A flexible model for survival data with a cure rate: a Bayesian approach

In this paper we deal with a Bayesian analysis for right-censored survival data suitable for populations with a cure rate. We consider a cure rate model based on the negative binomial distribution, encompassing as a special case the promotion time cure model. Bayesian analysis is based on Markov chain Monte Carlo (MCMC) methods. We also present some discussion on model selection and an illustration with a real data set.     

Multilevel models for longitudinal variables prognostic for survival

The issue of modelling the joint distribution of survival time and of prognostic variables measured periodically has recently become of interest in the AIDS literature but is of relevance in other applications. The focus of this paper is on clinical trials where follow-up measurements of potentially prognostic variables are often collected but not routinely used. These measurements can be used to study the biological evolution of the disease of interest; in particular the effect of an active treatment can be examined by comparing the time profiles of patients in the active and placebo group. It is proposed to use multilevel regression analysis to model the individual repeated observations as function of time and, possibly, treatment. To address the problem of informative drop-out—which may arise if deaths (or any other censoring events) are related to the unobserved values of the prognostic variables—we analyse sequentially overlapping portions of the follow-up information. An example arising from a randomized clinical trial for the treatment of primary biliary cirrhosis is examined in detail.     

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.     

Book Reviews

Books reviewed:
Robert, Hooke, How to Tell the Liars from the Statisticians
John D., Spurrier, The Practice of Statistics: Putting the Pieces Together
Clive, Loader, Local Regression and Likelihood
N., Balakrishnan; V.B., Melas and S., Ermakov, (eds) Advances in Stochastic Simulation Methods
J.W., Kay and D.M., Titterington, (eds) Statistics and Neural Networks: Advances at the Interface
B.S., Everitt, The Cambridge Dictionary of Statistics     

Testing for Homogeneity in an Exponential Mixture Model

This paper studies diagnostic procedures to test for homogeneity against unobserved heterogeneity in an exponential mixture model. The procedures include a dispersion score test, a likelihood ratio test, a moment likelihood approach and several goodness-of-fit tests. The paper compares the empirical power of these tests on a broad range of alternatives and proposes a new test that combines the dispersion score test with a properly chosen goodness-of-fit procedure; its empirical power comes close to the power of the best of the other tests.     

Mixture models in survival analysis: Are they worth the risk?

There has been a recurring interest in models for survival data which hypothesize subpopulations of individuals highly susceptible to some type of adverse event. Other individuals are assumed to be at much less risk. Most commonly, in clinical trials, these models attempt to estimate the fraction of patients cured of disease. The use of such models is examined, and the likelihood function is advocated as an informative inference tool.     

A fully nonparametric approach in survival models with explanatory variables

The most widely used model for multidimensional survival analysis is the Cox model. This model is semi-parametric, since its hazard function is the product of an unspecified baseline hazard, and a parametric functional form relating the hazard and the covariates. We consider a more flexible and fully nonparametric proportional hazards model, where the functional form of the covariates effect is left unspecified. In this model, estimation is based on the maximum likelihood method. Results obtained from a Monte-Carlo experiment and from real data are presented. Finally, the advantages and the limitations of the approacha are discussed.     

On a measure of information gain for regression models in survival analysis

Papers dealing with measures of predictive power in survival analysis have seen their independence of censoring, or their estimates being unbiased under censoring, as the most important property. We argue that this property has been wrongly understood. Discussing the so-called measure of information gain, we point out that we cannot have unbiased estimates if all values, greater than a given time τ, are censored. This is due to the fact that censoring before τ has a different effect than censoring after τ. Such τ is often introduced by design of a study. Independence can only be achieved under the assumption of the model being valid after τ, which is impossible to verify. But if one is willing to make such an assumption, we suggest using multiple imputation to obtain a consistent estimate. We further show that censoring has different effects on the estimation of the measure for the Cox model than for parametric models, and we discuss them separately. We also give some warnings about the usage of the measure, especially when it comes to comparing essentially different models.     

