marezzatura della carne. Inoltre, lo schema selettivo mira all’ottenimento di animali omogenei in termini di accrescimento al fine di permettere un’ottimale organizzazione produttiva all’interno degli allevamenti. Recentemente, anche la capacità di sopravvivenza e la robustness del suinetto sono divenuti oggetto di interesse selettivo. I dati di mortalità dei suinetti sino allo svezzamento sono stati raccolti sia presso il nucleo di selezione che presso il centro genetico di Todi a partire dal 2000. Nel primo contributo i dati di sopravvivenza dei suinetti fino allo svezzamento rilevati presso il centro genetico di Todi, sono stati analizzati utilizzando un modello dei rischi proporzionali e testando diverse baseline hazard function. Il tempo di sopravvivenza del suinetto, considerato come l’intervallo tra la nascita e lo svezzamento, è stato analizzato prendendo in esame gli effetti sistematici dovuti al sesso, messa a balia, mese-anno di nascita, ordine di parto della scrofa allattante, dimensione della nidiata e classi di indice genetico standardizzato dei verri. Quest’ultimo si è reso indispensabile per poter apprezzare le relazioni intercorrenti tra obiettivi di selezione della linea verri C21 attualmente perseguiti e sopravvivenza della progenie; nel modello sono stati inclusi anche gli effetti casuali della nidiata e la componente genetico additiva del verro. La mortalità in allattamento dei suinetti ibridi Goland si è attestata intorno al 14% con un tempo di morte medio pari a 6 giorni. L’effetto del sesso è risultato essere un fattore rilevante sulla mortalità in allattamento: le femmine hanno una probabilità di morire del 20% in meno rispetto alla classe di riferimento (maschi). Lo spostamento a balia ha anch’esso un effetto significativo sulla mortalità in allattamento. I soggetti trasferiti dalla madre “biologica” ad una balia presentano una probabilità di morire del 40% inferiore rispetto ai suinetti non spostati (classe di riferimento). Tali risultati confermano l’importanza di questa pratica manageriale, che porta ad una significativa riduzione della mortalità neonatale. Considerando il fattore “ordine di parto della balia”, si è osservato come i suinetti allattati principalmente da balie primipare abbiano manifestato una probabilità di morire superiore rispetto ai suinetti allattati da pluripare. In particolare, si è potuta osservare una diminuzione del rischio di morte fino al quarto ordine di parto, per il quale il rischio di morte si attestava attorno al 75% di quello che caratterizza suinetti nati da scrofe di secondo ordine di parto (considerate in questo caso come riferimento). Considerando la dimensione della nidiata, è stato possibile constatare che la probabilità di morire aumenta in modo significativo per i suinetti allattati in nidiate di dimensioni ridotte (inferiore a 5 suinetti) oppure molto numerose (superiore ai 15 suinetti) rispetto alla classe di riferimento che in questo caso è rappresentata da nidiate costituite da 9-11 suinetti. Nidiate molto numerose comportano una maggiore competizione tra i suinetti per la mammella (difficoltà ad assumere il colostro) e sovraffollamento con maggiore possibilità di schiacciamento. Per quanto riguarda le nidiate di dimensioni ridotte queste sono state osservate, generalmente, in scrofe che hanno avuto una gestazione non regolare. L’effetto dell’anno e della stagione di nascita è risultato essere un effetto altamente significativo, imputabile a fattori di natura climatica, epidemiologica e manageriale esistenti tra il 2000 ed il 2006. Per quanto riguarda l’indice genetico standardizzato dei verri, da questo studio è emerso che i verri con un indice di merito genetico globale superiore rispetto alla media di popolazione, hanno generato progenie, nel corso degli anni oggetto di studio, con un rischio di morte pre-svezzamento superiore a quelli con indice inferiore rispetto alla media di popolazione. Per quanto riguarda la stima della variabilità genetico additiva indotta dal verro e quella ambientale permanente indotta dalla nidiata sulla capacità di sopravvivenza del suinetto, è emerso che l’effetto della nidiata ha una rilevanza maggiore rispetto a quella del verro e mette in evidenza l’importanza dell’effetto ambientale esercitato dalla scrofa allattante. L’ereditabilità stimata per la sopravvivenza è risultata bassa (0.03), in accordo con stime di ereditabilità reperite in bibliografia. Tuttavia la variabilità genetica associata a questa caratteristica è risultata molto elevata e di grado tale da permettere interventi specifici di miglioramento dei verri appartenenti alla linea C21. I risultati ottenuti nell’ambito del presente lavoro sottolineano che la selezione per la diminuzione della mortalità dei suinetti in allattamento può essere perseguita attraverso l’inclusione della capacità di sopravvivenza del suinetto negli obiettivi di selezione della linea C21. Al fine di testare la possibilità di includere il carattere “sopravvivenza” tra gli obiettivi di selezione della linea verri C21, nel secondo contributo si è proceduto alla valutazione dell’importanza delle informazioni fenotipiche provenienti dal nucleo di selezione Gorzagri per la stima del valore riproduttivo della sopravvivenza alla nascita dei suini ibridi allevati presso il centro genetico. Obiettivo specifico di questo lavoro è stato quello di stimare le correlazioni genetiche tra sopravvivenza alla nascita dei suini puri e sopravvivenza alla nascita dei suini ibridi, originati dai medesimi verri della linea pura, in modo da testare la possibilità di introdurre metodologie selettive CCPS (combined crossbred and purebred selection). La stima della correlazione genetico additiva permette di quantificare, in parte, l’entità dell’interazione genotipo – ambiente degli animali allevati presso strutture differenti. Lo studio è stato condotto su 30,919 (3,162 nidiate) suini di linea pura e 13,643 (1,213 nidiate) suini ibridi. Gli animali di linea pura sono stati generati da 168 verri C21 e 1,413 scrofe C21 di linea pura. I suini ibridi, allevati presso il centro genetico di Todi, sono stati generati impiegando gli stessi 168 verri e 319 scrofe ibride di derivazione Large-White. Il carattere analizzato è stato la sopravvivenza alla nascita come carattere categorico (vivo o morto). Per la stima dei parametri genetici è stato fittato un modello statistico bivariato a soglie (threshold model) utilizzando un approccio Bayesiano. Il modello statistico ha considerato l’effetto del sesso, dell’ordine di parto della scrofa, della dimensione della nidiata e l’anno mese di nascita dei suinetti. Per la stima dei parametri del modello sono state adottate, per gli effetti “fissi”, delle flat priors, mentre per l’effetto della nidiata, della scrofa e la componente genetico additiva del verro, sono state adottate delle Gaussian prior distributions. La media della distribuzione marginale a posteriori della componente di varianza del verro, della scrofa e della nidiata nei suini puri è risultata pari a 0.018 (0.008), 0.077 (0.020), 0.347 (0.025), rispettivamente. Per quanto riguarda le stime delle componenti di varianza nei suini meticci, le stime sono risultate pari a 0.030 (0.018), 0.120 (0.034), and 0.189 (0.032), rispettivamente per la componete del verro, della scrofa e della nidiata. L’ereditabilità per sopravvivenza alla nascita nei suini puri e risultata pari a 0.049 (0.023) mentre quella dei meticci 0.091 (0.054). Per quanto riguarda la correlazione genetica tra questi due caratteri (sopravvivenza in soggetti puri e meticci) è risultata pari a 0.248 (0.336). Tuttavia, l’ampia variabilità di stima (95% Bayesian confidence region: -0.406 - 0.821) suggerisce che il progresso genetico atteso, quando la selezione è basata solamente soggetti puri, potrebbe essere nullo. Nel terzo contributo sono state messe a confronto diverse metodologie per la stima del valore riproduttivo della sopravvivenza del suinetto durante la fase di allattamento. Il modello dei rischi proporzionali, assumendo due differenti baseline hazard function (Cox e Weibull), è stato comparato con un thershold e un sequential threshold model, in termini di capacità predittiva del modello (predictive ability) e di goodness of fit. Le stime di ereditabilità sono risultate basse per tutti e quattro i modelli e variabili tra 0.04 e 0.06. Inoltre le stime dei valori riproduttivi dei verri non hanno provocato sostanziali re-ranking dei riproduttori. Tuttavia in termini di capacità predittiva dei modelli, il sequential threshold model ha manifestato le migliori performance e proprio per questo motivo e per la sua facile interpretazione, potrebbe essere proposto come sistema di valutazione genetica da implementare all’interno del programma di selezione della linea verri C21.

