Identification of Longitudinal Biomarkers in Survival Analysis for Competing Risks Data

In recent years, joint analysis of longitudinal measurements and survival data has received much attention. However, previous work has primarily focused on a single failure type for the event time. In this article, we consider joint modeling of repeated measurements and competing risks failure time data to allow for more than one distinct failure type in the survival endpoint so we fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure. Besides, previous work does not focus on the hypothesis to test a separate latent association between longitudinal measurements and each cause of failure. In this article, we derive a score test to identify longitudinal biomarkers or surrogates for a time to event outcome in competing risks data. With a carefully chosen definition of complete data, the maximum likelihood estimation of the cause-specific hazard functions is performed via an EM algorithm. We extend this work and allow random effects to be present in both the longitudinal biomarker and underlying survival function. The random effects in the biomarker are introduced via an explicit term while the random effect in the underlying survival function is introduced by the inclusion of frailty into the model.

We use simulations to explore how the number of individuals, the number of time points per individual and the functional form of the random effects from the longitudinal biomarkers considering heterogeneous baseline hazards in individuals influence the power to detect the association of a longitudinal biomarker and the survival time.     

A generalized Fleming and Harrington's class of tests for interval‐censored data

The class $G^{\rho,\lambda }$ of weighted log‐rank tests proposed by Fleming & Harrington [Fleming & Harrington (1991) Counting Processes and Survival Analysis, Wiley, New York] has been widely used in survival analysis and is nowadays, unquestionably, the established method to compare, nonparametrically, k different survival functions based on right‐censored survival data. This paper extends the $G^{\rho,\lambda }$ class to interval‐censored data. First we introduce a new general class of rank based tests, then we show the analogy to the above proposal of Fleming & Harrington. The asymptotic behaviour of the proposed tests is derived using an observed Fisher information approach and a permutation approach. Aiming to make this family of tests interpretable and useful for practitioners, we explain how to interpret different choices of weights and we apply it to data from a cohort of intravenous drug users at risk for HIV infection. The Canadian Journal of Statistics 40: 501–516; 2012 © 2012 Statistical Society of Canada     

Joint analysis of longitudinal measurements and survival times with a cure fraction based on partly linear mixed and semiparametric cure models

In a joint analysis of longitudinal quality of life (QoL) scores and relapse-free survival (RFS) times from a clinical trial on early breast cancer conducted by the Canadian Cancer Trials Group, we observed a complicated trajectory of QoL scores and existence of long-term survivors. Motivated by this observation, we proposed in this paper a flexible joint model for the longitudinal measurements and survival times. A partly linear mixed effect model is used to capture the complicated but smooth trajectory of longitudinal measurements and approximated by B-splines and a semiparametric mixture cure model with the B-spline baseline hazard to model survival times with a cure fraction. These two models are linked by shared random effects to explore the dependence between longitudinal measurements and survival times. A semiparametric inference procedure with an EM algorithm is proposed to estimate the parameters in the joint model. The performance of proposed procedures are evaluated by simulation studies and through the application to the analysis of data from the clinical trial which motivated this research.     

Analysis of censored longitudinal data with skewness and a terminal event

In HIV/AIDS study, the measurements viral load are often highly skewed and left-censored because of a lower detection limit. Furthermore, a terminal event (e.g., death) stops the follow-up process. The time to terminal event may be dependent on the viral load measurements. In this article, we present a joint analysis framework to model the censored longitudinal data with skewness and a terminal event process. The estimation is carried out by adaptive Gaussian quadrature techniques in SAS procedure NLMIXED. The proposed model is evaluated by a simulation study and is applied to the motivating Multicenter AIDS Cohort Study (MACS).     

Robust location estimation with missing data

In a missing data setting, we have a sample in which a vector of explanatory variables ${\bf x}_i$ is observed for every subject i, while scalar responses $y_i$ are missing by happenstance on some individuals. In this work we propose robust estimators of the distribution of the responses assuming missing at random (MAR) data, under a semiparametric regression model. Our approach allows the consistent estimation of any weakly continuous functional of the response's distribution. In particular, strongly consistent estimators of any continuous location functional, such as the median, L‐functionals and M‐functionals, are proposed. A robust fit for the regression model combined with the robust properties of the location functional gives rise to a robust recipe for estimating the location parameter. Robustness is quantified through the breakdown point of the proposed procedure. The asymptotic distribution of the location estimators is also derived. The proofs of the theorems are presented in Supplementary Material available online. The Canadian Journal of Statistics 41: 111–132; 2013 © 2012 Statistical Society of Canada     

