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Using computational approaches utilizing large datasets to investigate public health information is an important mechanism for institutions seeking to identify strategies for improving public health. The art in computational approaches, for example in health research, is managing the trade-offs between the two perspectives: first, inference and second, prediction. Many techniques from statistical methods (SM) and machine learning (ML) may, in principle, be used for both perspectives. However, SM has a well established focus on inference by building probabilistic models which allows us to determine a quantitative measure of confidence about the magnitude of the effect. Simulation-based validation approaches can be used in conjunction with SM to explicitly verify assumptions and redefine the specified model, if necessary. On the other hand, ML uses general-purpose algorithms to find patterns that best predict the outcome and makes minimal assumptions about the data-generating process; and may be more effective in a number of situations. My work employs both SM- and ML- based computational approaches to investigate particular public health problems. Chapter One provides philosophical background and compares the application of the two approaches in public health. Chapter Two describes and implements penalized Cox proportional hazard models for time-varying covariates time-to-event data. Chapter Three applies traditional survival models and machine learning algorithms to predict survival times of cancer patients, while incorporating the information about the time-varying covariates. Chapter Four discusses and implements various approaches for computing predictions and effects for generalized linear (mixed) models. Finally, Chapter Five implements and compares various statistical models for handling univariate and multivariate binary outcomes for water, sanitation and hygiene (WaSH) data. / Thesis / Doctor of Philosophy (PhD)

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This master thesis is aimed towards answering the question What is the contribution from a company’s sector with regards to its survival of a financial crisis? with the sub question Can we use survival analysis on financial data to answer this?. Thus survival analysis is used to answer our main question which is seldom used on financial data. This is interesting since it will study how well survival analysis can be used on financial data at the same time as it will evaluate if all companies experiences a financial crisis in the same way. The dataset consists of all companies traded on the Swedish stock market during 2008. The results show that the survival method is very suitable the data that is used. The sector a company operated in has a significant effect. However the power is to low too give any indication of specific differences between the different sectors. Further on it is found that the group of smallest companies had much better survival than larger companies.

We provide ways to test the fit of a parametric copula family for bivariate censored data with or without covariates. The proposed copula family is tested by embedding it in an expanded parametric family of copulas. When parameters in the proposed and the expanded copula models are estimated by maximum likelihood, a likelihood ratio test can be used. However, when they are estimated by two-stage pseudolikelihood estimation, the corresponding test is a pseudolikelihood ratio test. The two-stage procedures offer less computation, which is especially attractive when the marginal lifetime distributions are specified nonparametrically or semiparametrically. It is shown that the likelihood ratio test is consistent even when the expanded model is misspecified. Power comparisons of the likelihood ratio and the pseudolikelihood ratio tests with some other goodness-of-fit tests are performed both when the expanded family is correct and when it is misspecified. They indicate that model expansion provides a convenient, powerful and robust approach. We introduce a semiparametric maximum likelihood estimation method in which the copula parameter is estimated without assumptions on the marginal distributions. This method and the two-stage semiparametric estimation method suggested by Shih and Louis (1995) are generalized to regression models with Cox proportional hazards margins. The two-stage semiparametric estimator of the copula parameter is found to be about as good as the semiparametric maximum likelihood estimator. Semiparametric likelihood ratio and pseudolikelihood ratio tests are considered to provide goodness of fit tests for a copula model without making parametric assumptions for the marginal distributions. Both when the expanded family is correct and when it is misspecified, the semiparametric pseudolikelihood ratio test is almost as powerful as the parametric likelihood ratio and pseudolikelihood ratio tests while achieving robustness to the form of the marginal distributions. The methods are illustrated on applications in medicine and insurance. Sequentially observed survival times are of interest in many studies but there are difficulties in modeling and analyzing such data. First, when the duration of followup is limited and the times for a given individual are not independent, the problem of induced dependent censoring arises for the second and subsequent survival times. Non-identifiability of the marginal survival distributions for second and later times is another issue, since they are observable only if preceding survival times for an individual are uncensored. In addition, in some studies, a significant proportion of individuals may never have the first event. Fully parametric models can deal with these features, but lack of robustness is a concern, and methods of assessing fit are lacking. We introduce an approach to address these issues. We model the joint distribution of the successive survival times by using copula functions, and provide semiparametric estimation procedures in which copula parameters are estimated without parametric assumptions on the marginal distributions. The performance of semiparametric estimation methods is compared with some other estimation methods in simulation studies and shown to be good. The methodology is applied to a motivating example involving relapse and survival following colon cancer treatment.

