Impact of misspecified residual correlation structure on the parameter estimates in a shared spatial frailty model

In practice, survival data are often collected over geographical regions. Shared spatial frailty models have been used to model spatial variation in survival times, which are often implemented using the Bayesian Markov chain Monte Carlo method. However, this method comes at the price of slow mixing rates and heavy computational cost, which may render it impractical for data-intensive application. Alternatively, a frailty model assuming an independent and identically distributed (iid) random effect can be easily and efficiently implemented. Therefore, we used simulations to assess the bias and efficiency loss in the estimated parameters, if residual spatial correlation is present but using an iid random effect. Our simulations indicate that a shared frailty model with an iid random effect can estimate the regression coefficients reasonably well, even with residual spatial correlation present, when the percentage of censoring is not too high and the number of clusters and cluster size are not too low. Therefore, if the primary goal is to assess the covariate effects, one may choose the frailty model with an iid random effect; whereas if the goal is to predict the hazard, additional care needs to be given due to the efficiency loss in the parameter(s) for the baseline hazard.     

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.     

Integrated likelihoods in parametric survival models for highly clustered censored data

In studies that involve censored time-to-event data, stratification is frequently encountered due to different reasons, such as stratified sampling or model adjustment due to violation of model assumptions. Often, the main interest is not in the clustering variables, and the cluster-related parameters are treated as nuisance. When inference is about a parameter of interest in presence of many nuisance parameters, standard likelihood methods often perform very poorly and may lead to severe bias. This problem is particularly evident in models for clustered data with cluster-specific nuisance parameters, when the number of clusters is relatively high with respect to the within-cluster size. However, it is still unclear how the presence of censoring would affect this issue. We consider clustered failure time data with independent censoring, and propose frequentist inference based on an integrated likelihood. We then apply the proposed approach to a stratified Weibull model. Simulation studies show that appropriately defined integrated likelihoods provide very accurate inferential results in all circumstances, such as for highly clustered data or heavy censoring, even in extreme settings where standard likelihood procedures lead to strongly misleading results. We show that the proposed method performs generally as well as the frailty model, but it is superior when the frailty distribution is seriously misspecified. An application, which concerns treatments for a frequent disease in late-stage HIV-infected people, illustrates the proposed inferential method in Weibull regression models, and compares different inferential conclusions from alternative methods.     

Inference in generalized additive mixed modelsby using smoothing splines

Generalized additive mixed models are proposed for overdispersed and correlated data, which arise frequently in studies involving clustered, hierarchical and spatial designs. This class of models allows flexible functional dependence of an outcome variable on covariates by using nonparametric regression, while accounting for correlation between observations by using random effects. We estimate nonparametric functions by using smoothing splines and jointly estimate smoothing parameters and variance components by using marginal quasi-likelihood. Because numerical integration is often required by maximizing the objective functions, double penalized quasi-likelihood is proposed to make approximate inference. Frequentist and Bayesian inferences are compared. A key feature of the method proposed is that it allows us to make systematic inference on all model components within a unified parametric mixed model framework and can be easily implemented by fitting a working generalized linear mixed model by using existing statistical software. A bias correction procedure is also proposed to improve the performance of double penalized quasi-likelihood for sparse data. We illustrate the method with an application to infectious disease data and we evaluate its performance through simulation.     

Estimating Marginal Effects in Accelerated Failure Time Models for Serial Sojourn Times Among Repeated Events

Recurrent event data are commonly encountered in longitudinal studies when events occur repeatedly over time for each study subject. An accelerated failure time (AFT) model on the sojourn time between recurrent events is considered in this article. This model assumes that the covariate effect and the subject-specific frailty are additive on the logarithm of sojourn time, and the covariate effect maintains the same over distinct episodes, while the distributions of the frailty and the random error in the model are unspecified. With the ordinal nature of recurrent events, two scale transformations of the sojourn times are derived to construct semiparametric methods of log-rank type for estimating the marginal covariate effects in the model. The proposed estimation approaches/inference procedures also can be extended to the bivariate events, which alternate themselves over time. Examples and comparisons are presented to illustrate the performance of the proposed methods.     

