Predicting analysis time in events‐driven clinical trials using accumulating time‐to‐event surrogate information

For clinical trials with time‐to‐event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre‐specified number of deaths. Often, correlated surrogate information, such as time‐to‐progression (TTP) and progression‐free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression‐free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd.     

Modelling paired categorical outcomes in clinical trials

The goal of this paper is to discuss methods for testing the homogeneity of treatment‐induced changes in trials with paired categorical responses. Widely used marginal homogeneity tests ignore the information contained in concordant pairs of observations and become highly underpowered for configurations of parameters encountered in real trials. This paper considers models for paired binary or ordinal outcomes based on both discordant and concordant pairs that provide a natural extension of marginal models. Likelihood‐ratio tests associated with these models are developed and are demonstrated to be at least as powerful as or more powerful than marginal homogeneity tests. The proposed models are easy to fit using standard statistical software. Copyright © 2003 John Wiley & Sons, Ltd.     

A self-consistent estimator of marginal survival functions based on dependent competing risk data and an assumed copula

When the time to death, X, and the time to censoring, Y, are associated some additional information is need to identify the marginal survival functions. A natural function which provides this additional information is the copula of X and Y. Assuming that the copula is known, we use the notion of self consistency to construct an estimator of the marginal survival functions based on dependent competing risk data. Results of a small simulation study are shown to compare this estimator to other estimators of the marginal survival function based on an assumed copula.     

Marker processes in survival analysis

In the development of many diseases there are often associated variables which continuously measure the progress of an individual towards the final expression of the disease (failure). Such variables are stochastic processes, here called marker processes, and, at a given point in time, they may provide information about the current hazard and subsequently on the remaining time to failure. Here we consider a simple additive model for the relationship between the hazard function at time t and the history of the marker process up until time t. We develop some basic calculations based on this model. Interest is focused on statistical applications for markers related to estimation of the survival distribution of time to failure, including (i) the use of markers as surrogate responses for failure with censored data, and (ii) the use of markers as predictors of the time elapsed since onset of a survival process in prevalent individuals. Particular attention is directed to potential gains in efficiency incurred by using marker process information.     

A comparison of nonparametric priors in hierarchical mixture modelling for AFT regression

We will pursue a Bayesian nonparametric approach in the hierarchical mixture modelling of lifetime data in two situations: density estimation, when the distribution is a mixture of parametric densities with a nonparametric mixing measure, and accelerated failure time (AFT) regression modelling, when the same type of mixture is used for the distribution of the error term. The Dirichlet process is a popular choice for the mixing measure, yielding a Dirichlet process mixture model for the error; as an alternative, we also allow the mixing measure to be equal to a normalized inverse-Gaussian prior, built from normalized inverse-Gaussian finite dimensional distributions, as recently proposed in the literature. Markov chain Monte Carlo techniques will be used to estimate the predictive distribution of the survival time, along with the posterior distribution of the regression parameters. A comparison between the two models will be carried out on the grounds of their predictive power and their ability to identify the number of components in a given mixture density.     

Joint analysis of longitudinal data comprising repeated measures and times to events

In biomedical and public health research, both repeated measures of biomarkers Y as well as times T to key clinical events are often collected for a subject. The scientific question is how the distribution of the responses [ T , Y | X ] changes with covariates X . [ T | X ] may be the focus of the estimation where Y can be used as a surrogate for T . Alternatively, T may be the time to drop-out in a study in which [ Y | X ] is the target for estimation. Also, the focus of a study might be on the effects of covariates X on both T and Y or on some underlying latent variable which is thought to be manifested in the observable outcomes. In this paper, we present a general model for the joint analysis of [ T , Y | X ] and apply the model to estimate [ T | X ] and other related functionals by using the relevant information in both T and Y . We adopt a latent variable formulation like that of Fawcett and Thomas and use it to estimate several quantities of clinical relevance to determine the efficacy of a treatment in a clinical trial setting. We use a Markov chain Monte Carlo algorithm to estimate the model's parameters. We illustrate the methodology with an analysis of data from a clinical trial comparing risperidone with a placebo for the treatment of schizophrenia.     