Les données de survie en grappes sont souvent recueillies dans le cadre de la recherche médicale. Elles sont caractérisées par des corrélations entre des observations appartenant à un même groupe. Ici, nous discutons des extensions a des données en grappes dans différents contextes : évaluation de la performance d'un biomarqueur candidat, et l’estimation de l'effet du traitement dans une méta-analyse sur données individuels (IPD) avec risques concurrents. La première a été motivée par l'étude IMENEO, une méta-analyse où l'intérêt portait sur la validité pronostique des cellules tumorales circulantes (CTCs). Notre objectif était de déterminer dans quelle mesure les CTCs discriminent les patients qui sont morts de ceux qui ne l'ont pas fait dans les t-années, en comparant des individus ayant le même stade de tumeur. Bien que la courbe ROC dépendante du temps ait été largement utilisée pour la discrimination des biomarqueurs, il n'existe pas de méthodologie permettant de traiter des données en grappes censurées. Nous proposons un estimateur pour les courbes ROC dépendantes du temps et pour l'AUC lorsque les temps d'évènements sont correlés. Nous avons employé un modèle de fragilité partagée pour modéliser l'effet des covariables et du biomarqueur sur la réponse afin de tenir compte de l'effet de la grappe. Une étude de simulation a été réalisée et a montré un biais négligeable pour l'estimateur proposé et pour un estimateur non paramétrique fondé sur la pondération par la probabilité inverse d’être censuré (IPCW), tandis qu'un estimateur semi-paramétrique, ignorant la structure en grappe est nettement biaisé.Nous avons également considéré une méta-analyse IPD pour quantifier le bénéfice de l'ajout de la chimiothérapie à la radiothérapie sur chaque risque concurrent pour les patients avec un carcinome nasopharyngien . Les recommandations pour l'analyse des risques concurrents dans le cadre d'essais cliniques randomisés sont bien établies. Étonnamment, aucune recommendation n'a encore été proposée pour l’anlayse d'une méta-analyse IPD avec les risque concurrents. Pour combler cette lacune, ce travail a détaillé la manière de traiter l'hétérogénéité entre les essais par un modèle de régression stratifié pour les risques concurrents et il souligne que les mesures standardes d'hétérogénéité pour évaluer l'incohérence peuvent facilement être utilisées. Les problèmes typiques qui se posent avec les méta-analyses et les avantages dus à la disponibilité des caractéristiques au niveau du patient ont été soulignées. Nous avons proposé une approche landmark pour la fonction d'incidence cumulée afin d'étudier l'impact du temps de suivi sur l'effet du traitement.L'hypothèse d'une taille de grappe non informative était faite dans les deux analyses. On dit que la taille de grappe est informative lorsque la variable réponse dépend de la taille de grappe conditionnellement à un ensemble de variables explicatives. Intuitivement, une méta-analyse répondrait à cette hypothèse. Cependant, la taille de grappe non informative est généralement supposée, même si elle peut être fausse dans certaines situations, ce qui conduit à des résultats incorrects. La taille des grappes informatives (ICS) est un problème difficile et sa présence a un impact sur le choix de la méthodologie. Nous avons discuté plus en détail de l'interprétation des résultats et des quantités qui peuvent être estimées et dans quelles conditions. Nous avons proposé un test pour l'ICS avec des données en grappes censurées. À notre connaissance, il s'agit du premier test sur le contexte de l'analyse de survie. Une étude de simulation a été réalisée pour évaluer la puissance du test et quelques exemples sont fournis à titre d'illustration.L'implémentation de chacun de ces développements est disponible sur https://github.com/AMeddis<br>Clustered data often arises in medical research. These are characterized by correlations between observations belonging to the same cluster. Here, we discuss some extension to clustered data in different contexts: evaluating the performance of a candidate biomarker, and assessing the treatment effect in an individual patient data (IPD) meta-analysis with competing risks. The former was motivated by the IMENEO study, an IPD meta-analysis where the prognostic validity of the Circulating Tumor Cells (CTCs) was of interest. Our objective was to determine how well CTCs discriminates patients that died from the one that did not within the t-years, comparing individuals with same tumor stage. Although the covariate-specific time dependent ROC curve has been widely used for biomarker's discrimination, there is no methodology that can handle clusteres censored data. We proposed an estimator for the covariate-specific time dependent ROC curves and area under the ROC curve when clustered failure times are detected. We considered a shared frailty model for modeling the effect of the covariates and the biomarker on the outcome in order to account for the cluster effect. A simulation study was conducted and it showed negligible bias for the proposed estimator and a nonparametric one based on inverse probability censoring weighting, while a semiparametric estimator, ignoring the clustering, is markedly biased.We further considered an IPD meta-analysis with competing risks to assess the benefit of the addition of chemotherapy to radiotherapy on each competing endpoint for patients with nasopharyngeal carcinoma. Recommendations for the analysis of competing risks in the context of randomized clinical trials are well established. Surprisingly, no formal guidelines have been yet proposed to conduct an IPD meta-analysis with competing risk endpoints. To fill this gap, this work detailed: how to handle the heterogeneity between trials via a stratified regression model for competing risks and it highlights that the usual metrics of inconsistency to assess heterogeneity can readily be employed. The typical issues that arise with meta-analyses and the advantages due to the availability of patient-level characteristics were underlined. We proposed a landmark approach for the cumulative incidence function to investigate the impact of follow up on the treatment effect.The assumption of non informative cluster size was made in both the analyses. The cluster size is said to be informative when the outcome depends on the size of the cluster conditional on a set of covariates. Intuitively, a meta-analysis would meet this assumption. However, non informative cluster size is commonly assumed even though it may be not true in some situations and it leads to incorrect results. Informative cluster size (ICS) is a challenging problem and its presence has an impact on the choice of the correct methodology. We discussed more in details interpretation of results and which quantities can be estimated under which conditions. We proposed a test for ICS with censored clustered data. To our knowledge, this is the first test on the context of survival analysis. A simulation study was conducted to assess the power of the test and some illustrative examples were provided.The implementation of each of these developments are available at https://github.com/AMeddis