Discrete Duration Models Combining Dynamic and Random Effects

Survivaldata may include two different sources of variation, namely variationover time and variation over units. If both of these variationsare present, neglecting one of them can cause serious bias inthe estimations. Here we present an approach for discrete durationdata that includes both time–varying and unit–specificeffects to model these two variations simultaneously. The approachis a combination of a dynamic survival model with dynamic time–varyingbaseline and covariate effects and a frailty model measuringunobserved heterogeneity with random effects varying independentlyover units. Estimation is based on posterior modes, i.e., wemaximize the joint posterior distribution of the unknown parametersto avoid numerical integration and simulation techniques, thatare necessary in a full Bayesian analysis. Estimation of unknownhyperparameters is achieved by an EM–type algorithm. Finally,the proposed method is applied to data of the Veteran's AdministrationLung Cancer Trial.     

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.     

A Profile Conditional Likelihood Approach for the Semiparametric Transformation Regression Model with Missing Covariates

We propose a profile conditional likelihood approach to handle missing covariates in the general semiparametric transformation regression model. The method estimates the marginal survival function by the Kaplan-Meier estimator, and then estimates the parameters of the survival model and the covariate distribution from a conditional likelihood, substituting the Kaplan-Meier estimator for the marginal survival function in the conditional likelihood. This method is simpler than full maximum likelihood approaches, and yields consistent and asymptotically normally distributed estimator of the regression parameter when censoring is independent of the covariates. The estimator demonstrates very high relative efficiency in simulations. When compared with complete-case analysis, the proposed estimator can be more efficient when the missing data are missing completely at random and can correct bias when the missing data are missing at random. The potential application of the proposed method to the generalized probit model with missing continuous covariates is also outlined.     

A competing risks model for correlated data based on the subdistribution hazard

Family-based follow-up study designs are important in epidemiology as they enable investigations of disease aggregation within families. Such studies are subject to methodological complications since data may include multiple endpoints as well as intra-family correlation. The methods herein are developed for the analysis of age of onset with multiple disease types for family-based follow-up studies. The proposed model expresses the marginalized frailty model in terms of the subdistribution hazards (SDH). As with Pipper and Martinussen’s (Scand J Stat 30:509–521, 2003) model, the proposed multivariate SDH model yields marginal interpretations of the regression coefficients while allowing the correlation structure to be specified by a frailty term. Further, the proposed model allows for a direct investigation of the covariate effects on the cumulative incidence function since the SDH is modeled rather than the cause specific hazard. A simulation study suggests that the proposed model generally offers improved performance in terms of bias and efficiency when a sufficient number of events is observed. The proposed model also offers type I error rates close to nominal. The method is applied to a family-based study of breast cancer when death in absence of breast cancer is considered a competing risk.     

Additive transformation models for clustered failure time data

We propose a class of additive transformation risk models for clustered failure time data. Our models are motivated by the usual additive risk model for independent failure times incorporating a frailty with mean one and constant variability which is a natural generalization of the additive risk model from univariate failure time to multivariate failure time. An estimating equation approach based on the marginal hazards function is proposed. Under the assumption that cluster sizes are completely random, we show the resulting estimators of the regression coefficients are consistent and asymptotically normal. We also provide goodness-of-fit test statistics for choosing the transformation. Simulation studies and real data analysis are conducted to examine the finite-sample performance of our estimators.     

Semiparametric transformation models with random effects for clustered doubly censored data

For right-censored data, Zeng et al. [Semiparametirc transformation modes with random effects for clustered data. Statist Sin. 2008;18:355–377] proposed a class of semiparametric transformation models with random effects to formulate the effects of possibly time-dependent covariates on clustered failure times. In this article, we demonstrate that the approach of Zeng et al. can be extended to analyse clustered doubly censored data. The asymptotic properties of the nonparametric maximum likelihood estimators of the model parameters are derived. A simulation study is conducted to investigate the performance of the proposed estimators.     

Modelling Survival Events with Longitudinal Covariates Measured with Error

In survival analysis, time-dependent covariates are usually present as longitudinal data collected periodically and measured with error. The longitudinal data can be assumed to follow a linear mixed effect model and Cox regression models may be used for modelling of survival events. The hazard rate of survival times depends on the underlying time-dependent covariate measured with error, which may be described by random effects. Most existing methods proposed for such models assume a parametric distribution assumption on the random effects and specify a normally distributed error term for the linear mixed effect model. These assumptions may not be always valid in practice. In this article, we propose a new likelihood method for Cox regression models with error-contaminated time-dependent covariates. The proposed method does not require any parametric distribution assumption on random effects and random errors. Asymptotic properties for parameter estimators are provided. Simulation results show that under certain situations the proposed methods are more efficient than the existing methods.     

