Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-04-24T18:48:10Z No. of bitstreams: 1 TeseJSL.pdf: 1918523 bytes, checksum: 4d551d58b97032091209f65b7428e992 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-04-25T18:50:15Z (GMT) No. of bitstreams: 1 TeseJSL.pdf: 1918523 bytes, checksum: 4d551d58b97032091209f65b7428e992 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-04-25T18:50:23Z (GMT) No. of bitstreams: 1 TeseJSL.pdf: 1918523 bytes, checksum: 4d551d58b97032091209f65b7428e992 (MD5) / Made available in DSpace on 2017-04-25T18:59:25Z (GMT). No. of bitstreams: 1 TeseJSL.pdf: 1918523 bytes, checksum: 4d551d58b97032091209f65b7428e992 (MD5) Previous issue date: 2017-01-09 / Não recebi financiamento / In this thesis we propose models based on a reparameterized Birnbaum-Saunder (BS) distribution introduced by Santos-Neto et al. (2012) and Santos-Neto et al. (2014), to analyze survival data. Initially we introduce the Birnbaum-Saunders frailty model where we analyze the cases (i) with (ii) without covariates. Survival models with frailty are used when further information is nonavailable to explain the occurrence time of a medical event. The random effect is the “frailty”, which is introduced on the baseline hazard rate to control the unobservable heterogeneity of the patients. We use the maximum likelihood method to estimate the model parameters. We evaluate the performance of the estimators under different percentage of censured observations by a Monte Carlo study. Furthermore, we introduce a Birnbaum-Saunders regression frailty model where the maximum likelihood estimation of the model parameters with censored data as well as influence diagnostics for the new regression model are investigated. In the following we propose a cure rate Birnbaum-Saunders frailty model. An important advantage of this proposed model is the possibility to jointly consider the heterogeneity among patients by their frailties and the presence of a cured fraction of them. We consider likelihood-based methods to estimate the model parameters and to derive influence diagnostics for the model. In addition, we introduce a bivariate Birnbaum-Saunders distribution based on a parameterization of the Birnbaum-Saunders which has the mean as one of its parameters. We discuss the maximum likelihood estimation of the model parameters and show that these estimators can be obtained by solving non-linear equations. We then derive a regression model based on the proposed bivariate Birnbaum-Saunders distribution, which permits us to model data in their original scale. A simulation study is carried out to evaluate the performance of the maximum likelihood estimators. Finally, examples with real-data are performed to illustrate all the models proposed here. / Nesta tese propomos modelos baseados na distribuição Birnbaum-Saunders reparametrizada introduzida por Santos-Neto et al. (2012) e Santos-Neto et al. (2014), para análise dados de sobrevivência. Incialmente propomos o modelo de fragilidade Birnbaum-Saunders sem e com covariáveis observáveis. O modelo de fragilidade é caracterizado pela utilização de um efeito aleatório, ou seja, de uma variável aleatória não observável, que representa as informações que não podem ou não foram observadas tais como fatores ambientais ou genéticos, como também, informações que, por algum motivo, não foram consideradas no planejamento do estudo. O efeito aleatório (a “fragilidade”) é introduzido na função de risco de base para controlar a heterogeneidade não observável. Usamos o método de máxima verossimilhança para estimar os parâmetros do modelo. Avaliamos o desempenho dos estimadores sob diferentes percentuais de censura via estudo de simulações de Monte Carlo. Considerando variáveis regressoras, derivamos medidas de diagnóstico de influência. Os métodos de diagnóstico têm sido ferramentas importantes na análise de regressão para detectar anomalias, tais como quebra das pressuposições nos erros, presença de outliers e observações influentes. Em seguida propomos o modelo de fração de cura com fragilidade Birnbaum-Saunders. Os modelos para dados de sobrevivência com proporção de curados (também conhecidos como modelos de taxa de cura ou modelos de sobrevivência com longa duração) têm sido amplamente estudados. Uma vantagem importante do modelo proposto é a possibilidade de considerar conjuntamente a heterogeneidade entre os pacientes por suas fragilidades e a presença de uma fração curada. As estimativas dos parâmetros do modelo foram obtidas via máxima verossimilhança, medidas de influência e diagnóstico foram desenvolvidas para o modelo proposto. Por fim, avaliamos a distribuição bivariada Birnbaum-Saunders baseada na média, como também introduzimos um modelo de regressão para o modelo proposto. Utilizamos os métodos de máxima verossimilhança e método dos momentos modificados, para estimar os parâmetros do modelo. Avaliamos o desempenho dos estimadores via estudo de simulações de Monte Carlo. Aplicações a conjuntos de dados reais ilustram as potencialidades dos modelos abordados.

