Modelling udder infection data using copula models for quadruples

We study copula models for correlated infection times in the four udder quarters of dairy cows. Both a semi-parametric and a nonparametric approach are considered to estimate the marginal survival functions, taking into account the effect of a binary udder quarter level covariate. We use a two-stage estimation approach and we briefly discuss the asymptotic behaviour of the estimators obtained in the first and the second stage of the estimation. A pseudo-likelihood ratio test is used to select an appropriate copula from the power variance copula family that describes the association between the outcomes in a cluster. We propose a new bootstrap algorithm to obtain the p-value for this test. This bootstrap algorithm also provides estimates for the standard errors of the estimated parameters in the copula. The proposed methods are applied to the udder infection data. A small simulation study for a setting similar to the setting of the udder infection data gives evidence that the proposed method provides a valid approach to select an appropriate copula within the power variance copula family.     

Some recent developments for regression analysis of multivariate failure time data

Cox's seminal 1972 paper on regression methods for possibly censored failure time data popularized the use of time to an event as a primary response in prospective studies. But one key assumption of this and other regression methods is that observations are independent of one another. In many problems, failure times are clustered into small groups where outcomes within a group are correlated. Examples include failure times for two eyes from one person or for members of the same family.This paper presents a survey of models for multivariate failure time data. Two distinct classes of models are considered: frailty and marginal models. In a frailty model, the correlation is assumed to derive from latent variables (frailties) common to observations from the same cluster. Regression models are formulated for the conditional failure time distribution given the frailties. Alternatively, marginal models describe the marginal failure time distribution of each response while separately modelling the association among responses from the same cluster.We focus on recent extensions of the proportional hazards model for multivariate failure time data. Model formulation, parameter interpretation and estimation procedures are considered.     

Regression models for analyzing clustered binary and continuous outcomes under an assumption of exchangeability

Scientific experiments commonly result in clustered discrete and continuous data. Existing methods for analyzing such data include the use of quasi-likelihood procedures and generalized estimating equations to estimate marginal mean response parameters. In applications to areas such as developmental toxicity studies, where discrete and continuous measurements are recorded on each fetus, or clinical ophthalmologic trials, where different types of observations are made on each eye, the assumption that data within cluster are exchangeable is often very reasonable. We use this assumption to formulate fully parametric regression models for clusters of bivariate data with binary and continuous components. The regression models proposed have marginal interpretations and reproducible model structures. Tractable expressions for likelihood equations are derived and iterative schemes are given for computing efficient estimates (MLEs) of the marginal mean, correlations, variances and higher moments. We demonstrate the use the ‘exchangeable’ procedure with an application to a developmental toxicity study involving fetal weight and malformation data.     

A marginal regression model for multivariate failure time data with a surviving fraction

A marginal regression approach for correlated censored survival data has become a widely used statistical method. Examples of this approach in survival analysis include from the early work by Wei et al. (J Am Stat Assoc 84:1065–1073, 1989) to more recent work by Spiekerman and Lin (J Am Stat Assoc 93:1164–1175, 1998). This approach is particularly useful if a covariate’s population average effect is of primary interest and the correlation structure is not of interest or cannot be appropriately specified due to lack of sufficient information. In this paper, we consider a semiparametric marginal proportional hazard mixture cure model for clustered survival data with a surviving or “cure” fraction. Unlike the clustered data in previous work, the latent binary cure statuses of patients in one cluster tend to be correlated in addition to the possible correlated failure times among the patients in the cluster who are not cured. The complexity of specifying appropriate correlation structures for the data becomes even worse if the potential correlation between cure statuses and the failure times in the cluster has to be considered, and thus a marginal regression approach is particularly attractive. We formulate a semiparametric marginal proportional hazards mixture cure model. Estimates are obtained using an EM algorithm and expressions for the variance–covariance are derived using sandwich estimators. Simulation studies are conducted to assess finite sample properties of the proposed model. The marginal model is applied to a multi-institutional study of local recurrences of tonsil cancer patients who received radiation therapy. It reveals new findings that are not available from previous analyses of this study that ignored the potential correlation between patients within the same institution.     

