A copula model for marked point processes

Many chronic diseases feature recurring clinically important events. In addition, however, there often exists a random variable which is realized upon the occurrence of each event reflecting the severity of the event, a cost associated with it, or possibly a short term response indicating the effect of a therapeutic intervention. We describe a novel model for a marked point process which incorporates a dependence between continuous marks and the event process through the use of a copula function. The copula formulation ensures that event times can be modeled by any intensity function for point processes, and any multivariate model can be specified for the continuous marks. The relative efficiency of joint versus separate analyses of the event times and the marks is examined through simulation under random censoring. An application to data from a recent trial in transfusion medicine is given for illustration.     

Bayesian Modeling of Recurrent Event Data with Dependent Censoring

The recurrent-event setting, where the subjects experience multiple occurrences of the event of interest, are encountered in many biomedical applications. In analyzing recurrent event data, non informative censoring is often assumed for the implementation of statistical methods. However, when a terminating event such as death serves as part of the censoring mechanism, validity of the censoring assumption may be violated because recurrence can be a powerful risk factor for death. We consider joint modeling of recurrent event process and terminating event under a Bayesian framework in which a shared frailty is used to model the association between the intensity of the recurrent event process and the hazard of the terminating event. Our proposed model is implemented on data from a well-known cancer study.     

Semiparametric regression methods for temporal processes subject to multiple sources of censoring

Process regression methodology is underdeveloped relative to the frequency with which pertinent data arise. In this article, the response-190 is a binary indicator process representing the joint event of being alive and remaining in a specific state. The process is indexed by time (e.g., time since diagnosis) and observed continuously. Data of this sort occur frequently in the study of chronic disease. A general area of application involves a recurrent event with non-negligible duration (e.g., hospitalization and associated length of hospital stay) and subject to a terminating event (e.g., death). We propose a semiparametric multiplicative model for the process version of the probability of being alive and in the (transient) state of interest. Under the proposed methods, the regression parameter is estimated through a procedure that does not require estimating the baseline probability. Unlike the majority of process regression methods, the proposed methods accommodate multiple sources of censoring. In particular, we derive a computationally convenient variant of inverse probability of censoring weighting based on the additive hazards model. We show that the regression parameter estimator is asymptotically normal, and that the baseline probability function estimator converges to a Gaussian process. Simulations demonstrate that our estimators have good finite sample performance. We apply our method to national end-stage liver disease data. The Canadian Journal of Statistics 48: 222–237; 2020 © 2019 Statistical Society of Canada     

New approaches for censored longitudinal data in joint modelling of longitudinal and survival data,with application to HIV vaccine studies

In HIV vaccine studies, longitudinal immune response biomarker data are often left-censored due to lower limits of quantification of the employed immunological assays. The censoring information is important for predicting HIV infection, the failure event of interest. We propose two approaches to addressing left censoring in longitudinal data: one that makes no distributional assumptions for the censored data—treating left censored values as a “point mass” subgroup—and the other makes a distributional assumption for a subset of the censored data but not for the remaining subset. We develop these two approaches to handling censoring for joint modelling of longitudinal and survival data via a Cox proportional hazards model fit by h-likelihood. We evaluate the new methods via simulation and analyze an HIV vaccine trial data set, finding that longitudinal characteristics of the immune response biomarkers are highly associated with the risk of HIV infection.

     

Joint model for bivariate zero-inflated recurrent event data with terminal events

Bivariate recurrent event data are observed when subjects are at risk of experiencing two different type of recurrent events. In this paper, our interest is to suggest statistical model when there is a substantial portion of subjects not experiencing recurrent events but having a terminal event. In a context of recurrent event data, zero events can be related with either the risk free group or a terminal event. For simultaneously reflecting both a zero inflation and a terminal event in a context of bivariate recurrent event data, a joint model is implemented with bivariate frailty effects. Simulation studies are performed to evaluate the suggested models. Infection data from AML (acute myeloid leukemia) patients are analyzed as an application.     

