Using quantile regression for duration analysis

Summary Quantile regression methods are emerging as a popular technique in econometrics and biometrics for exploring the distribution of duration data. This paper discusses quantile regression for duration analysis allowing for a flexible specification of the functional relationship and of the error distribution. Censored quantile regression addresses the issue of right censoring of the response variable which is common in duration analysis. We compare quantile regression to standard duration models. Quantile regression does not impose a proportional effect of the covariates on the hazard over the duration time. However, the method cannot take account of time-varying covariates and it has not been extended so far to allow for unobserved heterogeneity and competing risks. We also discuss how hazard rates can be estimated using quantile regression methods. This paper benefitted from the helpful comments by an anonymous referee. Due to space constraints, we had to omit the details of the empirical application. These can be found in the long version of this paper, Fitzenberger and Wilke (2005). We gratefully acknowledge financial support by the German Research Foundation (DFG) through the research project ‘Microeconometric modelling of unemployment durations under consideration of the macroeconomic situation’. Thanks are due to Xuan Zhang for excellent research assistance. All errors are our sole responsibility.     

On proportional hazards assumption under the random effects models

The proportional hazards mixed-effects model (PHMM) was proposed to handle dependent survival data. Motivated by its application in genetic epidemiology, we study the interpretation of its parameter estimates under violations of the proportional hazards assumption. The estimated fixed effect turns out to be an averaged regression effect over time, while the estimated variance component could be unaffected, inflated or attenuated depending on whether the random effect is on the baseline hazard, and whether the non-proportional regression effect decreases or increases over time. Using the conditional distribution of the covariates we define the standardized covariate residuals, which can be used to check the proportional hazards assumption. The model checking technique is illustrated on a multi-center lung cancer trial.     

A Simulation Study Comparing Modeling Approaches in an Illness-Death Multi-State Model

In many medical studies, there are covariates that change their values over time and their analysis is most often modeled using the Cox regression model. However, many of these time-dependent covariates can be expressed as an intermediate event, which can be modeled using a multi-state model. Using the relationship of time-dependent (discrete) covariates and multi-state models, we compare (via simulation studies) the Cox model with time-dependent covariates with the most frequently used multi-state regression models. This article also details the procedures for generating survival data arising from all approaches, including the Cox model with time-dependent covariates.     

Models for papilloma multiplicity and regression: applications to transgenic mouse studies

In cancer studies that use transgenic or knockout mice, skin tumour counts are recorded over time to measure tumorigenicity. In these studies cancer biologists are interested in the effect of endogenous and/or exogenous factors on papilloma onset, multiplicity and regression. In this paper an analysis of data from a study conducted by the National Institute of Environmental Health Sciences on the effect of genetic factors on skin tumorigenesis is presented. Papilloma multiplicity and regression are modelled by using Bernoulli, Poisson and binomial latent variables, each of which can depend on covariates and previous outcomes. An EM algorithm is proposed for parameter estimation, and generalized estimating equations adjust for extra dependence between outcomes within individual animals. A Cox proportional hazards model is used to describe covariate effects on the onset of tumours.     

Regression models for time-varying extremes

A common approach to modelling extreme data are to consider the distribution of the exceedance value over a high threshold. This approach is based on the distribution of excess, which follows the generalized Pareto distribution (GPD) and has shown to be adequate for this type of situation. As with all data involving analysis in time, excesses above a threshold may also vary and suffer from the influence of covariates. Thus, the GPD distribution can be modelled by entering the presence of these factors. This paper presents a new model for extreme values, where GPD parameters are written on the basis of a dynamic regression model. The estimation of the model parameters is made under the Bayesian paradigm, with sampling points via MCMC. As with environmental data, behaviour data are related to other factors such as time and covariates such as latitude and distance from the sea. Simulation studies have shown the efficiency and identifiability of the model, and applying real rain data from the state of Piaui, Brazil, shows the advantage in predicting and interpreting the model against other similar models proposed in the literature.     

