A Semi‐parametric Transformation Frailty Model for Semi‐competing Risks Survival Data

In the analysis of semi‐competing risks data interest lies in estimation and inference with respect to a so‐called non‐terminal event, the observation of which is subject to a terminal event. Multi‐state models are commonly used to analyse such data, with covariate effects on the transition/intensity functions typically specified via the Cox model and dependence between the non‐terminal and terminal events specified, in part, by a unit‐specific shared frailty term. To ensure identifiability, the frailties are typically assumed to arise from a parametric distribution, specifically a Gamma distribution with mean 1.0 and variance, say, σ². When the frailty distribution is misspecified, however, the resulting estimator is not guaranteed to be consistent, with the extent of asymptotic bias depending on the discrepancy between the assumed and true frailty distributions. In this paper, we propose a novel class of transformation models for semi‐competing risks analysis that permit the non‐parametric specification of the frailty distribution. To ensure identifiability, the class restricts to parametric specifications of the transformation and the error distribution; the latter are flexible, however, and cover a broad range of possible specifications. We also derive the semi‐parametric efficient score under the complete data setting and propose a non‐parametric score imputation method to handle right censoring; consistency and asymptotic normality of the resulting estimators is derived and small‐sample operating characteristics evaluated via simulation. Although the proposed semi‐parametric transformation model and non‐parametric score imputation method are motivated by the analysis of semi‐competing risks data, they are broadly applicable to any analysis of multivariate time‐to‐event outcomes in which a unit‐specific shared frailty is used to account for correlation. Finally, the proposed model and estimation procedures are applied to a study of hospital readmission among patients diagnosed with pancreatic cancer.     

Pair‐copula constructions for non‐Gaussian DAG models

We propose a new type of multivariate statistical model that permits non‐Gaussian distributions as well as the inclusion of conditional independence assumptions specified by a directed acyclic graph. These models feature a specific factorisation of the likelihood that is based on pair‐copula constructions and hence involves only univariate distributions and bivariate copulas, of which some may be conditional. We demonstrate maximum‐likelihood estimation of the parameters of such models and compare them to various competing models from the literature. A simulation study investigates the effects of model misspecification and highlights the need for non‐Gaussian conditional independence models. The proposed methods are finally applied to modeling financial return data. The Canadian Journal of Statistics 40: 86–109; 2012 © 2012 Statistical Society of Canada     

Estimating Marginal Effects in Accelerated Failure Time Models for Serial Sojourn Times Among Repeated Events

Recurrent event data are commonly encountered in longitudinal studies when events occur repeatedly over time for each study subject. An accelerated failure time (AFT) model on the sojourn time between recurrent events is considered in this article. This model assumes that the covariate effect and the subject-specific frailty are additive on the logarithm of sojourn time, and the covariate effect maintains the same over distinct episodes, while the distributions of the frailty and the random error in the model are unspecified. With the ordinal nature of recurrent events, two scale transformations of the sojourn times are derived to construct semiparametric methods of log-rank type for estimating the marginal covariate effects in the model. The proposed estimation approaches/inference procedures also can be extended to the bivariate events, which alternate themselves over time. Examples and comparisons are presented to illustrate the performance of the proposed methods.     

Bivariate Birnbaum-Saunders accelerated lifetime model: estimation and diagnostic analysis

In this paper, we discuss the bivariate Birnbaum-Saunders accelerated lifetime model, in which we have modeled the dependence structure of bivariate survival data through the use of frailty models. Specifically, we propose the bivariate model Birnbaum-Saunders with the following frailty distributions: gamma, positive stable and logarithmic series. We present a study of inference and diagnostic analysis for the proposed model, more concisely, are proposed a diagnostic analysis based in local influence and residual analysis to assess the fit model, as well as, to detect influential observations. In this regard, we derived the normal curvatures of local influence under different perturbation schemes and we performed some simulation studies for assessing the potential of residuals to detect misspecification in the systematic component, the presence in the stochastic component of the model and to detect outliers. Finally, we apply the methodology studied to real data set from recurrence in times of infections of 38 kidney patients using a portable dialysis machine, we analyzed these data considering independence within the pairs and using the bivariate Birnbaum-Saunders accelerated lifetime model, so that we could make a comparison and verify the importance of modeling dependence within the times of infection associated with the same patient.     