Using recurrent time-to-event models with multinomial outcomes to generate toxicity profiles

Most clinical studies, which investigate the impact of therapy simultaneously, record the frequency of adverse events in order to monitor safety of the intervention. Study reports typically summarise adverse event data by tabulating the frequencies of the worst grade experienced but provide no details of the temporal profiles of specific types of adverse events. Such 'toxicity profiles' are potentially important tools in disease management and in the assessment of newer therapies including targeted treatments and immunotherapy where different types of toxicity may be more common at various times during long-term drug exposure. Toxicity profiles of commonly experienced adverse events occurring due to exposure to long-term treatment could assist in evaluating the costs of the health care benefits of therapy. We show how to generate toxicity profiles using an adaptation of the ordinal time-to-event model comprising of a two-step process, involving estimation of the multinomial response probabilities using multinomial logistic regression and combining these with recurrent time to event hazard estimates to produce cumulative event probabilities for each of the multinomial adverse event response categories. Such a model permits the simultaneous assessment of the risk of events over time and provides cumulative risk probabilities for each type of adverse event response. The method can be applied more generally by using different models to estimate outcome/response probabilities. The method is illustrated by developing toxicity profiles for three distinct types of adverse events associated with two treatment regimens for patients with advanced breast cancer.     

Simulated maximum likelihood estimation in joint models for multiple longitudinal markers and recurrent events of multiple types,in the presence of a terminal event

In medical studies we are often confronted with complex longitudinal data. During the follow-up period, which can be ended prematurely by a terminal event (e.g. death), a subject can experience recurrent events of multiple types. In addition, we collect repeated measurements from multiple markers. An adverse health status, represented by ‘bad’ marker values and an abnormal number of recurrent events, is often associated with the risk of experiencing the terminal event. In this situation, the missingness of the data is not at random and, to avoid bias, it is necessary to model all data simultaneously using a joint model. The correlations between the repeated observations of a marker or an event type within an individual are captured by normally distributed random effects. Because the joint likelihood contains an analytically intractable integral, Bayesian approaches or quadrature approximation techniques are necessary to evaluate the likelihood. However, when the number of recurrent event types and markers is large, the dimensionality of the integral is high and these methods are too computationally expensive. As an alternative, we propose a simulated maximum-likelihood approach based on quasi-Monte Carlo integration to evaluate the likelihood of joint models with multiple recurrent event types and markers.     

Joint modelling of pre-randomisation event counts and multiple post-randomisation survival times with cure rates: application to data for early epilepsy and single seizures

In this paper, we consider the analysis of recurrent event data that examines the differences between two treatments. The outcomes that are considered in the analysis are the pre-randomisation event count and post-randomisation times to first and second events with associated cure fractions. We develop methods that allow pre-randomisation counts and two post-randomisation survival times to be jointly modelled under a Poisson process framework, assuming that outcomes are predicted by (unobserved) event rates. We apply these methods to data that examine the difference between immediate and deferred treatment policies in patients presenting with single seizures or early epilepsy. We find evidence to suggest that post-randomisation seizure rates change at randomisation and following a first seizure after randomisation. We also find that there are cure rates associated with the post-randomisation times to first and second seizures. The increase in power over standard survival techniques, offered by the joint models that we propose, resulted in more precise estimates of the treatment effect and the ability to detect interactions with covariate effects.     

Joint modeling of longitudinal data with a dependent terminal event

ABSTRACT

Longitudinal data often arise in longitudinal follow-up studies, and there may exist a dependent terminal event such as death that stops the follow-up. In this article, we propose a new joint modeling for the analysis of longitudinal data with informative observation times via a dependent terminal event and two latent variables. Estimating equations are developed for parameter estimation, and asymptotic properties of the resulting estimators are established. In addition, a generalization of the joint model with time-varying coefficients for the longitudinal response variable is considered, and goodness-of-fit methods for assessing the adequacy of the model are also provided. The proposed method works well in our simulation studies, and is applied to a data set from a bladder cancer study.     