Partial orders with respect to continuous covariates and tests for the proportional hazards model

Several omnibus tests of the proportional hazards assumption have been proposed in the literature. In the two-sample case, tests have also been developed against ordered alternatives like monotone hazard ratio and monotone ratio of cumulative hazards. Here we propose a natural extension of these partial orders to the case of continuous and potentially time varying covariates, and develop tests for the proportional hazards assumption against such ordered alternatives. The work is motivated by applications in biomedicine and economics where covariate effects often decay over lifetime. The proposed tests do not make restrictive assumptions on the underlying regression model, and are applicable in the presence of time varying covariates, multiple covariates and frailty. Small sample performance and an application to real data highlight the use of the framework and methodology to identify and model the nature of departures from proportionality.     

Long-term experiments and strip plot designs

In a long-term experiment usually the experimenter needs to know whether the effect of a treatment varies over time. But time usually has both a fixed and a random effects over the output and the difficulty in the analysis depends on the particular design considered and the availability of covariates. Actually, as shown in the paper, the presence of covariates can be very useful to model the random effect of time. In this paper a model to analyze data from a long-term strip plot design with covariates is proposed. Its effectiveness will be tested using both simulated and real data from a crop rotation experiment.     

On computing estimates of a change-point in the Weibull regression hazard model

The hazard function describes the instantaneous rate of failure at a time t, given that the individual survives up to t. In applications, the effect of covariates produce changes in the hazard function. When dealing with survival analysis, it is of interest to identify where a change point in time has occurred. In this work, covariates and censored variables are considered in order to estimate a change-point in the Weibull regression hazard model, which is a generalization of the exponential model. For this more general model, it is possible to obtain maximum likelihood estimators for the change-point and for the parameters involved. A Monte Carlo simulation study shows that indeed, it is possible to implement this model in practice. An application with clinical trial data coming from a treatment of chronic granulomatous disease is also included.     

Semi-parametric survival analysis via Dirichlet process mixtures of the First Hitting Time model

Time-to-event data often violate the proportional hazards assumption inherent in the popular Cox regression model. Such violations are especially common in the sphere of biological and medical data where latent heterogeneity due to unmeasured covariates or time varying effects are common. A variety of parametric survival models have been proposed in the literature which make more appropriate assumptions on the hazard function, at least for certain applications. One such model is derived from the First Hitting Time (FHT) paradigm which assumes that a subject’s event time is determined by a latent stochastic process reaching a threshold value. Several random effects specifications of the FHT model have also been proposed which allow for better modeling of data with unmeasured covariates. While often appropriate, these methods often display limited flexibility due to their inability to model a wide range of heterogeneities. To address this issue, we propose a Bayesian model which loosens assumptions on the mixing distribution inherent in the random effects FHT models currently in use. We demonstrate via simulation study that the proposed model greatly improves both survival and parameter estimation in the presence of latent heterogeneity. We also apply the proposed methodology to data from a toxicology/carcinogenicity study which exhibits nonproportional hazards and contrast the results with both the Cox model and two popular FHT models.

     

Structural Equation Models for Dealing With Spatial Confounding

In regression analyses of spatially structured data, it is common practice to introduce spatially correlated random effects into the regression model to reduce or even avoid unobserved variable bias in the estimation of other covariate effects. If besides the response the covariates are also spatially correlated, the spatial effects may confound the effect of the covariates or vice versa. In this case, the model fails to identify the true covariate effect due to multicollinearity. For highly collinear continuous covariates, path analysis and structural equation modeling techniques prove to be helpful to disentangle direct covariate effects from indirect covariate effects arising from correlation with other variables. This work discusses the applicability of these techniques in regression setups, where spatial and covariate effects coincide at least partly and classical geoadditive models fail to separate these effects. Supplementary materials for this article are available online.     

Accelerated Rates Regression Models for Recurrent Failure Time Data

In this article, we formulate a semiparametric model for counting processes in which the effect of covariates is to transform the time scale for a baseline rate function. We assume an arbitrary dependence structure for the counting process and propose a class of estimating equations for the regression parameters. Asymptotic results for these estimators are derived. In addition, goodness of fit methods for assessing the adequacy of the accelerated rates model are proposed. The finite-sample behavior of the proposed methods is examined in simulation studies, and data from a chronic granulomatous disease study are used to illustrate the methodology.     

