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 general hazard model for lifetime data in the presence of cure rate

Historically, the cure rate model has been used for modeling time-to-event data within which a significant proportion of patients are assumed to be cured of illnesses, including breast cancer, non-Hodgkin lymphoma, leukemia, prostate cancer, melanoma, and head and neck cancer. Perhaps the most popular type of cure rate model is the mixture model introduced by Berkson and Gage [1]. In this model, it is assumed that a certain proportion of the patients are cured, in the sense that they do not present the event of interest during a long period of time and can found to be immune to the cause of failure under study. In this paper, we propose a general hazard model which accommodates comprehensive families of cure rate models as particular cases, including the model proposed by Berkson and Gage. The maximum-likelihood-estimation procedure is discussed. A simulation study analyzes the coverage probabilities of the asymptotic confidence intervals for the parameters. A real data set on children exposed to HIV by vertical transmission illustrates the methodology.     

The Dynamic Model for Cancer Relapse Based on Two-Stage Model of Carcinogenesis

In this article, the time from the start of chemotherapy randomization until cancer relapse is of primary interest. Here, cancer relapse refers to the appearance of the first observable malignant clone after therapy. A dynamic model for cancer relapse after chemotherapy is developed. The model differs from the traditional cure rate models in that it takes into consideration the growth kinetics of malignant tumors using a two-stage carcinogenesis model. The survival and hazard functions for cancer relapse time are derived, and a simulation study is performed to validate the underlying model.     

Accounting for uncertainty in extremal dependence modeling using Bayesian model averaging techniques

Modeling the joint tail of an unknown multivariate distribution can be characterized as modeling the tail of each marginal distribution and modeling the dependence structure between the margins. Classical methods for modeling multivariate extremes are based on the class of multivariate extreme value distributions. However, such distributions do not allow for the possibility of dependence at finite levels that vanishes in the limit. Alternative models have been developed that account for this asymptotic independence, but inferential statistical procedures seeking to combine the classes of asymptotically dependent and asymptotically independent models have been of limited use. We overcome these difficulties by employing Bayesian model averaging to account for both types of asymptotic behavior, and for subclasses within the asymptotically independent framework. Our approach also allows for the calculation of posterior probabilities of different classes of models, allowing for direct comparison between them. We demonstrate the use of joint tail models based on our broader methodology using two oceanographic datasets and a brief simulation study.     

A weighted Poisson distribution and its application to cure rate models

The family of weighted Poisson distributions offers great flexibility in modeling discrete data due to its potential to capture over/under-dispersion by an appropriate selection of the weight function. In this paper, we introduce a flexible weighted Poisson distribution and further study its properties by using it in the context of cure rate modeling under a competing cause scenario. A special case of the new distribution is the COM-Poisson distribution which in turn encompasses the Bernoulli, Poisson, and geometric distributions; hence, many of the well-studied cure rate models may be seen as special cases of the proposed model. We focus on the estimation, through the maximum likelihood method, of the cured proportion and the properties of the failure time of the susceptibles/non cured individuals; a profile likelihood approach is also adopted for estimating the parameters of the weighted Poisson distribution. A Monte Carlo simulation study demonstrates the accuracy of the proposed inferential method. Finally, as an illustration, we fit the proposed model to a cutaneous melanoma data set.     

Defective models induced by gamma frailty term for survival data with cured fraction

In this paper, we propose a defective model induced by a frailty term for modeling the proportion of cured. Unlike most of the cure rate models, defective models have advantage of modeling the cure rate without adding any extra parameter in model. The introduction of an unobserved heterogeneity among individuals has bring advantages for the estimated model. The influence of unobserved covariates is incorporated using a proportional hazard model. The frailty term assumed to follow a gamma distribution is introduced on the hazard rate to control the unobservable heterogeneity of the patients. We assume that the baseline distribution follows a Gompertz and inverse Gaussian defective distributions. Thus we propose and discuss two defective distributions: the defective gamma-Gompertz and gamma-inverse Gaussian regression models. Simulation studies are performed to verify the asymptotic properties of the maximum likelihood estimator. Lastly, in order to illustrate the proposed model, we present three applications in real data sets, in which one of them we are using for the first time, related to a study about breast cancer in the A.C.Camargo Cancer Center, São Paulo, Brazil.     

