This thesis considers a variety of statistical issues related to the design and analysis of clinical trials involving multiple lifetime events. The use of composite endpoints, multivariate survival methods with dependent censoring, and recurrent events with dependent termination are considered. Much of this work is based on problems arising in oncology research. Composite endpoints are routinely adopted in multi-centre randomized trials designed to evaluate the effect of experimental interventions in cardiovascular disease, diabetes, and cancer. Despite their widespread use, relatively little attention has been paid to the statistical properties of estimators of treatment effect based on composite endpoints. In Chapter 2 we consider this issue in the context of multivariate models for time to event data in which copula functions link marginal distributions with a proportional hazards structure. We then examine the asymptotic and empirical properties of the estimator of treatment effect arising from a Cox regression model for the time to the first event. We point out that even when the treatment effect is the same for the component events, the limiting value of the estimator based on the composite endpoint is usually inconsistent for this common value. The limiting value is determined by the degree of association between the events, the stochastic ordering of events, and the censoring distribution. Within the framework adopted, marginal methods for the analysis of multivariate failure time data yield consistent estimators of treatment effect and are therefore preferred. We illustrate the methods by application to a recent asthma study. While there is considerable potential for more powerful tests of treatment effect when marginal methods are used, it is possible that problems related to dependent censoring can arise. This happens when the occurrence of one type of event increases the risk of withdrawal from a study and hence alters the probability of observing events of other types. The purpose of Chapter 3 is to formulate a model which reflects this type of mechanism, to evaluate the effect on the asymptotic and finite sample properties of marginal estimates, and to examine the performance of estimators obtained using flexible inverse probability weighted marginal estimating equations. Data from a motivating study are used for illustration. Clinical trials are often designed to assess the effect of therapeutic interventions on occurrence of recurrent events in the presence of a dependent terminal event such as death. Statistical methods based on multistate analysis have considerable appeal in this setting since they can incorporate changes in risk with each event occurrence, a dependence between the recurrent event and the terminal event and event-dependent censoring. To date, however, there has been limited methodology for the design of trials involving recurrent and terminal events, and we addresses this in Chapter 4. Based on the asymptotic distribution of regression coefficients from a multiplicative intensity Markov regression model, we derive sample size formulae to address power requirements for both the recurrent and terminal event processes. Superiority and non-inferiority trial designs are dealt with. Simulation studies confirm that the designs satisfy the nominal power requirements in both settings, and an application to a trial evaluating the effect of a bisphosphonate on skeletal complications is given for illustration.

Longitudinal studies, where data on study subjects are collected over time, is increasingly involving multivariate longitudinal responses. Frequently, the heterogeneity observed in a multivariate longitudinal response can be attributed to underlying unobserved disease states in addition to any between-subject differences. We propose modeling such disease states using a hidden Markov model (HMM) approach and expand upon previous work, which incorporated random effects into HMMs for the analysis of univariate longitudinal data, to the setting of a multivariate longitudinal response. Multivariate longitudinal data are modeled jointly using separate but correlated random effects between longitudinal responses of mixed data types in addition to a shared underlying hidden process. We use a computationally efficient Bayesian approach via Markov chain Monte Carlo (MCMC) to fit such models. We apply this methodology to bivariate longitudinal response data from a smoking cessation clinical trial. Under these models, we examine how to incorporate a treatment effect on the disease states, as well as develop methods to classify observations by disease state and to attempt to understand patient dropout. Simulation studies were performed to evaluate the properties of such models and their applications under a variety of realistic situations.

Interval censoring arises frequently in life history data, as individuals are often only observed at a sequence of assessment times. This leads to a situation where we do not know when an event of interest occurs, only that it occurred somewhere between two assessment times. Here, the focus will be on methods of estimation for recurrent event data, current status data, and multistate data, subject to interval censoring. With recurrent event data, the focus is often on estimating the rate and mean functions. Nonparametric estimates are readily available, but are not smooth. Methods based on local likelihood and the assumption of a Poisson process are developed to obtain smooth estimates of the rate and mean functions without specifying a parametric form. Covariates and extra-Poisson variation are accommodated by using a pseudo-profile local likelihood. The methods are assessed by simulations and applied to a number of datasets, including data from a psoriatic arthritis clinic. Current status data is an extreme form of interval censoring that occurs when each individual is observed at only one assessment time. If current status data arise in clusters, this must be taken into account in order to obtain valid conclusions. Copulas offer a convenient framework for modelling the association separately from the margins. Estimating equations are developed for estimating marginal parameters as well as association parameters. Efficiency and robustness to the choice of copula are examined for first and second order estimating equations. The methods are applied to data from an orthopedic surgery study as well as data on joint damage in psoriatic arthritis. Multistate models can be used to characterize the progression of a disease as individuals move through different states. Considerable attention is given to a three-state model to characterize the development of a back condition known as spondylitis in psoriatic arthritis, along with the associated risk of mortality. Robust estimates of the state occupancy probabilities are derived based on a difference in distribution functions of the entry times. A five-state model which differentiates between left-side and right-side spondylitis is also considered, which allows us to characterize what effect spondylitis on one side of the body has on the development of spondylitis on the other side. Covariate effects are considered through multiplicative time homogeneous Markov models. The robust state occupancy probabilities are also applied to data on CMV infection in patients with HIV.