A two-stage estimation in the Clayton–Oakes model with marginal linear transformation models for multivariate failure time data

This paper considers the analysis of multivariate survival data where the marginal distributions are specified by semiparametric transformation models, a general class including the Cox model and the proportional odds model as special cases. First, consideration is given to the situation where the joint distribution of all failure times within the same cluster is specified by the Clayton–Oakes model (Clayton, Biometrika 65:141–151, l978; Oakes, J R Stat Soc B 44:412–422, 1982). A two-stage estimation procedure is adopted by first estimating the marginal parameters under the independence working assumption, and then the association parameter is estimated from the maximization of the full likelihood function with the estimators of the marginal parameters plugged in. The asymptotic properties of all estimators in the semiparametric model are derived. For the second situation, the third and higher order dependency structures are left unspecified, and interest focuses on the pairwise correlation between any two failure times. Thus, the pairwise association estimate can be obtained in the second stage by maximizing the pairwise likelihood function. Large sample properties for the pairwise association are also derived. Simulation studies show that the proposed approach is appropriate for practical use. To illustrate, a subset of the data from the Diabetic Retinopathy Study is used.     

Regression analysis of clustered interval-censored failure time data with linear transformation models in the presence of informative cluster size

This paper discusses regression analysis of clustered interval-censored failure time data, which often occur in medical follow-up studies among other areas. For such data, sometimes the failure time may be related to the cluster size, the number of subjects within each cluster or we have informative cluster sizes. For the problem, we present a within-cluster resampling method for the situation where the failure time of interest can be described by a class of linear transformation models. In addition to the establishment of the asymptotic properties of the proposed estimators of regression parameters, an extensive simulation study is conducted for the assessment of the finite sample properties of the proposed method and suggests that it works well in practical situations. An application to the example that motivated this study is also provided.     

Modeling the Agreement of Discrete Bivariate Survival Times using Kappa Coefficient

Using local kappa coefficients, we develop a method to assess the agreement between two discrete survival times that are measured on the same subject by different raters or methods. We model the marginal distributions for the two event times and local kappa coefficients in terms of covariates. An estimating equation is used for modeling the marginal distributions and a pseudo-likelihood procedure is used to estimate the parameters in the kappa model. The performance of the estimation procedure is examined through simulations. The proposed method can be extended to multivariate discrete survival distributions.     

A generalized linear mixed model for longitudinal binary data with a marginal logit link function

Longitudinal studies of a binary outcome are common in the health, social, and behavioral sciences. In general, a feature of random effects logistic regression models for longitudinal binary data is that the marginal functional form, when integrated over the distribution of the random effects, is no longer of logistic form. Recently, Wang and Louis (2003) proposed a random intercept model in the clustered binary data setting where the marginal model has a logistic form. An acknowledged limitation of their model is that it allows only a single random effect that varies from cluster to cluster. In this paper, we propose a modification of their model to handle longitudinal data, allowing separate, but correlated, random intercepts at each measurement occasion. The proposed model allows for a flexible correlation structure among the random intercepts, where the correlations can be interpreted in terms of Kendall's τ. For example, the marginal correlations among the repeated binary outcomes can decline with increasing time separation, while the model retains the property of having matching conditional and marginal logit link functions. Finally, the proposed method is used to analyze data from a longitudinal study designed to monitor cardiac abnormalities in children born to HIV-infected women.     

A PRESS statistic for working correlation structure selection in generalized estimating equations

Generalized estimating equations (GEE) is one of the most commonly used methods for regression analysis of longitudinal data, especially with discrete outcomes. The GEE method accounts for the association among the responses of a subject through a working correlation matrix and its correct specification ensures efficient estimation of the regression parameters in the marginal mean regression model. This study proposes a predicted residual sum of squares (PRESS) statistic as a working correlation selection criterion in GEE. A simulation study is designed to assess the performance of the proposed GEE PRESS criterion and to compare its performance with its counterpart criteria in the literature. The results show that the GEE PRESS criterion has better performance than the weighted error sum of squares SC criterion in all cases but is surpassed in performance by the Gaussian pseudo-likelihood criterion. Lastly, the working correlation selection criteria are illustrated with data from the Coronary Artery Risk Development in Young Adults study.     

Composite Likelihood Estimation for Multivariate Probit Latent Traits Models

Inference in generalized linear mixed models with multivariate random effects is often made cumbersome by the high-dimensional intractable integrals involved in the marginal likelihood. This article presents an inferential methodology based on the marginal composite likelihood approach for the probit latent traits models. This method belonging to the broad class of pseudo-likelihood involves marginal pairs probabilities of the responses which has analytical expression. The different results are illustrated with a simulation study and with an analysis of real data from health related quality of life.     

