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.     

A note on the invertibility of nonlinear ARMA models

We review the concepts of local and global invertibility for a nonlinear auto-regressive moving-average (NLARMA) model. Under very general conditions, a local invertibility analysis of an NLARMA model shows the generic dichotomy that the innovation reconstruction errors either diminish geometrically fast or grow geometrically fast. We derive a simple sufficient condition for an NLARMA model to be locally invertible. The invertibility of the polynomial MA models is revisited. Moreover, we show that the threshold MA models may be globally invertible even though some component MA models are non-invertible. One novelty of our approach is its cross-fertilization with dynamical systems.     

Modeling restricted mean survival time under general censoring mechanisms

Restricted mean survival time (RMST) is often of great clinical interest in practice. Several existing methods involve explicitly projecting out patient-specific survival curves using parameters estimated through Cox regression. However, it would often be preferable to directly model the restricted mean for convenience and to yield more directly interpretable covariate effects. We propose generalized estimating equation methods to model RMST as a function of baseline covariates. The proposed methods avoid potentially problematic distributional assumptions pertaining to restricted survival time. Unlike existing methods, we allow censoring to depend on both baseline and time-dependent factors. Large sample properties of the proposed estimators are derived and simulation studies are conducted to assess their finite sample performance. We apply the proposed methods to model RMST in the absence of liver transplantation among end-stage liver disease patients. This analysis requires accommodation for dependent censoring since pre-transplant mortality is dependently censored by the receipt of a liver transplant.     

The Lehmann Model with Time-dependent Covariates

Consider the Lehmann model with time-dependent covariates, which is different from Cox’s model. We find out that (1) the parameter space for β under the Lehmann model is restricted, and the maximum point of the parametric likelihood for β may lie outside the parameter space; (2) for some particular time-dependent covariate, under the standard generalized likelihood the semiparametric maximum likelihood estimator (SMLE) is inconsistent and we propose a modified generalized likelihood which leads to the consistent SMLE.     

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.     

Survival estimation through the cumulative hazard function with monotone natural cubic splines

In this paper we explore the estimation of survival probabilities via a smoothed version of the survival function, in the presence of censoring. We investigate the fit of a natural cubic spline on the cumulative hazard function under appropriate constraints. Under the proposed technique the problem reduces to a restricted least squares one, leading to convex optimization. The approach taken in this paper is evaluated and compared via simulations to other known methods such as the Kaplan Meier and the logspline estimator. Our approach is easily extended to address estimation of survival probabilities in the presence of covariates when the proportional hazards model assumption holds. In this case the method is compared to a restricted cubic spline approach that involves maximum likelihood. The proposed approach can be also adjusted to accommodate left censoring.     

Semiparametric inference for the proportional odds model with time-dependent covariates

This paper studies estimation in the proportional odds model, with time-dependent covariates, based on right-censored data. The estimation procedure is an extension of the Yang and Prentice (J. Amer. Statist. Assoc. 94 (1999) 125) approach to the time-dependent covariate case. The proposed estimators include a class of minimum distance estimators defined through weighted empirical odds function. These estimators are shown to be strongly consistent and asymptotically normal, with variances that can be consistently estimated. It also contains a simulation study making comparison of some of the estimators in the class.     

A linear model-based test for the heterogeneity of conditional correlations

Current methods of testing the equality of conditional correlations of bivariate data on a third variable of interest (covariate) are limited due to discretizing of the covariate when it is continuous. In this study, we propose a linear model approach for estimation and hypothesis testing of the Pearson correlation coefficient, where the correlation itself can be modeled as a function of continuous covariates. The restricted maximum likelihood method is applied for parameter estimation, and the corrected likelihood ratio test is performed for hypothesis testing. This approach allows for flexible and robust inference and prediction of the conditional correlations based on the linear model. Simulation studies show that the proposed method is statistically more powerful and more flexible in accommodating complex covariate patterns than the existing methods. In addition, we illustrate the approach by analyzing the correlation between the physical component summary and the mental component summary of the MOS SF-36 form across a fair number of covariates in the national survey data.     

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.     

