Assessing gamma frailty models for clustered failure time data

Proportional hazards frailty models use a random effect, so called frailty, to construct association for clustered failure time data. It is customary to assume that the random frailty follows a gamma distribution. In this paper, we propose a graphical method for assessing adequacy of the proportional hazards frailty models. In particular, we focus on the assessment of the gamma distribution assumption for the frailties. We calculate the average of the posterior expected frailties at several followup time points and compare it at these time points to 1, the known mean frailty. Large discrepancies indicate lack of fit. To aid in assessing the goodness of fit, we derive and estimate the standard error of the mean of the posterior expected frailties at each time point examined. We give an example to illustrate the proposed methodology and perform sensitivity analysis by simulations.     

An Additive Genetic Gamma Frailty Model for Linkage Analysis of Diseases with Variable Age of Onset Using Nuclear Families

Many late-onset complex diseases exhibit variable age of onset. Efficiently incorporating age of onset information into linkage analysis can potentially increase the power of dissecting complex diseases. In this paper, we treat age of onset as a genetic trait with censored observations. We use multiple markers to infer the inheritance vector at the disease susceptibility (DS) locus in order to extract information about the inheritance pattern of the disease allele in a pedigree. Given the inheritance distribution at the DS locus, we define the genetic frailty for each individual within a nuclear family as the sum of frailties due to a putative major disease gene and a polygenic effect due to any remaining DS loci. Conditioning on these frailties we use the proportional hazards model for the risk of developing disease. We show that a test of linkage can be formulated as a test of zero variance due to a specific locus of the additive gamma frailties. Maximum likelihood estimation, using the EM algorithm, and likelihood ratio tests are employed for parameter estimation and tests of linkage. A simulation study presented indicates that the proposed method is well behaved and can be more powerful than the currently available allele-sharing based linkage methods. A breast cancer data example is used for illustration.     

Bivariate frailty model for the analysis of multivariate survival time

Because of limitations of the univariate frailty model in analysis of multivariate survival data, a bivariate frailty model is introduced for the analysis of bivariate survival data. This provides tremendous flexibility especially in allowing negative associations between subjects within the same cluster. The approach involves incorporating into the model two possibly correlated frailties for each cluster. The bivariate lognormal distribution is used as the frailty distribution. The model is then generalized to multivariate survival data with two distinguished groups and also to alternating process data. A modified EM algorithm is developed with no requirement of specification of the baseline hazards. The estimators are generalized maximum likelihood estimators with subject-specific interpretation. The model is applied to a mental health study on evaluation of health policy effects for inpatient psychiatric care.     

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 Weibull Regression Model with Gamma Frailties for Multivariate Survival Data

Frequently in the analysis of survival data, survival times within the same group are correlated due to unobserved co-variates. One way these co-variates can be included in the model is as frailties. These frailty random block effects generate dependency between the survival times of the individuals which are conditionally independent given the frailty. Using a conditional proportional hazards model, in conjunction with the frailty, a whole new family of models is introduced. By considering a gamma frailty model, often the issue is to find an appropriate model for the baseline hazard function. In this paper a flexible baseline hazard model based on a correlated prior process is proposed and is compared with a standard Weibull model. Several model diagnostics methods are developed and model comparison is made using recently developed Bayesian model selection criteria. The above methodologies are applied to the McGilchrist and Aisbett (1991) kidney infection data and the analysis is performed using Markov Chain Monte Carlo methods. This revised version was published online in July 2006 with corrections to the Cover Date.     

