Joint models for multiple longitudinal processes and time-to-event outcome

ABSTRACT

Joint models are statistical tools for estimating the association between time-to-event and longitudinal outcomes. One challenge to the application of joint models is its computational complexity. Common estimation methods for joint models include a two-stage method, Bayesian and maximum-likelihood methods. In this work, we consider joint models of a time-to-event outcome and multiple longitudinal processes and develop a maximum-likelihood estimation method using the expectation–maximization algorithm. We assess the performance of the proposed method via simulations and apply the methodology to a data set to determine the association between longitudinal systolic and diastolic blood pressure measures and time to coronary artery disease.     

Semiparametric regression estimation for longitudinal data in models with martingale difference error's structure

An inherent characteristic of longitudinal data is the dependence among the observations within the same subject. For exhibiting dependencies among the observations within the same subject, this paper considers a semiparametric partially linear regression model for longitudinal data based on martingale difference error's structure. We establish a strong consistency for the least squares estimator of a parametric component and the estimator of a non-parametric function under some mild conditions. A simulation study shows the performance of the proposed estimator in finite samples.     

Recurrent time-to-event models with ordinal outcomes

A model to accommodate time-to-event ordinal outcomes was proposed by Berridge and Whitehead. Very few studies have adopted this approach, despite its appeal in incorporating several ordered categories of event outcome. More recently, there has been increased interest in utilizing recurrent events to analyze practical endpoints in the study of disease history and to help quantify the changing pattern of disease over time. For example, in studies of heart failure, the analysis of a single fatal event no longer provides sufficient clinical information to manage the disease. Similarly, the grade/frequency/severity of adverse events may be more important than simply prolonged survival in studies of toxic therapies in oncology. We propose an extension of the ordinal time-to-event model to allow for multiple/recurrent events in the case of marginal models (where all subjects are at risk for each recurrence, irrespective of whether they have experienced previous recurrences) and conditional models (subjects are at risk of a recurrence only if they have experienced a previous recurrence). These models rely on marginal and conditional estimates of the instantaneous baseline hazard and provide estimates of the probabilities of an event of each severity for each recurrence over time. We outline how confidence intervals for these probabilities can be constructed and illustrate how to fit these models and provide examples of the methods, together with an interpretation of the results.     

Semiparametric analysis of transformation models with doubly censored data

Double censoring arises when T represents an outcome variable that can only be accurately measured within a certain range, [L, U], where L and U are the left- and right-censoring variables, respectively. In this note, using Martingale arguments of Chen et al. [3 Chen, K., Jin, Z. and Ying, Z. 2002. Semiparametric analysis of transformation models with censored data. Biometrika, 89: 659–668. [Crossref], [Web of Science ®] [Google Scholar]], we propose an estimator (denoted by ?β) for estimating regression coefficients of transformation model when L is always observed. Under Cox proportional hazards model, the proposed estimator is equivalent to the partial likelihood estimator for left-truncated and right-censored data if the left-censoring variables L were regarded as left-truncated variables. In this case, the estimator ?β can be obtained by the standard software. A simulation study is conducted to investigate the performance of ?β. For the purpose of comparison, the simulation study also includes the estimator proposed by Cai and Cheng [2 Cai, T. and Cheng, S. 2004. Semiparametric regression analysis for doubly censored data. Biometrika, 91: 277–290. [Crossref], [Web of Science ®] [Google Scholar]] for the case when L and U are always observed.     

Semiparametric transformation models with random effects for clustered doubly censored data

For right-censored data, Zeng et al. [Semiparametirc transformation modes with random effects for clustered data. Statist Sin. 2008;18:355–377] proposed a class of semiparametric transformation models with random effects to formulate the effects of possibly time-dependent covariates on clustered failure times. In this article, we demonstrate that the approach of Zeng et al. can be extended to analyse clustered doubly censored data. The asymptotic properties of the nonparametric maximum likelihood estimators of the model parameters are derived. A simulation study is conducted to investigate the performance of the proposed estimators.     

Penalized spline joint models for longitudinal and time-to-event data

The joint models for longitudinal data and time-to-event data have recently received numerous attention in clinical and epidemiologic studies. Our interest is in modeling the relationship between event time outcomes and internal time-dependent covariates. In practice, the longitudinal responses often show non linear and fluctuated curves. Therefore, the main aim of this paper is to use penalized splines with a truncated polynomial basis to parameterize the non linear longitudinal process. Then, the linear mixed-effects model is applied to subject-specific curves and to control the smoothing. The association between the dropout process and longitudinal outcomes is modeled through a proportional hazard model. Two types of baseline risk functions are considered, namely a Gompertz distribution and a piecewise constant model. The resulting models are referred to as penalized spline joint models; an extension of the standard joint models. The expectation conditional maximization (ECM) algorithm is applied to estimate the parameters in the proposed models. To validate the proposed algorithm, extensive simulation studies were implemented followed by a case study. In summary, the penalized spline joint models provide a new approach for joint models that have improved the existing standard joint models.     