The role of reversals in order‐restricted inference

A statistical model is said to be an order‐restricted statistical model when its parameter takes its values in a closed convex cone C of the Euclidean space. In recent years, order‐restricted likelihood ratio tests and maximum likelihood estimators have been criticized on the grounds that they may violate a cone order monotonicity (COM) property, and hence reverse the cone order induced by C. The authors argue here that these reversals occur only in the case that C is an obtuse cone, and that in this case COM is an inappropriate requirement for likelihood‐based estimates and tests. They conclude that these procedures thus remain perfectly reasonable procedures for order‐restricted inference.     

Confidence Bands for Comparison of Transition Probabilities in a Markov Chain Model

We consider graphs, confidence procedures and tests that can be used to compare transition probabilities in a Markov chain model with intensities specified by a Cox proportional hazard model. Under assumptions of this model, the regression coefficients provide information about the relative risks of covariates in one–step transitions, however, they cannot in general be used to to assess whether or not the covariates have a beneficial or detrimental effect on the endpoint events. To alleviate this problem, we consider graphical tests based on confidence procedures for a generalized Q–Q plot and for the difference between transition probabilities. The procedures are illustrated using data of the International Bone Marrow Transplant Registry.     

On maximum likelihood estimation in parametric regression with missing covariates

We consider parametric regression problems with some covariates missing at random. It is shown that the regression parameter remains identifiable under natural conditions. When the always observed covariates are discrete, we propose a semiparametric maximum likelihood method, which does not require parametric specification of the missing data mechanism or the covariate distribution. The global maximum likelihood estimator (MLE), which maximizes the likelihood over the whole parameter set, is shown to exist under simple conditions. For ease of computation, we also consider a restricted MLE which maximizes the likelihood over covariate distributions supported by the observed values. Under regularity conditions, the two MLEs are asymptotically equivalent and strongly consistent for a class of topologies on the parameter set.     

Bayesian semi-parametric analysis of Poisson change-point regression models: application to policy-making in Cali,Colombia

A Poisson regression model with an offset assumes a constant baseline rate after accounting for measured covariates, which may lead to biased estimates of coefficients in an inhomogeneous Poisson process. To correctly estimate the effect of time-dependent covariates, we propose a Poisson change-point regression model with an offset that allows a time-varying baseline rate. When the non-constant pattern of a log baseline rate is modeled with a non-parametric step function, the resulting semi-parametric model involves a model component of varying dimensions and thus requires a sophisticated varying-dimensional inference to obtain the correct estimates of model parameters of a fixed dimension. To fit the proposed varying-dimensional model, we devise a state-of-the-art Markov chain Monte Carlo-type algorithm based on partial collapse. The proposed model and methods are used to investigate the association between the daily homicide rates in Cali, Colombia, and the policies that restrict the hours during which the legal sale of alcoholic beverages is permitted. While simultaneously identifying the latent changes in the baseline homicide rate which correspond to the incidence of sociopolitical events, we explore the effect of policies governing the sale of alcohol on homicide rates and seek a policy that balances the economic and cultural dependencies on alcohol sales to the health of the public.     

Multiple imputation of censored survival data in the presence of missing covariates using restricted mean survival time

Missing covariates data with censored outcomes put a challenge in the analysis of clinical data especially in small sample settings. Multiple imputation (MI) techniques are popularly used to impute missing covariates and the data are then analyzed through methods that can handle censoring. However, techniques based on MI are available to impute censored data also but they are not much in practice. In the present study, we applied a method based on multiple imputation by chained equations to impute missing values of covariates and also to impute censored outcomes using restricted survival time in small sample settings. The complete data were then analyzed using linear regression models. Simulation studies and a real example of CHD data show that the present method produced better estimates and lower standard errors when applied on the data having missing covariate values and censored outcomes than the analysis of the data having censored outcome but excluding cases with missing covariates or the analysis when cases with missing covariate values and censored outcomes were excluded from the data (complete case analysis).     

Non-penalty shrinkage estimation of random effect models for longitudinal data with AR(1) errors