Survival analysis is a statistical discipline that analyzes the time to occurrence of certain events. The aim of this thesis is to describe the possibilities of survival analysis in the environment of statistical software R. Theoretical knowledge is applied to real data, parametric and nonparametric estimates of survival functions are evaluated by different methods and compared with each other. In the section focusing on nonparametric models Kaplan-Meier and Nelson-Aalen functions are described. Among the parametric estimates there were included well-known probability distributions, survival functions and risk functions derived from these distributions are presented and there is discussed their usefulness in survival analysis. Another aim is to show the possibility of deriving transition probabilities from estimates and building a Markov chain model to capture the changes of studied cohort over time. The second part of the work contains a description of the applications of the theory of survival analysis. In this section there are shown possibilities of statistical modeling in the field of survival analysis using the software R. Outputs from R were used to create Markov model. There are presented possibilities of pharmacoeconomic models and description of the basic concepts of HTA. Cost-effectiveness calculations using ICER were conducted in accordance with the methodology of SUKL. It was shown that the statistical modelling of survival plays an important role in the evaluation of the cost-effectiveness of medicines.

Dissertation (Ph.D.)--University of Toledo, 2005.<br>Typescript. "A dissertation [submitted] as partial fulfillment of the requirements of the Doctor of Philosophy degree in Engineering." Bibliography: leaves 69-74.

Selection of signi?cant genes via expression patterns is important in a microarray problem. Owing to small sample size and large number of variables (genes), the selection process can be unstable. This research proposes a hierarchical Bayesian model for gene (variable) selection. We employ latent variables in a regression setting and use a Bayesian mixture prior to perform the variable selection. Due to the binary nature of the data, the posterior distributions of the parameters are not in explicit form, and we need to use a combination of truncated sampling and Markov Chain Monte Carlo (MCMC) based computation techniques to simulate the posterior distributions. The Bayesian model is ?exible enough to identify the signi?cant genes as well as to perform future predictions. The method is applied to cancer classi?cation via cDNA microarrays. In particular, the genes BRCA1 and BRCA2 are associated with a hereditary disposition to breast cancer, and the method is used to identify the set of signi?cant genes to classify BRCA1 and others. Microarray data can also be applied to survival models. We address the issue of how to reduce the dimension in building model by selecting signi?cant genes as well as assessing the estimated survival curves. Additionally, we consider the wellknown Weibull regression and semiparametric proportional hazards (PH) models for survival analysis. With microarray data, we need to consider the case where the number of covariates p exceeds the number of samples n. Speci?cally, for a given vector of response values, which are times to event (death or censored times) and p gene expressions (covariates), we address the issue of how to reduce the dimension by selecting the responsible genes, which are controlling the survival time. This approach enables us to estimate the survival curve when n << p. In our approach, rather than ?xing the number of selected genes, we will assign a prior distribution to this number. The approach creates additional ?exibility by allowing the imposition of constraints, such as bounding the dimension via a prior, which in e?ect works as a penalty. To implement our methodology, we use a Markov Chain Monte Carlo (MCMC) method. We demonstrate the use of the methodology with (a) di?use large B??cell lymphoma (DLBCL) complementary DNA (cDNA) data and (b) Breast Carcinoma data. Lastly, we propose a mixture of Dirichlet process models using discrete wavelet transform for a curve clustering. In order to characterize these time??course gene expresssions, we consider them as trajectory functions of time and gene??speci?c parameters and obtain their wavelet coe?cients by a discrete wavelet transform. We then build cluster curves using a mixture of Dirichlet process priors.