Variable selection for semiparametric errors-in-variables regression model with longitudinal data

In this paper, we focus on the variable selection for the semiparametric regression model with longitudinal data when some covariates are measured with errors. A new bias-corrected variable selection procedure is proposed based on the combination of the quadratic inference functions and shrinkage estimations. With appropriate selection of the tuning parameters, we establish the consistency and asymptotic normality of the resulting estimators. Extensive Monte Carlo simulation studies are conducted to examine the finite sample performance of the proposed variable selection procedure. We further illustrate the proposed procedure with an application.     

Multivariate extreme-value distributions with applications to environmental data

Some parametric families of multivariate extreme-value distributions have been proposed in recent years; several additional parametric families are derived here. The parametric models are fitted, using numerical maximum likelihood, to some environmental multivariate extreme data sets consisting of extreme concentrations of a pollutant at several monitoring stations in a region. Some multivariate nonnormal data analysis techniques are proposed to aid in the likelihood analysis. The new models, together with previous models, appear to be adequate for inferences in that they cover a wide range of possible dependence patterns.     

Robust inference in generalized linear models for longitudinal data

The author develops a robust quasi‐likelihood method, which appears to be useful for down‐weighting any influential data points when estimating the model parameters. He illustrates the computational issues of the method in an example. He uses simulations to study the behaviour of the robust estimates when data are contaminated with outliers, and he compares these estimates to those obtained by the ordinary quasi‐likelihood method.     

Block empirical likelihood for longitudinal partially linear regression models

The authors propose a block empirical likelihood procedure to accommodate the within‐group correlation in longitudinal partially linear regression models. This leads them to prove a nonparametric version of the Wilks theorem. In comparison with normal approximations, their method does not require a consistent estimator for the asymptotic covariance matrix, which makes it easier to conduct inference on the parametric component of the model. An application to a longitudinal study on fluctuations of progesterone level in a menstrual cycle is used to illustrate the procedure developed here.     

Analysis of transformation models with right-truncated data

In many applications, statistical data are frequently observed subject to a retrospective sampling criterion resulting in right-truncated data. In this article, a general class of semiparametric transformation models that include proportional hazards model and proportional odds model as special cases is studied for the analysis of right-truncated data. We proposed two estimators for regression coefficients. The first estimator is based on martingale estimating equations. The second estimator is based on the conditional likelihood function given the truncation times. The asymptotic properties of both estimators are derived. The finite sample performance is examined through a simulation study.     

Shrinkage and pretest estimators for longitudinal data analysis under partially linear models

In this paper, we develop marginal analysis methods for longitudinal data under partially linear models. We employ the pretest and shrinkage estimation procedures to estimate the mean response parameters as well as the association parameters, which may be subject to certain restrictions. We provide the analytic expressions for the asymptotic biases and risks of the proposed estimators, and investigate their relative performance to the unrestricted semiparametric least-squares estimator (USLSE). We show that if the dimension of association parameters exceeds two, the risk of the shrinkage estimators is strictly less than that of the USLSE in most of the parameter space. On the other hand, the risk of the pretest estimator depends on the validity of the restrictions of association parameters. A simulation study is conducted to evaluate the performance of the proposed estimators relative to that of the USLSE. A real data example is applied to illustrate the practical usefulness of the proposed estimation procedures.     

Two-step and likelihood methods for HIV viral dynamic models with covariate measurement errors and missing data

HIV viral dynamic models have received much attention in the literature. Long-term viral dynamics may be modelled by semiparametric nonlinear mixed-effect models, which incorporate large variation between subjects and autocorrelation within subjects and are flexible in modelling complex viral load trajectories. Time-dependent covariates may be introduced in the dynamic models to partially explain the between-individual variations. In the presence of measurement errors and missing data in time-dependent covariates, we show that the commonly used two-step method may give approximately unbiased estimates but may under-estimate standard errors. We propose a two-stage bootstrap method to adjust the standard errors in the two-step method and a likelihood method.     