In this paper, we consider the non-penalty shrinkage estimation method of random effect models with autoregressive errors for longitudinal data when there are many covariates and some of them may not be active for the response variable. In observational studies, subjects are followed over equally or unequally spaced visits to determine the continuous response and whether the response is associated with the risk factors/covariates. Measurements from the same subject are usually more similar to each other and thus are correlated with each other but not with observations of other subjects. To analyse this data, we consider a linear model that contains both random effects across subjects and within-subject errors that follows autoregressive structure of order 1 (AR(1)). Considering the subject-specific random effect as a nuisance parameter, we use two competing models, one includes all the covariates and the other restricts the coefficients based on the auxiliary information. We consider the non-penalty shrinkage estimation strategy that shrinks the unrestricted estimator in the direction of the restricted estimator. We discuss the asymptotic properties of the shrinkage estimators using the notion of asymptotic biases and risks. A Monte Carlo simulation study is conducted to examine the relative performance of the shrinkage estimators with the unrestricted estimator when the shrinkage dimension exceeds two. We also numerically compare the performance of the shrinkage estimators to that of the LASSO estimator. A longitudinal CD4 cell count data set will be used to illustrate the usefulness of shrinkage and LASSO estimators.     

Automatic structure discovery for varying-coefficient partially linear models

Varying-coefficient partially linear models provide a useful tools for modeling of covariate effects on the response variable in regression. One key question in varying-coefficient partially linear models is the choice of model structure, that is, how to decide which covariates have linear effect and which have non linear effect. In this article, we propose a profile method for identifying the covariates with linear effect or non linear effect. Our proposed method is a penalized regression approach based on group minimax concave penalty. Under suitable conditions, we show that the proposed method can correctly determine which covariates have a linear effect and which do not with high probability. The convergence rate of the linear estimator is established as well as the asymptotical normality. The performance of the proposed method is evaluated through a simulation study which supports our theoretical results.     

A Corrected Pseudo-score Approach for Additive Hazards Model with Longitudinal Covariates Measured with Error

In medical studies, it is often of interest to characterize the relationship between a time-to-event and covariates, not only time-independent but also time-dependent. Time-dependent covariates are generally measured intermittently and with error. Recent interests focus on the proportional hazards framework, with longitudinal data jointly modeled through a mixed effects model. However, approaches under this framework depend on the normality assumption of the error, and might encounter intractable numerical difficulties in practice. This motivates us to consider an alternative framework, that is, the additive hazards model, about which little research has been done when time-dependent covariates are measured with error. We propose a simple corrected pseudo-score approach for the regression parameters with no assumptions on the distribution of the random effects and the error beyond those for the variance structure of the latter. The estimator has an explicit form and is shown to be consistent and asymptotically normal. We illustrate the method via simulations and by application to data from an HIV clinical trial.     

Bayesian variable selection for the Cox regression model with missing covariates

In this paper, we develop Bayesian methodology and computational algorithms for variable subset selection in Cox proportional hazards models with missing covariate data. A new joint semi-conjugate prior for the piecewise exponential model is proposed in the presence of missing covariates and its properties are examined. The covariates are assumed to be missing at random (MAR). Under this new prior, a version of the Deviance Information Criterion (DIC) is proposed for Bayesian variable subset selection in the presence of missing covariates. Monte Carlo methods are developed for computing the DICs for all possible subset models in the model space. A Bone Marrow Transplant (BMT) dataset is used to illustrate the proposed methodology.     

Restricted alternatives tests in a bivariate exponential model with covariates

This paper is about the analysis of paired survival data using the exponential bivariate model of Sarkar for the underlying survival times, (X,Y), subject to censoring. Under this parametric model we test parameters in the presence of covariates. We consider first, tests of hypotheses of independence and equality of survival marginals, and second, test of hypotheses of covariate effects and survival superiority of one marginal over the other are considered. For this last question we applied a statistical test based on the Union-intersection principle.     

Testing for state dependence in binary panel data with individual covariates by a modified quadratic exponential model

We propose a test for state dependence in binary panel data with individual covariates. For this aim, we rely on a quadratic exponential model in which the association between the response variables is accounted for in a different way with respect to more standard formulations. The level of association is measured by a single parameter that may be estimated by a Conditional Maximum Likelihood (CML) approach. Under the dynamic logit model, the conditional estimator of this parameter converges to zero when the hypothesis of absence of state dependence is true. Therefore, it is possible to implement a t-test for this hypothesis which may be very simply performed and attains the nominal significance level under several structures of the individual covariates. Through an extensive simulation study, we find that our test has good finite sample properties and it is more robust to the presence of (autocorrelated) covariates in the model specification in comparison with other existing testing procedures for state dependence. The proposed approach is illustrated by two empirical applications: the first is based on data coming from the Panel Study of Income Dynamics and concerns employment and fertility; the second is based on the Health and Retirement Study and concerns the self reported health status.