Modeling longitudinal and survival data jointly offers many advantages such as addressing measurement error and missing data in the longitudinal processes, understanding and quantifying the association between the longitudinal markers and the survival events and predicting the risk of events based on the longitudinal markers. A joint model involves multiple submodels (one for each longitudinal/survival outcome) usually linked together through correlated or shared random effects. Their estimation is computationally expensive (particularly due to a multidimensional integration of the likelihood over the random effects distribution) so that inference methods become rapidly intractable, and restricts applications of joint models to a small number of longitudinal markers and/or random effects. We introduce a Bayesian approximation based on the Integrated Nested Laplace Approximation algorithm implemented in the R package R-INLA to alleviate the computational burden and allow the estimation of multivariate joint models with fewer restrictions. Our simulation studies show that R-INLA substantially reduces the computation time and the variability of the parameter estimates compared to alternative estimation strategies. We further apply the methodology to analyze 5 longitudinal markers (3 continuous, 1 count, 1 binary, and 16 random effects) and competing risks of death and transplantation in a clinical trial on primary biliary cholangitis. R-INLA provides a fast and reliable inference technique for applying joint models to the complex multivariate data encountered in health research.
Joint modeling of geometric features of longitudinal process and discrete survival time measured on nested timescales: an application to fecundity studies
This paper studies Cox's regression hazard model with an unobservable random frailty where no specific distribution is postulated for the frailty variable, and the marginal lifetime distribution allows both parametric and non-parametric models. Laplace's approximation method and gradient search on smooth manifolds embedded in Euclidean space are applied, and a non-iterative profile likelihood optimization method is proposed for estimating the regression coefficients. The proposed method is compared with the Expected-Maximization method developed based on a gamma frailty assumption, and also in…
J- and MJ-Type Tests for Non-Nested Parametric Survival Models with a Cure Fraction: A Score Test Approach
Institute of Mathematics and Statistics, Federal University of Goiás（戈亚斯联邦大学数学与统计学院）；Department of Statistics, Federal University of Paraíba（帕拉伊巴联邦大学统计学系）；Department of Statistics, Federal University of Pernambuco（伯南布哥联邦大学统计学系）
Extended cure survival models enable to separate covariates that affect the probability of an event (or `long-term' survival) from those only affecting the event timing (or `short-term' survival). We propose to generalize the bounded cumulative hazard model to handle additive terms for time-varying (exogenous) covariates jointly impacting long- and short-term survival. The selection of the penalty parameters is a challenge in that framework. A fast algorithm based on Laplace approximations in Bayesian P-spline models is proposed. The methodology is motivated by fertility studies where women's …
Illness-death models are a class of stochastic models inside the multi-state framework. In those models, individuals are allowed to move over time between different states related to illness and death. They are of special interest when working with non-terminal diseases, as they not only consider the competing risk of death but also allow to study progression from illness to death. The intensity of each transition can be modelled including both fixed and random effects of covariates. In particular, spatially structured random effects or their multivariate versions can be used to assess spatial…
We propose a two-stage design for a clinical trial with an early stopping rule for safety. We use different criteria to assess early stopping and efficacy. The early stopping rule is based on a criteria that can be determined more quickly than that of efficacy. These separate criteria are also nested in the sense that efficacy is a special case of, but not identical to, the early stopping criteria. The design readily allows for planning in terms of statistical significance, power, and expected sample size necessary to assess an early stopping rule. This method is illustrated with a Phase II de…
The integrated nested Laplace approximation (INLA) for Bayesian inference is an efficient approach to estimate the posterior marginal distributions of the parameters and latent effects of Bayesian hierarchical models that can be expressed as latent Gaussian Markov random fields (GMRF). The representation as a GMRF allows the associated software R-INLA to estimate the posterior marginals in a fraction of the time as typical Markov chain Monte Carlo algorithms. INLA can be extended by means of Bayesian model averaging (BMA) to increase the number of models that it can fit to conditional latent G…
We propose the approximate Laplace approximation (ALA) to evaluate integrated likelihoods, a bottleneck in Bayesian model selection. The Laplace approximation (LA) is a popular tool that speeds up such computation and equips strong model selection properties. However, when the sample size is large or one considers many models the cost of the required optimizations becomes impractical. ALA reduces the cost to that of solving a least-squares problem for each model. Further, it enables efficient computation across models such as sharing pre-computed sufficient statistics and certain operations in…