Mestrado em Actuarial Science<br>Os benefícios para a saúde resultantes da prática regular de exercício físico, de uma forma moderada, estão cientificamente comprovados. Contudo, quando se trata de uma abordagem sobre atletas profissionais, os benefícios deixam de ser uma clara evidência, surgindo por vezes sinais de alerta para os seus possíveis efeitos adversos. Para alimentar esta controvérsia, muito têm contribuído os estudos recentes que evidenciam anomalias e doenças cardiovasculares, bem como as frequentes lesões em atletas de elite. É neste contexto que surge o principal objectivo deste trabalho: investigar se os atletas de elite vivem mais do que a população em geral. Após uma profunda revisão literária inicial relativa à mortalidade dos atletas de elite, procede-se a uma análise de sobrevivência que tem como foco dois grupos de jogadores de futebol profissionais. Recolheram-se dados relativos à data de nascimento e morte dos jogadores portugueses e espanhóis que representaram a sua selecção, bem como de outras variáveis de interesse para o estudo. Cada grupo de jogadores é comparado com a população geral do respectivo país, usando dados disponíveis na Human Mortality Database, através da estimação de standardised mortality ratios e de curvas de sobrevivência. O years-lost method é também aplicado, fornecendo uma medida de longevidade dos referidos atletas de elite. Ainda é averiguado se a posição dos jogadores e o número de jogos na sua carreira afectam diferencialmente a mortalidade dos mesmos, através dos Cox Proportional Hazard Models. Por fim, as populações dos jogadores portugueses e espanhóis são comparadas entre si.<br>The health benefits of moderate regular physical activity have been clearly demonstrated and are widely consensual. However, there is a growing debate over the potential adverse effects of strenuous physical activity, particularly at a professional level. Recent findings of cardiovascular anomalies in elite athletes coupled with the high frequency of injuries have brought some sports under increased scrutiny. In this context, the main goal of this work is to investigate whether elite athletes live longer than the general population. After an initial review of the literature on elite athletes' mortality, a comprehensive survival analysis is applied to two populations of professional football players. Lifespan data and specific occupational variables of Portuguese and Spanish football players, who have represented their national teams in their career, were collected from recognized publicly available sources. Each cohort is then compared to the respective standard population, using available data in the Human Mortality Database, through the estimation of standardised mortality ratios and survival curves. The years-lost method is applied to provide a time dimension measure for these elite athletes' longevity. Furthermore, the association of position on the field and the number of games with overall mortality is accessed using Cox Proportional Hazard Models. At the end, a comparison between the mortality of Portuguese and Spanish football players is carried out.<br>info:eu-repo/semantics/publishedVersion

Orientador: Maria Márcia Pereira Sartori<br>Resumo: O estudo da longevidade é uma ferramenta importante na análise da qualidade fisiológica em sementes. A modelagem da curva de sobrevivência em sementes permite a predição do seu período de vida, que baliza os mais variados estudos em conservação e tecnologia de sementes. O modelo de Probit foi inicialmente proposto como o modelo ideal para predição da longevidade das sementes, contudo, estudos têm reportado certa dificuldade de predição do modelo em diferentes condições de estresse e armazenagem a que as sementes são submetidas. A equação da viabilidade em sementes a partir do modelo de Probit permite calcular o valor do P50, que é o período em que um lote de sementes leva para perder 50% da sua viabilidade. O modelo de Logit é similar ao de Probit, com a vantagem de ser mais simples, e de se adequar melhor ao comportamento dos dados com caudas pesadas. Assim, o objetivo deste estudo foi avaliar os modelos de Probit e Logit quanto a sua robustez na predição da longevidade das sementes. Para tanto, sementes de soja foram selecionadas quanto ao seu vigor, em delineamento inteiramente casualizado, e armazenadas à 35°C e 75% de umidade relativa, até que fosse constatada sua morte, por meio de testes de germinação realizados periodicamente. A construção das curvas de sobrevivência, após o experimento encerrado, permitiu a análise dos modelos de Probit e Logit, por meio dos parâmetros R2, Rajustado, e do coeficiente de correlação de Pearson. O estudo da normalidade dos resíduos tamb... (Resumo completo, clicar acesso eletrônico abaixo)<br>Abstract: The study of longevity is an important tool in the analysis of physiological quality in seeds. The modeling of the survival curve in seeds allows the prediction of their half time life, which could be used to reference for the most varied studies on conservation and seed technology. The Probit model was initially proposed as the ideal model for seed longevity prediction, however, studies have reported about some errors found after applying the model under different stress and storage conditions in which seeds are submitted. The seed viability equation from the Probit model allows to calculate the value of P50, which is the period in which a seed lot loss 50% of its viability. The Logit model is similar to the Probit model, with the advantage of being simpler and better suited to heavy tails data, as occurs in seed longevity data. The aim of this study was to evaluate the Probit and Logit models for their robustness in predicting seed longevity. For this purpose, soybean seeds were selected according to their vigor, in a completely randomized design, and stored in 35 °C and 75% relative humidity until their death was verified by periodic germination tests. The construction of survival curves, after the experiment ended, allowed the analysis of Probit and Logit models, through the parameters R2 , Radjusted, and the Pearson correlation coefficient. The study of the normality of the residues was also performed to evaluate the models. The results showed the superiority of the Logi... (Complete abstract click electronic access below)<br>Doutor

