Modeling heterogeneity for bivariate survival data by the Weibull distribution

We propose bivariate Weibull regression model with heterogeneity (frailty or random effect) which is generated by Weibull distribution. We assume that the bivariate survival data follow bivariate Weibull of Hanagal (Econ Qual Control 19:83–90, 2004). There are some interesting situations like survival times in genetic epidemiology, dental implants of patients and twin births (both monozygotic and dizygotic) where genetic behavior (which is unknown and random) of patients follows a known frailty distribution. These are the situations which motivate to study this particular model. We propose two-stage maximum likelihood estimation for hierarchical likelihood in the proposed model. We present a small simulation study to compare these estimates with the true value of the parameters and it is observed that these estimates are very close to the true values of the parameters.     

Weibull extension of bivariate exponential regression model with different frailty distributions

We propose bivariate Weibull regression model with frailty in which dependence is generated by a gamma or positive stable or power variance function distribution. We assume that the bivariate survival data follows bivariate Weibull of Hanagal (Econ Qual Control 19:83–90, 2004; Econ Qual Control 20:143–150, 2005a; Stat Pap 47:137–148, 2006a; Stat Methods, 2006b). There are some interesting situations like survival times in genetic epidemiology, dental implants of patients and twin births (both monozygotic and dizygotic) where genetic behavior (which is unknown and random) of patients follows known frailty distribution. These are the situations which motivate to study this particular model. David D. Hanagal is on leave from Department of Statistics, University of Pune, Pune 411007, India.     

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.     

Analysis of Bivariate Survival Data using Shared Inverse Gaussian Frailty Model

In this article, we consider shared frailty model with inverse Gaussian distribution as frailty distribution and log-logistic distribution (LLD) as baseline distribution for bivariate survival times. We fit this model to three real-life bivariate survival data sets. The problem of analyzing and estimating parameters of shared inverse Gaussian frailty is the interest of this article and then compare the results with shared gamma frailty model under the same baseline for considered three data sets. Data are analyzed using Bayesian approach to the analysis of clustered survival data in which there is a dependence of failure time observations within the same group. The variance component estimation provides the estimated dispersion of the random effects. We carried out a test for frailty (or heterogeneity) using Bayes factor. Model comparison is made using information criteria and Bayes factor. We observed that the shared inverse Gaussian frailty model with LLD as baseline is the better fit for all three bivariate data sets.     

Gamma shared frailty model based on reversed hazard rate

Abstract

Frailty models are used in survival analysis to account for unobserved heterogeneity in individual risks to disease and death. To analyze bivariate data on related survival times (e.g., matched pairs experiments, twin, or family data), shared frailty models were suggested. Shared frailty models are frequently used to model heterogeneity in survival analysis. The most common shared frailty model is a model in which hazard function is a product of random factor(frailty) and baseline hazard function which is common to all individuals. There are certain assumptions about the baseline distribution and distribution of frailty. In this paper, we introduce shared gamma frailty models with reversed hazard rate. We introduce Bayesian estimation procedure using Markov Chain Monte Carlo (MCMC) technique to estimate the parameters involved in the model. We present a simulation study to compare the true values of the parameters with the estimated values. Also, we apply the proposed model to the Australian twin data set.     

Robust Poisson likelihood estimation for frailty Cox models: A simulation study

Frailty models can be fit as mixed-effects Poisson models after transforming time-to-event data to the Poisson model framework. We assess, through simulations, the robustness of Poisson likelihood estimation for Cox proportional hazards models with log-normal frailties under misspecified frailty distribution. The log-gamma and Laplace distributions were used as true distributions for frailties on a natural log scale. Factors such as the magnitude of heterogeneity, censoring rate, number and sizes of groups were explored. In the simulations, the Poisson modeling approach that assumes log-normally distributed frailties provided accurate estimates of within- and between-group fixed effects even under a misspecified frailty distribution. Non-robust estimation of variance components was observed in the situations of substantial heterogeneity, large event rates, or high data dimensions.     

A frailty model for (interval) censored family survival data,applied to the age at onset of non-physical problems

Family survival data can be used to estimate the degree of genetic and environmental contributions to the age at onset of a disease or of a specific event in life. The data can be modeled with a correlated frailty model in which the frailty variable accounts for the degree of kinship within the family. The heritability (degree of heredity) of the age at a specific event in life (or the onset of a disease) is usually defined as the proportion of variance of the survival age that is associated with genetic effects. If the survival age is (interval) censored, heritability as usually defined cannot be estimated. Instead, it is defined as the proportion of variance of the frailty associated with genetic effects. In this paper we describe a correlated frailty model to estimate the heritability and the degree of environmental effects on the age at which individuals contact a social worker for the first time and to test whether there is a difference between the survival functions of this age for twins and non-twins.     

Stochastic comparisons of multivariate frailty models

A multivariate frailty model in which survival function depends on baseline distributions of components and the frailty random variable is considered. Since misspecification in choice of frailty distribution and/or baseline distribution may affect the distribution of multivariate frailty model, using theory of stochastic orders, we compare multivariate frailty models arising from different choices of frailty distribution.     

