Estimating the cure fraction in population-based cancer studies by using finite mixture models

Summary.  The cure fraction (the proportion of patients who are cured of disease) is of interest to both patients and clinicians and is a useful measure to monitor trends in survival of curable disease. The paper extends the non-mixture and mixture cure fraction models to estimate the proportion cured of disease in population-based cancer studies by incorporating a finite mixture of two Weibull distributions to provide more flexibility in the shape of the estimated relative survival or excess mortality functions. The methods are illustrated by using public use data from England and Wales on survival following diagnosis of cancer of the colon where interest lies in differences between age and deprivation groups. We show that the finite mixture approach leads to improved model fit and estimates of the cure fraction that are closer to the empirical estimates. This is particularly so in the oldest age group where the cure fraction is notably lower. The cure fraction is broadly similar in each deprivation group, but the median survival of the 'uncured' is lower in the more deprived groups. The finite mixture approach overcomes some of the limitations of the more simplistic cure models and has the potential to model the complex excess hazard functions that are seen in real data.     

The negative binomial–beta Weibull regression model to predict the cure of prostate cancer

In this article, for the first time, we propose the negative binomial–beta Weibull (BW) regression model for studying the recurrence of prostate cancer and to predict the cure fraction for patients with clinically localized prostate cancer treated by open radical prostatectomy. The cure model considers that a fraction of the survivors are cured of the disease. The survival function for the population of patients can be modeled by a cure parametric model using the BW distribution. We derive an explicit expansion for the moments of the recurrence time distribution for the uncured individuals. The proposed distribution can be used to model survival data when the hazard rate function is increasing, decreasing, unimodal and bathtub shaped. Another advantage is that the proposed model includes as special sub-models some of the well-known cure rate models discussed in the literature. We derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes. We analyze a real data set for localized prostate cancer patients after open radical prostatectomy.     

Accelerated hazards mixture cure model

We propose a new cure model for survival data with a surviving or cure fraction. The new model is a mixture cure model where the covariate effects on the proportion of cure and the distribution of the failure time of uncured patients are separately modeled. Unlike the existing mixture cure models, the new model allows covariate effects on the failure time distribution of uncured patients to be negligible at time zero and to increase as time goes by. Such a model is particularly useful in some cancer treatments when the treat effect increases gradually from zero, and the existing models usually cannot handle this situation properly. We develop a rank based semiparametric estimation method to obtain the maximum likelihood estimates of the parameters in the model. We compare it with existing models and methods via a simulation study, and apply the model to a breast cancer data set. The numerical studies show that the new model provides a useful addition to the cure model literature.     

Bayesian Semiparametric Cure Rate Model with an Unknown Threshold

Abstract.  We propose a Bayesian semiparametric model for survival data with a cure fraction. We explicitly consider a finite cure time in the model, which allows us to separate the cured and the uncured populations. We take a mixture prior of a Markov gamma process and a point mass at zero to model the baseline hazard rate function of the entire population. We focus on estimating the cure threshold after which subjects are considered cured. We can incorporate covariates through a structure similar to the proportional hazards model and allow the cure threshold also to depend on the covariates. For illustration, we undertake simulation studies and a full Bayesian analysis of a bone marrow transplant data set.     

A marginal regression model for multivariate failure time data with a surviving fraction

A marginal regression approach for correlated censored survival data has become a widely used statistical method. Examples of this approach in survival analysis include from the early work by Wei et al. (J Am Stat Assoc 84:1065–1073, 1989) to more recent work by Spiekerman and Lin (J Am Stat Assoc 93:1164–1175, 1998). This approach is particularly useful if a covariate’s population average effect is of primary interest and the correlation structure is not of interest or cannot be appropriately specified due to lack of sufficient information. In this paper, we consider a semiparametric marginal proportional hazard mixture cure model for clustered survival data with a surviving or “cure” fraction. Unlike the clustered data in previous work, the latent binary cure statuses of patients in one cluster tend to be correlated in addition to the possible correlated failure times among the patients in the cluster who are not cured. The complexity of specifying appropriate correlation structures for the data becomes even worse if the potential correlation between cure statuses and the failure times in the cluster has to be considered, and thus a marginal regression approach is particularly attractive. We formulate a semiparametric marginal proportional hazards mixture cure model. Estimates are obtained using an EM algorithm and expressions for the variance–covariance are derived using sandwich estimators. Simulation studies are conducted to assess finite sample properties of the proposed model. The marginal model is applied to a multi-institutional study of local recurrences of tonsil cancer patients who received radiation therapy. It reveals new findings that are not available from previous analyses of this study that ignored the potential correlation between patients within the same institution.     