A Bayesian approach to Weibull survival models—Application to a cancer clinical trial

In this paper we outline a class of fully parametric proportional hazards models, in which the baseline hazard is assumed to be a power transform of the time scale, corresponding to assuming that survival times follow a Weibull distribution. Such a class of models allows for the possibility of time varying hazard rates, but assumes a constant hazard ratio. We outline how Bayesian inference proceeds for such a class of models using asymptotic approximations which require only the ability to maximize the joint log posterior density. We apply these models to a clinical trial to assess the efficacy of neutron therapy compared to conventional treatment for patients with tumors of the pelvic region. In this trial there was prior information about the log hazard ratio both in terms of elicited clinical beliefs and the results of previous studies. Finally, we consider a number of extensions to this class of models, in particular the use of alternative baseline functions, and the extension to multi-state data.     

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.     

Mixtures of autoregressive-autoregressive conditionally heteroscedastic models: semi-parametric approach

We propose data generating structures which can be represented as a mixture of autoregressive-autoregressive conditionally heteroscedastic models. The switching between the states is governed by a hidden Markov chain. We investigate semi-parametric estimators for estimating the functions based on the quasi-maximum likelihood approach and provide sufficient conditions for geometric ergodicity of the process. We also present an expectation–maximization algorithm for calculating the estimates numerically.     

Discrete and continuous bivariate lifetime models in presence of cure rate: a comparative study under Bayesian approach

The modeling and analysis of lifetime data in which the main endpoints are the times when an event of interest occurs is of great interest in medical studies. In these studies, it is common that two or more lifetimes associated with the same unit such as the times to deterioration levels or the times to reaction to a treatment in pairs of organs like lungs, kidneys, eyes or ears. In medical applications, it is also possible that a cure rate is present and needed to be modeled with lifetime data with long-term survivors. This paper presented a comparative study under a Bayesian approach among some existing continuous and discrete bivariate distributions such as the bivariate exponential distributions and the bivariate geometric distributions in presence of cure rate, censored data and covariates. In presence of lifetimes related to cured patients, it is assumed standard mixture cure rate models in the data analysis. The posterior summaries of interest are obtained using Markov Chain Monte Carlo methods. To illustrate the proposed methodology two real medical data sets are considered.     

Using regression mixture models with non-normal data: examining an ordered polytomous approach

Mild to moderate skew in errors can substantially impact regression mixture model results; one approach for overcoming this includes transforming the outcome into an ordered categorical variable and using a polytomous regression mixture model. This is effective for retaining differential effects in the population; however, bias in parameter estimates and model fit warrant further examination of this approach at higher levels of skew. The current study used Monte Carlo simulations; 3000 observations were drawn from each of two subpopulations differing in the effect of X on Y. Five hundred simulations were performed in each of the 10 scenarios varying in levels of skew in one or both classes. Model comparison criteria supported the accurate two-class model, preserving the differential effects, while parameter estimates were notably biased. The appropriate number of effects can be captured with this approach but we suggest caution when interpreting the magnitude of the effects.     

Modified profile likelihood estimation for the Weibull regression models in survival analysis

In this study, adjustment of profile likelihood function of parameter of interest in presence of many nuisance parameters is investigated for survival regression models. Our objective is to extend the Barndorff–Nielsen’s technique to Weibull regression models for estimation of shape parameter in presence of many nuisance and regression parameters. We conducted Monte-Carlo simulation studies and a real data analysis, all of which demonstrate and suggest that the modified profile likelihood estimators outperform the profile likelihood estimators in terms of three comparison criterion: mean squared errors, bias and standard errors.     