Variable selection via the weighted group lasso for factor analysis models

We consider the problem of selecting variables in factor analysis models. The $L_1$ regularization procedure is introduced to perform an automatic variable selection. In the factor analysis model, each variable is controlled by multiple factors when there are more than one underlying factor. We treat parameters corresponding to the multiple factors as grouped parameters, and then apply the group lasso. Furthermore, the weight of the group lasso penalty is modified to obtain appropriate estimates and improve the performance of variable selection. Crucial issues in this modeling procedure include the selection of the number of factors and a regularization parameter. Choosing these parameters can be viewed as a model selection and evaluation problem. We derive a model selection criterion for evaluating the factor analysis model via the weighted group lasso. Monte Carlo simulations are conducted to investigate the effectiveness of the proposed procedure. A real data example is also given to illustrate our procedure. The Canadian Journal of Statistics 40: 345–361; 2012 © 2012 Statistical Society of Canada     

A joint marginalized multilevel model for longitudinal outcomes

The shared-parameter model and its so-called hierarchical or random-effects extension are widely used joint modeling approaches for a combination of longitudinal continuous, binary, count, missing, and survival outcomes that naturally occurs in many clinical and other studies. A random effect is introduced and shared or allowed to differ between two or more repeated measures or longitudinal outcomes, thereby acting as a vehicle to capture association between the outcomes in these joint models. It is generally known that parameter estimates in a linear mixed model (LMM) for continuous repeated measures or longitudinal outcomes allow for a marginal interpretation, even though a hierarchical formulation is employed. This is not the case for the generalized linear mixed model (GLMM), that is, for non-Gaussian outcomes. The aforementioned joint models formulated for continuous and binary or two longitudinal binomial outcomes, using the LMM and GLMM, will naturally have marginal interpretation for parameters associated with the continuous outcome but a subject-specific interpretation for the fixed effects parameters relating covariates to binary outcomes. To derive marginally meaningful parameters for the binary models in a joint model, we adopt the marginal multilevel model (MMM) due to Heagerty [13] and Heagerty and Zeger [14] and formulate a joint MMM for two longitudinal responses. This enables to (1) capture association between the two responses and (2) obtain parameter estimates that have a population-averaged interpretation for both outcomes. The model is applied to two sets of data. The results are compared with those obtained from the existing approaches such as generalized estimating equations, GLMM, and the model of Heagerty [13]. Estimates were found to be very close to those from single analysis per outcome but the joint model yields higher precision and allows for quantifying the association between outcomes. Parameters were estimated using maximum likelihood. The model is easy to fit using available tools such as the SAS NLMIXED procedure.     

Multivariate Kendall's tau for change‐point detection in copulas

Statistical procedures for the detection of a change in the dependence structure of a series of multivariate observations are studied in this work. The test statistics that are proposed are $L_1$ , $L_2$ , and $L_{\infty }$ distances computed from vectors of differences of Kendall's tau; two multivariate extensions of Kendall's measure of association are used. Since the distributions of these statistics under the null hypothesis of no change depend on the unknown underlying copula of the vectors, a procedure based on the multiplier central limit theorem is used for the computation of p‐values; the method is shown to be valid both asymptotically and for moderate sample sizes. Alternative versions of the tests that take into account possible breakpoints in the marginal distributions are also investigated. Monte Carlo simulations show that the tests are powerful under many scenarios of change‐point. In addition, two estimators of the time of change are proposed and their efficiency is carefully studied. The methodologies are illustrated on simulated series from the Canadian Regional Climate Model. The Canadian Journal of Statistics 41: 65–82; 2013 © 2012 Statistical Society of Canada     

Testing uniformity for the case of a planar unknown support

A new test is proposed for the hypothesis of uniformity on bi‐dimensional supports. The procedure is an adaptation of the “distance to boundary test” (DB test) proposed in Berrendero, Cuevas, & Vázquez‐Grande (2006). This new version of the DB test, called DBU test, allows us (as a novel, interesting feature) to deal with the case where the support S of the underlying distribution is unknown. This means that S is not specified in the null hypothesis so that, in fact, we test the null hypothesis that the underlying distribution is uniform on some support S belonging to a given class ${\cal C}$ . We pay special attention to the case that ${\cal C}$ is either the class of compact convex supports or the (broader) class of compact λ‐convex supports (also called r‐convex or α‐convex in the literature). The basic idea is to apply the DB test in a sort of plug‐in version, where the support S is approximated by using methods of set estimation. The DBU method is analysed from both the theoretical and practical point of view, via some asymptotic results and a simulation study, respectively. The Canadian Journal of Statistics 40: 378–395; 2012 © 2012 Statistical Society of Canada     

Estimating prediction error in microarray classification: Modifications of the 0.632+ bootstrap when ${\bf n} < {\bf p}$

