A Class of Parametric Dynamic Survival Models

A class of parametric dynamic survival models are explored in which only limited parametric assumptions are made, whilst avoiding the assumption of proportional hazards. Both the log-baseline hazard and covariate effects are modelled by piecewise constant and correlated processes. The method of estimation is to use Markov chain Monte Carlo simulations Gibbs sampling with a Metropolis–Hastings step. In addition to standard right censored data sets, extensions to accommodate interval censoring and random effects are included. The model is applied to two well known and illustrative data sets, and the dynamic variability of covariate effects investigated.     

The Influence of Random Effects on Univariate and Bivariate Discrete Proportional Hazards Models

The random effects survival model has been widely used in the recent literature as a generalization of the continuous proportional hazards model. When a random effect is present, it is known that the hazard rates are generally underestimated in the context of continuous proportional hazards models. This article establishes theorems for the influence of random effects on both univariate and bivariate discrete proportional hazards models.     

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.     

Generalized Score Test of Homogeneity Based on Correlated Random Effects Models

We present a family of tests based on correlated random effects models which provides a synthesis and a generalization of recent work on homogeneity testing. In these models each subject has a particular random effect, but the random effects between subjects are correlated. We derive the general form of the score statistic for testing that the random effects have a variance equal to 0. We apply this result to both parametric and semi-parametric models. In both cases we show that under certain conditions the score statistic has an asymptotic normal distribution. We consider several applications of this theory, including overdispersion, heterogeneity between groups, spatial correlations and genetic linkage.     

Marginal Regression of Multivariate Event Times Based on Linear Transformation Models

Multivariate event time data are common in medical studies and have received much attention recently. In such data, each study subject may potentially experience several types of events or recurrences of the same type of event, or event times may be clustered. Marginal distributions are specified for the multivariate event times in multiple events and clustered events data, and for the gap times in recurrent events data, using the semiparametric linear transformation models while leaving the dependence structures for related events unspecified. We propose several estimating equations for simultaneous estimation of the regression parameters and the transformation function. It is shown that the resulting regression estimators are asymptotically normal, with variance–covariance matrix that has a closed form and can be consistently estimated by the usual plug-in method. Simulation studies show that the proposed approach is appropriate for practical use. An application to the well-known bladder cancer tumor recurrences data is also given to illustrate the methodology.     

Inference in Approximately Sparse Correlated Random Effects Probit Models With Panel Data

Abstract

We propose a simple procedure based on an existing “debiased” l₁-regularized method for inference of the average partial effects (APEs) in approximately sparse probit and fractional probit models with panel data, where the number of time periods is fixed and small relative to the number of cross-sectional observations. Our method is computationally simple and does not suffer from the incidental parameters problems that come from attempting to estimate as a parameter the unobserved heterogeneity for each cross-sectional unit. Furthermore, it is robust to arbitrary serial dependence in underlying idiosyncratic errors. Our theoretical results illustrate that inference concerning APEs is more challenging than inference about fixed and low-dimensional parameters, as the former concerns deriving the asymptotic normality for sample averages of linear functions of a potentially large set of components in our estimator when a series approximation for the conditional mean of the unobserved heterogeneity is considered. Insights on the applicability and implications of other existing Lasso-based inference procedures for our problem are provided. We apply the debiasing method to estimate the effects of spending on test pass rates. Our results show that spending has a positive and statistically significant average partial effect; moreover, the effect is comparable to found using standard parametric methods.     

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.     

A Simulation-based Goodness-of-fit Test for Random Effects in Generalized Linear Mixed Models

Abstract.  The goodness-of-fit of the distribution of random effects in a generalized linear mixed model is assessed using a conditional simulation of the random effects conditional on the observations. Provided that the specified joint model for random effects and observations is correct, the marginal distribution of the simulated random effects coincides with the assumed random effects distribution. In practice, the specified model depends on some unknown parameter which is replaced by an estimate. We obtain a correction for this by deriving the asymptotic distribution of the empirical distribution function obtained from the conditional sample of the random effects. The approach is illustrated by simulation studies and data examples.     