Interval censoring arises frequently in life history data, as individuals are often only observed at a sequence of assessment times. This leads to a situation where we do not know when an event of interest occurs, only that it occurred somewhere between two assessment times. Here, the focus will be on methods of estimation for recurrent event data, current status data, and multistate data, subject to interval censoring. With recurrent event data, the focus is often on estimating the rate and mean functions. Nonparametric estimates are readily available, but are not smooth. Methods based on local likelihood and the assumption of a Poisson process are developed to obtain smooth estimates of the rate and mean functions without specifying a parametric form. Covariates and extra-Poisson variation are accommodated by using a pseudo-profile local likelihood. The methods are assessed by simulations and applied to a number of datasets, including data from a psoriatic arthritis clinic. Current status data is an extreme form of interval censoring that occurs when each individual is observed at only one assessment time. If current status data arise in clusters, this must be taken into account in order to obtain valid conclusions. Copulas offer a convenient framework for modelling the association separately from the margins. Estimating equations are developed for estimating marginal parameters as well as association parameters. Efficiency and robustness to the choice of copula are examined for first and second order estimating equations. The methods are applied to data from an orthopedic surgery study as well as data on joint damage in psoriatic arthritis. Multistate models can be used to characterize the progression of a disease as individuals move through different states. Considerable attention is given to a three-state model to characterize the development of a back condition known as spondylitis in psoriatic arthritis, along with the associated risk of mortality. Robust estimates of the state occupancy probabilities are derived based on a difference in distribution functions of the entry times. A five-state model which differentiates between left-side and right-side spondylitis is also considered, which allows us to characterize what effect spondylitis on one side of the body has on the development of spondylitis on the other side. Covariate effects are considered through multiplicative time homogeneous Markov models. The robust state occupancy probabilities are also applied to data on CMV infection in patients with HIV.

Empirical likelihood, which was pioneered by Thomas and Grunkemeier (1975) and Owen (1988), is a powerful nonparametric method of statistical inference that has been widely used in the statistical literature. In this thesis, we investigate the merits of empirical likelihood for various problems arising in ratio estimation. First, motivated by the smooth empirical likelihood (SEL) approach proposed by Zhou & Jing (2003), we develop empirical likelihood estimators for diagnostic test likelihood ratios (DLRs), and derive the asymptotic distributions for suitable likelihood ratio statistics under certain regularity conditions. To skirt the bandwidth selection problem that arises in smooth estimation, we propose an empirical likelihood estimator for the same DLRs that is based on non-smooth estimating equations (NEL). Via simulation studies, we compare the statistical properties of these empirical likelihood estimators (SEL, NEL) to certain natural competitors, and identify situations in which SEL and NEL provide superior estimation capabilities. Next, we focus on deriving an empirical likelihood estimator of a baseline cumulative hazard ratio with respect to covariate adjustments under two nonproportional hazard model assumptions. Under typical regularity conditions, we show that suitable empirical likelihood ratio statistics each converge in distribution to a 2 random variable. Through simulation studies, we investigate the advantages of this empirical likelihood approach compared to use of the usual normal approximation. Two examples from previously published clinical studies illustrate the use of the empirical likelihood methods we have described. Empirical likelihood has obvious appeal in deriving point and interval estimators for time-to-event data. However, when we use this method and its asymptotic critical value to construct simultaneous confidence bands for survival or cumulative hazard functions, it typically necessitates very large sample sizes to achieve reliable coverage accuracy. We propose using a bootstrap method to recalibrate the critical value of the sampling distribution of the sample log-likelihood ratios. Via simulation studies, we compare our EL-based bootstrap estimator for the survival function with EL-HW and EL-EP bands proposed by Hollander et al. (1997) and apply this method to obtain a simultaneous confidence band for the cumulative hazard ratios in the two clinical studies that we mentioned above. While copulas have been a popular statistical tool for modeling dependent data in recent years, selecting a parametric copula is a nontrivial task that may lead to model misspecification because different copula families involve different correlation structures. This observation motivates us to use empirical likelihood to estimate a copula nonparametrically. With this EL-based estimator of a copula, we derive a goodness-of-fit test for assessing a specific parametric copula model. By means of simulations, we demonstrate the merits of our EL-based testing procedure. We demonstrate this method using the data from Wieand et al. (1989). In the final chapter of the thesis, we provide a brief introduction to several areas for future research involving the empirical likelihood approach.