Made available in DSpace on 2016-06-02T20:04:52Z (GMT). No. of bitstreams: 1 4552.pdf: 1449121 bytes, checksum: 5d02e70bde72ea9ef3c257c80ceed1dc (MD5) Previous issue date: 2012-05-03<br>Financiadora de Estudos e Projetos<br>In this dissertation we propose new models for survival with cure fraction to describe the biological mechanism of the event of interest (cancer) in studies of carcinogenesis in the presence of competing causes latent independent or correlated. The formulation of new models is based on stochastic modeling of the occurrence of tumors through three stages: initiation of a tumor not detectable, promotion and progression of the tumor to a detectable cancer. These models allow a simple pattern of the dynamics of tumor growth, and incorporate into the analysis features of the stage of tumor progression that is not possible in most survival models with cure fraction commonly used. For the proposed models, the inferential process was discussed in terms of classical and Bayesian point of view. Simulations studies were conducted in order to analyze the asymptotical properties of the classical estimation procedure. Real data applications demonstrate of use of the models.<br>Neste trabalho propomos modelos de sobrevivência com fração de cura para descrever o mecanismo biológico da ocorrência do evento de interesse (câncer) em estudos da carcinogênese na presença de causas competitivas latentes independentes ou correlacionadas. A formulação dos novos modelos é baseada na modelagem estocástica da ocorrência dos tumores através de três estágios: iniciação de um tumor não detectável, promoção e a progressão do tumor até um câncer detectável. Estes modelos permitem um padrão simples da dinâmica de crescimento do tumor, além de incorporarem características do estágio de progressão do tumor, que não é possível na maioria dos modelos de sobrevivência com fração de cura comumente utilizados. Para os modelos propostos, discutimos o processo inferencial do ponto de vista clássico e bayesiano. Estudos de simulações foram feitos com o objetivo de analisar as propriedades assintóticas do processo de estimação clássico. Aplicações a conjuntos de dados reais mostraram a aplicabilidade dos modelos.

碩士<br>國立中正大學<br>數學系統計科學研究所<br>104<br>In biomedical studies, two sample survival curves testing problem is commonly seen. The most popular approach is the log-rank test. However, the log-rank test may lead to misleading results when two survival curves cross each other. Moreover, it is difficult to find an appropriate method for all situations. Hence, we propose an approach, which is the extension of Fisher exact test and two strategies, Strategy 1 and Strategy 2. Then, we conduct simulations to investigate the power and type I error rate and compare the proposed methods with five competitive approaches from Li et al. (2015) under various crossing situations of two survival curves. From the results, we suggest the Strategy 2 for the two survival curves testing problem, which has higher power and appropriate type I error for each situation. Finally, we analyze two real data examples with the proposed methods for illustrations.

The cell survival curve is the only means by which to both qualitatively and quantitatively assess morphologic alterations directly resulting from in vitro irradiation of the cell. A ������Co cell survival curve experiment has successfully demonstrated the response of the AtT-20 clone mammalian cell line to the effects of gamma rays. With the results of this experiment, a low LET radiation cell survival curve now exists to be used as a comparative upon the completion of BNCT cell survival curves.<br>Graduation date: 1995

A research report submitted in partial fulfilment of the requirements for the degree of Masters of Science in Engineering to the Faculty of Engineering and the Built Environment, University of the Witwatersrand, Johannesburg, 2019<br>The report considers survival mechanisms used by Platinum Group Metal (PGM) producers over the period 2008 to 2017 when mining operations were considered marginal for an extended period. Various methods to build cost curves for the PGM industry were tested, with co-product costing, inclusive of sustaining capital, selected. Industry cost curves were developed for the period, showing that a significant portion of producers were marginal from 2014 to 2017, with Impala lease area, Rustenburg mines and Lonmin marginal for more than two years in that period. Survival was achieved through cross-subsidisation, utilising cash reserves, deferring sustaining capital, re-capitalisation and working capital management, before ultimately restructuring through sale or closure took place. While industry cost curves were effective at indicating operational competitiveness in a particular year, a mechanism to indicate relative financial strength (ability to sustain this position) needs to be sought.<br>TL (2020)

碩士<br>國立臺灣大學<br>數學研究所<br>102<br>Benefited from the advanced technology and medical science, more and more effective treatments for different kinds of incurable diseases have been invented. For instance, patients will not die of cancer if the radiation kills all cancer cells, so there are plenty of right-censored data at the end of the observation period. The Kaplan-Meier type estimator of survival curve shows a long and stable plateau in the tail. A characteristic of such survival data is that the survival function does not converge to zero as time goes to infinity. It is called "cure survival data". As a result, using biomarkers to discriminate uncured patients from all subjects becomes an important issue. It is related to the connection between classifications and the true status. Our primary research aim is to extend the application of true positive rate (TPR), false positive rate (FPR), and the area under receiver operating characteristic (ROC) curve (AUC) from classical survival data to cure survival data. And we will analyze the data of an angiography cohort study.

L’Inventaire des risques et des besoins liés aux facteurs criminogènes (IRBC) est un instrument utilisé depuis le début des années 1990 pour évaluer les risques de récidive des jeunes contrevenants québécois. Il est le produit d’une collaboration du Québec avec l’Ontario, survenue dans le cadre de travaux de recherche effectués sur les instruments d’évaluation du risque de récidive des jeunes contrevenants. L’IRBC est donc le seul instrument précisément conçu pour évaluer les risques de récidive des jeunes contrevenants québécois et il n’a jamais fait l’objet d’une démarche visant à tester sa validité prédictive. Le but de ce projet de mémoire est de tester la validité prédictive de l’IRBC. Des analyses de courbes ROC et des analyses de survie ont été utilisées pour tester les propriétés métriques de l’instrument. Ces analyses suggèrent que, dans l’ensemble, l’IRBC arrive à prédire la récidive de façon acceptable. Quatre des huit grands domaines associés à la récidive, communément appelé BIG FOUR, seraient des prédicteurs modérés de la récidive lorsque testés avec les données issues de l’IRBC. Il s’agit des domaines Antécédents, Pairs, Personnalité-Comportements, et Attitudes-Tendances. Des aspects en lien avec la fidélité de l’instrument témoignent toutefois d’irrégularités dans le processus d’évaluation, ce qui interroge le niveau de rigueur maintenu au jour le jour par les professionnels. Des aspects en lien avec la fidélité de l’IRBC demeureraient à investiguer.<br>The Inventaire des risques et des besoins liés aux facteurs criminogènes (IRBC) is a test used since the early 1990s to assess young offenders’s risk of recidivism in Quebec. It is the product of a collaboration between Quebec and Ontario which occurred in the context of research work on instruments used to evaluate young offenders’s risk of recidivism. The IRBC is the only instrument specifically designed to assess the risk of recidivism of young offenders in Quebec and has never been subject of a predictive validity study. The aim of this master project is to test the predictive validity of the IRBC. ROC curves analysis and survival analysis were used to test the metric properties of the instrument. The results suggest that overall the IRBC is capable of predicting recidivism acceptably. Four of the eight domains associated with criminal recidivism, commonly called BIG FOUR, would be moderate predictors of recidivism when tested with data from the IRBC. These are Antécédents, Pairs, Personnalité-Comportements, and Attitudes-Tendances. However, aspects related to the fidelity of the instrument show irregularities in the assessment process, which questioned the rigor maintained daily by professionals. Aspects related to the fidelity of the IRBC would remain to be investigated.