Multivariate Parametric Spatiotemporal Models for County Level Breast Cancer Survival Data

In clustered survival settings where the clusters correspond to geographic regions, biostatisticians are increasingly turning to models with spatially distributed random effects. These models begin with spatially oriented frailty terms, but may also include further region-level terms in the parametrization of the baseline hazards or various covariate effects (as in a spatially-varying coefficients model). In this paper, we propose a multivariate conditionally autoregressive (MCAR) model as a mixing distribution for these random effects, as a way of capturing correlation across both the regions and the elements of the random effect vector for any particular region. We then extend this model to permit analysis of temporal cohort effects, where we use the term temporal cohort to mean a group of subjects all of whom were diagnosed with the disease of interest (and thus, entered the study) during the same time period (say, calendar year). We show how our spatiotemporal model may be efficiently fit in a hierarchical Bayesian framework implemented using Markov chain Monte Carlo (MCMC) computational techniques. We illustrate our approach in the context of county-level breast cancer data from 22 annual cohorts of women living in the state of Iowa, as recorded by the Surveillance, Epidemiology, and End Results (SEER) database. Hierarchical model comparison using the Deviance Information Criterion (DIC), as well as maps of the fitted county-level effects, reveal the benefit of our approach.     

Marginal Regression of Gaps Between Recurrent Events

Recurrent event data typically exhibit the phenomenon of intra-individual correlation, owing to not only observed covariates but also random effects. In many applications, the population may be reasonably postulated as a heterogeneous mixture of individual renewal processes, and the inference of interest is the effect of individual-level covariates. In this article, we suggest and investigate a marginal proportional hazards model for gaps between recurrent events. A connection is established between observed gap times and clustered survival data with informative cluster size. We subsequently construct a novel and general inference procedure for the latter, based on a functional formulation of standard Cox regression. Large-sample theory is established for the proposed estimators. Numerical studies demonstrate that the procedure performs well with practical sample sizes. Application to the well-known bladder tumor data is given as an illustration.     

Multilevel Mixed Linear Models for Survival Data

For the analysis of correlated survival data mixed linear models are useful alternatives to frailty models. By their use the survival times can be directly modelled, so that the interpretation of the fixed and random effects is straightforward. However, because of intractable integration involved with the use of marginal likelihood the class of models in use has been severely restricted. Such a difficulty can be avoided by using hierarchical-likelihood, which provides a statistically efficient and fast fitting algorithm for multilevel models. The proposed method is illustrated using the chronic granulomatous disease data. A simulation study is carried out to evaluate the performance.     

How Cox models react to a study-specific confounder in a patient-level pooled dataset: random effects better cope with an imbalanced covariate across trials unless baseline hazards differ

Combining patient-level data from clinical trials can connect rare phenomena with clinical endpoints, but statistical techniques applied to a single trial may become problematical when trials are pooled. Estimating the hazard of a binary variable unevenly distributed across trials showcases a common pooled database issue. We studied how an unevenly distributed binary variable can compromise the integrity of fixed and random effects Cox proportional hazards (cph) models. We compared fixed effect and random effects cph models on a set of simulated datasets inspired by a 17-trial pooled database of patients presenting with ST segment elevation myocardial infarction (STEMI) and non-STEMI undergoing percutaneous coronary intervention. An unevenly distributed covariate can bias hazard ratio estimates, inflate standard errors, raise type I error, and reduce power. While uneveness causes problems for all cph models, random effects suffer least. Compared to fixed effect models, random effects suffer lower bias and trade inflated type I errors for improved power. Contrasting hazard rates between trials prevent accurate estimates from both fixed and random effects models.     

Testing for Random Effects in Growth Curve Models

Growth curve models (GCMs) are useful and Demidenko (2004 Demidenko, E. (2004). Mixed Models: Theory and Applications. New York: Wiley.[Crossref] , [Google Scholar]) considered the presence of random effects under the normal assumptions about random effects and random errors. It is also of interest to remove distribution assumptions to investigate the same problem. A difference-based test is constructed for GCMs, which can be regarded as an extension of Li and Zhu (2010 Li, Z.X., Zhu, L.X. (2010). On variance components in semiparametric mixed models for longitudinal data. Scand. J. Statist. 37:442–457.[Crossref], [Web of Science ®] , [Google Scholar])’s method and a complement to Demidenko (2004 Demidenko, E. (2004). Mixed Models: Theory and Applications. New York: Wiley.[Crossref] , [Google Scholar]) where his test is exact in small samples. Without any distribution assumptions, our test derived for GCMs is asymptotically a standard normal. The power properties are also investigated. Besides, simulations are carried out to examine its performance.     