Empirical likelihood, which was pioneered by Thomas and Grunkemeier (1975) and Owen (1988), is a powerful nonparametric method of statistical inference that has been widely used in the statistical literature. In this thesis, we investigate the merits of empirical likelihood for various problems arising in ratio estimation. First, motivated by the smooth empirical likelihood (SEL) approach proposed by Zhou & Jing (2003), we develop empirical likelihood estimators for diagnostic test likelihood ratios (DLRs), and derive the asymptotic distributions for suitable likelihood ratio statistics under certain regularity conditions. To skirt the bandwidth selection problem that arises in smooth estimation, we propose an empirical likelihood estimator for the same DLRs that is based on non-smooth estimating equations (NEL). Via simulation studies, we compare the statistical properties of these empirical likelihood estimators (SEL, NEL) to certain natural competitors, and identify situations in which SEL and NEL provide superior estimation capabilities. Next, we focus on deriving an empirical likelihood estimator of a baseline cumulative hazard ratio with respect to covariate adjustments under two nonproportional hazard model assumptions. Under typical regularity conditions, we show that suitable empirical likelihood ratio statistics each converge in distribution to a 2 random variable. Through simulation studies, we investigate the advantages of this empirical likelihood approach compared to use of the usual normal approximation. Two examples from previously published clinical studies illustrate the use of the empirical likelihood methods we have described. Empirical likelihood has obvious appeal in deriving point and interval estimators for time-to-event data. However, when we use this method and its asymptotic critical value to construct simultaneous confidence bands for survival or cumulative hazard functions, it typically necessitates very large sample sizes to achieve reliable coverage accuracy. We propose using a bootstrap method to recalibrate the critical value of the sampling distribution of the sample log-likelihood ratios. Via simulation studies, we compare our EL-based bootstrap estimator for the survival function with EL-HW and EL-EP bands proposed by Hollander et al. (1997) and apply this method to obtain a simultaneous confidence band for the cumulative hazard ratios in the two clinical studies that we mentioned above. While copulas have been a popular statistical tool for modeling dependent data in recent years, selecting a parametric copula is a nontrivial task that may lead to model misspecification because different copula families involve different correlation structures. This observation motivates us to use empirical likelihood to estimate a copula nonparametrically. With this EL-based estimator of a copula, we derive a goodness-of-fit test for assessing a specific parametric copula model. By means of simulations, we demonstrate the merits of our EL-based testing procedure. We demonstrate this method using the data from Wieand et al. (1989). In the final chapter of the thesis, we provide a brief introduction to several areas for future research involving the empirical likelihood approach.

Modern medical practice and science involve complex phenotypic definitions. Understanding patterns of association across this range of phenotypes requires co-analysis of high-dimensional association studies in order to characterise shared and distinct elements. In this thesis I address several problems in this area, with a general linking aim of making more efficient use of available data. The main application of these methods is in the analysis of genome-wide association studies (GWAS) and similar studies. Firstly, I developed methodology for a Bayesian conditional false discovery rate (cFDR) for levering GWAS results using summary statistics from a related disease. I extended an existing method to enable a shared control design, increasing power and applicability, and developed an approximate bound on false-discovery rate (FDR) for the procedure. Using the new method I identified several new variant-disease associations. I then developed a second application of shared control design in the context of study replication, enabling improvement in power at the cost of changing the spectrum of sensitivity to systematic errors in study cohorts. This has application in studies on rare diseases or in between-case analyses. I then developed a method for partially characterising heterogeneity within a disease by modelling the bivariate distribution of case-control and within-case effect sizes. Using an adaptation of a likelihood-ratio test, this allows an assessment to be made of whether disease heterogeneity corresponds to differences in disease pathology. I applied this method to a range of simulated and real datasets, enabling insight into the cause of heterogeneity in autoantibody positivity in type 1 diabetes (T1D). Finally, I investigated the relation of subtypes of juvenile idiopathic arthritis (JIA) to adult diseases, using modified genetic risk scores and linear discriminants in a penalised regression framework. The contribution of this thesis is in a range of methodological developments in the analysis of high-dimensional association study comparison. Methods such as these will have wide application in the analysis of GWAS and similar areas, particularly in the development of stratified medicine.