Flexible modelling of simultaneously interval censored and truncated time‐to‐event data

This paper deals with the analysis of data from a HET‐CAM^VT experiment. From a statistical perspective, such data yield many challenges. First of all, the data are typically time‐to‐event like data, which are at the same time interval censored and right truncated. In addition, one has to cope with overdispersion as well as clustering. Traditional analysis approaches ignore overdispersion and clustering and summarize the data into a continuous score that can be analysed using simple linear models. In this paper, a novel combined frailty model is developed that simultaneously captures all of the aforementioned statistical challenges posed by the data. Copyright © 2015 John Wiley & Sons, Ltd.     

Asymptotic properties of likelihood ratio test statistics in affected‐sib‐pair analysis

In an affected‐sib‐pair genetic linkage analysis, identical by descent data for affected sib pairs are routinely collected at a large number of markers along chromosomes. Under very general genetic assumptions, the IBD distribution at each marker satisfies the possible triangle constraint. Statistical analysis of IBD data should thus utilize this information to improve efficiency. At the same time, this constraint renders the usual regularity conditions for likelihood‐based statistical methods unsatisfied. In this paper, the authors study the asymptotic properties of the likelihood ratio test (LRT) under the possible triangle constraint. They derive the limiting distribution of the LRT statistic based on data from a single locus. They investigate the precision of the asymptotic distribution and the power of the test by simulation. They also study the test based on the supremum of the LRT statistics over the markers distributed throughout a chromosome. Instead of deriving a limiting distribution for this test, they use a mixture of chi‐squared distributions to approximate its true distribution. Their simulation results show that this approach has desirable simplicity and satisfactory precision.     

Marginal and Conditional Distribution Estimation from Double‐sampled Semi‐competing Risks Data

Informative dropout is a vexing problem for any biomedical study. Most existing statistical methods attempt to correct estimation bias related to this phenomenon by specifying unverifiable assumptions about the dropout mechanism. We consider a cohort study in Africa that uses an outreach programme to ascertain the vital status for dropout subjects. These data can be used to identify a number of relevant distributions. However, as only a subset of dropout subjects were followed, vital status ascertainment was incomplete. We use semi‐competing risk methods as our analysis framework to address this specific case where the terminal event is incompletely ascertained and consider various procedures for estimating the marginal distribution of dropout and the marginal and conditional distributions of survival. We also consider model selection and estimation efficiency in our setting. Performance of the proposed methods is demonstrated via simulations, asymptotic study and analysis of the study data.     

Analysis of Bivariate Survival Data using Shared Inverse Gaussian Frailty Model

In this article, we consider shared frailty model with inverse Gaussian distribution as frailty distribution and log-logistic distribution (LLD) as baseline distribution for bivariate survival times. We fit this model to three real-life bivariate survival data sets. The problem of analyzing and estimating parameters of shared inverse Gaussian frailty is the interest of this article and then compare the results with shared gamma frailty model under the same baseline for considered three data sets. Data are analyzed using Bayesian approach to the analysis of clustered survival data in which there is a dependence of failure time observations within the same group. The variance component estimation provides the estimated dispersion of the random effects. We carried out a test for frailty (or heterogeneity) using Bayes factor. Model comparison is made using information criteria and Bayes factor. We observed that the shared inverse Gaussian frailty model with LLD as baseline is the better fit for all three bivariate data sets.     

A Multivariate Model for Repeated Failure Time Measurements

A parametric multivariate failure time distribution is derived from a frailty-type model with a particular frailty distribution. It covers as special cases certain distributions which have been used for multivariate survival data in recent years. Some properties of the distribution are derived: its marginal and conditional distributions lie within the parametric family, and association between the component variates can be positive or, to a limited extent, negative. The simple closed form of the survivor function is useful for right-censored data, as occur commonly in survival analysis, and for calculating uniform residuals. Also featured is the distribution of ratios of paired failure times. The model is applied to data from the literature     

A Copula‐Based Non‐parametric Measure of Regression Dependence

Abstract. This article presents a framework for comparing bivariate distributions according to their degree of regression dependence. We introduce the general concept of a regression dependence order (RDO). In addition, we define a new non‐parametric measure of regression dependence and study its properties. Besides being monotone in the new RDOs, the measure takes on its extreme values precisely at independence and almost sure functional dependence, respectively. A consistent non‐parametric estimator of the new measure is constructed and its asymptotic properties are investigated. Finally, the finite sample properties of the estimate are studied by means of a small simulation study.     