Comparing Survival Times for Treatments with Those for a Control Under Proportional Hazards

Inferences for survival curves based on right censored data are studied for situations in which it is believed that the treatments have survival times at least as large as the control or at least as small as the control. Testing homogeneity with the appropriate order restricted alternative and testing the order restriction as the null hypothesis are considered. Under a proportional hazards model, the ordering on the survival curves corresponds to an ordering on the regression coefficients. Approximate likelihood methods, which are obtained by applying order restricted procedures to the estimates of the regression coefficients, and ordered analogues to the log rank test, which are based on the score statistics, are considered. Mau's (1988) test, which does not require proportional hazards, is extended to this ordering on the survival curves. Using Monte Carlo techniques, the type I error rates are found to be close to the nominal level and the powers of these tests are compared. Other order restrictions on the survival curves are discussed briefly.     

A joint modelling approach for clustered recurrent events and death events

In dental implant research studies, events such as implant complications including pain or infection may be observed recurrently before failure events, i.e. the death of implants. It is natural to assume that recurrent events and failure events are correlated to each other, since they happen on the same implant (subject) and complication times have strong effects on the implant survival time. On the other hand, each patient may have more than one implant. Therefore these recurrent events or failure events are clustered since implant complication times or failure times within the same patient (cluster) are likely to be correlated. The overall implant survival times and recurrent complication times are both interesting to us. In this paper, a joint modelling approach is proposed for modelling complication events and dental implant survival times simultaneously. The proposed method uses a frailty process to model the correlation within cluster and the correlation within subjects. We use Bayesian methods to obtain estimates of the parameters. Performance of the joint models are shown via simulation studies and data analysis.     

Parameter Orthogonality in Mixed Regression Models for Survival Data

The implications of parameter orthogonality for the robustness of survival regression models are considered. The question of which of the proportional hazards or the accelerated life families of models would be more appropriate for analysis is usually ignored, and the proportional hazards family is applied, particularly in medicine, for convenience. Accelerated life models have conventionally been used in reliability applications. We propose a one-parameter family mixture survival model which includes both the accelerated life and the proportional hazards models. By orthogonalizing relative to the mixture parameter, we can show that, for small effects of the covariates, the regression parameters under the alternative families agree to within a constant. This recovers a known misspecification result. We use notions of parameter orthogonality to explore robustness to other types of misspecification including misspecified base-line hazards. The results hold in the presence of censoring. We also study the important question of when proportionality matters.     

Efficient Semiparametric Bayesian Estimation of Multivariate Discrete Proportional Hazards Model with Random Effects

We incorporate a random effect into a multivariate discrete proportional hazards model and propose an efficient semiparametric Bayesian estimation method. By introducing a prior process for the parameters of baseline hazards, we consider a nonparametric estimation of baseline hazards function. Using a state space representation, we derive a dynamic modeling of baseline hazards function and propose an efficient block sampler for Markov chain Monte Carlo method. A numerical example using kidney patients data is given.     

On Block Updating in Markov Random Field Models for Disease Mapping

Gaussian Markov random field (GMRF) models are commonly used to model spatial correlation in disease mapping applications. For Bayesian inference by MCMC, so far mainly single-site updating algorithms have been considered. However, convergence and mixing properties of such algorithms can be extremely poor due to strong dependencies of parameters in the posterior distribution. In this paper, we propose various block sampling algorithms in order to improve the MCMC performance. The methodology is rather general, allows for non-standard full conditionals, and can be applied in a modular fashion in a large number of different scenarios. For illustration we consider three different applications: two formulations for spatial modelling of a single disease (with and without additional unstructured parameters respectively), and one formulation for the joint analysis of two diseases. The results indicate that the largest benefits are obtained if parameters and the corresponding hyperparameter are updated jointly in one large block. Implementation of such block algorithms is relatively easy using methods for fast sampling of Gaussian Markov random fields ( Rue, 2001 ). By comparison, Monte Carlo estimates based on single-site updating can be rather misleading, even for very long runs. Our results may have wider relevance for efficient MCMC simulation in hierarchical models with Markov random field components.     

Outcome Prediction for Heart Failure Telemonitoring Via Generalized Linear Models with Functional Covariates

An effective methodology for dealing with data extracted from clinical surveys on heart failure linked to the Public Health Database is proposed. A model for recurrent events is used for modelling the occurrence of hospital readmissions in time, thus deriving a suitable way to compute individual cumulative hazard functions. Estimated cumulative hazard trajectories are then treated as functional data, and they are used as covariates along with clinical survey data within the framework of generalized linear models with functional covariates.