Population-based absolute risk estimation with survey data

Absolute risk is the probability that a cause-specific event occurs in a given time interval in the presence of competing events. We present methods to estimate population-based absolute risk from a complex survey cohort that can accommodate multiple exposure-specific competing risks. The hazard function for each event type consists of an individualized relative risk multiplied by a baseline hazard function, which is modeled nonparametrically or parametrically with a piecewise exponential model. An influence method is used to derive a Taylor-linearized variance estimate for the absolute risk estimates. We introduce novel measures of the cause-specific influences that can guide modeling choices for the competing event components of the model. To illustrate our methodology, we build and validate cause-specific absolute risk models for cardiovascular and cancer deaths using data from the National Health and Nutrition Examination Survey. Our applications demonstrate the usefulness of survey-based risk prediction models for predicting health outcomes and quantifying the potential impact of disease prevention programs at the population level.     

A dynamic Mover–Stayer model for recurrent event processes subject to resolution

In studies of affective disorder, individuals are often observed to experience recurrent symptomatic exacerbations warranting hospitalization. Interest may lie in modeling the occurrence of such exacerbations over time and identifying associated risk factors. In some patients, recurrent exacerbations are temporally clustered following disease onset, but cease to occur after a period of time. We develop a dynamic Mover–Stayer model in which a canonical binary variable associated with each event indicates whether the underlying disease has resolved. An individual whose disease process has not resolved will experience events following a standard point process model governed by a latent intensity. When the disease process resolves, the complete data intensity becomes zero and no further event will occur. An expectation–maximization algorithm is described for parametric and semiparametric model fitting based on a discrete time dynamic Mover–Stayer model and a latent intensity-based model of the underlying point process.     

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.     

A new test for single against competing risks models in duration analysis

This paper shows that the single-risk duration model with two event types is a limiting case of bivariate dependent competing risks model, where the joint distribution of event times are degenerate. Then a new test is proposed for the null hypothesis of single risk against dependent competing risks model under the proportional hazard model assumption.     

Joint modeling of correlated binary outcomes: HIV-1 and HSV-2 co-infection

Herpes Simplex Virus Type 2 (HSV-2) facilitates the sexual acquisition and transmission of HIV-1 infection and is highly prevalent in most regions experiencing severe HIV epidemics. In sub-Saharan Africa, where HIV infection is a public health burden, the prevalence of HSV-2 is substantially high. The high prevalence of HSV-2 and the association between HSV-2 infection and HIV-1 acquisition could play a significant role in the spread of HIV-1 in the region. The objective of our study was to identify risk factors for HSV-2 and HIV-1 infections among men in sub-Saharan Africa. We used a joint response model that accommodates the interdependence between the two infections in assessing their risk factors. Simulation studies show superiority of the joint response model compared to the traditional models which ignore the dependence between the two infections. We found higher odds of having HSV-2/HIV-1 among older men, in men who had multiple sexual partners, abused alcohol, or reported symptoms of sexually transmitted infections. These findings suggest that interventions that identify and control the risk factors of the two infections should be part of HIV-1 prevention programs in sub-Saharan Africa where antiretroviral therapy is not readily available.     

Single-Index-Based CoVaR With Very High-Dimensional Covariates

Systemic risk analysis reveals the interdependencies of risk factors especially in tail event situations. In applications the focus of interest is on capturing joint tail behavior rather than a variation around the mean. Quantile and expectile regression are used here as tools of data analysis. When it comes to characterizing tail event curves one faces a dimensionality problem, which is important for CoVaR (Conditional Value at Risk) determination. A projection-based single-index model specification may come to the rescue but for ultrahigh-dimensional regressors one faces yet another dimensionality problem and needs to balance precision versus dimension. Such a balance is achieved by combining semiparametric ideas with variable selection techniques. In particular, we propose a projection-based single-index model specification for very high-dimensional regressors. This model is used for practical CoVaR estimates with a systemically chosen indicator. In simulations we demonstrate the practical side of the semiparametric CoVaR method. The application to the U.S. financial sector shows good backtesting results and indicate market coagulation before the crisis period. Supplementary materials for this article are available online.     