Generalized estimating equations for mixtures with varying concentrations

A finite mixture model is considered in which the mixing probabilities vary from observation to observation. A parametric model is assumed for one mixture component distribution, while the others are nonparametric nuisance parameters. Generalized estimating equations (GEE) are proposed for the semi‐parametric estimation. Asymptotic normality of the GEE estimates is demonstrated and the lower bound for their dispersion (asymptotic covariance) matrix is derived. An adaptive technique is developed to derive estimates with nearly optimal small dispersion. An application to the sociological analysis of voting results is discussed. The Canadian Journal of Statistics 41: 217–236; 2013 © 2013 Statistical Society of Canada     

Vertical modeling: analysis of competing risks data with a cure fraction

In this paper, we extend the vertical modeling approach for the analysis of survival data with competing risks to incorporate a cure fraction in the population, that is, a proportion of the population for which none of the competing events can occur. The proposed method has three components: the proportion of cure, the risk of failure, irrespective of the cause, and the relative risk of a certain cause of failure, given a failure occurred. Covariates may affect each of these components. An appealing aspect of the method is that it is a natural extension to competing risks of the semi-parametric mixture cure model in ordinary survival analysis; thus, causes of failure are assigned only if a failure occurs. This contrasts with the existing mixture cure model for competing risks of Larson and Dinse, which conditions at the onset on the future status presumably attained. Regression parameter estimates are obtained using an EM-algorithm. The performance of the estimators is evaluated in a simulation study. The method is illustrated using a melanoma cancer data set.

     

Analysis of cure rate survival data under proportional odds model

Due to significant progress in cancer treatments and management in survival studies involving time to relapse (or death), we often need survival models with cured fraction to account for the subjects enjoying prolonged survival. Our article presents a new proportional odds survival models with a cured fraction using a special hierarchical structure of the latent factors activating cure. This new model has same important differences with classical proportional odds survival models and existing cure-rate survival models. We demonstrate the implementation of Bayesian data analysis using our model with data from the SEER (Surveillance Epidemiology and End Results) database of the National Cancer Institute. Particularly aimed at survival data with cured fraction, we present a novel Bayes method for model comparisons and assessments, and demonstrate our new tool’s superior performance and advantages over competing tools.     

A new approach for joint modelling of longitudinal measurements and survival times with a cure fraction

The joint analysis of longitudinal measurements and survival data is useful in clinical trials and other medical studies. In this paper, we consider a joint model which assumes a linear mixed $tt$ model for longitudinal measurements and a promotion time cure model for survival data and links these two models through a latent variable. A semiparametric inference procedure with an EM algorithm implementation is developed for the parameters in the joint model. The proposed procedure is evaluated in a simulation study and applied to analyze the quality of life and time to recurrence data from a clinical trial on women with early breast cancer. The Canadian Journal of Statistics 40: 207–224; 2012 © 2012 Statistical Society of Canada     

A new threshold regression model for survival data with a cure fraction

Due to the fact that certain fraction of the population suffering a particular type of disease get cured because of advanced medical treatment and health care system, we develop a general class of models to incorporate a cure fraction by introducing the latent number N of metastatic-competent tumor cells or infected cells caused by bacteria or viral infection and the latent antibody level R of immune system. Various properties of the proposed models are carefully examined and a Markov chain Monte Carlo sampling algorithm is developed for carrying out Bayesian computation for model fitting and comparison. A real data set from a prostate cancer clinical trial is analyzed in detail to demonstrate the proposed methodology.     