Bayesian model selection for D‐vine pair‐copula constructions

In recent years analyses of dependence structures using copulas have become more popular than the standard correlation analysis. Starting from Aas et al. ( 2009 ) regular vine pair‐copula constructions (PCCs) are considered the most flexible class of multivariate copulas. PCCs are involved objects but (conditional) independence present in data can simplify and reduce them significantly. In this paper the authors detect (conditional) independence in a particular vine PCC model based on bivariate t copulas by deriving and implementing a reversible jump Markov chain Monte Carlo algorithm. However, the methodology is general and can be extended to any regular vine PCC and to all known bivariate copula families. The proposed approach considers model selection and estimation problems for PCCs simultaneously. The effectiveness of the developed algorithm is shown in simulations and its usefulness is illustrated in two real data applications. The Canadian Journal of Statistics 39: 239–258; 2011 © 2011 Statistical Society of Canada     

Control‐based imputation for sensitivity analyses in informative censoring for recurrent event data

In clinical trials, missing data commonly arise through nonadherence to the randomized treatment or to study procedure. For trials in which recurrent event endpoints are of interests, conventional analyses using the proportional intensity model or the count model assume that the data are missing at random, which cannot be tested using the observed data alone. Thus, sensitivity analyses are recommended. We implement the control‐based multiple imputation as sensitivity analyses for the recurrent event data. We model the recurrent event using a piecewise exponential proportional intensity model with frailty and sample the parameters from the posterior distribution. We impute the number of events after dropped out and correct the variance estimation using a bootstrap procedure. We apply the method to an application of sitagliptin study.     

Bivariate frailty model for the analysis of multivariate survival time

Because of limitations of the univariate frailty model in analysis of multivariate survival data, a bivariate frailty model is introduced for the analysis of bivariate survival data. This provides tremendous flexibility especially in allowing negative associations between subjects within the same cluster. The approach involves incorporating into the model two possibly correlated frailties for each cluster. The bivariate lognormal distribution is used as the frailty distribution. The model is then generalized to multivariate survival data with two distinguished groups and also to alternating process data. A modified EM algorithm is developed with no requirement of specification of the baseline hazards. The estimators are generalized maximum likelihood estimators with subject-specific interpretation. The model is applied to a mental health study on evaluation of health policy effects for inpatient psychiatric care.     

A multivariate von mises distribution with applications to bioinformatics

Motivated by problems of modelling torsional angles in molecules, Singh, Hnizdo & Demchuk (2002) proposed a bivariate circular model which is a natural torus analogue of the bivariate normal distribution and a natural extension of the univariate von Mises distribution to the bivariate case. The authors present here a multivariate extension of the bivariate model of Singh, Hnizdo & Demchuk (2002). They study the conditional distributions and investigate the shapes of marginal distributions for a special case. The methods of moments and pseudo‐likelihood are considered for the estimation of parameters of the new distribution. The authors investigate the efficiency of the pseudo‐likelihood approach in three dimensions. They illustrate their methods with protein data of conformational angles     

Robust Poisson likelihood estimation for frailty Cox models: A simulation study

Frailty models can be fit as mixed-effects Poisson models after transforming time-to-event data to the Poisson model framework. We assess, through simulations, the robustness of Poisson likelihood estimation for Cox proportional hazards models with log-normal frailties under misspecified frailty distribution. The log-gamma and Laplace distributions were used as true distributions for frailties on a natural log scale. Factors such as the magnitude of heterogeneity, censoring rate, number and sizes of groups were explored. In the simulations, the Poisson modeling approach that assumes log-normally distributed frailties provided accurate estimates of within- and between-group fixed effects even under a misspecified frailty distribution. Non-robust estimation of variance components was observed in the situations of substantial heterogeneity, large event rates, or high data dimensions.     