We are interested in estimating prediction error for a classification model built on high dimensional genomic data when the number of genes (p) greatly exceeds the number of subjects (n). We examine a distance argument supporting the conventional 0.632+ bootstrap proposed for the $n > p$ scenario, modify it for the $n < p$ situation and develop learning curves to describe how the true prediction error varies with the number of subjects in the training set. The curves are then applied to define adjusted resampling estimates for the prediction error in order to achieve a balance in terms of bias and variability. The adjusted resampling methods are proposed as counterparts of the 0.632+ bootstrap when $n < p$ , and are found to improve on the 0.632+ bootstrap and other existing methods in the microarray study scenario when the sample size is small and there is some level of differential expression. The Canadian Journal of Statistics 41: 133–150; 2013 © 2012 Statistical Society of Canada     

Using the Score Test to Identify the Longitudinal Biomarker Considering Accelerate Failure Time Model with the Frailty in Survival Analysis

Quality of life (QOL) is looked upon as a multidimensional entity comprising physical, psychological, social, and medical parameters. QOL is a good prognostic factor for the cancer patients. In this article, we want to determine if QOL is a good biomarker as a surrogate to indicate the survival time of gastric cancer patients. We conducted a single institutional trial and examines QOL of gastric cancer patients receiving the different surgery. In this trial, QOL is a longitudinal measurement. The accelerated failure time model can be used to deal with survival data when the proportionality assumption fails to capture the relationship between the survival time and covariates. In this article, similar to Henderson et al. (2000 Henderson , R. , Diggle , P. , Dobson , A. ( 2000 ). Joint modelling of longitudinal measurements and event time data . Biostatistics 1 ( 4 ): 465 – 480 .[Crossref], [PubMed] , [Google Scholar], 2002 Henderson , R. , Diggle , P. J. , Dobson , A. ( 2002 ). Identification and efficacy of longitudinal markers for survival . Biostatistics 3 ( 1 ): 33 – 50 .[Crossref], [PubMed], [Web of Science ®] , [Google Scholar]), a joint likelihood function combines the likelihood functions of the longitudinal biomarkers and the survival times under the accelerated failure time assumption. We introduce a method employing a frailty model to identify longitudinal biomarkers or surrogates for a time to event outcome. We allow random effects to be present in both the longitudinal biomarker and underlying survival function. The random effects in the biomarker are introduced via an explicit term while the random effect in the underlying survival function is introduced by the inclusion of frailty into the model. We will introduce a method to identify longitudinal biomarkers or surrogates for a time to event outcome based on the accelerated failure time assumption.     

A Generalized Log-Normal Model for Grouped Survival Data

It is common to have experiments in which it is not possible to observe the exact lifetimes but only the interval where they occur. This sort of data presents a high number of ties and it is called grouped or interval-censored survival data. Regression methods for grouped data are available in the statistical literature. The regression structure considers modeling the probability of a subject's survival past a visit time conditional on his survival at the previous visit. Two approaches are presented: assuming that lifetimes come from (1) a continuous proportional hazards model and (2) a logistic model. However, there may be situations in which none of the models are adequate for a particular data set. This article proposes the generalized log-normal model as an alternative model for discrete survival data. This model was introduced by Chen (1995 Chen , G. ( 1995 ). Generalized Log-normal distributions with reliability application . Comput. Stat. Data Anal. 19 : 300 – 319 . [Google Scholar]) and it is extended in this article for grouped survival data. A real example related to a Chagas disease illustrates the proposed model.     

A general joint model for longitudinal measurements and competing risks survival data with heterogeneous random effects

This article studies a general joint model for longitudinal measurements and competing risks survival data. The model consists of a linear mixed effects sub-model for the longitudinal outcome, a proportional cause-specific hazards frailty sub-model for the competing risks survival data, and a regression sub-model for the variance–covariance matrix of the multivariate latent random effects based on a modified Cholesky decomposition. The model provides a useful approach to adjust for non-ignorable missing data due to dropout for the longitudinal outcome, enables analysis of the survival outcome with informative censoring and intermittently measured time-dependent covariates, as well as joint analysis of the longitudinal and survival outcomes. Unlike previously studied joint models, our model allows for heterogeneous random covariance matrices. It also offers a framework to assess the homogeneous covariance assumption of existing joint models. A Bayesian MCMC procedure is developed for parameter estimation and inference. Its performances and frequentist properties are investigated using simulations. A real data example is used to illustrate the usefulness of the approach.     

