Foram analisados 50 casos de osteossarcoma não metastáticos das extremidades tratados no Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo entre 1986 e 2006 no que se refere à expressão de VEGF. Dezenove pacientes do sexo feminino e 31 do sexo masculino foram a casuística do trabalho. A idade variou de 5 a 28 anos (média de 16 anos) e o seguimento dos pacientes variou de 25 a 167 meses (média de 60,6 meses). As variáveis estudadas foram idade, sexo, localização anatômica, tipo de cirurgia, margens cirúrgicas, tamanho do tumor, necrose pós QT, recidiva local, metástase pulmonar e óbito. Trinta e seis pacientes apresentaram expressão de VEGF menor ou igual a 30% das células tumorais (baixa expressão), ao passo que os 14 restantes apresentaram expressão acima de 30% das células (alta expressão). Dos 36 pacientes com baixa expressão de VEGF, nove evoluíram com metástases pulmonares, dos quais quatro foram a óbito (11,1%). Dentre os 14 casos com alta expressão de VEGF, seis evoluíram com metástases pulmonares e três foram a óbito (21,4%). Porém, não houve correlação estatisticamente significante entre a expressão de VEGF e qualquer das variáveis estudadas / Fifty cases of nonmetastatic osteosarcoma of the extremities treated between 1986 and 2006 at the Instituto de Ortopedia e Traumatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo were evaluated regarding the expression of VEGF. There were 19 females and 31 males. The mean age was 16 years (528) and the mean followup was 60,6 months (25 167). The variables studied were age, gender, anatomic location, type of surgery, surgical margins, tumor size, post chemotherapy necrosis, local recurrence, pulmonary metastasis and death. Thirtysix patients showed VEGF expression equal or under 30% of the cells (low expression), as the remaining 14 cases had VEGF expression above 30% (high expression). Among the 36 patients with low VEGF expression, nine developed pulmonary metastasis and four died (11,1%). Among the 14 patients with high VEGF expression, six developed pulmonary metastasis and three died (21,4%). There was no statistical significant correlation between the VEGF expression and any of the variables studied

Neste trabalho considera-se uma reparametrização no modelo log-gama generalizado para a inclusão de dados com sobreviventes de longa duração. Os modelos tentam estimar separadamente os efeitos das covariáveis na aceleração ou desaceleração no tempo e na fração de sobreviventes que é a proporção da população para o qual o evento não ocorre. A função logística é usada para o modelo de regressão com fração de cura. Os parâmetros do modelo, serão estimados através do método de máxima verossimilhança. Alguns métodos de influência, como a influência local e a influência local total de um indivíduo, serão introduzidos, calculados, analisados e discutidos. Finalmente, um conjunto de dados médicos será analisado sob o modelo log-gama generalizado com fração de cura. Uma análise de resíduos será executada para verificar a qualidade de ajuste do modelo. / In this work the generalized log-gama model is modified for possibility that long-term survivors are present in the data . The models attempt to estimate separately the effects of covariates on the accelaration/decelaration of the timing of a given event and surviving fraction; that is, the proportion of the population for which the event never occurs. The logistic function is used for the regression model of the surviving fraction. Inference for the model parameters is considered via maximum likelihood. Some influence methods, such as the local influence, total local influence of an individual are derived, analyzed and discussed. Finally, a data set from the medical area is analyzed under log-gama generalized mixture model. A residual analysis is performed in order to select an appropriate model.