Nonparametric hierarchical Bayes analysis of binomial data via Bernstein polynomial priors

For binomial data analysis, many methods based on empirical Bayes interpretations have been developed, in which a variance‐stabilizing transformation and a normality assumption are usually required. To achieve the greatest model flexibility, we conduct nonparametric Bayesian inference for binomial data and employ a special nonparametric Bayesian prior—the Bernstein–Dirichlet process (BDP)—in the hierarchical Bayes model for the data. The BDP is a special Dirichlet process (DP) mixture based on beta distributions, and the posterior distribution resulting from it has a smooth density defined on [0, 1]. We examine two Markov chain Monte Carlo procedures for simulating from the resulting posterior distribution, and compare their convergence rates and computational efficiency. In contrast to existing results for posterior consistency based on direct observations, the posterior consistency of the BDP, given indirect binomial data, is established. We study shrinkage effects and the robustness of the BDP‐based posterior estimators in comparison with several other empirical and hierarchical Bayes estimators, and we illustrate through examples that the BDP‐based nonparametric Bayesian estimate is more robust to the sample variation and tends to have a smaller estimation error than those based on the DP prior. In certain settings, the new estimator can also beat Stein's estimator, Efron and Morris's limited‐translation estimator, and many other existing empirical Bayes estimators. The Canadian Journal of Statistics 40: 328–344; 2012 © 2012 Statistical Society of Canada     

Testing for the Presence of a Cure Fraction in Clustered Interval‐Censored Survival Data

Clustered interval‐censored survival data are often encountered in clinical and epidemiological studies due to geographic exposures and periodic visits of patients. When a nonnegligible cured proportion exists in the population, several authors in recent years have proposed to use mixture cure models incorporating random effects or frailties to analyze such complex data. However, the implementation of the mixture cure modeling approaches may be cumbersome. Interest then lies in determining whether or not it is necessary to adjust the cured proportion prior to the mixture cure analysis. This paper mainly focuses on the development of a score for testing the presence of cured subjects in clustered and interval‐censored survival data. Through simulation, we evaluate the sampling distribution and power behaviour of the score test. A bootstrap approach is further developed, leading to more accurate significance levels and greater power in small sample situations. We illustrate applications of the test using data sets from a smoking cessation study and a retrospective study of early breast cancer patients.     

Large sample interval mapping method for genetic trait loci in finite regression mixture models

This article investigates the large sample interval mapping method for genetic trait loci (GTL) in a finite non-linear regression mixture model. The general model includes most commonly used kernel functions, such as exponential family mixture, logistic regression mixture and generalized linear mixture models, as special cases. The populations derived from either the backcross or intercross design are considered. In particular, unlike all existing results in the literature in the finite mixture models, the large sample results presented in this paper do not require the boundness condition on the parametric space. Therefore, the large sample theory presented in this article possesses general applicability to the interval mapping method of GTL in genetic research. The limiting null distribution of the likelihood ratio test statistics can be utilized easily to determine the threshold values or p-values required in the interval mapping. The limiting distribution is proved to be free of the parameter values of null model and free of the choice of a kernel function. Extension to the multiple marker interval GTL detection is also discussed. Simulation study results show favorable performance of the asymptotic procedure when sample sizes are moderate.     

Cure rate survival models with missing covariates: a simulation study

In this paper we study the cure rate survival model involving a competitive risk structure with missing categorical covariates. A parametric distribution that can be written as a sequence of one-dimensional conditional distributions is specified for the missing covariates. We consider the missing data at random situation so that the missing covariates may depend only on the observed ones. Parameter estimates are obtained by using the EM algorithm via the method of weights. Extensive simulation studies are conducted and reported to compare estimates efficiency with and without missing data. As expected, the estimation approach taking into consideration the missing covariates presents much better efficiency in terms of mean square errors than the complete case situation. Effects of increasing cured fraction and censored observations are also reported. We demonstrate the proposed methodology with two real data sets. One involved the length of time to obtain a BS degree in Statistics, and another about the time to breast cancer recurrence.     