Statistical models are often used for the prediction of future random variables. There are two types of prediction, point prediction and probabilistic prediction. The prediction accuracy is quantified by performance measures, which are typically based on loss functions. We study the estimators of these performance measures, the prediction error and performance scores, for point and probabilistic predictors, respectively. The focus of this thesis is to assess the prediction performance of survival models that analyze censored survival times. To accommodate censoring, we extend the inverse probability censoring weighting (IPCW) method, thus arbitrary loss functions can be handled. We also develop confidence interval procedures for these performance measures. We compare model-based, apparent loss based and cross-validation estimators of prediction error under model misspecification and variable selection, for absolute relative error loss (in chapter 3) and misclassification error loss (in chapter 4). Simulation results indicate that cross-validation procedures typically produce reliable point estimates and confidence intervals, whereas model-based estimates are often sensitive to model misspecification. The methods are illustrated for two medical contexts in chapter 5. The apparent loss based and cross-validation estimators of performance scores for probabilistic predictor are discussed and illustrated with an example in chapter 6. We also make connections for performance.

碩士<br>臺灣大學<br>流行病學研究所<br>98<br>Although the concept and method of treating cancer have substantial improvement in recent years, there is limited improvement in treatment of esophageal cancer. Radical esophagectomy is still the mainstay for the resectable esophageal cancer, which provided the chance for long-term survival and better local control rate. However, the five-year survival is still low for esophagectomy, which is only 0~10%. Current trend of treatment in locally advanced esophageal cancer is tri-modality treatment (neoadjuvant chemoradiotherapy and surgery). Over ten randomized controlled tries have been conducted to elucidate the following question:” Is tri-modality treatment better than surgery alone?” However, as the results of these trials are not consistent the clinical decision-makers are puzzled. More importantly, one of reasons accounting for the discrepancy of results is attributed to the cross-over phenomenon of neoadjuvant therapy. The current thesis aimed to investigate this issue. We first generated the data from randomized controlled trials by using the simulation approach. We assessed the proportional hazard assumption of these trials by checking the cross-over of survival with time-dependent Cox regression model. We also tried to conduct a meta-analysis to get the pooled estimates by three categories in the light of presence of cross-over phenomenon. It is found that relative risk of death between two groups changed by different follow-up times. Only Walsh and Tepper’s study fitted the proportional hazard assumption. After using time-dependent Cox regression model, we found that we could divide the nine trials into three groups: no cross-over, positive cross-over and negative cross-over. The time dependent variables were not statistically significant in individual trial. However, in pooled analysis, the time-dependent interaction term was statistically significant in pooled negative cross-over group (p=0.027) and marginally statistically significant (p=0.10) in positive cross-over group. All results show that the hazard ratio of treatment group varied with time. We conclude it is inappropriate to use log-rank test or the time-independent Cox-regression model before testing whether the cross-over survival exists.

L’intérêt porté à l’évaluation du risque de récidive chez les délinquants ayant une déficience intellectuelle (DI) a notablement augmenté depuis les 10 dernières années. D’ailleurs, certains croient que les instruments utilisés pour mesurer le risque chez les auteurs d’infractions sexuelles neurotypiques peuvent s’appliquer aux auteurs d’infractions sexuelles ayant une DI tandis que d’autres appuient l’idée d’utiliser et de développer des mesures actuarielles propres à ces individus. Trois objectifs ont été posés pour tenter d’éclaircir ces deux visions, soit 1) Comparer les taux de récidive entre les deux groupes d’auteurs d’infractions sexuelles (ayant une DI et neurotypiques), en plus de déterminer lequel récidive plus rapidement sur une courte période de temps, 2) Analyser la validité prédictive de huit instruments actuariels (et de la PCL-R) auprès d’un échantillon d’auteurs d’infractions sexuelles ayant une DI et 3) Analyser la composition des instruments par domaines (Knight et Thornton, 2007). L’échantillon est composé de 550 auteurs d’infractions sexuelles dont 54 ont une DI. Les résultats suggèrent que les deux groupes d’auteurs d’infractions sexuelles (neurotypiques et ayant une DI) présentent des taux de récidive similaires. Un nombre restreint d’instruments semblent par contre efficaces chez les auteurs d’infractions sexuelles ayant une DI. De ce fait, le SVR-20 s’est révélé avoir une validité prédictive pour la récidive sexuelle, le RMC, le RMV et le MnSOST-R pour la récidive violente et le VRAG pour la récidive non violente. Il est toutefois justifié de se questionner sur la manière d’évaluer le risque chez cette clientèle particulière. L’analyse de la composition des instruments semble importante puisque certains domaines pourraient prédire différemment la récidive chez les auteurs d’infractions sexuelles ayant une DI. Une grande partie des facteurs pouvant être utiles dans la prédiction de la récidive ne semblent toujours pas avoir été identifiés, repoussant ainsi la création d’instruments propres aux délinquants ayant une DI.<br>Interest in the risk assessment for offenders with intellectual disabilities (ID) has particularly grown during the last 10 years. Two opinions are shared on this subject: some believe that the instruments used to measure risk in sexual offenders can apply to sexual offenders with ID while others support the idea of using and developing actuarial measures for these people. Three objectives were set in an attempt to clarify these two visions: 1) Compare recidivism rates between the two groups of sexual offenders (with and without ID), 2) Analyze the predictive validity of the eight most commonly used actuarial instruments (and the PCL-R) based on a sample of sex offenders with ID and 3) Analyze the composition of the instruments according to their domains (Knight and Thornton, 2007). The sample consisted of 550 sex offenders of which 54 have an ID. The results suggest that the two groups of sexual offenders have similar rates of recidivism. A limited number of instruments also seems to be effective for sex offenders with ID. The SVR-20 was found to have predictive validity regarding sexual recidivism, the RMC, the RMV and the MnSOST-R for violent recidivism and the VRAG for non-violent recidivism. However, it is justified to question how the risk of recidivism is assessed for this particular clientele. The composition analysis of the actuarial instruments seems important among sex offenders with ID since some domains could predict differently the risk of recidivism. Finally, many of the risk factors that may be more useful in predicting recidivism has not been identified yet, thus delaying the creation of instruments tailored to offenders with ID.