Hypothesis Testing of Hazard Ratio Parameters in Marginal Models for Multivariate Failure Time Data

Marginal hazard models for multivariate failure time data have been studied extensively in recent literature. However, standard hypothesis test statistics based on the likelihood method are not exactly appropriate for this kind of model. In this paper, extensions of the three commonly used likelihood hypothesis test statistics are discussed. Generalized Wald, generalized score and generalized likelihood ratio tests for hazard ratio parameters in a marginal hazard model for multivariate failure time data are proposed and their asymptotic distributions examined. The finite sample properties of these statistics are studied through simulations. The proposed method is applied to data from Busselton Population Health Surveys.     

A joint modelling approach for clustered recurrent events and death events

In dental implant research studies, events such as implant complications including pain or infection may be observed recurrently before failure events, i.e. the death of implants. It is natural to assume that recurrent events and failure events are correlated to each other, since they happen on the same implant (subject) and complication times have strong effects on the implant survival time. On the other hand, each patient may have more than one implant. Therefore these recurrent events or failure events are clustered since implant complication times or failure times within the same patient (cluster) are likely to be correlated. The overall implant survival times and recurrent complication times are both interesting to us. In this paper, a joint modelling approach is proposed for modelling complication events and dental implant survival times simultaneously. The proposed method uses a frailty process to model the correlation within cluster and the correlation within subjects. We use Bayesian methods to obtain estimates of the parameters. Performance of the joint models are shown via simulation studies and data analysis.     

Analysis of Multivariate Interval Censoring by Diabetic Retinopathy Study

Multivariate failure time data are commonly encountered in biomedical research since each study subject may experience multiple events or because there exists clustering of subjects such that failure times within the same cluster are correlated. In this article, we use the frailty approach to catch the related survival variables and assume each event is a discrete analog as an interval of clinical examinations periodically. For estimation, an Expectation–Maximization (EM) algorithm is developed and is applied to the diabetic retinopathy study (DRS).     

Modeling statistical dependence of Markov chains via copula models

Conditional probability distributions have been commonly used in modeling Markov chains. In this paper we consider an alternative approach based on copulas to investigate Markov-type dependence structures. Based on the realization of a single Markov chain, we estimate the parameters using one- and two-stage estimation procedures. We derive asymptotic properties of the marginal and copula parameter estimators and compare performance of the estimation procedures based on Monte Carlo simulations. At low and moderate dependence structures the two-stage estimation has comparable performance as the maximum likelihood estimation. In addition we propose a parametric pseudo-likelihood ratio test for copula model selection under the two-stage procedure. We apply the proposed methods to an environmental data set.     

Marginalized transition random effect models for multivariate longitudinal binary data

Generalized linear models with random effects and/or serial dependence are commonly used to analyze longitudinal data. However, the computation and interpretation of marginal covariate effects can be difficult. This led Heagerty (1999, 2002) to propose models for longitudinal binary data in which a logistic regression is first used to explain the average marginal response. The model is then completed by introducing a conditional regression that allows for the longitudinal, within‐subject, dependence, either via random effects or regressing on previous responses. In this paper, the authors extend the work of Heagerty to handle multivariate longitudinal binary response data using a triple of regression models that directly model the marginal mean response while taking into account dependence across time and across responses. Markov Chain Monte Carlo methods are used for inference. Data from the Iowa Youth and Families Project are used to illustrate the methods.     

Bayesian analysis of multivariate survival data using Monte Carlo methods

This paper deals with the analysis of multivariate survival data from a Bayesian perspective using Markov-chain Monte Carlo methods. The Metropolis along with the Gibbs algorithm is used to calculate some of the marginal posterior distributions. A multivariate survival model is proposed, since survival times within the same group are correlated as a consequence of a frailty random block effect. The conditional proportional-hazards model of Clayton and Cuzick is used with a martingale structured prior process (Arjas and Gasbarra) for the discretized baseline hazard. Besides the calculation of the marginal posterior distributions of the parameters of interest, this paper presents some Bayesian EDA diagnostic techniques to detect model adequacy. The methodology is exemplified with kidney infection data where the times to infections within the same patients are expected to be correlated.     