We provide ways to test the fit of a parametric copula family for bivariate censored data with or without covariates. The proposed copula family is tested by embedding it in an expanded parametric family of copulas. When parameters in the proposed and the expanded copula models are estimated by maximum likelihood, a likelihood ratio test can be used. However, when they are estimated by two-stage pseudolikelihood estimation, the corresponding test is a pseudolikelihood ratio test. The two-stage procedures offer less computation, which is especially attractive when the marginal lifetime distributions are specified nonparametrically or semiparametrically. It is shown that the likelihood ratio test is consistent even when the expanded model is misspecified. Power comparisons of the likelihood ratio and the pseudolikelihood ratio tests with some other goodness-of-fit tests are performed both when the expanded family is correct and when it is misspecified. They indicate that model expansion provides a convenient, powerful and robust approach. We introduce a semiparametric maximum likelihood estimation method in which the copula parameter is estimated without assumptions on the marginal distributions. This method and the two-stage semiparametric estimation method suggested by Shih and Louis (1995) are generalized to regression models with Cox proportional hazards margins. The two-stage semiparametric estimator of the copula parameter is found to be about as good as the semiparametric maximum likelihood estimator. Semiparametric likelihood ratio and pseudolikelihood ratio tests are considered to provide goodness of fit tests for a copula model without making parametric assumptions for the marginal distributions. Both when the expanded family is correct and when it is misspecified, the semiparametric pseudolikelihood ratio test is almost as powerful as the parametric likelihood ratio and pseudolikelihood ratio tests while achieving robustness to the form of the marginal distributions. The methods are illustrated on applications in medicine and insurance. Sequentially observed survival times are of interest in many studies but there are difficulties in modeling and analyzing such data. First, when the duration of followup is limited and the times for a given individual are not independent, the problem of induced dependent censoring arises for the second and subsequent survival times. Non-identifiability of the marginal survival distributions for second and later times is another issue, since they are observable only if preceding survival times for an individual are uncensored. In addition, in some studies, a significant proportion of individuals may never have the first event. Fully parametric models can deal with these features, but lack of robustness is a concern, and methods of assessing fit are lacking. We introduce an approach to address these issues. We model the joint distribution of the successive survival times by using copula functions, and provide semiparametric estimation procedures in which copula parameters are estimated without parametric assumptions on the marginal distributions. The performance of semiparametric estimation methods is compared with some other estimation methods in simulation studies and shown to be good. The methodology is applied to a motivating example involving relapse and survival following colon cancer treatment.

For both randomized clinical trials and prospective cohort studies, the Cox regression model is a powerful tool for evaluating the effect of a treatment or an explanatory variable on time-to-event outcome. This method assumes proportional hazards over time. Systematic approaches to efficiently evaluate non-proportionality and to model data in the presence of non-proportionality are investigated. Six graphical methods are assessed to verify the proportional hazards assumption based on characteristics of the survival function, cumulative hazard, or the feature of residuals. Their performances are empirically evaluated with simulations by checking their ability to be consistent and sensitive in detecting proportionality or non-proportionality. Two-sample data are generated in three scenarios of proportional hazards and five types of alternatives (that is, non-proportionality). The usefulness of these graphical assessment methods depends on the event rate and type of non-proportionality. Three numerical (statistical testing) methods are compared via simulation studies to investigate the proportional hazards assumption. In evaluating data for proportionality versus non-proportionality, the goal is to test a non-zero slope in a regression of the variable or its residuals on a specific function of time, or a Kolmogorov-type supremum test. Our simulation results show that statistical test performance is affected by the number of events, event rate, and degree of divergence of non-proportionality for a given hazards scenario. Determining which test will be used in practice depends on the specific situation under investigation. Both graphical and numerical approaches have benefits and costs, but they are complementary to each other. Several approaches to model and summarize non-proportionality data are presented, including non-parametric measurements and testing, semi-parametric models, and a parametric approach. Some illustrative examples using simulated data and real data are also presented. In summary, we present a systemic approach using both graphical and numerical methods to identify non-proportionality, and to provide numerous modeling strategies when proportionality is violated in time-to-event data.

Chemotherapy is a method used to treat cancer but it has a number of side-effects. Research conducted by the Department of Chemical Engineering at BYU involves a new method of administering chemotherapy using ultrasound waves and water-soluble capsules. The goal is to reduce the side-effects by localizing the delivery of the medication. As part of this research, a two-factor experiment was conducted on rats to test if the water-soluble capsules and ultrasound waves by themselves have an effect on tumor growth or patient survival. Our project emphasizes the usage of Bayesian Hierarchical Models and Win-BUGS to jointly model the survival data and the longitudinal data—mass. The results of the joint analysis indicate that the use of ultrasound and water-soluble microcapsules have no negative effect on survival. In fact, there appears to be a positive effect on the survival since the rats in the ultrasound-capsule group had higher survival rates than the rats in other treatment groups. From these results, it does appear that the new technology involving ultrasound waves and microcapsules is a promising way to reduce the side-effects of chemotherapy. It is strongly advocated that the formulation of a joint model for any longitudinal and survival data be performed. For future work for the ultrasound-microcapsule data it is recommended that joint modeling of the mass, tumor volume, and survival data be conducted to obtain additional information.

