Il Do Ha

Estimating Frailty Models via Poisson Hierarchical Generalized Linear Models

Frailty models extend proportional hazards models to multivariate survival data. Hierarchical-likelihood provides a simple unified framework for various random effect models such as hierarchical generalized linear models, frailty models, and mixed linear models with censoring. Wereview the hierarchical-likelihood estimation methods for frailty models. Hierarchical-likelihood for frailty models can be expressed as that for Poisson hierarchical generalized linear models. Frailty models can thus be fitted using Poisson hierarchical generalized linear models. Properties of the new methodology are demonstrated by simulation. The new method reduces the bias of maximum likelihood and penalized likelihood estimates.

Frailty modelling for survival data from multi-centre clinical trials

Despite the use of standardized protocols in, multi-centre, randomized clinical trials, outcome may vary between centres. Such heterogeneity may alter the interpretation and reporting of the treatment effect. Below, we propose a general frailty modelling approach for investigating, inter alia, putative treatment-by-centre interactions in time-to-event data in multi-centre clinical trials. A correlated random effects model is used to model the baseline risk and the treatment effect across centres. It may be based on shared, individual or correlated random effects. For inference we develop the hierarchical-likelihood (or h-likelihood) approach which facilitates computation of prediction intervals for the random effects with proper precision. We illustrate our methods using disease-free time-to-event data on bladder cancer patients participating in an European Organization for Research and Treatment of Cancer trial, and a simulation study. We also demonstrate model selection using h-likelihood criteria.

Hierarchical-Likelihood Approach for Mixed Linear Models with Censored Data

Mixed linear models describe the dependence via random effects in multivariate normal survival data. Recently they have received considerable attention in the biomedical literature. They model the conditional survival times, whereas the alternative frailty model uses the conditional hazard rate. We develop an inferential method for the mixed linear model via Lee and Nelders (1996) hierarchical-likelihood (h-likelihood). Simulation and a practical example are presented to illustrate the new method.

Orthodox BLUP versus h-likelihood methods for inferences about random effects in Tweedie mixed models

Recently, the orthodox best linear unbiased predictor (BLUP) method was introduced for inference about random effects in Tweedie mixed models. With the use of h-likelihood, we illustrate that the standard likelihood procedures, developed for inference about fixed unknown parameters, can be used for inference about random effects. We show that the necessary standard error for the prediction interval of the random effect can be computed from the Hessian matrix of the h-likelihood. We also show numerically that the h-likelihood provides a prediction interval that maintains a more precise coverage probability than the BLUP method.

Analysis of clustered competing risks data using subdistribution hazard models with multivariate frailties

Competing risks data often exist within a center in multi-center randomized clinical trials where the treatment effects or baseline risks may vary among centers. In this paper, we propose a subdistribution hazard regression model with multivariate frailty to investigate heterogeneity in treatment effects among centers from multi-center clinical trials. For inference, we develop a hierarchical likelihood (or h-likelihood) method, which obviates the need for an intractable integration over the frailty terms. We show that the profile likelihood function derived from the h-likelihood is identical to the partial likelihood, and hence it can be extended to the weighted partial likelihood for the subdistribution hazard frailty models. The proposed method is illustrated with a dataset from a multi-center clinical trial on breast cancer as well as with a simulation study. We also demonstrate how to present heterogeneity in treatment effects among centers by using a confidence interval for the frailty for each individual center and how to perform a statistical test for such heterogeneity using a restricted h-likelihood.

Variable selection in subdistribution hazard frailty models with competing risks data

The proportional subdistribution hazards model (i.e. Fine-Gray model) has been widely used for analyzing univariate competing risks data. Recently, this model has been extended to clustered competing risks data via frailty. To the best of our knowledge, however, there has been no literature on variable selection method for such competing risks frailty models. In this paper, we propose a simple but unified procedure via a penalized h-likelihood (HL) for variable selection of fixed effects in a general class of subdistribution hazard frailty models, in which random effects may be shared or correlated. We consider three penalty functions, least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and HL, in our variable selection procedure. We show that the proposed method can be easily implemented using a slight modification to existing h-likelihood estimation approaches. Numerical studies demonstrate that the proposed procedure using the HL penalty performs well, providing a higher probability of choosing the true model than LASSO and SCAD methods without losing prediction accuracy. The usefulness of the new method is illustrated using two actual datasets from multi-center clinical trials.

Variable Selection in General Frailty Models using Penalized H-likelihood

Variable selection methods using a penalized likelihood have been widely studied in various statistical models. However, in semiparametric frailty models, these methods have been relatively less studied because the marginal likelihood function involves analytically intractable integrals, particularly when modeling multicomponent or correlated frailties. In this article, we propose a simple but unified procedure via a penalized h-likelihood (HL) for variable selection of fixed effects in a general class of semiparametric frailty models, in which random effects may be shared, nested, or correlated. We consider three penalty functions (least absolute shrinkage and selection operator [LASSO], smoothly clipped absolute deviation [SCAD], and HL) in our variable selection procedure. We show that the proposed method can be easily implemented via a slight modification to existing HL estimation approaches. Simulation studies also show that the procedure using the SCAD or HL penalty performs well. The usefulness of the new method is illustrated using three practical datasets too. Supplementary materials for the article are available online.

Hierarchical likelihood inference on clustered competing risks data

The frailty model, an extension of the proportional hazards model, is often used to model clustered survival data. However, some extension of the ordinary frailty model is required when there exist competing risks within a cluster. Under competing risks, the underlying processes affecting the events of interest and competing events could be different but correlated. In this paper, the hierarchical likelihood method is proposed to infer the cause-specific hazard frailty model for clustered competing risks data. The hierarchical likelihood incorporates fixed effects as well as random effects into an extended likelihood function, so that the method does not require intensive numerical methods to find the marginal distribution. Simulation studies are performed to assess the behavior of the estimators for the regression coefficients and the correlation structure among the bivariate frailty distribution for competing events. The proposed method is illustrated with a breast cancer dataset.

Frailty modeling for clustered competing risks data with missing cause of failure

Competing risks data often occur within a center in multi-center clinical trials where the event times within a center may be correlated due to unobserved factors across individuals. In this paper, we consider the cause-specific proportional hazards model with a shared frailty to model the association between the event times within a center in the framework of competing risks. We use a hierarchical likelihood approach, which does not require any intractable integration over the frailty terms. In a clinical trial, cause of death information may not be observed for some patients. In such a case, analyses through exclusion of cases with missing cause of death may lead to biased inferences. We propose a hierarchical likelihood approach for fitting the cause-specific proportional hazards model with a shared frailty in the presence of missing cause of failure. We use multiple imputation methods to address missing cause of death information under the assumption of missing at random. Simulation studies show that the proposed procedures perform well, even if the imputation model is misspecified. The proposed methods are illustrated with data from EORTC trial 30791 conducted by European Organization for Research and Treatment of Cancer (EORTC).

Robust frailty modelling using non-proportional hazards models:

Correlated survival times can be modelled by introducing a random effect, or frailty component, into the hazard function. For multivariate survival data, we extend a non-proportional hazards (PH) model, the generalized time-dependent logistic survival model, to include random effects. The hierarchical likelihood procedure, which obviates the need for marginalization over the random effect distribution, is derived for this extended model and its properties are discussed. The extended model leads to a robust estimation result for the regression parameters against the misspecification of the form of the basic hazard function or frailty distribution compared to PH-based alternatives. The proposed method is illustrated by two practical examples and a simulation study which demonstrate the advantages of the new model.