Semiparametric regression of clustered current status data

This paper discusses regression analysis of clustered current status data under semiparametric additive hazards models. In particular, we consider the situation when cluster sizes can be informative about correlated failure times from the same cluster. To address the problem, we present estimating equation-based estimation procedures and establish asymptotic properties of the resulting estimates. Finite sample performance of the proposed method is assessed through an extensive simulation study, which indicates the procedure works well. The method is applied to a motivating data set from a lung tumorigenicity study.     

Confidence intervals for the difference between two median survival times for clustered survival data

Clustered survival data arise often in clinical trial design, where the correlated subunits from the same cluster are randomized to different treatment groups. Under such design, we consider the problem of constructing confidence interval for the difference of two median survival time given the covariates. We use Cox gamma frailty model to account for the within-cluster correlation. Based on the conditional confidence intervals, we can identify the possible range of covariates over which the two groups would provide different median survival times. The associated coverage probability and the expected length of the proposed interval are investigated via a simulation study. The implementation of the confidence intervals is illustrated using a real data set.     

Semiparametric Efficient Estimation in the Generalized Odds-Rate Class of Regression Models for Right-Censored Time-to-Event Data

The generalized odds-rate class of regression models for time to event data is indexed by a non-negative constant and assumes thatg(S(t|Z)) = (t) + Zwhere g(s) = log(^-1(s-) for > 0, g₀(s) = log(- log s), S(t|Z) is the survival function of the time to event for an individual with qx1 covariate vector Z, is a qx1 vector of unknown regression parameters, and (t) is some arbitrary increasing function of t. When =0, this model is equivalent to the proportional hazards model and when =1, this model reduces to the proportional odds model. In the presence of right censoring, we construct estimators for and exp((t)) and show that they are consistent and asymptotically normal. In addition, we show that the estimator for is semiparametric efficient in the sense that it attains the semiparametric variance bound.     

Isotontic regression for interval censored survival data using an e-m algorithm

This paper develops a nonparametric model of the relationship between survival S and a dichotomous random variable X under the order constraint that P(X=1|S=s) is increasing (or decreasing) with s. The estimation procedure, called isotonic regression, has been studied in some depth for the case of uncensored data, but we give a methodology which is appropriate in the more general context of right, left, and interval censored data. An E-M Algorithm (Dempster et. al., 1977) is used for maximum likelihood estimation.     

Effect of censoring on adjusting for covariates in comparison of survival times

The increase in the variance of the estimate of treatment effect which results from omitting a dichotomous or continuous covariate is quantified as a function of censoring. The efficiency of not adjusting for a covariate is measured by the ratio of the variance obtained with and without adjustment for the covariate. The variance is derived using the Weibull proportional hazards model. Under random censoring, the efficiency of not adjusting for a continuous covariate is an increasing function of the percentage of censored observations.     

Unified multivariate survival model with a surviving fraction: an application to a Brazilian customer churn data

In this paper we propose a new lifetime model for multivariate survival data in presence of surviving fractions and examine some of its properties. Its genesis is based on situations in which there are m types of unobservable competing causes, where each cause is related to a time of occurrence of an event of interest. Our model is a multivariate extension of the univariate survival cure rate model proposed by Rodrigues et al. [37 J. Rodrigues, V.G. Cancho, M. de Castro, and F. Louzada-Neto, On the unification of long-term survival models, Statist. Probab. Lett. 79 (2009), pp. 753–759. doi: 10.1016/j.spl.2008.10.029[Crossref], [Web of Science ®] , [Google Scholar]]. The inferential approach exploits the maximum likelihood tools. We perform a simulation study in order to verify the asymptotic properties of the maximum likelihood estimators. The simulation study also focus on size and power of the likelihood ratio test. The methodology is illustrated on a real data set on customer churn data.     

Mixture cure model with an application to interval mapping of quantitative trait loci

When censored time-to-event data are used to map quantitative trait loci (QTL), the existence of nonsusceptible subjects entails extra challenges. If the heterogeneous susceptibility is ignored or inappropriately handled, we may either fail to detect the responsible genetic factors or find spuriously significant locations. In this article, an interval mapping method based on parametric mixture cure models is proposed, which takes into consideration of nonsusceptible subjects. The proposed model can be used to detect the QTL that are responsible for differential susceptibility and/or time-to-event trait distribution. In particular, we propose a likelihood-based testing procedure with genome-wide significance levels calculated using a resampling method. The performance of the proposed method and the importance of considering the heterogeneous susceptibility are demonstrated by simulation studies and an application to survival data from an experiment on mice infected with Listeria monocytogenes.     

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.     

High dimensional variable selection with clustered data: an application of random multivariate survival forests for detection of outlier medical device components

In many medical studies patients are nested or clustered within doctor. With many explanatory variables, variable selection with clustered data can be challenging. We propose a method for variable selection based on random forest that addresses clustered data through stratified binary splits. Our motivating example involves the detection orthopedic device components from a large pool of candidates, where each patient belongs to a surgeon. Simulations compare the performance of survival forests grown using the stratified logrank statistic to conventional and robust logrank statistics, as well as a method to select variables using a threshold value based on a variable's empirical null distribution. The stratified logrank test performs superior to conventional and robust methods when data are generated to have cluster-specific effects, and when cluster sizes are sufficiently large, perform comparably to the splitting alternatives in the absence of cluster-specific effects. Thresholding was effective at distinguishing between important and unimportant variables.     