Semiparametric estimation for the dispersion parameter in the analysis of over- or underdispersed count data

This paper investigates several semiparametric estimators of the dispersion parameter in the analysis of over- or underdispersed count data when there is no likelihood available. In the context of estimating the dispersion parameter, we consider the double-extended quasi-likelihood (DEQL), the pseudo-likelihood and the optimal quadratic estimating (OQE) equations method and compare them with the maximum likelihood method, the method of moments and the extended quasi-likelihood through simulation study. The simulation study shows that the estimator based on the DEQL has superior bias and efficiency property for moderate and large sample size, and for small sample size the estimator based on the OQE equations outperforms the other estimators. Three real-life data sets arising in biostatistical practices are analyzed, and the findings from these analyses are quite similar to what are found from the simulation study.     

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.     

Semiparametric analysis of longitudinal data with informative observation times and censoring times

We focus on regression analysis of irregularly observed longitudinal data which often occur in medical follow-up studies and observational investigations. The model for such data involves two processes: a longitudinal response process of interest and an observation process controlling observation times. Restrictive models and questionable assumptions, such as Poisson assumption and independent censoring time assumption, were posed in previous works for analysing longitudinal data. In this paper, we propose a more general model together with a robust estimation approach for longitudinal data with informative observation times and censoring times, and the asymptotic normalities of the proposed estimators are established. Both simulation studies and real data application indicate that the proposed method is promising.     

Inverse probability of censoring weighting for visual predictive checks of time-to-event models with time-varying covariates

When constructing models to summarize clinical data to be used for simulations, it is good practice to evaluate the models for their capacity to reproduce the data. This can be done by means of Visual Predictive Checks (VPC), which consist of several reproductions of the original study by simulation from the model under evaluation, calculating estimates of interest for each simulated study and comparing the distribution of those estimates with the estimate from the original study. This procedure is a generic method that is straightforward to apply, in general. Here we consider the application of the method to time-to-event data and consider the special case when a time-varying covariate is not known or cannot be approximated after event time. In this case, simulations cannot be conducted beyond the end of the follow-up time (event or censoring time) in the original study. Thus, the simulations must be censored at the end of the follow-up time. Since this censoring is not random, the standard KM estimates from the simulated studies and the resulting VPC will be biased. We propose to use inverse probability of censoring weighting (IPoC) method to correct the KM estimator for the simulated studies and obtain unbiased VPCs. For analyzing the Cantos study, the IPoC weighting as described here proved valuable and enabled the generation of VPCs to qualify PKPD models for simulations. Here, we use a generated data set, which allows illustration of the different situations and evaluation against the known truth.     

Likelihood analysis of joint marginal and conditional models for longitudinal categorical data

The authors develop a Markov model for the analysis of longitudinal categorical data which facilitates modelling both marginal and conditional structures. A likelihood formulation is employed for inference, so the resulting estimators enjoy the optimal properties such as efficiency and consistency, and remain consistent when data are missing at random. Simulation studies demonstrate that the proposed method performs well under a variety of situations. Application to data from a smoking prevention study illustrates the utility of the model and interpretation of covariate effects. The Canadian Journal of Statistics © 2009 Statistical Society of Canada     

Empirical likelihood inference in mixture of semiparametric varying-coefficient models for longitudinal data with non-ignorable dropout

In this paper, empirical likelihood inference in mixture of semiparametric varying-coefficient models for longitudinal data with non-ignorable dropout is investigated. We estimate the non-parametric function based on the estimating equations and the local linear profile-kernel method. An empirical log-likelihood ratio statistic for parametric components is proposed to construct confidence regions and is shown to be an asymptotically chi-squared distribution. The non-parametric version of Wilk's theorem is also derived. A simulation study is undertaken to illustrate the finite sample performance of the proposed method.     

Semiparametric analysis of mixture regression models with competing risks data

In the analysis of competing risks data, cumulative incidence function is a useful summary of the overall crude risk for a failure type of interest. Mixture regression modeling has served as a natural approach to performing covariate analysis based on this quantity. However, existing mixture regression methods with competing risks data either impose parametric assumptions on the conditional risks or require stringent censoring assumptions. In this article, we propose a new semiparametric regression approach for competing risks data under the usual conditional independent censoring mechanism. We establish the consistency and asymptotic normality of the resulting estimators. A simple resampling method is proposed to approximate the distribution of the estimated parameters and that of the predicted cumulative incidence functions. Simulation studies and an analysis of a breast cancer dataset demonstrate that our method performs well with realistic sample sizes and is appropriate for practical use.