Joint modelling of longitudinal biomarker and gap time between recurrent events: copula-based dependence

In this paper, we will extend the joint model of longitudinal biomarker and recurrent event via copula function for accounting the dependence between the two processes. The general idea of joining separate processes by allowing model-specific random effect may come from different families distribution. It is a main advantage of the proposed method that a copula construction does not constrain the choice of marginal distributions of random effects. A maximum likelihood estimation with importance sampling technique as a simple and easy understanding method is employed to model inference. To evaluate and verify the validation of the proposed joint model, a bootstrapping method as a model-based resampling is developed. Our proposed joint model is also applied to pemphigus disease data for assessing the effect of biomarker trajectory on risk of recurrence.     

Semiparametric inference for the recurrent events process by means of a single-index model

In this paper, we introduce new parametric and semiparametric regression techniques for a recurrent event process subject to random right censoring. We develop models for the cumulative mean function and provide asymptotically normal estimators. Our semiparametric model which relies on a single-index assumption can be seen as a dimension reduction technique that, contrary to a fully nonparametric approach, is not stroke by the curse of dimensionality when the number of covariates is high. We discuss data-driven techniques to choose the parameters involved in the estimation procedures and provide a simulation study to support our theoretical results.     

Analysis of longitudinal data unbalanced over time

Summary.  The paper considers modelling, estimating and diagnostically verifying the response process generating longitudinal data, with emphasis on association between repeated meas-ures from unbalanced longitudinal designs. Our model is based on separate specifications of the moments for the mean, standard deviation and correlation, with different components possibly sharing common parameters. We propose a general class of correlation structures that comprise random effects, measurement errors and a serially correlated process. These three elements are combined via flexible time-varying weights, whereas the serial correlation can depend flexibly on the mean time and lag. When the measurement schedule is independent of the response process, our estimation procedure yields consistent and asymptotically normal estimates for the mean parameters even when the standard deviation and correlation are misspecified, and for the standard deviation parameters even when the correlation is misspecified. A generic diagnostic method is developed for verifying the models for the mean, standard deviation and, in particular, the correlation, which is applicable even when the data are severely unbalanced. The methodology is illustrated by an analysis of data from a longitudinal study that was designed to characterize pulmonary growth in girls.     

Exact filtering for partially observed continuous time models

Summary.  The forward–backward algorithm is an exact filtering algorithm which can efficiently calculate likelihoods, and which can be used to simulate from posterior distributions. Using a simple result which relates gamma random variables with different rates, we show how the forward–backward algorithm can be used to calculate the distribution of a sum of gamma random variables, and to simulate from their joint distribution given their sum. One application is to calculating the density of the time of a specific event in a Markov process, as this time is the sum of exponentially distributed interevent times. This enables us to apply the forward–backward algorithm to a range of new problems. We demonstrate our method on three problems: calculating likelihoods and simulating allele frequencies under a non-neutral population genetic model, analysing a stochastic epidemic model and simulating speciation times in phylogenetics.     

Functional variance estimation using penalized splines with principal component analysis

In many fields of empirical research one is faced with observations arising from a functional process. If so, classical multivariate methods are often not feasible or appropriate to explore the data at hand and functional data analysis is prevailing. In this paper we present a method for joint modeling of mean and variance in longitudinal data using penalized splines. Unlike previous approaches we model both components simultaneously via rich spline bases. Estimation as well as smoothing parameter selection is carried out using a mixed model framework. The resulting smooth covariance structures are then used to perform principal component analysis. We illustrate our approach by several simulations and an application to financial interest data.