Orientador: Hildete Prisco Pinheiro / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Matemática, Estatística e Computação Científica / Made available in DSpace on 2018-08-24T02:10:38Z (GMT). No. of bitstreams: 1 Argenton_JulianaLuzPassos_M.pdf: 2087574 bytes, checksum: b6014c3478501f5128fd13ddf952e6dd (MD5) Previous issue date: 2013 / Resumo: O objetivo deste trabalho é apresentar uma metodologia de árvore de regressão para dados censurados e correlacionados. O conjunto de dados analisado foi obtido a partir de uma pesquisa realizada entre Dezembro de 2005 e Janeiro de 2006, que entrevistou 119 famílias (1712 indivíduos) que vivem no pequeno vilarejo de Baependi, no Estado de Minas Gerais. São apresentadas duas metodologias com base no modelo de riscos proporcionais, a primeira desconsidera a possível correlação existente entre os indivíduos de uma mesma família e usa a primeira iteração da estimativa da verossimilhança completa nas divisões dos nós. Na segunda metodologia apresentada, a correlação entre os indivíduos de uma mesma família é incorporada no modelo de riscos proporcionais através de uma variável de fragilidade com distribuição Gama, neste caso o valor da estatística Escore é usado para escolher a melhor divisão dos nós. O objetivo da análise é avaliar as variáveis que aumentam o risco de apresentar hipertensão, diabetes tipo II e colesterol alto, que são os três principais fatores que aumentam o risco de doenças no coração. As variáveis respostas são as idades de diagnóstico desses fatores de risco. A censura é definida de acordo com a observação da idade do indivíduo no momento do diagnóstico da doença e a idade do indivíduo no momento da pesquisa. Desta forma, uma idade de diagnóstico maior que a idade no momento da pesquisa caracteriza a censura. / Abstract: The objective of this work is to present methods of regression trees for censored and correlated data. The dataset analyzed was obtained from a survey, in which 119 families (1712 individuals) living in Baependi village, in the Brazilian state of Minas Gerais, were interviewed. Two methodologies based on the proportional hazard model are presented. The first disregards the possible correlation among the individuals of the same family, using the first step of a full likelihood estimation procedure for splitting nodes. In the second methodology, the correlation among the individuals of the same family is incorporated in the proportional hazard model through a frailty variable with Gamma distribution. In this case, the value of the Score statistic is used for choosing the best splitting node. The main purpose of the analysis is to evaluate the variables that increase the risk of hypertension, type II diabetes and high cholesterol, which are the top three main factors that increase the risk of heart conditions. The response variables are the age-of-onset of these risk factors. Censoring is defined by observing the individual's age-of-onset at the moment of diagnosis and also at the moment of the survey. This way, an age-of-onset higher than the age at the moment of the survey indicates censoring. / Mestrado / Estatistica / Mestra em Estatística