Review and implementation of cure models based on first hitting times for Wiener processes

The development of models and methods for cure rate estimation has recently burgeoned into an important subfield of survival analysis. Much of the literature focuses on the standard mixture model. Recently, process-based models have been suggested. We focus on several models based on first passage times for Wiener processes. Whitmore and others have studied these models in a variety of contexts. Lee and Whitmore (Stat Sci 21(4):501–513, 2006) give a comprehensive review of a variety of first hitting time models and briefly discuss their potential as cure rate models. In this paper, we study the Wiener process with negative drift as a possible cure rate model but the resulting defective inverse Gaussian model is found to provide a poor fit in some cases. Several possible modifications are then suggested, which improve the defective inverse Gaussian. These modifications include: the inverse Gaussian cure rate mixture model; a mixture of two inverse Gaussian models; incorporation of heterogeneity in the drift parameter; and the addition of a second absorbing barrier to the Wiener process, representing an immunity threshold. This class of process-based models is a useful alternative to the standard model and provides an improved fit compared to the standard model when applied to many of the datasets that we have studied. Implementation of this class of models is facilitated using expectation-maximization (EM) algorithms and variants thereof, including the gradient EM algorithm. Parameter estimates for each of these EM algorithms are given and the proposed models are applied to both real and simulated data, where they perform well.     

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.     

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.     

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.     

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.     

A general long-term aging model with different underlying activation mechanisms: Modeling,Bayesian estimation,and case influence diagnostics

In this paper we propose a general cure rate aging model. Our approach enables different underlying activation mechanisms which lead to the event of interest. The number of competing causes of the event of interest is assumed to follow a logarithmic distribution. The model is parameterized in terms of the cured fraction which is then linked to covariates. We explore the use of Markov chain Monte Carlo methods to develop a Bayesian analysis for the proposed model. Moreover, some discussions on the model selection to compare the fitted models are given, as well as case deletion influence diagnostics are developed for the joint posterior distribution based on the ψ-divergence, which has several divergence measures as particular cases, such as the Kullback–Leibler (K-L), J-distance, L₁ norm, and χ²-square divergence measures. Simulation studies are performed and experimental results are illustrated based on a real malignant melanoma data.     

A class of semiparametric transformation models for survival data with a cured proportion

We propose a new class of semiparametric regression models based on a multiplicative frailty assumption with a discrete frailty, which may account for cured subgroup in population. The cure model framework is then recast as a problem with a transformation model. The proposed models can explain a broad range of nonproportional hazards structures along with a cured proportion. An efficient and simple algorithm based on the martingale process is developed to locate the nonparametric maximum likelihood estimator. Unlike existing expectation-maximization based methods, our approach directly maximizes a nonparametric likelihood function, and the calculation of consistent variance estimates is immediate. The proposed method is useful for resolving identifiability features embedded in semiparametric cure models. Simulation studies are presented to demonstrate the finite sample properties of the proposed method. A case study of stage III soft-tissue sarcoma is given as an illustration.     

Describing the Dynamics of Attention to TV Commercials: A Hierarchical Bayes Analysis of the Time to Zap an Ad

This paper provides insights into the dynamics of attention to TV commercials via an analysis of the length of time that commercials are viewed before being 'zapped'. The model, which incorporates a flexible baseline hazard rate and captures unobserved heterogeneity across both consumers and commercials using a hierarchical Bayes approach, is estimated on two datasets in which commercial viewing is captured by a passive online device that continually monitors a household's TV viewing. Consistent with previous findings in psychology about the nature of attentional engagement in TV viewing, baseline hazard rates are found to be non-monotonic. In addition, the data show considerable ad-to-ad and household-to-household heterogeneity in zapping behavior. While one of the datasets contains some information on characteristics of the ads, these data do not reveal any firm links between the ad heterogeneity and the ad characteristics. A number of methodological and computational issues arise in the hierarchical Bayes analysis.     