Ascertainment-Adjusted Maximum Likelihood Estimation for the Additive Genetic Gamma Frailty Model

The additive genetic gamma frailty model has been proposed for genetic linkage analysis for complex diseases to account for variable age of onset and possible covariates effects. To avoid ascertainment biases in parameter estimates, retrospective likelihood ratio tests are often used, which may result in loss of efficiency due to conditioning. This paper considers when the sibships are ascertained by having at least two affected sibs with the disease before a given age and provides two approaches for estimating the parameters in the additive gamma frailty model. One approach is based on the likelihood function conditioning on the ascertainment event, the other is based on maximizing a full ascertainment-adjusted likelihood. Explicit forms for these likelihood functions are derived. Simulation studies indicate that when the baseline hazard function can be correctly pre-specified, both approaches give accurate estimates of the model parameters. However, when the baseline hazard function has to be estimated simultaneously, only the ascertainment-adjusted likelihood method gives an unbiased estimate of the parameters. These results imply that the ascertainment-adjusted likelihood ratio test in the context of the additive genetic gamma frailty may be used for genetic linkage analysis.     

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.     

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 frailty modeling approach for parental effects in animal breeding

Survival models involving frailties are commonly applied in studies where correlated event time data arise due to natural or artificial clustering. In this paper we present an application of such models in the animal breeding field. Specifically, a mixed survival model with a multivariate correlated frailty term is proposed for the analysis of data from over 3611 Brazilian Nellore cattle. The primary aim is to evaluate parental genetic effects on the trait length in days that their progeny need to gain a commercially specified standard weight gain. This trait is not measured directly but can be estimated from growth data. Results point to the importance of genetic effects and suggest that these models constitute a valuable data analysis tool for beef cattle breeding.     

On a convergent stochastic estimation algorithm for frailty models

A maximum likelihood estimation procedure is presented for the frailty model. The procedure is based on a stochastic Expectation Maximization algorithm which converges quickly to the maximum likelihood estimate. The usual expectation step is replaced by a stochastic approximation of the complete log-likelihood using simulated values of unobserved frailties whereas the maximization step follows the same lines as those of the Expectation Maximization algorithm. The procedure allows to obtain at the same time estimations of the marginal likelihood and of the observed Fisher information matrix. Moreover, this stochastic Expectation Maximization algorithm requires less computation time. A wide variety of multivariate frailty models without any assumption on the covariance structure can be studied. To illustrate this procedure, a Gaussian frailty model with two frailty terms is introduced. The numerical results based on simulated data and on real bladder cancer data are more accurate than those obtained by using the Expectation Maximization Laplace algorithm and the Monte-Carlo Expectation Maximization one. Finally, since frailty models are used in many fields such as ecology, biology, economy, …, the proposed algorithm has a wide spectrum of applications.     

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.     

General frailty model and stochastic orderings

In this paper, we propose a general frailty model and develop its properties including some results for stochastic comparisons. More specifically, our main results lie in seeing how the well known stochastic orderings between distributions of two frailties translate into the orderings between the corresponding survival functions. These results are used to obtain the properties of the classical multiplicative frailty model and the additive frailty model. Several of the results, in the literature, are obtained as special cases.     

A class of semiparametric transormation frailty models with application to estimating treatment effects and heterogenity in aids clinical traials

Muitivariate failure time data are common in medical research; com¬monly used statistical models for such correlated failure-time data include frailty and marginal models. Both types of models most often assume pro¬portional hazards (Cox, 1972); but the Cox model may not fit the data well This article presents a class of linear transformation frailty models that in¬cludes, as a special case, the proportional hazards model with frailty. We then propose approximate procedures to derive the best linear unbiased es¬timates and predictors of the regression parameters and frailties. We apply the proposed methods to analyze results of a clinical trial of different dose levels of didansine (ddl) among HIV-infected patients who were intolerant of zidovudine (ZDV). These methods yield estimates of treatment effects and of frailties corresponding to patient groups defined by clinical history prior to entry into the trial.     

A Comparison of Methods for Analysing a Nested Frailty Model to Child Survival in Malawi

Demographic and Health Surveys collect child survival times that are clustered at the family and community levels. It is assumed that each cluster has a specific, unobservable, random frailty that induces an association in the survival times within the cluster. The Cox proportional hazards model, with family and community random frailties acting multiplicatively on the hazard rate, is presented. The estimation of the fixed effect and the association parameters of the modified model is then examined using the Gibbs sampler and the expectation–maximization (EM) algorithm. The methods are compared using child survival data collected in the 1992 Demographic and Health Survey of Malawi. The two methods lead to very similar estimates of fixed effect parameters. However, the estimates of random effect variances from the EM algorithm are smaller than those of the Gibbs sampler. Both estimation methods reveal considerable family variation in the survival of children, and very little variability over the communities.     