Orientadores: Gustavo Antonio de Souza, Sophie Françoise Mauricette Derchain / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-19T18:43:22Z (GMT). No. of bitstreams: 1 Ramalho_SusanaOliveiraBotelho_M.pdf: 1500372 bytes, checksum: 04f5c0de427c8917a798d6fef8b46619 (MD5) Previous issue date: 2012 / Resumo: Introdução: O câncer da mama é a segunda neoplasia mais frequente no mundo. Sem considerar os tumores de pele não melanoma, é a neoplasia mais incidente no sexo feminino. No Brasil, a estimativa do câncer da mama para o ano de 2012 é de 52.608 novos casos. Os cânceres da mama que não expressam receptores de estrógeno (RE) e progesterona (RP) apresentam uma sobrevida pior comparada aos cânceres da mama que expressam esses receptores. O Human Epidermal growth fator Receptor 2 (HER-2) é uma oncoproteína cuja hiperexpressão ocorre em aproximadamente 20% dos carcinomas da mama e associa-se a um fenótipo mais agressivo. Nos carcinomas da mama RE e RP negativos, a expressão do HER-2 identifica dois grupos: os carcinomas da mama que hiperexpressam o HER-2, chamados duplo negativo com HER-2 hiperexpressado, e os carcinomas da mama que não hiperexpressam o HER-2, chamados triplo negativos. Objetivo: Avaliar a relação entre os fatores clínicos e patológicos e a sobrevida em pacientes com carcinomas da mama duplo negativo HER-2 hiperexpressado e triplo negativo. Sujeitos e Métodos: Foram selecionadas as pacientes com carcinoma invasivo da mama diagnosticadas e tratadas no Hospital da Mulher Prof. Dr. José Aristodemo Pinotti - Centro de Atenção Integral à Saúde da Mulher da Universidade Estadual de Campinas (Unicamp), entre abril de 2004 e outubro de 2008, seguidas até outubro de 2010. A expressão dos RE e RP foi avaliada por imunoistoquímica (IIQ) em microarranjo de tecidos (TMA). A expressão de HER-2 foi avaliada por IIQ e Hibridização Fluorescente in situ (FISH). A expressão do HER-2 foi classificada pela IIQ exclusiva nos casos HER-2 escore 0 ou 1+ e 3+. Nos casos em que a IIQ mostrou-se indeterminada (2+) foi realizado FISH. Assim, foram classificados como HER-2 negativos os casos escore 0 e 1+, e os casos escore 2+ com FISH negativo. Foram considerados HER-2 positivos os casos escore 3+ e os casos escore 2+ com FISH positivo. Foram incluídas no estudo 161 pacientes, sendo 58 duplo negativo HER-2 hiperexpressado (RE e RP negativos e HER-2 positivo) e 103 triplo negativo (RE, RP e HER-2 negativos). Foram avaliados: idade ao diagnóstico, estádio, grau nuclear, grau histológico, presença de invasão vascular e tipo histológico. Também foi avaliada utilização de quimioterapia adjuvante e neoadjuvante baseada em antraciclina, e se foi associado taxano. Foram calculados os odds ratios (OR) brutos e os odds ratios ajustados com os respectivos intervalos de confiança (IC95%) para as características clínicas e patológicas, comparando carcinomas da mama duplo negativo HER-2 hiperexpressado e triplo negativo. Foram calculados os Hazard Ratios (HR) com os respectivos IC95% em relação à sobrevida geral, para as variáveis clínicas e patológicas. Resultados: Comparando as pacientes com carcinomas da mama duplo negativo HER-2 hiperexpressado e triplo negativo, observou se que as medianas da idade foram de 54 e 52, respectivamente. Não houve diferença na distribuição por idade em função da expressão do HER-2. Nesta casuística, mais de 80% das pacientes apresentaram a doença em estádios II e III. Houve o predomínio do grau histológico III e do grau nuclear 3 em ambos os grupos. As pacientes com carcinomas da mama duplo negativo HER-2 hiperexpressado apresentaram invasão vascular em 27,5% dos casos quando comparadas com 14,5% nas pacientes triplo negativo (p= 0,06). Nas pacientes com carcinoma da mama triplo negativo observou-se 11% de tipo histológicos mais indiferenciados. Em relação ao local das metástases, ambos os grupos tiveram um percentual maior que 50% de metástases viscerais. A mediana de seguimento foi de 36 meses (percentiles 25/75: 25/78 meses). A expressão do HER-2 não interferiu com a sobrevida. O estádio III e a utilização de antraciclina aumentaram significativamente o risco de morte pela doença (p<0,001 e p=0,007 respectivamente). A presença de invasão vascular não se relacionou com a sobrevida (p=0,05). A sobrevida das pacientes com estádios I-II foi significativamente maior do que daquelas com estádio III, tanto para carcinomas duplo negativo com HER-2 hiperexpressado (p<0,.0001) quanto para os triplo negativos (p=0,03). Não houve diferença na sobrevida das pacientes com carcinoma duplo negativo HER-2 hiperexpressado e carcinoma triplo negativo nos estádio I + II (p= 0,13) e estádios III (p= 0,34). Conclusão: Nesta casuística de 161 pacientes com carcinoma da mama RE e RP, independente da expressão do HER-2, houve um predomínio de estádios avançados e de tumores indiferenciados. A expressão do HER-2 não se associou com a sobrevida global. Apenas o estádio III e a utilização de antraciclina estiveram relacionados com maior probabilidade de óbito pela doença / Abstract: Introduction: Breast cancer is the second most common malignancy worldwide. Aside from non-melanoma skin cancers, breast cancer is the most common malignancy among women. In Brazil, approximately 52,608 new cases of breast cancer are predicted to occur in 2012. Breast cancers that do not express estrogen receptors (ER) and progesterone receptors (PR) have a worse survival rate, in comparison to breast cancers that express these receptors. Human Epidermal Growth Factor Receptor 2 (HER2) is an oncoprotein that is overexpressed in approximately 20% of breast carcinomas and is associated with a more aggressive phenotype. In ER and PR receptor-negative breast carcinomas, HER2 expression identifies two groups: breast carcinomas that overexpress HER2, termed double negative HER2-overexpressing tumors and breast carcinomas that do not overexpress HER2, termed triple negative. Objective: To assess the relationship between clinical-pathological factors and survival in patients with double negative HER2-overexpressing and triple negative breast carcinomas. Subjects and Methods: Patients with invasive breast carcinoma diagnosed and treated in the Prof. Dr. José Aristodemo Pinotti's Women' Hospital - Integrated Healthcare Center of the Universidade Estadual de Campinas (Unicamp) were selected from April 2004 to October 2008, receiving follow-up care until October 2010. ER and PR expression was evaluated by immunohistochemistry (IHC) in tissue microarray (TMA). HER2 expression was evaluated by IHC and Fluorescent in situ Hybridization (FISH) analysis. HER2 expression was assessed exclusively by IHC in cases scored 0 or 1+ and 3+ HER2. If IHC test scored 2+ (equivocal), FISH analysis was performed. Thus, scores 0/1+, and 2+/FISH-negative were classified as HER2-negative. Score 3+, and score 2+/ FISH-positive cases were classified as HER2-positive. One hundred and sixty-one (161) patients were included in the study. Of these patients, 58 had double negative HER2-overexpressing (ER/PR-negative, HER2-positive) breast tumor and 103 had triple negative (ER-negative/PR-negative/HER2-negative) breast tumor. Age at the time of diagnosis, stage, nuclear grade, histologic grade, presence of vascular invasion and histologic type were evaluated. The use of adjuvant and neoadjuvant anthracycline-based chemotherapy was assessed and also whether this regimen was combined with taxane. The crude odds ratios (OR) and adjusted odds ratios with their respective confidence intervals (95%CI) for clinical and pathological characteristics were calculated, comparing double negative HER2-overexpressing breast carcinoma with triple negative breast carcinoma. The Hazard Ratio (HR) with the respective 95%CI in relation to overall survival was calculated for clinical and pathological variables. Results: Patients with double negative HER2-overexpressing breast tumors were compared to those with triple-negative breast tumors (median patient age: 54 and 52 years, respectively). There was no difference in age distribution according to HER2 expression. In this case study, more than 80% of patients had Stage II and III disease, with a predominance of histologic grade III and nuclear grade 3 in both groups. Patients bearing double negative HER2-overexpressing breast carcinomas had vascular invasion in 27.5% of cases compared to 14.5% of triple negative patients (p= 0.06). In patients with triple negative breast carcinoma, more undifferentiated histologic types were observed in 11% of cases. Regarding metastasis site, the incidence of visceral metastasis was higher than 50% in both groups. The median follow-up period was 36 months (percentiles 25/75: 25/78 months). HER2 expression did not interfere with patient survival. Stage III disease and the use of anthracycline significantly increased the risk of death from the disease (p<0.001 and p=0.007, respectively). The presence of vascular invasion was not related to survival (p=0.05). Patients with Stage I-II disease survived significantly longer than those with Stage III disease in both double negative HER2-overexpressing tumors (p<0.0001) and triple negative tumors (p=0.03). There was no difference in survival of patients with double negative HER2-overexpressing carcinomas and triple negative carcinomas in Stages I + II (p= 0.13) and Stages III (p= 0.34). Conclusion: In this case study of 161 patients with ER/PR-negative breast carcinoma, there was a predominance of advanced stages. Virtually 50% of the patients seen in this service presented with Stage III disease. Regardless of HER2 expression, undifferentiated tumors (histologic grade III and nuclear grade 3 predominated. It was observed that triple negative carcinomas had a higher proportion of special histologic types. Vascular invasion was slightly more frequent in double negative HER2-overexpressing carcinoma and was not associated with survival. HER2 expression was not associated with overall survival. Only Stage III and the use of anthracycline were related to a higher probability of death due to the disease / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde

Background: Parasite evolution is hypothesized to select for levels of parasite virulence that maximise transmission success. When host population densities fluctuate, low levels of virulence with limited impact on the host are expected, as this should increase the likelihood of surviving periods of low host density. We examined the effects of Morogoro arenavirus on the survival and recapture probability of multimammate mice (Mastomys natalensis) using a seven-year capture-mark-recapture time series. Mastomys natalensis is the natural host of Morogoro virus and is known for its strong seasonal density fluctuations. Results: Antibody presence was negatively correlated with survival probability (effect size: 5-8% per month depending on season) but positively with recapture probability (effect size: 8%). Conclusions: The small negative correlation between host survival probability and antibody presence suggests that either the virus has a negative effect on host condition, or that hosts with lower survival probability are more likely to obtain Morogoro virus infection, for example due to particular behavioural or immunological traits. The latter hypothesis is supported by the positive correlation between antibody status and recapture probability which suggests that risky behaviour might increase the probability of becoming infected.

Abstract The aims of this study were to evaluate the treatment need of fixed bridges according to the distribution of pontics in dentition in different age groups, and to investigate the primary and late complications and survival of the conventional fixed metal ceramic prostheses, as well as patients' satisfaction with the prosthetic treatment. The whole material consisted of the patients treated with fixed metal ceramic prostheses by undergraduate students at the Institute of Dentistry during the years 1984 - 1996. There were altogether 772 patients, 460 women (60 %) and 312 men (40 %). Their mean age was 47 years (23 - 81 years). Altogether 944 single metal ceramic crowns and 543 fixed bridges (1374 abutments and 807 pontics) were prepared. It can be concluded that the fixed bridges are most often prepared to replace upper first premolars and lower first molars also in the future. The most usual primary complications related to fixed bridges occurred during preprosthetic endodontic treatment of abutment teeth and during the preparation of the root canals. Previous restoration of the prepared tooth does not have any marked effect on the prognosis of single crowns with dowels, although anatomically complicated upper lateral incisors and upper first premolars need special attention in the treatment planning. Patients were satisfied with aesthetics and function of the fixed metal ceramic prostheses. Late complications found in clinical examinations were few, and the survival rate for the fixed metal ceramic bridge prostheses was calculated to be 84 % after 10 years, long fixed bridges having a lower survival than the shorter ones. The treatment need for conventional fixed bridges seems to be highest among patients over 50 years of age in the future. Age does not influence the longevity of the fixed prostheses, but basic circumstances of the mouth, especially low secretion of saliva affected by diseases and/or medications and high scores of lactobacilli and streptococcus mutans of the saliva seem to decrease the survival.