Na literatura da área da análise de sobrevivência existem os modelos tradicionais, ou sem fração de cura, e os modelos de longa duração, ou com fração de cura. Recentemente tem sido proposto um modelo mais geral, conhecido como o modelo com fatores de risco latentes com esquemas de ativação. Nesta tese são deduzidas novas propriedades que possuem a função de sobrevivência, a função de taxa de risco e o valor esperado, quando e considerado o modelo com fatores de risco latentes. Estas propriedades são importantes, já que muitos outros modelos que tem aparecido na literatura recentemente podem ser considerados como casos particulares do modelo com fatores de risco latentes. Além disto, são propostos novos modelos de sobrevivência e estes são aplicados a conjuntos de dados reais. Também é realizado um estudo de simulação e uma análise de sensibilidade, para mostrar a qualidade destes modelos / In the survival literature we can find traditional models without cure fraction and longterm models with cure fraction. A more general risk factor model with latent activation scheme has been recently proposed. In this thesis we deduce new properties for the survival function, hazard function and expected value for this model. Since many recent survival models can be regarded as particular cases of the risk factor model with latent activation scheme these properties are of great relevance. In addition we propose new survival models that are applied to real data examples. A simulation and sensibility analysis are also performed to asses the goodness of fit of these models

Cure rate models, introduced by Boag (1949), are very commonly used while modelling lifetime data involving long time survivors. Applications of cure rate models can be seen in biomedical science, industrial reliability, finance, manufacturing, demography and criminology. In this thesis, cure rate models are discussed under a competing cause scenario, with the assumption of proportional odds (PO) lifetime distributions for the susceptibles, and statistical inferential methods are then developed based on right-censored data. In Chapter 2, a flexible cure rate model is discussed by assuming the number of competing causes for the event of interest following the Conway-Maxwell (COM) Poisson distribution, and their corresponding lifetimes of non-cured or susceptible individuals can be described by PO model. This provides a natural extension of the work of Gu et al. (2011) who had considered a geometric number of competing causes. Under right censoring, maximum likelihood estimators (MLEs) are obtained by the use of expectation-maximization (EM) algorithm. An extensive Monte Carlo simulation study is carried out for various scenarios, and model discrimination between some well-known cure models like geometric, Poisson and Bernoulli is also examined. The goodness-of-fit and model diagnostics of the model are also discussed. A cutaneous melanoma dataset example is used to illustrate the models as well as the inferential methods. Next, in Chapter 3, the destructive cure rate models, introduced by Rodrigues et al. (2011), are discussed under the PO assumption. Here, the initial number of competing causes is modelled by a weighted Poisson distribution with special focus on exponentially weighted Poisson, length-biased Poisson and negative binomial distributions. Then, a damage distribution is introduced for the number of initial causes which do not get destroyed. An EM-type algorithm for computing the MLEs is developed. An extensive simulation study is carried out for various scenarios, and model discrimination between the three weighted Poisson distributions is also examined. All the models and methods of estimation are evaluated through a simulation study. A cutaneous melanoma dataset example is used to illustrate the models as well as the inferential methods. In Chapter 4, frailty cure rate models are discussed under a gamma frailty wherein the initial number of competing causes is described by a Conway-Maxwell (COM) Poisson distribution in which the lifetimes of non-cured individuals can be described by PO model. The detailed steps of the EM algorithm are then developed for this model and an extensive simulation study is carried out to evaluate the performance of the proposed model and the estimation method. A cutaneous melanoma dataset as well as a simulated data are used for illustrative purposes. Finally, Chapter 5 outlines the work carried out in the thesis and also suggests some problems of further research interest. / Thesis / Doctor of Philosophy (PhD)