Invariant tests based on M-estimators,estimating functions,and the generalized method of moments

We study the invariance properties of various test criteria which have been proposed for hypothesis testing in the context of incompletely specified models, such as models which are formulated in terms of estimating functions (Godambe, 1960) or moment conditions and are estimated by generalized method of moments (GMM) procedures (Hansen, 1982), and models estimated by pseudo-likelihood (Gouriéroux, Monfort, and Trognon, 1984b,c) and M-estimation methods. The invariance properties considered include invariance to (possibly nonlinear) hypothesis reformulations and reparameterizations. The test statistics examined include Wald-type, LR-type, LM-type, score-type, and C(α)?type criteria. Extending the approach used in Dagenais and Dufour (1991), we show first that all these test statistics except the Wald-type ones are invariant to equivalent hypothesis reformulations (under usual regularity conditions), but all five of them are not generally invariant to model reparameterizations, including measurement unit changes in nonlinear models. In other words, testing two equivalent hypotheses in the context of equivalent models may lead to completely different inferences. For example, this may occur after an apparently innocuous rescaling of some model variables. Then, in view of avoiding such undesirable properties, we study restrictions that can be imposed on the objective functions used for pseudo-likelihood (or M-estimation) as well as the structure of the test criteria used with estimating functions and generalized method of moments (GMM) procedures to obtain invariant tests. In particular, we show that using linear exponential pseudo-likelihood functions allows one to obtain invariant score-type and C(α)?type test criteria, while in the context of estimating function (or GMM) procedures it is possible to modify a LR-type statistic proposed by Newey and West (1987) to obtain a test statistic that is invariant to general reparameterizations. The invariance associated with linear exponential pseudo-likelihood functions is interpreted as a strong argument for using such pseudo-likelihood functions in empirical work.     

Failure Inference From a Marker Process Based on a Bivariate Wiener Model

Many models have been proposed that relate failure times and stochastic time-varying covariates. In some of these models, failure occurs when a particular observable marker crosses a threshold level. We are interested in the more difficult, and often more realistic, situation where failure is not related deterministically to an observable marker. In this case, joint models for marker evolution and failure tend to lead to complicated calculations for characteristics such as the marginal distribution of failure time or the joint distribution of failure time and marker value at failure. This paper presents a model based on a bivariate Wiener process in which one component represents the marker and the second, which is latent (unobservable), determines the failure time. In particular, failure occurs when the latent component crosses a threshold level. The model yields reasonably simple expressions for the characteristics mentioned above and is easy to fit to commonly occurring data that involve the marker value at the censoring time for surviving cases and the marker value and failure time for failing cases. Parametric and predictive inference are discussed, as well as model checking. An extension of the model permits the construction of a composite marker from several candidate markers that may be available. The methodology is demonstrated by a simulated example and a case application.     

Additive transformation models for clustered failure time data

We propose a class of additive transformation risk models for clustered failure time data. Our models are motivated by the usual additive risk model for independent failure times incorporating a frailty with mean one and constant variability which is a natural generalization of the additive risk model from univariate failure time to multivariate failure time. An estimating equation approach based on the marginal hazards function is proposed. Under the assumption that cluster sizes are completely random, we show the resulting estimators of the regression coefficients are consistent and asymptotically normal. We also provide goodness-of-fit test statistics for choosing the transformation. Simulation studies and real data analysis are conducted to examine the finite-sample performance of our estimators.     

Implications of Model Misspecification in Robust Tests for Recurrent Events

Chronic disease processes often feature transient recurrent adverse clinical events. Treatment comparisons in clinical trials of such disorders must be based on valid and efficient methods of analysis. We discuss robust strategies for testing treatment effects with recurrent events using methods based on marginal rate functions, partially conditional rate functions, and methods based on marginal failure time models. While all three approaches lead to valid tests of the null hypothesis when robust variance estimates are used, they differ in power. Moreover, some approaches lead to estimators of treatment effect which are more easily interpreted than others. To investigate this, we derive the limiting value of estimators of treatment effect from marginal failure time models and illustrate their dependence on features of the underlying point process, as well as the censoring mechanism. Through simulation, we show that methods based on marginal failure time distributions are shown to be sensitive to treatment effects delaying the occurrence of the very first recurrences. Methods based on marginal or partially conditional rate functions perform well in situations where treatment effects persist or in settings where the aim is to summarizee long-term data on efficacy.