The definition of start time in cancer treatment studies analysed by non-mixture cure models

Non-mixture cure models 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 the cancer in studies when a proportion of those treated are completely cured. However, for many studies, other start times are more relevant. In a clinical trial, it may be more natural to model the time from randomisation rather than the time from the end of treatment and in an epidemiological study, the time from diagnosis might be more meaningful. Some simulations and two real studies of childhood cancer are presented to show that starting from time of diagnosis or randomisation can affect the estimates of the cure fraction. The susceptibility of different parametric kernels to errors caused by using start times other than the end of treatment is also assessed. Analysing failures on treatment and relapse after completing the treatment as two processes offers a simple way of overcoming many of these problems.     

Investigating emergent nested geographic structure in consumer purchases: a Bayesian dynamic multi-scale spatiotemporal modeling approach

Spatial modeling of consumer response data has gained increased interest recently in the marketing literature. In this paper, we extend the (spatial) multi-scale model by incorporating both spatial and temporal dimensions in the dynamic multi-scale spatiotemporal modeling approach. Our empirical application with a US company’s catalog purchase data for the period 1997–2001 reveals a nested geographic market structure that spans geopolitical boundaries such as state borders. This structure identifies spatial clusters of consumers who exhibit similar spatiotemporal behavior, thus pointing to the importance of emergent geographic structure, emergent nested structure and dynamic patterns in multi-resolution methods. The multi-scale model also has better performance in estimation and prediction compared with several spatial and spatiotemporal models and uses a scalable and computationally efficient Markov chain Monte Carlo method that makes it suitable for analyzing large spatiotemporal consumer purchase datasets.KEYWORDS: Clustering, dynamic linear models, empirical Bayes methods, Markov chain Monte Carlo methods, multi-scale modeling, spatial models     

The odd log-logistic Lindley Poisson model for lifetime data

We define two new lifetime models called the odd log-logistic Lindley (OLL-L) and odd log-logistic Lindley Poisson (OLL-LP) distributions with various hazard rate shapes such as increasing, decreasing, upside-down bathtub, and bathtub. Various structural properties are derived. Certain characterizations of OLL-L distribution are presented. The maximum likelihood estimators of the unknown parameters are obtained. We propose a flexible cure rate survival model by assuming that the number of competing causes of the event of interest has a Poisson distribution and the time to event has an OLL-L distribution. The applicability of the new models is illustrated by means real datasets.     

Estimating the causal effects in randomized trials for survival data with a cure fraction and non compliance

We consider causal inference in randomized studies for survival data with a cure fraction and all-or-none treatment non compliance. To describe the causal effects, we consider the complier average causal effect (CACE) and the complier effect on survival probability beyond time t (CESP), where CACE and CESP are defined as the difference of cure rate and non cured subjects’ survival probability between treatment and control groups within the complier class. These estimands depend on the distributions of survival times in treatment and control groups. Given covariates and latent compliance type, we model these distributions with transformation promotion time cure model whose parameters are estimated by maximum likelihood. Both the infinite dimensional parameter in the model and the mixture structure of the problem create some computational difficulties which are overcome by an expectation-maximization (EM) algorithm. We show the estimators are consistent and asymptotically normal. Some simulation studies are conducted to assess the finite-sample performance of the proposed approach. We also illustrate our method by analyzing a real data from the Healthy Insurance Plan of Greater New York.     

Hierarchical CUB Models for Ordinal Variables

Hierarchical CUB models are a generalization of CUB models in which parameters are allowed to be random. The main feature that distinguishes such proposal from the standard one is the modeling of variation among groups. We illustrate the usefulness of these hierarchical structures by discussing model specification, inferential issues, and empirical results with reference to a real data set.     

Smooth Semi‐nonparametric Analysis for Mixture Cure Models and Its Application to Breast Cancer

Mixture cure models are widely used when a proportion of patients are cured. The proportional hazards mixture cure model and the accelerated failure time mixture cure model are the most popular models in practice. Usually the expectation–maximisation (EM) algorithm is applied to both models for parameter estimation. Bootstrap methods are used for variance estimation. In this paper we propose a smooth semi‐nonparametric (SNP) approach in which maximum likelihood is applied directly to mixture cure models for parameter estimation. The variance can be estimated by the inverse of the second derivative of the SNP likelihood. A comprehensive simulation study indicates good performance of the proposed method. We investigate stage effects in breast cancer by applying the proposed method to breast cancer data from the South Carolina Cancer Registry.