碩士<br>逢甲大學<br>統計與精算所<br>97<br>The applicative device of the similarity indices in estimating survival curve in the Jolly-Seber model through open capture-recapture experiment is the main purposes of this proposal. Survival curve is the trend line of the survival rate for a long time, different from the survival rate in Jolly-Seber models. Similarity indices are widely used in the ecological study. Differ from the similarity indices of any two communities, the similarity indices in this proposal are used to derive the estimation of any two strata in different sampling. In open capture-recapture experiment, Jolly-Seber model with its three sub-models are the most popular models in present. Many methods about estimation of survival rate in the Jolly-Seber model were reviewed in the proposal, and these estimations of survival rate are still difficult. And using survival rate to estimate survival curve is also difficult and unsuitable. In order to find a simpler method about estimation of survival curve, we try to analyze the change in similarity indices of any two strata. The estimation of survival curve in the Jolly-Seber model can be derived in a convenient way. We also use the simulation method to check the performance of the estimation, and the Lanyu Scops Owls data is applied in the data analysis. All the work will be stated in the paper.

Health technology assessment: case study on breast carcinoma treatment in the Czech Republic Bc. Lenka Šlegerová January 4, 2019 Abstract This thesis proposes an original method for assessing total costs of med- ical treatment. It defines the semi-Markov model with four states that are associated with specific costs of the treatment, and not with patients' health statuses. This method is applied to individuals' treatment data drawn from the Czech clinical practice in the treatment of the metastatic HER2+ breast cancer. The aim is to assess the cost-effectiveness of adding medication per- tuzumab to the combination of trastuzumab+docetaxel within first-line therapy and to examine whether using individual data on Czech patients and the economic conditions leads to different results from foreign stud- ies. Furthermore, employing censored data from the clinical practice in the thesis complicates the estimation of patients' overall survival in compari- son to clinical-trials data that form random samples. Therefore, survival functions were not only estimated by the Kaplan-Meier estimator but also using the Cox proportional hazard model and the Accelerated failure time model that both control for the effects of included covariates. The addition of pertuzumab does not result in significantly longer pa- tients'...

Huit instruments d’évaluation du risque ont été appliqués sur 580 délinquants sexuels. Il s’agit du VRAG, du SORAG, du RRASOR, de la Statique-99, de la Statique-2002, du RM-2000, du MnSORT-R et du SVR-20. De plus, les sujets ont été cotés sur la PCL-R, qui vise la mesure de la psychopathie, mais qui a fait ses preuves en matière de prédiction de la récidive (Gendreau, Little, et Goggin, 1996). En vue de mesurer l’efficacité de ces instruments et de la PCL-R, une période de suivi de 25 ans a été observée. Aussi, une division de l’échantillon a été faite par rapport à l’âge au moment de la libération, afin de mesurer les différences entre les délinquants âgés de 34 ans et moins et ceux de 35 ans et plus. Le présent travail vise à répondre à trois objectifs de recherche, soit 1) Décrire l’évolution du risque en fonction de l’âge, 2) Étudier le lien entre l’âge, le type de délinquant et la récidive et 3) Comparer l’efficacité de neuf instruments structurés à prédire quatre types de récidive en fonction de l’âge. Les résultats de l’étude suggèrent que l’âge influence le niveau de risque représenté par les délinquants. Par ailleurs, les analyses des différents types de récidive indiquent que le type de victime privilégié par les délinquants influence également ce niveau de risque. Les implications théoriques et pratiques seront discutées.<br>Eight evaluation techniques demonstrating high risk sexual offenders has been taken upon 580 individual sexual offenders. They are among the VRAG, the SORAG, the RRASOR, the Static-99, the Static-2002, the RM-2000, the MnSORT-R ans the SVR-20. Also, the subjects have been quoted according to the PCL-R, which focuses on their mental health, however supporting the quotes by prediction and relaps (Gendreau, Little, et Goggin, 1996). With the ongoing measuring of the suitability of these instruments as well as the PCL-R, it will take a period of 25 years for the observance. As well, a group of subjects have been studied from the age they were let out of prison, to come up with conclusions differentiating the offenders aging 34 and less with the offenders aging 35 and older. The present work on this subject matter hopes to focus on three research objectives: 1) Describe the evolution of risk according to the age, 2) To study the common point between age, they type of offender, and their relaps, and 3) To compare the suitability of 9 instruments the predict 4 types of relaps according to their age. The study results suggest that age affects the level of risk posed by offenders. Furthermore, analyses of different types of recidivism indicate that the preferred type of victim offender also influences the level of risk. The theoretical and practical implications are discussed.