當造成失敗的原因不只一種時，若各對象同一時間最多只經歷一種失敗原因，則這些失敗原因稱為競爭風險。然而，有些個體不會失敗或者經過治療之後已痊癒，我們稱這部分的群體為治癒群。本文考慮同時處理競爭風險及治癒率的混合模式，即競爭風險的治癒率模式，亦將解釋變數結合到治癒率、競爭風險的條件失敗機率，或未治癒下競爭風險的條件存活函數中，並以建立在完整資料上之擴充的概似函數為貝氏分析的架構。對於右設限對象則以插補方式決定是否會治癒或會因何種風險而失敗，並推導各參數的完全條件後驗分配及其性質。由於邊際後驗分配的數學形式無法明確呈現，再加上需對右設限者判斷其狀態，所以採用屬於馬可夫鏈蒙地卡羅法的Gibbs抽樣法及適應性拒絕抽樣法(adaptive rejection sampling) ，執行參數之模擬抽樣及設算右設限者之治癒或失敗狀態。實證部分，我們分析Klein and Moeschberger (1997)書中骨髓移植後的血癌病患的資料，並用不同模式之下的參數模擬值計算各對象之條件預測指標(CPO)，換算成各模式的對數擬邊際概似函數值(LPML)，比較不同模式的優劣。 / In case that there are more than one possible failure types, if each subject experiences at most one failure type at one time, then these failure types are called competing risks. Moreover, some subjects have been cured or are immune so they never fail, then they are called the cured ones. This dissertation discusses several mixture models containing competing risks and cure rate. Furthermore, covariates are associated with cure rate, conditional failure rate of each risk, or conditional survival function of each risk, and we propose the Bayesian procedure based on the augmented likelihood function of complete data. For right censored subjects, we make use of imputation to determine whether they were cured or failed by which risk and derive full conditional posterior distributions. Since all marginal posterior distributions don’t have closed forms and right censored subjects need to be identified their statuses, we take Gibbs sampling and adaptive rejection sampling of Markov chain Monte Carlo method to simulate parameter values. We illustrate how to conduct Bayesian analysis by using the bone marrow transplant data from the book written by Klein and Moeschberger (1997). To do model selection, we compute the conditional predictive ordinate(CPO) for every subject under each model, then the goodness is determined by the comparing the value of log of pseudo marginal likelihood (LMPL) of each model.

當母體中有部份對象因被治癒或免疫而不會失敗時，需考慮這群對象所佔的比率，即存活分率。本文主要在探討如何以貝氏方法對含存活分率之治癒率模式進行分析，並特別針對兩種含存活分率的迴歸模式，分別是Weibull迴歸模式以及對數邏輯斯迴歸模式，導出概似函數與各參數之完全條件後驗分配及其性質。由於聯合後驗分配相當複雜，各參數之邊際後驗分配之解析形式很難表達出。所以，我們採用了馬可夫鏈蒙地卡羅方法（MCMC）中的Gibbs抽樣法及Metropolis法，模擬產生參數值，以進行貝氏分析。實證部份，我們分析了黑色素皮膚癌的資料，這是由美國Eastern Cooperative Oncology Group所進行的第三階段臨床試驗研究。有關模式選取的部份，我們先分別求出各對象在每個模式之下的條件預測指標（CPO），再據以算出各模式的對數擬邊際概似函數值（LPML），以比較各模式之適合性。 / When we face the problem that part of subjects have been cured or are immune so they never fail, we need to consider the fraction of this group among the whole population, which is the so called survival fraction. This article discuss that how to analyze cure rate models containing survival fraction based on Bayesian method. Two cure rate models containing survival fraction are focused; one is based on the Weibull regression model and the other is based on the log-logistic regression model. Then, we derive likelihood functions and full conditional posterior distributions under these two models. Since joint posterior distributions are both complicated, and marginal posterior distributions don’t have closed form, we take Gibbs sampling and Metropolis sampling of Markov Monte Carlo chain method to simulate parameter values. We illustrate how to conduct Bayesian analysis by using the data from a melanoma clinical trial in the third stage conducted by Eastern Cooperative Oncology Group. To do model selection, we compute the conditional predictive ordinate (CPO) for every subject under each model, then the goodness is determined by the comparing the value of log of pseudomarginal likelihood (LPML) of each model.