Variable selection and estimation for multivariate panel count data via the seamless‐${\it L}_{{\rm 0}}$ penalty

This paper considers regression analysis of multivariate panel count data with the focus on variable selection and estimation of significant covariate effects. For the problem, we adopt the penalized estimating equation approach with a focus on the use of the seamless‐$L_0$ penalty. The proposed approach selects variables and estimates regression coefficients simultaneously and the asymptotic properties of the resulting estimates are established. The procedure can be easily carried out with the Newton–Raphson algorithm and is evaluated by simulation studies. Also it is applied to a motivating data set arising from a skin cancer study. The Canadian Journal of Statistics 41: 368–385; 2013 © 2013 Statistical Society of Canada     

Consistency of maximum likelihood estimators in a large class of deconvolution models

We consider the maximum likelihood estimator $\hat{F}_n$ of a distribution function in a class of deconvolution models where the known density of the noise variable is of bounded variation. This class of noise densities contains in particular bounded, decreasing densities. The estimator $\hat{F}_n$ is defined, characterized in terms of Fenchel optimality conditions and computed. Under appropriate conditions, various consistency results for $\hat{F}_n$ are derived, including uniform strong consistency. The Canadian Journal of Statistics 41: 98–110; 2013 © 2012 Statistical Society of Canada     

Joint modeling of censored longitudinal and event time data

Censoring of a longitudinal outcome often occurs when data are collected in a biomedical study and where the interest is in the survival and or longitudinal experiences of a study population. In the setting considered herein, we encountered upper and lower censored data as the result of restrictions imposed on measurements from a kinetic model producing “biologically implausible” kidney clearances. The goal of this paper is to outline the use of a joint model to determine the association between a censored longitudinal outcome and a time to event endpoint. This paper extends Guo and Carlin's [6] paper to accommodate censored longitudinal data, in a commercially available software platform, by linking a mixed effects Tobit model to a suitable parametric survival distribution. Our simulation results showed that our joint Tobit model outperforms a joint model made up of the more naïve or “fill-in” method for the longitudinal component. In this case, the upper and/or lower limits of censoring are replaced by the limit of detection. We illustrated the use of this approach with example data from the hemodialysis (HEMO) study [3] and examined the association between doubly censored kidney clearance values and survival.     

Contaminated normal modeling with application to microarray data analysis

A contaminated beta model $(1-\gamma) B(1,1) + \gamma B(\alpha,\beta)$ is often used to describe the distribution of $P$ ‐values arising from a microarray experiment. The authors propose and examine a different approach: namely, using a contaminated normal model $(1-\gamma) N(0,\sigma^2) + \gamma N(\mu,\sigma^2)$ to describe the distribution of $Z$ statistics or suitably transformed $T$ statistics. The authors then address whether a researcher who has $Z$ statistics should analyze them using the contaminated normal model or whether the $Z$ statistics should be converted to $P$ ‐values to be analyzed using the contaminated beta model. The authors also provide a decision‐theoretic perspective on the analysis of $Z$ statistics. The Canadian Journal of Statistics 38: 315–332; 2010 © 2010 Statistical Society of Canada     

New estimation and feature selection methods in mixture‐of‐experts models

We study estimation and feature selection problems in mixture‐of‐experts models. An $l_2$ ‐penalized maximum likelihood estimator is proposed as an alternative to the ordinary maximum likelihood estimator. The estimator is particularly advantageous when fitting a mixture‐of‐experts model to data with many correlated features. It is shown that the proposed estimator is root‐$n$ consistent, and simulations show its superior finite sample behaviour compared to that of the maximum likelihood estimator. For feature selection, two extra penalty functions are applied to the $l_2$ ‐penalized log‐likelihood function. The proposed feature selection method is computationally much more efficient than the popular all‐subset selection methods. Theoretically it is shown that the method is consistent in feature selection, and simulations support our theoretical results. A real‐data example is presented to demonstrate the method. The Canadian Journal of Statistics 38: 519–539; 2010 © 2010 Statistical Society of Canada     

A joint model of binary and longitudinal data with non-ignorable missingness,with application to marital stress and late-life major depression in women

Understanding how long-term marital stress affects major depressive disorder (MDD) in older women has clinical implications for the treatment of women at risk. In this paper, we consider the problem of predicting MDD in older women (mean age 60) from a marital stress scale administered four times during the preceding 20-year period, with a greater dropout by women experiencing marital stress or MDD. To analyze these data, we propose a Bayesian joint model consisting of: (1) a linear mixed effects model for the longitudinal measurements, (2) a generalized linear model for the binary primary endpoint, and (3) a shared parameter model for the missing data mechanism. Our analysis indicates that MDD in older women is significantly associated with higher levels of prior marital stress and increasing marital stress over time, although there is a generally decreasing trend in marital stress. This is the first study to propose a joint model for incompletely observed longitudinal measurements, a binary primary endpoint, and non-ignorable missing data; a comparison shows that the joint model yields better predictive accuracy than a two-stage model. These findings suggest that women who experience marital stress in mid-life need treatment to help prevent late-life MDD, which has serious consequences for older persons.