Parametric versus semi-parametric models for the analysis of correlated survival data: A case study in veterinary epidemiology

Correlated survival data arise frequently in biomedical and epidemiologic research, because each patient may experience multiple events or because there exists clustering of patients or subjects, such that failure times within the cluster are correlated. In this paper, we investigate the appropriateness of the semi-parametric Cox regression and of the generalized estimating equations as models for clustered failure time data that arise from an epidemiologic study in veterinary medicine. The semi-parametric approach is compared with a proposed fully parametric frailty model. The frailty component is assumed to follow a gamma distribution. Estimates of the fixed covariates effects were obtained by maximizing the likelihood function, while an estimate of the variance component ( frailty parameter) was obtained from a profile likelihood construction.     

Maximum Penalized Likelihood Estimation in a Gamma-Frailty Model

The shared frailty models allow for unobserved heterogeneity or for statistical dependence between observed survival data. The most commonly used estimation procedure in frailty models is the EM algorithm, but this approach yields a discrete estimator of the distribution and consequently does not allow direct estimation of the hazard function. We show how maximum penalized likelihood estimation can be applied to nonparametric estimation of a continuous hazard function in a shared gamma-frailty model with right-censored and left-truncated data. We examine the problem of obtaining variance estimators for regression coefficients, the frailty parameter and baseline hazard functions. Some simulations for the proposed estimation procedure are presented. A prospective cohort (Paquid) with grouped survival data serves to illustrate the method which was used to analyze the relationship between environmental factors and the risk of dementia.     

A Distribution for Multivariate Frailty Based on the Compound Poisson Distribution with Random Scale

Frailty models are often used to model heterogeneity in survival analysis. The most common frailty model has an individual intensity which is a product of a random factor and a basic intensity common to all individuals. This paper uses the compound Poisson distribution as the random factor. It allows some individuals to be non-susceptible, which can be useful in many settings. In some diseases, one may suppose that a number of families have an increased susceptibility due to genetic circumstances. Then, it is logical to use a frailty model where the individuals within each family have some shared factor, while individuals between families have different factors. This can be attained by randomizing the Poisson parameter in the compound Poisson distribution. To our knowledge, this is a new distribution. The power variance function distributions are used for the Poisson parameter. The subsequent appearing distributions are studied in some detail, both regarding appearance and various statistical properties. An application to infant mortality data from the Medical Birth Registry of Norway is included, where the model is compared to more traditional shared frailty models.     

Comparison of Shared Frailty Models for Kidney Infection Data under Exponential Power Baseline Distribution

Shared frailty models are often used to model heterogeneity in survival analysis. There are certain assumptions about the baseline distribution and distribution of frailty. In this paper, four shared frailty models with frailty distribution gamma, inverse Gaussian, compound Poisson, and compound negative binomial with exponential power as baseline distribution are proposed. These models are fitted using Markov Chain Monte Carlo methods. These models are illustrated with a real life bivariate survival data set of McGilchrist and Aisbett (1991) related to kidney infection, and the best model is suggested for the data using different model comparison criteria.     

Inference Methods for Correlated Left Truncated Lifetimes: Parent and Offspring Relations in an Adoption Study

The associations in mortality of adult adoptees and their biological or adoptive parents have been studied in order to separate genetic and environmental influences. The 1003 Danish adoptees born 1924–26 have previously been analysed in a Cox regression model, using dichotomised versions of the parents’ lifetimes as covariates. This model will be referred to as the conditional Cox model, as it analyses lifetimes of adoptees conditional on parental lifetimes. Shared frailty models may be more satisfactory by using the entire observed lifetime of the parents. In a simulation study, sample size, distribution of lifetimes, truncation- and censoring patterns were chosen to illustrate aspects of the adoption dataset, and were generated from the conditional Cox model or a shared frailty model with gamma distributed frailties. First, efficiency was compared in the conditional Cox model and a shared frailty model, based on the conditional approach. For data with type 1 censoring the models showed no differences, whereas in data with random or no censoring, the models had different power in favour of the one from which data were generated. Secondly, estimation in the shared frailty model by a conditional approach or a two-stage copula approach was compared. Both approaches worked well, with no sign of dependence upon the truncation pattern, but some sign of bias depending on the censoring. For frailty parameters close to zero, we found bias when the estimation procedure used did not allow negative estimates. Based on this evaluation, we prefer to use frailty models allowing for negative frailty parameter estimates. The conclusions from earlier analyses of the adoption study were confirmed, though without greater precision than using the conditional Cox model. Analyses of associations between parental lifetimes are also presented.     