Modeling categorical covariates for lifetime data in the presence of cure fraction by Bayesian partition structures

In this paper, we propose a Bayesian partition modeling for lifetime data in the presence of a cure fraction by considering a local structure generated by a tessellation which depends on covariates. In this modeling we include information of nominal qualitative variables with more than two categories or ordinal qualitative variables. The proposed modeling is based on a promotion time cure model structure but assuming that the number of competing causes follows a geometric distribution. It is an alternative modeling strategy to the conventional survival regression modeling generally used for modeling lifetime data in the presence of a cure fraction, which models the cure fraction through a (generalized) linear model of the covariates. An advantage of our approach is its ability to capture the effects of covariates in a local structure. The flexibility of having a local structure is crucial to capture local effects and features of the data. The modeling is illustrated on two real melanoma data sets.     

Efficiency of reduced logistic regression models

One feature of the usual polychotomous logistic regression model for categorical outcomes is that a covariate must be included in all the regression equations. If a covariate is not important in all of them, the procedure will estimate unnecessary parameters. More flexible approaches allow different subsets of covariates in different regressions. One alternative uses individualized regressions which express the polychotomous model as a series of dichotomous models. Another uses a model in which a reduced set of parameters is simultaneously estimated for all the regressions. Large-sample efficiencies of these procedures were compared in a variety of circumstances in which there was a common baseline category for the outcome and the covariates were normally distributed. For a correctly specified model, the reduced estimates were over 100% efficient for nonzero slope parameters and up to 500% efficient when the baseline frequency and the effect of interest were small. The individualized estimates could have efficiencies less than 50% when the effect of interest was large, but were also up to 130% efficient when the baseline frequency was large and the effect of interest was small. Efficiency was usually enhanced by correlation among the covariates. For an underspecified reduced model, asymptotic bias in the reduced estimates was approximately proportional to the magnitude of the omitted parameter and to the reciprocal of the baseline frequency.     

Dynamic path analysis—a new approach to analyzing time-dependent covariates

In this article we introduce a general approach to dynamic path analysis. This is an extension of classical path analysis to the situation where variables may be time-dependent and where the outcome of main interest is a stochastic process. In particular we will focus on the survival and event history analysis setting where the main outcome is a counting process. Our approach will be especially fruitful for analyzing event history data with internal time-dependent covariates, where an ordinary regression analysis may fail. The approach enables us to describe how the effect of a fixed covariate partly is working directly and partly indirectly through internal time-dependent covariates. For the sequence of times of event, we define a sequence of path analysis models. At each time of an event, ordinary linear regression is used to estimate the relation between the covariates, while the additive hazard model is used for the regression of the counting process on the covariates. The methodology is illustrated using data from a randomized trial on survival for patients with liver cirrhosis.     

Testing the effect of treatment on survival time with an immediate intermediate event

In this paper, we consider testing the effects of treatment on survival time when a subject experiences an immediate intermediate event (IE) prior to death or predetermined endpoint. A two-stage model incorporating both (i) the effects of the covariates on the immediate IE and (ii) survival regression with the immediate IE and other covariates is presented. We study the likelihood ratio test (LRT) for testing the treatment effect based on the proposed two stage model. We propose two procedures: an asymptotic-based procedure and a resampling-based procedure, to approximate the null distribution of the LRT. We numerically show the advantages of the two stage modeling over the existing single stage survival model with interactions between the covariates and the immediate IE. In addition, an illustrative empirical example is provided.     

Robust Principal Component Functional Logistic Regression

In this article, we discuss the estimation of the parameter function for a functional logistic regression model in the presence of outliers. We consider ways that allow for the parameter estimator to be resistant to outliers, in addition to minimizing multicollinearity and reducing the high dimensionality, which is inherent with functional data. To achieve this, the functional covariates and functional parameter of the model are approximated in a finite-dimensional space generated by an appropriate basis. This approach reduces the functional model to a standard multiple logistic model with highly collinear covariates and potential high-dimensionality issues. The proposed estimator tackles these issues and also minimizes the effect of functional outliers. Results from a simulation study and a real world example are also presented to illustrate the performance of the proposed estimator.     