<p>Modeling microbial inactivation has a great influence on the optimization, control and design of food processes. In the area of food safety, modeling is a valuable tool for characterizing survival curves and for supporting food safety decisions. The modeling of microbial behavior is based on the premise that the response of the microbial population to the environment factors is reproducible. And that from the past, it is possible to predict how these microorganisms would respond in other similar environments. Thus, the use of mathematical models has become an attractive and relevant tool in the food industry.</p> <p>This research provides tools to relate the inactivation of microorganisms of public health importance with processing conditions used in nonisothermal and non-thermal food processing technologies. Current models employ simple approaches that do not capture the realistic behavior of microbial inactivation. This oversight brings a number of fundamental and practical issues, such as excessive or insufficient processing, which can result in quality problems (when foods are over-processed) or safety problems (when foods are under-processed). Given these issues, there is an urgent need to develop reliable models that accurately describe the inactivation of dangerous microbial cells under more realistic processing conditions and that take into account the variability on microbial population, for instance their resistance to lethal agents. To address this urgency, this dissertation focused on mathematical models, combined mathematical tools with microbiological science to develop models that, by resembling realistic and practical processing conditions, can provide a better estimation of the efficacy of food processes. The objective of the approach is to relate the processing conditions to microbial inactivation. The development of the modeling approach went through all the phases of a modeling cycle from planning, data collection, formulation of the model approach according to the data analysis, and validation of the model under different conditions than those that the approach was developed.</p> <p>A non-linear ordinary differential equation was used to describe the inactivation curves with the hypothesis that the momentary inactivation rate is not constant and depends on the instantaneous processing conditions. The inactivation rate was related to key process parameters to describe the inactivation kinetics under more realistic processing conditions. From the solution of the non-linear ordinary differential equation and the optimization algorithm, safety inferences in the microbial response can be retrieved, such as the critical lethal variable that increases microbial inactivation. For example, for nonisothermal processes such as microwave heating, time-temperature profiles were modeled and incorporated into the inactivation rate equation. The critical temperature required to increase the microbial inactivation was obtained from the optimization analysis. For non-thermal processes, such as cold plasma, the time-varying concentration of reactive gas species was incorporated into the inactivation rate equation. The approach allowed the estimation of the critical gas concentration above which microbial inactivation becomes effective. For Pulsed Electric Fields (PEF), the energy density is the integral parameter that groups the wide range of parameters of the PEF process, such as the electric field strength, the treatment time and the electrical conductivity of the sample. The literature has shown that all of these parameters impact microbial inactivation. It has been hyphothesized that the inactivation rate is a function of the energy density and that above a threshold value significant microbial inactivation begins. </p> <p>The differential equation was solved numerically using the Runge-Kutta method (<i>ode45</i> in MATLAB ®). The<i> lsqcurvefit</i> function in MATLAB ® estimated the kinetic parameters. The approach to model microbial inactivation, whether when samples were subjected to nonisothermal or to non-thermal food processes, was validated using data published in the literature and/or in other samples and treatment conditions. The modeling approaches developed by this dissertation are expected to assist the food industry in the development and validation process to achieve the level of microbial reduction required by regulatory agencies. In addition, it is expected to assist the food industry in managing food safety systems through support food safety decision-making, such as the designation of the minimal critical parameter that may increase microbial inactivation. Finally, this dissertation will contribute in depth to the field of food safety and engineering, with the ultimate outcome of having a broad and highly positive impact on human health by ensuring the consumption of safe food products.</p>

Esta dissertação assentou em investigar o percurso escolar dos alunos dos quatro Cursos Técnicos Superiores Profissionais (CTeSP) (Agricultura Biológica, Contabilidade e Fiscalidade, Redes e Siste mas Informáticos e Guias da Natureza) da Escola Superior de Tecnologias e Gestão da UMa, entre os anos letivos 2015/2016 e 2019/2020. Numa primeira vertente foi feita uma análise descritiva dos dados com base em indicadores de três dimensões: social, pessoal e escolar. Em seguida, aplicou-se a teoria da Análise de Sobrevivência ao tempo que os alunos levam até concluir o curso. Da análise univariada efetuada às 15 variáveis presentes do estudo, verificámos que as variáveis CTeSP, ano letivo de início, ex-aluno, apoio social e trabalhador-estudante se mostraram significativas ao nível de significância 5%, em relação ao tempo até à conclusão do curso. No que se refere ao modelo de Cox, verificou-se que os antigos alunos da UMa apresentam um menor risco em terminar o curso (36,10% inferior) comparativamente aos alunos que nunca o foram. Os alunos com apoio social apresentam uma tendência positiva no seu desempenho comparativamente aos que não o têm e, por fim, comparando o CTeSP em Guias da Natureza com os restantes, verificou-se que os alunos que ingressaram nos CTeSP em Contabilidade e Fiscalidade e em Redes e Sistemas Informáticos, apresentam um risco de terminar o curso de 68,32% e 126,27%, respetivamente, superior. No caso do CTeSP em Agricultura Biológica, o risco é o mesmo. Assim, estas três covariáveis demonstraram ter um forte impacto no tempo de duração de um curso.<br>This dissertation was based on investigating the academic trajectory of students from the four Higher Technical Professional Courses (CTeSP) (Biological Agriculture, Accounting and Taxation, Networks and Computer Systems and Nature Guides) of the UMa School of Technology and Mana gement, between academic years 2015/2016 and 2019/2020. In the first aspect, a descriptive analysis of the data was carried out based on indicators of three dimensions: social, personal and school. Then, the Survival Analysis theory was applied to the time it takes students to complete the course. From the univariate analysis performed on the 15 variables present in the study, we found that the variables CTeSP, starting school year, ex-student, social support and student-worker were significant at the 5% significance level, in relation to the time until completion of the course. With regard to the Cox model, it was found that former UMa students have a lower risk of finishing the course (36,10% lower) compared to students who have never been. Students with social support show a positive trend in their performance compared to those who do not and, finally, comparing the CTeSP in Nature Guides with the others, it was found that students who joined the CTeSP in Accounting and Taxation and Computer Networks and Systems, present a higher risk of finishing the course of 68,32% and 126,27%, respectively, higher. In the case of CTeSP in Organic Agriculture, the risk is the same. Thus, these three covariates have been shown to have a strong impact on the duration of a course.