Latent cure rate model under repair system and threshold effect

In this paper, we formulate a simple latent cure rate model with repair mechanism for a cell exposed to radiation. This latent approach is a flexible alternative to the models proposed by Klebanov et al. [A stochastic model of radiation carcinogenesis: latent time distributions and their properties. Math Biosci. 1993;18:51–75], Kim et al. [A new threshold regression model for survival data with a cure fraction. Lifetime Data Anal. 2011;17:101–122], and is along the lines of the destructive cure rate model formulated recently by Rodrigues et al. [Destructive weighted Poisson cure rate model. Lifetime Data Anal. 2011b;17:333–346]. A new version of the modified Gompertz model and the promotion cure rate model that takes into account the first passage time of reaching the critical point are discussed, and the estimation of tumor size at detection is then addressed from the Bayesian viewpoint. In addition, a simulation study and an application to real data set illustrate the usefulness of the proposed cure rate model.     

Semiparametric inference for survival models with step process covariates

The authors consider Bayesian methods for fitting three semiparametric survival models, incorporating time‐dependent covariates that are step functions. In particular, these are models due to Cox [Cox ( 1972 ) Journal of the Royal Statistical Society, Series B, 34, 187–208], Prentice & Kalbfleisch and Cox & Oakes [Cox & Oakes ( 1984 ) Analysis of Survival Data, Chapman and Hall, London]. The model due to Prentice & Kalbfleisch [Prentice & Kalbfleisch ( 1979 ) Biometrics, 35, 25–39], which has seen very limited use, is given particular consideration. The prior for the baseline distribution in each model is taken to be a mixture of Polya trees and posterior inference is obtained through standard Markov chain Monte Carlo methods. They demonstrate the implementation and comparison of these three models on the celebrated Stanford heart transplant data and the study of the timing of cerebral edema diagnosis during emergency room treatment of diabetic ketoacidosis in children. An important feature of their overall discussion is the comparison of semi‐parametric families, and ultimate criterion based selection of a family within the context of a given data set. The Canadian Journal of Statistics 37: 60–79; © 2009 Statistical Society of Canada     

Modelling survival data using mixtures of frailties

Frailty models are often used to describe the extra heterogeneity in survival data by introducing an individual random, unobserved effect. The frailty term is usually assumed to act multiplicatively on a baseline hazard function common to all individuals. In order to apply the frailty model, a specific frailty distribution has to be assumed. If at least one of the latent variables is continuous, the frailty must follow a continuous distribution. In this paper, a finite mixture of continuous frailty distributions is used in order to describe situations in which one (or more) of the latent variables separates the population in study into two (or more) subpopulations. Closure properties of the unobserved quantity are given along with the maximum-likelihood estimates under the most common choices of frailty distributions. The model is illustrated on a set of lifetime data.     

EM algorithm-based likelihood estimation for a generalized Gompertz regression model in presence of survival data with long-term survivors: an application to uterine cervical cancer data

In this paper we develop a regression model for survival data in the presence of long-term survivors based on the generalized Gompertz distribution introduced by El-Gohary et al. [The generalized Gompertz distribution. Appl Math Model. 2013;37:13–24] in a defective version. This model includes as special case the Gompertz cure rate model proposed by Gieser et al. [Modelling cure rates using the Gompertz model with covariate information. Stat Med. 1998;17:831–839]. Next, an expectation maximization algorithm is then developed for determining the maximum likelihood estimates (MLEs) of the parameters of the model. In addition, we discuss the construction of confidence intervals for the parameters using the asymptotic distributions of the MLEs and the parametric bootstrap method, and assess their performance through a Monte Carlo simulation study. Finally, the proposed methodology was applied to a database on uterine cervical cancer.     

Modeling survival in childhood cancer studies using two-stage non-mixture cure models

Non-mixture cure models (NMCMs) are derived from a simplified representation of the biological process that takes place after treatment for cancer. These models are intended to represent the time from the end of treatment to the time of first recurrence of cancer in studies when a proportion of those treated are completely cured. However, for many studies overall survival is also of interest. A two-stage NMCM that estimates the overall survival from a combination of two cure models, one from end of treatment to first recurrence and one from first recurrence to death, is proposed. The model is applied to two studies of Ewing's tumor in young patients. Caution needs to be exercised when extrapolating from cure models fitted to short follow-up times, but these data and associated simulations show how, when follow-up is limited, a two-stage model can give more stable estimates of the cure fraction than a one-stage model applied directly to overall survival.     

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.