Accelerated failure time models for the analysis of competing risks

Competing risks are common in clinical cancer research, as patients are subject to multiple potential failure outcomes, such as death from the cancer itself or from complications arising from the disease. In the analysis of competing risks, several regression methods are available for the evaluation of the relationship between covariates and cause-specific failures, many of which are based on Cox’s proportional hazards model. Although a great deal of research has been conducted on estimating competing risks, less attention has been devoted to linear regression modeling, which is often referred to as the accelerated failure time (AFT) model in survival literature. In this article, we address the use and interpretation of linear regression analysis with regard to the competing risks problem. We introduce two types of AFT modeling framework, where the influence of a covariate can be evaluated in relation to either a cause-specific hazard function, referred to as cause-specific AFT (CS-AFT) modeling in this study, or the cumulative incidence function of a particular failure type, referred to as crude-risk AFT (CR-AFT) modeling. Simulation studies illustrate that, as in hazard-based competing risks analysis, these two models can produce substantially different effects, depending on the relationship between the covariates and both the failure type of principal interest and competing failure types. We apply the AFT methods to data from non-Hodgkin lymphoma patients, where the dataset is characterized by two competing events, disease relapse and death without relapse, and non-proportionality. We demonstrate how the data can be analyzed and interpreted, using linear competing risks regression models.     

An Accelerated Model for Recurrence Data

Recurrence data usually come from sampling a system in different ages. It is common in areas of manufacturing, reliability, medicine, and risk analysis. In this article, an accelerated model for recurrence data is proposed. The model is based on the time between failures (TBFs) for an accelerated time regression method using the number of failures as a dummy covariate. Using this model, the repair (or cure) effect can also be studied. A graphical display of recurrence data created by plotting the log-TBFs versus the number of failures is proposed to detect any linear or nonlinear trend for log-TBFs. The model is then extended to incorporate covariates and/or time factors. Two data sets are used to demonstrate the usefulness of the proposed model.     

Inference in Semi‐Parametric Dynamic Models for Repeated Count Data

This paper deals with a longitudinal semi‐parametric regression model in a generalised linear model setup for repeated count data collected from a large number of independent individuals. To accommodate the longitudinal correlations, we consider a dynamic model for repeated counts which has decaying auto‐correlations as the time lag increases between the repeated responses. The semi‐parametric regression function involved in the model contains a specified regression function in some suitable time‐dependent covariates and a non‐parametric function in some other time‐dependent covariates. As far as the inference is concerned, because the non‐parametric function is of secondary interest, we estimate this function consistently using the independence assumption‐based well‐known quasi‐likelihood approach. Next, the proposed longitudinal correlation structure and the estimate of the non‐parametric function are used to develop a semi‐parametric generalised quasi‐likelihood approach for consistent and efficient estimation of the regression effects in the parametric regression function. The finite sample performance of the proposed estimation approach is examined through an intensive simulation study based on both large and small samples. Both balanced and unbalanced cluster sizes are incorporated in the simulation study. The asymptotic performances of the estimators are given. The estimation methodology is illustrated by reanalysing the well‐known health care utilisation data consisting of counts of yearly visits to a physician by 180 individuals for four years and several important primary and secondary covariates.     

An index of local sensitivity to non-ignorability for parametric survival models with potential non-random missing covariate: an application to the SEER cancer registry data

Several survival regression models have been developed to assess the effects of covariates on failure times. In various settings, including surveys, clinical trials and epidemiological studies, missing data may often occur due to incomplete covariate data. Most existing methods for lifetime data are based on the assumption of missing at random (MAR) covariates. However, in many substantive applications, it is important to assess the sensitivity of key model inferences to the MAR assumption. The index of sensitivity to non-ignorability (ISNI) is a local sensitivity tool to measure the potential sensitivity of key model parameters to small departures from the ignorability assumption, needless of estimating a complicated non-ignorable model. We extend this sensitivity index to evaluate the impact of a covariate that is potentially missing, not at random in survival analysis, using parametric survival models. The approach will be applied to investigate the impact of missing tumor grade on post-surgical mortality outcomes in individuals with pancreas-head cancer in the Surveillance, Epidemiology, and End Results data set. For patients suffering from cancer, tumor grade is an important risk factor. Many individuals in these data with pancreas-head cancer have missing tumor grade information. Our ISNI analysis shows that the magnitude of effect for most covariates (with significant effect on the survival time distribution), specifically surgery and tumor grade as some important risk factors in cancer studies, highly depends on the missing mechanism assumption of the tumor grade. Also a simulation study is conducted to evaluate the performance of the proposed index in detecting sensitivity of key model parameters.