Correlated gamma frailty models for bivariate survival data

Frailty models are used in the survival analysis to account for the unobserved heterogeneity in individual risks to disease and death. To analyze the bivariate data on related survival times (e.g., matched pairs experiments, twin or family data) the shared frailty models were suggested. Shared frailty models are used despite their limitations. To overcome their disadvantages correlated frailty models may be used. In this article, we introduce the gamma correlated frailty models with two different baseline distributions namely, the generalized log logistic, and the generalized Weibull. We introduce the Bayesian estimation procedure using Markov chain Monte Carlo (MCMC) technique to estimate the parameters involved in these models. We present a simulation study to compare the true values of the parameters with the estimated values. Also we apply these models to a real life bivariate survival dataset related to the kidney infection data and a better model is suggested for the data.     

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.     

Testing Heterogeneity for Frailty Distribution in Shared Frailty Model

Abstract

The frailties, representing extra variations due to unobserved measurements, are often assumed to be iid in shared frailty models. In medical applications, however, a speculation can arise that a data set might violate the iid assumption. In this paper we investigate this conjecture through an analysis of the kidney infection data in McGilchrist and Aisbett (McGilchrist, C. A., Aisbett, C. W. (1991). Regression with frailty in survival analysis. Biometrics 47:461–466). As a test procedure, we consider the cusum of squares test which is frequently used for monitoring a variance change in statistical models. Our result strongly sustains the heterogeneity of the frailty distribution.     

Shared frailty model for recurrent event data with multiple causes

The topic of heterogeneity in the analysis of recurrent event data has received considerable attention recent times. Frailty models are widely employed in such situations as they allow us to model the heterogeneity through common random effect. In this paper, we introduce a shared frailty model for gap time distributions of recurrent events with multiple causes. The parameters of the model are estimated using EM algorithm. An extensive simulation study is used to assess the performance of the method. Finally, we apply the proposed model to a real-life data.     

Small Sample Bias in the Gamma Frailty Model for Univariate Survival

The gamma frailty model is a natural extension of the Cox proportional hazards model in survival analysis. Because the frailties are unobserved, an E-M approach is often used for estimation. Such an approach is shown to lead to finite sample underestimation of the frailty variance, with the corresponding regression parameters also being underestimated as a result. For the univariate case, we investigate the source of the bias with simulation studies and a complete enumeration. The rank-based E-M approach, we note, only identifies frailty through the order in which failures occur; additional frailty which is evident in the survival times is ignored, and as a result the frailty variance is underestimated. An adaption of the standard E-M approach is suggested, whereby the non-parametric Breslow estimate is replaced by a local likelihood formulation for the baseline hazard which allows the survival times themselves to enter the model. Simulations demonstrate that this approach substantially reduces the bias, even at small sample sizes. The method developed is applied to survival data from the North West Regional Leukaemia Register.     

A Semi‐parametric Transformation Frailty Model for Semi‐competing Risks Survival Data

In the analysis of semi‐competing risks data interest lies in estimation and inference with respect to a so‐called non‐terminal event, the observation of which is subject to a terminal event. Multi‐state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non‐terminal and terminal events specified, in part, by a unit‐specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ². When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi‐competing risks analysis that permit the non‐parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi‐parametric efficient score under the complete data setting and propose a non‐parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small‐sample operating characteristics evaluated via simulation. Although the proposed semi‐parametric transformation model and non‐parametric score imputation method are motivated by the analysis of semi‐competing risks data, they are broadly applicable to any analysis of multivariate time‐to‐event outcomes in which a unit‐specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.