Treatment effect quantification for time‐to‐event endpoints–Estimands,analysis strategies,and beyond

A draft addendum to ICH E9 has been released for public consultation in August 2017. The addendum focuses on two topics particularly relevant for randomized confirmatory clinical trials: estimands and sensitivity analyses. The need to amend ICH E9 grew out of the realization of a lack of alignment between the objectives of a clinical trial stated in the protocol and the accompanying quantification of the “treatment effect” reported in a regulatory submission. We embed time‐to‐event endpoints in the estimand framework and discuss how the four estimand attributes described in the addendum apply to time‐to‐event endpoints. We point out that if the proportional hazards assumption is not met, the estimand targeted by the most prevalent methods used to analyze time‐to‐event endpoints, logrank test, and Cox regression depends on the censoring distribution. We discuss for a large randomized clinical trial how the analyses for the primary and secondary endpoints as well as the sensitivity analyses actually performed in the trial can be seen in the context of the addendum. To the best of our knowledge, this is the first attempt to do so for a trial with a time‐to‐event endpoint. Questions that remain open with the addendum for time‐to‐event endpoints and beyond are formulated, and recommendations for planning of future trials are given. We hope that this will provide a contribution to developing a common framework based on the final version of the addendum that can be applied to design, protocols, statistical analysis plans, and clinical study reports in the future.     

Shared gamma frailty models based on reversed hazard rate for modeling Australian twin data

In this paper, we consider shared gamma frailty model with the reversed hazard rate (RHR) with two different baseline distributions, namely the generalized inverse Rayleigh and the exponentiated Gumbel distributions. With these two baseline distributions we propose two different shared frailty models. We develop the Bayesian estimation procedure using Markov Chain Monte Carlo technique to estimate the parameters involved in these models. We present a simulation study to compare the true values of the parameters with the estimated values. A search of the literature suggests that currently no work has been done for these two baseline distributions with a shared gamma frailty with the RHR so far. We also apply these two models by using a real life bivariate survival data set of Australian twin data given by Duffy et a1. (1990) and a better model is suggested for the data.     

A grouped beta process model for multivariate resting‐state EEG microstate analysis on twins

EEG microstate analysis investigates the collection of distinct temporal blocks that characterize the electrical activity of the brain. Brain activity within each microstate is stable, but activity switches rapidly between different microstates in a nonrandom way. We propose a Bayesian nonparametric model that concurrently estimates the number of microstates and their underlying behaviour. We use a Markov switching vector autoregressive (VAR) framework, where a hidden Markov model (HMM) controls the nonrandom state switching dynamics of the EEG activity and a VAR model defines the behaviour of all time points within a given state. We analyze the resting‐state EEG data from twin pairs collected through the Minnesota Twin Family Study, consisting of 70 epochs per participant, where each epoch corresponds to 2 s of EEG data. We fit our model at the twin pair level, sharing information within epochs from the same participant and within epochs from the same twin pair. We capture within twin‐pair similarity, using an Indian buffet process, to consider an infinite library of microstates, allowing each participant to select a finite number of states from this library. The state spaces of highly similar twins may completely overlap while dissimilar twins could select distinct state spaces. In this way, our Bayesian nonparametric model defines a sparse set of states that describe the EEG data. All epochs from a single participant use the same set of states and are assumed to adhere to the same state switching dynamics in the HMM model, enforcing within‐participant similarity.     

Two‐stage phase II survival trial design

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression‐free survival or event‐free survival is often a primary endpoint for the trial design. However, methods to evaluate two‐stage single‐arm phase II trials with a time‐to‐event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two‐stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two‐stage design can be routinely used for single‐arm phase II trial designs with a time‐to‐event endpoint as a complement to the commonly used Simon's two‐stage design for the binary outcome.     

Non‐parametric Copula Estimation Under Bivariate Censoring

In this paper, we consider non‐parametric copula inference under bivariate censoring. Based on an estimator of the joint cumulative distribution function, we define a discrete and two smooth estimators of the copula. The construction that we propose is valid for a large range of estimators of the distribution function and therefore for a large range of bivariate censoring frameworks. Under some conditions on the tails of the distributions, the weak convergence of the corresponding copula processes is obtained in l^∞([0,1]²). We derive the uniform convergence rates of the copula density estimators deduced from our smooth copula estimators. Investigation of the practical behaviour of these estimators is performed through a simulation study and two real data applications, corresponding to different censoring settings. We use our non‐parametric estimators to define a goodness‐of‐fit procedure for parametric copula models. A new bootstrap scheme is proposed to compute the critical values.