Partially linear transformation model for length-biased and right-censored data

In this paper, we consider a partially linear transformation model for data subject to length-biasedness and right-censoring which frequently arise simultaneously in biometrics and other fields. The partially linear transformation model can account for nonlinear covariate effects in addition to linear effects on survival time, and thus reconciles a major disadvantage of the popular semiparamnetric linear transformation model. We adopt local linear fitting technique and develop an unbiased global and local estimating equations approach for the estimation of unknown covariate effects. We provide an asymptotic justification for the proposed procedure, and develop an iterative computational algorithm for its practical implementation, and a bootstrap resampling procedure for estimating the standard errors of the estimator. A simulation study shows that the proposed method performs well in finite samples, and the proposed estimator is applied to analyse the Oscar data.     

Semiparametric mixed-effects models for clustered doubly censored data

The Cox proportional frailty model with a random effect has been proposed for the analysis of right-censored data which consist of a large number of small clusters of correlated failure time observations. For right-censored data, Cai et al. [3] proposed a class of semiparametric mixed-effects models which provides useful alternatives to the Cox model. We demonstrate that the approach of Cai et al. [3] can be used to analyze clustered doubly censored data when both left- and right-censoring variables are always observed. The asymptotic properties of the proposed estimator are derived. A simulation study is conducted to investigate the performance of the proposed estimator.     

Composite conditional likelihood for sparse clustered data

Summary.  Sparse clustered data arise in finely stratified genetic and epidemiologic studies and pose at least two challenges to inference. First, it is difficult to model and interpret the full joint probability of dependent discrete data, which limits the utility of full likelihood methods. Second, standard methods for clustered data, such as pairwise likelihood and the generalized estimating function approach, are unsuitable when the data are sparse owing to the presence of many nuisance parameters. We present a composite conditional likelihood for use with sparse clustered data that provides valid inferences about covariate effects on both the marginal response probabilities and the intracluster pairwise association. Our primary focus is on sparse clustered binary data, in which case the method proposed utilizes doubly discordant quadruplets drawn from each stratum to conduct inference about the intracluster pairwise odds ratios.     

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.     

Effects of unmeasured heterogeneity in the linear transformation model for censored data

We investigate the effect of unobserved heterogeneity in the context of the linear transformation model for censored survival data in the clinical trials setting. The unobserved heterogeneity is represented by a frailty term, with unknown distribution, in the linear transformation model. The bias of the estimate under the assumption of no unobserved heterogeneity when it truly is present is obtained. We also derive the asymptotic relative efficiency of the estimate of treatment effect under the incorrect assumption of no unobserved heterogeneity. Additionally we investigate the loss of power for clinical trials that are designed assuming the model without frailty when, in fact, the model with frailty is true. Numerical studies under a proportional odds model show that the loss of efficiency and the loss of power can be substantial when the heterogeneity, as embodied by a frailty, is ignored. An erratum to this article can be found at     

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 Nonparametric Frailty Model for Clustered Survival Data

Clayton-type counting process formulations for survival data and parametric gamma models for cluster-specific frailty quantities are now routinely applied in analyses of clustered survival data. On the other hand, although nonparametric frailty models have been studied, they are not used much in practice. In this article, the distribution of the frailty terms is assumed to be an unknown random variable. The unknown frailty distribution is then modelled completely with a Dirichlet process prior. This prior assigns cluster units into sub-classes whose members have the same random frailty effect. The Gibbs sampler algorithm is used for computing posterior parameter estimates of the fixed effect hazards regression and the frailty distribution. The methodology is used to analyze community-clustered child survival in sub-Saharan Africa. The results show that the communities could be separated into fewer distinct classes of risk of childhood mortality; the fewer classes could be studied easily in order to provide useful guidance on the more effective use of resources for child health intervention programmes.     

Residual-based specification of the random-effects distribution for cluster data

We propose a method for specifying the distribution of random effects included in a model for cluster data. The class of models we consider includes mixed models and frailty models whose random effects and explanatory variables are constant within clusters. The method is based on cluster residuals obtained by assuming that the random effects are equal between clusters. We exhibit an asymptotic relationship between the cluster residuals and variations of the random effects as the number of observations increases and the variance of the random effects decreases. The asymptotic relationship is used to specify the random-effects distribution. The method is applied to a frailty model and a model used to describe the spread of plant diseases.