Os modelos de fragilidade são utilizados para modelar as possíveis associações entre os tempos de sobrevivência. Uma outra alternativa desenvolvida para modelar a dependência entre dados multivariados é o uso dos modelos baseados em funções cópulas. Neste trabalho propusemos dois modelos de sobrevivência derivados das cópulas de Ali- Mikhail-Haq (AMH) e de Frank para modelar a dependência de dados bivariados na presença de covariáveis e observações censuradas. Para fins inferenciais, realizamos uma abordagem bayesiana usando métodos Monte Carlo em Cadeias de Markov (MCMC). Algumas discussões sobre os critérios de seleção de modelos são apresentadas. Com o objetivo de detectar observações influentes utilizamos o método bayesiano de análise de influência de deleção de casos baseado na divergência ψ. Por fim, mostramos a aplicabilidade dos modelos propostos a conjuntos de dados simulados e reais. Apresentamos, também, um novo modelo de sobrevivência bivariado com fração de cura, que leva em consideração três configurações para o mecanismo de ativação latente: ativação aleatória, primeira ativação é última ativação. Aplicamos este modelo a um conjunto de dados de empréstimo de Crédito Direto ao modo do Consumidor (DCC) e comparamos os ajustes por meio dos critérios bayesianos de seleção de modelos para verificar qual dos três modelos melhor se ajustou. Por fim, mostramos nossa proposta futura para a continuação da pesquisa. / The frailty models are used to model the possible associations between survival times. Another alternative developed for modeling the dependence between multivariate data is the use of models based on copulas functions. In this paper we propose two derived survival models of copula of the Ali-Mikhail-Haq (AMH) and of the Frank to model the dependence of bivariate data in the presence of covariates and censored observations. For inferential purposes, we conducted a Bayesian approach using Monte Carlo methods in Markov Chain (MCMC). Some discussions on the model selection criteria were presented. In order to detect influential observations we use the Bayesian method of cases of deletion of influence analysis based on the difference ψ. Finally, we show the applicability of the proposed models to sets of simulated and real data. We present, too, a new survival model with bivariate fraction of healing, which takes into account three settings for the latent activation mechanism: random activation, first activation and final activation. We apply this model to a set of Direct Credit loan data to the Consumer mode (DCC) and compare the settings, through Bayesian criteria for selection of models, which of the three models best fit. Finally, we show our future proposal for further research.

Joint modeling of longitudinal and survival data has received much attention and is becoming increasingly useful. In clinical studies, longitudinal biomarkers are used to monitor disease progression and to predict survival. These longitudinal measures are often missing at failure times and may be prone to measurement errors. In previous studies these two types of data are frequently analyzed separately where a mixed effects model is used for longitudinal data and a survival model is applied to event outcomes. The argument in favor of a joint model has been the efficient use of the data as the survival information goes into modeling the longitudinal process and vice versa. In this thesis, we present joint maximum likelihood methods, a two stage approach and time dependent covariate methods that link longitudinal data to survival data. First, we use simulation studies to explore and assess the performance of these methods with bias, accuracy and coverage probabilities. Then, we focus on four time dependent methods considering models that are unadjusted and adjusted for time. Finally, we consider mediation analysis for longitudinal and survival data. Mediation analysis is introduced and applied in a research framework based on genetic variants, longitudinal measures and disease risk. We implement accelerated failure time regression using the joint maximum likelihood approach (AFT-joint) and an accelerated failure time regression model using the observed longitudinal measures as time dependent covariates (AFT-observed) to assess the mediated effect. We found that the two stage approach (TSA) performed best at estimating the link parameter. The joint maximum likelihood methods that used the predicted values of the longitudinal measures, similar to the TSA, provided larger estimates. The time dependent covariate methods that used the observed longitudinal measures in the survival analysis underestimated the true estimates. The mediation results showed that the AFT-joint and the AFT-observed underestimated the mediated effect. Comparison of the methods in Framingham Heart Study data revealed similar patterns. We recommend adjusting for time when estimating the association parameter in time dependent Cox and logistic models. Additional work is needed for estimating the mediated effect with longitudinal and survival data.