Fast two-stage estimator for clustered count data with overdispersion

Clustered count data are commonly analysed by the generalized linear mixed model (GLMM). Here, the correlation due to clustering and some overdispersion is captured by the inclusion of cluster-specific normally distributed random effects. Often, the model does not capture the variability completely. Therefore, the GLMM can be extended by including a set of gamma random effects. Routinely, the GLMM is fitted by maximizing the marginal likelihood. However, this process is computationally intensive. Although feasible with medium to large data, it can be too time-consuming or computationally intractable with very large data. Therefore, a fast two-stage estimator for correlated, overdispersed count data is proposed. It is rooted in the split-sample methodology. Based on a simulation study, it shows good statistical properties. Furthermore, it is computationally much faster than the full maximum likelihood estimator. The approach is illustrated using a large dataset belonging to a network of Belgian general practices.     

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 Nelder's (1996) hierarchical-likelihood (h-likelihood). Simulation and a practical example are presented to illustrate the new method.     

A real survival analysis application via variable selection methods for Cox's proportional hazards model

Variable selection is fundamental to high-dimensional statistical modeling in diverse fields of sciences. In our health study, different statistical methods are applied to analyze trauma annual data, collected by 30 General Hospitals in Greece. The dataset consists of 6334 observations and 111 factors that include demographic, transport, and clinical data. The statistical methods employed in this work are the nonconcave penalized likelihood methods, Smoothly Clipped Absolute Deviation, Least Absolute Shrinkage and Selection Operator, and Hard, the maximum partial likelihood estimation method, and the best subset variable selection, adjusted to Cox's proportional hazards model and used to detect possible risk factors, which affect the length of stay in a hospital. A variety of different statistical models are considered, with respect to the combinations of factors while censored observations are present. A comparative survey reveals several differences between results and execution times of each method. Finally, we provide useful biological justification of our results.     

Kernel-based global MLE of partial linear random effects models for longitudinal data

Random effects models have been playing a critical role for modelling longitudinal data. However, there are little studies on the kernel-based maximum likelihood method for semiparametric random effects models. In this paper, based on kernel and likelihood methods, we propose a pooled global maximum likelihood method for the partial linear random effects models. The pooled global maximum likelihood method employs the local approximations of the nonparametric function at a group of grid points simultaneously, instead of one point. Gaussian quadrature is used to approximate the integration of likelihood with respect to random effects. The asymptotic properties of the proposed estimators are rigorously studied. Simulation studies are conducted to demonstrate the performance of the proposed approach. We also apply the proposed method to analyse correlated medical costs in the Medical Expenditure Panel Survey data set.     

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.     

Analyzing multivariate longitudinal binary data: A generalized estimating equations approach

The authors consider regression analysis for binary data collected repeatedly over time on members of numerous small clusters of individuals sharing a common random effect that induces dependence among them. They propose a mixed model that can accommodate both these structural and longitudinal dependencies. They estimate the parameters of the model consistently and efficiently using generalized estimating equations. They show through simulations that their approach yields significant gains in mean squared error when estimating the random effects variance and the longitudinal correlations, while providing estimates of the fixed effects that are just as precise as under a generalized penalized quasi‐likelihood approach. Their method is illustrated using smoking prevention data.     

A class of nonparametric bivariate survival function estimators for randomly censored and truncated data

This paper proposes a class of nonparametric estimators for the bivariate survival function estimation under both random truncation and random censoring. In practice, the pair of random variables under consideration may have certain parametric relationship. The proposed class of nonparametric estimators uses such parametric information via a data transformation approach and thus provides more accurate estimates than existing methods without using such information. The large sample properties of the new class of estimators and a general guidance of how to find a good data transformation are given. The proposed method is also justified via a simulation study and an application on an economic data set.     

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.     

A multicollinearity diagnostic for models fit to censored data

A multicollinearity diagnostic is discussed for parametric models fit to censored data. The models considered include the Weibull, exponential and lognormal models as well as the Cox proportional hazards model. This diagnostic is an extension of the diagnostic proposed by Belsley, Kuh, and Welsch (1980). The diagnostic is based on the condition indicies and variance proportions of the variance covariance matrix. Its use and properties are studied through a series of examples. The effect of centering variables included in model is also discussed.     

Maximum likelihood methods for complex sample data: logistic regression and discrete proportional hazards models

To estimate model parameters from complex sample data. we apply maximum likelihood techniques to the complex sample data from the finite population, which is treated as a sample from an i nfinite superpopulation. General asymptotic distribution theory is developed and then applied to both logistic regression and discrete proportional hazards models. Data from the Lipid Research Clinics Program areused to illustrate each model, demonstrating the effects on inference of neglecting the sampling design during parameter estimation. These empirical results also shed light on the issue of model-based vs. design-based inferences.     

Maximum Likelihood Inference for Multivariate Frailty Models Using an Automated Monte Carlo EM Algorithm

We present a maximum likelihood estimation procedure for the multivariate frailty model. The estimation is based on a Monte Carlo EM algorithm. The expectation step is approximated by averaging over random samples drawn from the posterior distribution of the frailties using rejection sampling. The maximization step reduces to a standard partial likelihood maximization. We also propose a simple rule based on the relative change in the parameter estimates to decide on sample size in each iteration and a stopping time for the algorithm. An important new concept is acquiring absolute convergence of the algorithm through sample size determination and an efficient sampling technique. The method is illustrated using a rat carcinogenesis dataset and data on vase lifetimes of cut roses. The estimation results are compared with approximate inference based on penalized partial likelihood using these two examples. Unlike the penalized partial likelihood estimation, the proposed full maximum likelihood estimation method accounts for all the uncertainty while estimating standard errors for the parameters.