Philosophiae Doctor - PhD / Subscription-based industries have seen a massive expansion in recent decades. In this type of industry the customer has to subscribe to be able to enjoy the service; there-fore, well-de ned start and end points of the customer relationship with the service provider are known. The length of this relationship, that is the time from subscription to service cancellation, is de ned as customer survival time. Unlike transaction-based businesses, where the emphasis is on the quality of a product and customer acquisition, subscription-based businesses focus on the customer and customer retention. A customer focus requires a new approach: managing according to customer equity (the value of a rm's customers) rather than brand equity (the value of a rm's brands). The concept of customer equity is attractive and straightforward, but the implementation and management of the customer equity approach do present some challenges. Amongst these challenges is that customer asset metric - customer lifetime value (the present value of all future pro ts generated from a customer) - depends upon assumptions about the expected survival time of the customer (Bell et al., 2002; Gupta and Lehmann, 2003). In addition, managing and valuing customers as an asset require extensive data and complex modelling. The aim of this study is to illustrate, adapt and develop methods of survival analysis in analysing and estimating customer survival time in subscription-based businesses. Two particular objectives are studied. The fi rst objective is to rede ne the existing survival analysis techniques in business terms and to discuss their uses in order to understand various issues related to the customer-fi rm relationship. The lesson to be learnt here is the ability of survival analysis techniques to extract important information on customers with regard to their loyalties, risk of cancellation of the service, and lifetime value. The ultimate outcome of this process of studying customer survival time will be to understand the dynamics and behaviour of customers with respect to their risk of cancellation, survival probability and lifetime value. The results of the estimates of customer mean survival time obtained from different nonparametric and parametric approaches; namely, the Kaplan-Meier method as well as exponential, Weibull and gamma regression models were found to vary greatly showing the importance of the assumption imposed on the distribution of the survival time. The second objective is to extrapolate the customer survival curve beyond the empirical distribution. The practical motivation for extrapolating the survival curve beyond the empirical distribution originates from two issues; that of calculating survival probabilities (retention rate) beyond the empirical data and of calculating the conditional survival probability and conditional mean survival time at a speci c point in time and for a speci c time window in the future. The survival probabilties are the main components needed to calculate customer lifetime value and thereafter customer equity. In this regard, we propose a survivor function that can be used to extrapolate the survival probabilities beyond the last observed failure time; the estimation of parameters of the newly proposed extrapolation function is based completely on the Kaplan-Meier estimate of the survival probabilities. The proposed function has shown a good mathematical accuracy. Furthermore, the standard error of the estimate of the extrapolation survival function has been derived. The function is ready to be used by business managers where the objective is to enhance customer retention and to emphasise a customer-centric approach. The extrapolation function can be applied and used beyond the customer survival time data to cover clinical trial applications. In general the survival analysis techniques were found to be valuable in understanding and managing a customer- rm relationship; yet, much still needs to be done in this area of research to make these techniques that are traditionally used in medical studies more useful and applicable in business settings. / South Africa

This diploma thesis deals with various ways of treatment of selected oncological diseases and the effectiveness of treatment methods and evaluation of the influence of various factors influencing the survival of patients. The activity of individual healing processes is evaluated by survival analysis. The subjects of the study are patients with breast, lung and prostate cancer. The survival analysis considers the sex of the patient, the age and stage of his illness, and other factors to avoid distorted results. The aim of the work is to find out the effects of selected therapeutic procedures on patients' health and to identify factors that have a significant impact on the survival of patients. The data for the diploma thesis was provided by the Institute of Health Information and Statistics of the Czech Republic, the Statistical Office, the National Cancer Register (NOR), the US SEER database and the German Breast Cancer Study.

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. / 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)

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.