Modeling Event Times with Multiple Outcomes Using the Wiener Process with Drift

Length of stay in hospital (LOS) is a widely used outcome measure in Health Services research, often acting as a surrogate for resource consumption or as a measure of efficiency. The distribution of LOS is typically highly skewed, with a few large observations. An interesting feature is the presence of multiple outcomes (e.g. healthy discharge, death in hospital, transfer to another institution). Health Services researchers are interested in modeling the dependence of LOS on covariates, often using administrative data collected for other purposes, such as calculating fees for doctors. Even after all available covariates have been included in the model, unexplained heterogeneity usually remains. In this article, we develop a parametric regression model for LOS that addresses these features. The model is based on the time, T, that a Wiener process with drift (representing an unobserved health level process) hits one of two barriers, one representing healthy discharge and the other death in hospital. Our approach to analyzing event times has many parallels with competing risks analysis (Kalbfleisch and Prentice, The Statistical Analysis of Failure Time Data, New York: John Wiley and Sons, 1980)), and can be seen as a way of formalizing a competing risks situation. The density of T is an infinite series, and we outline a proof that the density and its derivatives are absolutely and uniformly convergent, and regularity conditions are satisfied. Expressions for the expected value of T, the conditional expectation of T given outcome, and the probability of each outcome are available in terms of model parameters. The proposed regression model uses an approximation to the density formed by truncating the series, and its parameters are estimated by maximum likelihood. An extension to allow a third outcome (e.g. transfers out of hospital) is discussed, as well as a mixture model that addresses the issue of unexplained heterogeneity. The model is illustrated using administrative data.     

Bivariate Kumaraswamy distribution: properties and a new method to generate bivariate classes

In this paper, we introduce a bivariate Kumaraswamy (BVK) distribution whose marginals are Kumaraswamy distributions. The cumulative distribution function of this bivariate model has absolutely continuous and singular parts. Representations for the cumulative and density functions are presented and properties such as marginal and conditional distributions, product moments and conditional moments are obtained. We show that the BVK model can be obtained from the Marshall and Olkin survival copula and obtain a tail dependence measure. The estimation of the parameters by maximum likelihood is discussed and the Fisher information matrix is determined. We propose an EM algorithm to estimate the parameters. Some simulations are presented to verify the performance of the direct maximum-likelihood estimation and the proposed EM algorithm. We also present a method to generate bivariate distributions from our proposed BVK distribution. Furthermore, we introduce a BVK distribution which has only an absolutely continuous part and discuss some of its properties. Finally, a real data set is analysed for illustrative purposes.     

The validation of surrogate end points by using data from randomized clinical trials: a case-study in advanced colorectal cancer

Summary.  In many therapeutic areas, the identification and validation of surrogate end points is of prime interest to reduce the duration and/or size of clinical trials. Buyse and co-workers and Burzykowski and co-workers have proposed a validation strategy for end points that are either normally distributed or (possibly censored) failure times. In this paper, we address the problem of validating an ordinal categorical or binary end point as a surrogate for a failure time true end point. In particular, we investigate the validity of tumour response as a surrogate for survival time in evaluating fluoropyrimidine-based experimental therapies for advanced colorectal cancer. Our analysis is performed on data from 28 randomized trials in advanced colorectal cancer, which are available through the Meta-Analysis Group in Cancer.     

Models for residual time to AIDS

The distributions of the time from Human Immunodeficiency Virus (HIV) infection to the onset of Acquired Immune Deficiency Syndrome (AIDS) and of the residual time to AIDS diagnosis are important for modeling the growth of the AIDS epidemic and for predicting onset of the disease in an individual. Markers such as CD4 counts carry valuable information about disease progression and therefore about the two survival distributions. Building on the framework set out by Jewell and Kalbfleisch (1992), we study these two survival distributions based on stochastic models for the marker process (X(t)) and a marker-dependent hazard (h()). We examine various plausible CD4 marker processes and marker-dependent hazard functions for AIDS proposed in recent literature. For a random effects plus Brownian motion marker process X(t)=(a+bt+BM(t))⁴, where a has a normal distribution, b<0 is an unknown parameter and BM(t) is Brownian motion, and marker-dependent hazard h(X(t)), we prove that, given CD4 cell count X(t), the residual time to AIDS distribution does not depend on the time since infection t. Using simulation and numerical integration, we find the marginal incubation period distribution, the marginal hazard and the residual time distribution for several combinations of marker processes and marker-dependent hazards. An example using data from the Multicenter AIDS Cohort Study is given. A simple regression model relating the cube root of residual time to AIDS to CD4 count is suggested.     