A hierarchical frailty model applied to two-generation melanoma data

We present a hierarchical frailty model based on distributions derived from non-negative Lévy processes. The model may be applied to data with several levels of dependence, such as family data or other general clusters, and is an alternative to additive frailty models. We present several parametric examples of the model, and properties such as expected values, variance and covariance. The model is applied to a case-cohort sample of age at onset for melanoma from the Swedish Multi-Generation Register, organized in nuclear families of parents and one or two children. We compare the genetic component of the total frailty variance to the common environmental term, and estimate the effect of birth cohort and gender.     

Non-parametric Bayesian analysis of clustered survival data

Clustered survival data are often modelled with frailty models which incorporate frailties to model the cluster specific heterogeneity and the dependence between observations in the same cluster. For the analysis of the frailty models, we propose Bayesian modelling with beta process prior on the cumulative hazard function and describe the details of the posterior computation. We demonstrate the method with two data sets using three different frailty distributions: gamma, log-normal and log-logistic distributions. We also empirically demonstrate the difficulty in checking the assumed frailty distribution with the posterior sample of the frailties.     

Estimation in Semiparametric Marginal Shared Gamma Frailty Models

The semiparametric marginal shared frailty models in survival analysis have the non–parametric hazard functions multiplied by a random frailty in each cluster, and the survival times conditional on frailties are assumed to be independent. In addition, the marginal hazard functions have the same form as in the usual Cox proportional hazard models. In this paper, an approach based on maximum likelihood and expectation–maximization is applied to semiparametric marginal shared gamma frailty models, where the frailties are assumed to be gamma distributed with mean 1 and variance θ. The estimates of the fixed–effect parameters and their standard errors obtained using this approach are compared in terms of both bias and efficiency with those obtained using the extended marginal approach. Similarly, the standard errors of our frailty variance estimates are found to compare favourably with those obtained using other methods. The asymptotic distribution of the frailty variance estimates is shown to be a 50–50 mixture of a point mass at zero and a truncated normal random variable on the positive axis for θ₀ = 0. Simulations demonstrate that, for θ₀ < 0, it is approximately an x −(100 − x )%, 0 ≤ x ≤ 50, mixture between a point mass at zero and a truncated normal random variable on the positive axis for small samples and small values of θ₀; otherwise, it is approximately normal.     

Shared frailty models with baseline generalized Pareto distribution

Abstract

In this article, we have considered three different shared frailty models under the assumption of generalized Pareto Distribution as baseline distribution. Frailty models have been used in the survival analysis to account for the unobserved heterogeneity in an individual risks to disease and death. These three frailty models are with gamma frailty, inverse Gaussian frailty and positive stable frailty. Then we introduce the Bayesian estimation procedure using Markov chain Monte Carlo (MCMC) technique to estimate the parameters. We applied these three models to a kidney infection data and find the best fitted model for kidney infection data. We present a simulation study to compare true value of the parameters with the estimated values. Model comparison is made using Bayesian model selection criterion and a well-fitted model is suggested for the kidney infection data.     

The Additive Genetic Gamma Frailty Model

In this paper the additive genetic gamma frailty model is defined. Individual frailties are correlated as a result of an additive genetic model. An algorithm to construct additive genetic gamma frailties for any pedigree is given so that the variance–covariance structure among individual frailties equals the numerator relationship matrix times a variance. The EM algorithm can be used to estimate the parameters in the model. Calculations are similar using the EM algorithm in the shared frailty model, however the E step is not correspondingly simple. This is illustrated re-analysing data, analysed by the shared frailty model in Nielsen et al . (1992), from the Danish adoptive register. Goodness of fit of the additive genetic gamma frailty model can be tested after analysing data with the correlated frailty model. Doing so, a "defect" in the often used and otherwise well behaving likelihood was found     

Survival functions for the frailty models based on the discrete compound Poisson process

Frailty models are often used to model heterogeneity in survival analysis. The distribution of the frailty is generally assumed to be continuous. In some circumstances, it is appropriate to consider discrete frailty distributions. Having zero frailty can be interpreted as being immune, and population heterogeneity may be analysed using discrete frailty models. In this paper, survival functions are derived for the frailty models based on the discrete compound Poisson process. Maximum likelihood estimation procedures for the parameters are studied. We examine the fit of the models to earthquake and the traffic accidents’ data sets from Turkey.     

Frailty models for survival data

A frailty model is a random effects model for time variables, where the random effect (the frailty) has a multiplicative effect on the hazard. It can be used for univariate (independent) failure times, i.e. to describe the influence of unobserved covariates in a proportional hazards model. More interesting, however, is to consider multivariate (dependent) failure times generated as conditionally independent times given the frailty. This approach can be used both for survival times for individuals, like twins or family members, and for repeated events for the same individual. The standard assumption is to use a gamma distribution for the frailty, but this is a restriction that implies that the dependence is most important for late events. More generally, the distribution can be stable, inverse Gaussian, or follow a power variance function exponential family. Theoretically, large differences are seen between the choices. In practice, using the largest model makes it possible to allow for more general dependence structures, without making the formulas too complicated.This paper is a revised version of a review, which together with ten papers by the author made up a thesis for a Doctor of Science degree at the University of Copenhagen.