A Bayesian approach to mixture cure models with spatial frailties for population‐based cancer relative survival data

As the treatments of cancer progress, a certain number of cancers are curable if diagnosed early. In population‐based cancer survival studies, cure is said to occur when mortality rate of the cancer patients returns to the same level as that expected for the general cancer‐free population. The estimates of cure fraction are of interest to both cancer patients and health policy makers. Mixture cure models have been widely used because the model is easy to interpret by separating the patients into two distinct groups. Usually parametric models are assumed for the latent distribution for the uncured patients. The estimation of cure fraction from the mixture cure model may be sensitive to misspecification of latent distribution. We propose a Bayesian approach to mixture cure model for population‐based cancer survival data, which can be extended to county‐level cancer survival data. Instead of modeling the latent distribution by a fixed parametric distribution, we use a finite mixture of the union of the lognormal, loglogistic, and Weibull distributions. The parameters are estimated using the Markov chain Monte Carlo method. Simulation study shows that the Bayesian method using a finite mixture latent distribution provides robust inference of parameter estimates. The proposed Bayesian method is applied to relative survival data for colon cancer patients from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the cure fractions. The Canadian Journal of Statistics 40: 40–54; 2012 © 2012 Statistical Society of Canada     

The glm log-rank test:general linear modeling of log-rank scores as a method of analysis for survival data

The use of general linear modeling (GLM) procedures based on log-rank scores is proposed for the analysis of survival data and compared to standard survival analysis procedures. For the comparison of two groups, this approach performed similarly to the traditional log-rank test. In the case of more complicated designs - without ties in the survival times - the approach was only marginally less powerful than tests from proportional hazards models, and clearly less powerful than a likelihood ratio test for a fully parametric model; however, with ties in the survival time, the approach proved more powerful than tests from Cox's semi-parametric proportional hazards procedure. The method appears to provide a reasonably powerful alternative for the analysis of survival data, is easily used in complicated study designs, avoids (semi-)parametric assumptions, and is quite computationally easy and inexpensive to employ.     

Bayesian Weibull tree models for survival analysis of clinico-genomic data

An important goal of research involving gene expression data for outcome prediction is to establish the ability of genomic data to define clinically relevant risk factors. Recent studies have demonstrated that microarray data can successfully cluster patients into low- and high-risk categories. However, the need exists for models which examine how genomic predictors interact with existing clinical factors and provide personalized outcome predictions. We have developed clinico-genomic tree models for survival outcomes which use recursive partitioning to subdivide the current data set into homogeneous subgroups of patients, each with a specific Weibull survival distribution. These trees can provide personalized predictive distributions of the probability of survival for individuals of interest. Our strategy is to fit multiple models; within each model we adopt a prior on the Weibull scale parameter and update this prior via Empirical Bayes whenever the sample is split at a given node. The decision to split is based on a Bayes factor criterion. The resulting trees are weighted according to their relative likelihood values and predictions are made by averaging over models. In a pilot study of survival in advanced stage ovarian cancer we demonstrate that clinical and genomic data are complementary sources of information relevant to survival, and we use the exploratory nature of the trees to identify potential genomic biomarkers worthy of further study.     

Symmetric pattern models: a latent variable approach to item non-response in attitude scales

This paper proposes a new approach to the treatment of item non-response in attitude scales. It combines the ideas of latent variable identification with the issues of non-response adjustment in sample surveys. The latent variable approach allows missing values to be included in the analysis and, equally importantly, allows information about attitude to be inferred from non-response. We present a symmetric pattern methodology for handling item non-response in attitude scales. The methodology is symmetric in that all the variables are given equivalent status in the analysis (none is designated a 'dependent' variable) and is pattern based in that the pattern of responses and non-responses across individuals is a key element in the analysis. Our approach to the problem is through a latent variable model with two latent dimensions: one to summarize response propensity and the other to summarize attitude, ability or belief. The methodology presented here can handle binary, metric and mixed (binary and metric) manifest items with missing values. Examples using both artificial data sets and two real data sets are used to illustrate the mechanism and the advantages of the methodology proposed.