A flexible parametric survival model for fitting time to event data in clinical trials

Time‐to‐event data are common in clinical trials to evaluate survival benefit of a new drug, biological product, or device. The commonly used parametric models including exponential, Weibull, Gompertz, log‐logistic, log‐normal, are simply not flexible enough to capture complex survival curves observed in clinical and medical research studies. On the other hand, the nonparametric Kaplan Meier (KM) method is very flexible and successful on catching the various shapes in the survival curves but lacks ability in predicting the future events such as the time for certain number of events and the number of events at certain time and predicting the risk of events (eg, death) over time beyond the span of the available data from clinical trials. It is obvious that neither the nonparametric KM method nor the current parametric distributions can fulfill the needs in fitting survival curves with the useful characteristics for predicting. In this paper, a full parametric distribution constructed as a mixture of three components of Weibull distribution is explored and recommended to fit the survival data, which is as flexible as KM for the observed data but have the nice features beyond the trial time, such as predicting future events, survival probability, and hazard function.     

Structural changes in multivariate regression models

This study generalizes the work of chin choy and Broemeling (1980) who investigated the change in the regression parameters of univariate linear models.

The marginal posterior distributions of the change point, the regression matrices,and the precision matrix are found with the use of a proper multivariate normal-Wishart distribution for the parameters of the model.

A numerical study is undertaken in order to gain some insight into the effect that changes in sample size and certain parameter values have on these marginal posterior distributions.     

Models for potentially biased evidence in meta-analysis using empirically based priors

Summary.  We present models for the combined analysis of evidence from randomized controlled trials categorized as being at either low or high risk of bias due to a flaw in their conduct. We formulate a bias model that incorporates between-study and between-meta-analysis heterogeneity in bias, and uncertainty in overall mean bias. We obtain algebraic expressions for the posterior distribution of the bias-adjusted treatment effect, which provide limiting values for the information that can be obtained from studies at high risk of bias. The parameters of the bias model can be estimated from collections of previously published meta-analyses. We explore alternative models for such data, and alternative methods for introducing prior information on the bias parameters into a new meta-analysis. Results from an illustrative example show that the bias-adjusted treatment effect estimates are sensitive to the way in which the meta-epidemiological data are modelled, but that using point estimates for bias parameters provides an adequate approximation to using a full joint prior distribution. A sensitivity analysis shows that the gain in precision from including studies at high risk of bias is likely to be low, however numerous or large their size, and that little is gained by incorporating such studies, unless the information from studies at low risk of bias is limited. We discuss approaches that might increase the value of including studies at high risk of bias, and the acceptability of the methods in the evaluation of health care interventions.     

Report of the ASA Technical Panel on the Census Undercount

A new model is proposed for the joint distribution of paired survival times generated from clinical trials and certain reliability settings. The new model can be considered an extension to the bivariate exponential models studied in the literature. Here, a more flexible bivariate Weibull model will be derived, and two exact parametric tests for testing the equality of marginal survival distributions are developed.     

Fisher Information for Two Gamma Frailty Bivariate Weibull Models

The asymptotic properties of frailty models for multivariate survival data are not well understood. To study this aspect, the Fisher information is derived in the standard bivariate gamma frailty model, where the survival distribution is of Weibull form conditional on the frailty. For comparison, the Fisher information is also derived in the bivariate gamma frailty model, where the marginal distribution is of Weibull form.     

An objective Bayesian analysis of the two-parameter half-logistic distribution based on progressively type-II censored samples

This paper develops an objective Bayesian analysis method for estimating unknown parameters of the half-logistic distribution when a sample is available from the progressively Type-II censoring scheme. Noninformative priors such as Jeffreys and reference priors are derived. In addition, derived priors are checked to determine whether they satisfy probability-matching criteria. The Metropolis–Hasting algorithm is applied to generate Markov chain Monte Carlo samples from these posterior density functions because marginal posterior density functions of each parameter cannot be expressed in an explicit form. Monte Carlo simulations are conducted to investigate frequentist properties of estimated models under noninformative priors. For illustration purposes, a real data set is presented, and the quality of models under noninformative priors is evaluated through posterior predictive checking.     

An individual measure of relative survival

Summary.  Relative survival techniques are used to compare survival experience in a study cohort with that expected if background population rates apply. The techniques are especially useful when cause-specific death information is not accurate or not available as they provide a measure of excess mortality in a group of patients with a certain disease. Whereas these methods are based on group comparisons, we present here a transformation approach which instead gives for each individual an outcome measure relative to the appropriate background population. The new outcome measure is easily interpreted and can be analysed by using standard survival analysis techniques. It provides additional information on relative survival and gives new options in regression analysis. For example, one can estimate the proportion of patients who survived longer than a given percentile of the respective general population or compare survival experience of individuals while accounting for the population differences. The regression models for the new outcome measure are different from existing models, thus providing new possibilities in analysing relative survival data. One distinctive feature of our approach is that we adjust for expected survival before modelling. The paper is motivated by a study into the survival of patients after acute myocardial infarction.     

Exact Bayesian modeling for bivariate Poisson data and extensions

Bivariate count data arise in several different disciplines (epidemiology, marketing, sports statistics just to name a few) and the bivariate Poisson distribution being a generalization of the Poisson distribution plays an important role in modelling such data. In the present paper we present a Bayesian estimation approach for the parameters of the bivariate Poisson model and provide the posterior distributions in closed forms. It is shown that the joint posterior distributions are finite mixtures of conditionally independent gamma distributions for which their full form can be easily deduced by a recursively updating scheme. Thus, the need of applying computationally demanding MCMC schemes for Bayesian inference in such models will be removed, since direct sampling from the posterior will become available, even in cases where the posterior distribution of functions of the parameters is not available in closed form. In addition, we define a class of prior distributions that possess an interesting conjugacy property which extends the typical notion of conjugacy, in the sense that both prior and posteriors belong to the same family of finite mixture models but with different number of components. Extension to certain other models including multivariate models or models with other marginal distributions are discussed.     

An index of local sensitivity to non-ignorability for parametric survival models with potential non-random missing covariate: an application to the SEER cancer registry data

Several survival regression models have been developed to assess the effects of covariates on failure times. In various settings, including surveys, clinical trials and epidemiological studies, missing data may often occur due to incomplete covariate data. Most existing methods for lifetime data are based on the assumption of missing at random (MAR) covariates. However, in many substantive applications, it is important to assess the sensitivity of key model inferences to the MAR assumption. The index of sensitivity to non-ignorability (ISNI) is a local sensitivity tool to measure the potential sensitivity of key model parameters to small departures from the ignorability assumption, needless of estimating a complicated non-ignorable model. We extend this sensitivity index to evaluate the impact of a covariate that is potentially missing, not at random in survival analysis, using parametric survival models. The approach will be applied to investigate the impact of missing tumor grade on post-surgical mortality outcomes in individuals with pancreas-head cancer in the Surveillance, Epidemiology, and End Results data set. For patients suffering from cancer, tumor grade is an important risk factor. Many individuals in these data with pancreas-head cancer have missing tumor grade information. Our ISNI analysis shows that the magnitude of effect for most covariates (with significant effect on the survival time distribution), specifically surgery and tumor grade as some important risk factors in cancer studies, highly depends on the missing mechanism assumption of the tumor grade. Also a simulation study is conducted to evaluate the performance of the proposed index in detecting sensitivity of key model parameters.