The introduction of machine learning (ML) techniques to the field of survival analysis has increased the flexibility of modeling approaches, and ML based models have become state-of-the-art. These models optimize their own cost functions, and their performance is often evaluated using the concordance index (C-index). From a statistical learning perspective, it is therefore an important problem to analyze the relationship between the optimizers of the C-index and those of the ML cost functions. We address this issue by providing C-index Fisher-consistency results and excess risk bounds for seve…
The European Medicines Agency has in recent years allowed licensing of new pharmaceuticals at an earlier stage in the clinical trial process. When trial evidence is obtained at an early stage, the events of interest, such as disease progression or death, may have only been observed in a small proportion of patients. Health care authorities therefore must decide on the adoption of new technologies based on less mature evidence than previously, resulting in greater uncertainty about clinical- and cost-effectiveness. When a trial is ongoing at the point of decision making, there may be value in c…
In recent years, spatial and spatio-temporal modeling have become an important area of research in many fields (epidemiology, environmental studies, disease mapping). In this work we propose different spatial models to study hospital recruitment, including some potentially explicative variables. Interest is on the distribution per geographical unit of the ratio between the number of patients living in this geographical unit and the population in the same unit. Models considered are within the framework of Bayesian Latent Gaussian models. Our response variable is assumed to follow a binomial di…
The Integrated Nested Laplace Approximation (INLA) is a deterministic approach to Bayesian inference on latent Gaussian models (LGMs) and focuses on fast and accurate approximation of posterior marginals for the parameters in the models. Recently, methods have been developed to extend this class of models to those that can be expressed as conditional LGMs by fixing some of the parameters in the models to descriptive values. These methods differ in the manner descriptive values are chosen. This paper proposes to combine importance sampling with INLA (IS-INLA), and extends this approach with the…
Double hierarchical generalized linear models (DHGLM) are a family of models that are flexible enough as to model hierarchically the mean and scale parameters. In a Bayesian framework, fitting highly parameterized hierarchical models is challenging when this problem is addressed using typical Markov chain Monte Carlo (MCMC) methods due to the potential high correlation between different parameters and effects in the model. The integrated nested Laplace approximation (INLA) could be considered instead to avoid dealing with these problems. However, DHGLM do not fit within the latent Gaussian Mar…
Datasets containing large samples of time-to-event data arising from several small heterogeneous groups are commonly encountered in statistics. This presents problems as they cannot be pooled directly due to their heterogeneity or analyzed individually because of their small sample size. Bayesian nonparametric modelling approaches can be used to model such datasets given their ability to flexibly share information across groups. In this paper, we will compare three popular Bayesian nonparametric methods for modelling the survival functions of heterogeneous groups. Specifically, we will first c…
University of Isfahan（伊斯法罕大学）；Institute for Research in Fundamental Sciences（基础科学研究所）；Fox Chase Cancer Center（福克斯·蔡斯癌症中心）；Temple University Health System（天普大学卫生系统）；Northern Illinois University（北伊利诺伊大学）；University of Wisconsin-Milwaukee（威斯康星大学密尔沃基分校）；Temple University（天普大学）
This paper introduces link functions for transforming one probability distribution to another such that the Kullback-Leibler and Rényi divergences between the two distributions are symmetric. Two general classes of link models are proposed. The first model links two survival functions and is applicable to models such as the proportional odds and change point, which are used in survival analysis and reliability modeling. A prototype application involving the proportional odds model demonstrates advantages of symmetric divergence measures over asymmetric measures for assessing the efficacy of fe…
Measurement error (ME) and missing values in covariates are often unavoidable in disciplines that deal with data, and both problems have separately received considerable attention during the past decades. However, while most researchers are familiar with methods for treating missing data, accounting for ME in covariates of regression models is less common. In addition, ME and missing data are typically treated as two separate problems, despite practical and theoretical similarities. Here, we exploit the fact that missing data in a continuous covariate is an extreme case of classical ME, allowi…
Several methods have been proposed in the spatial statistics literature for the analysis of big data sets in continuous domains. However, new methods for analyzing high-dimensional areal data are still scarce. Here, we propose a scalable Bayesian modeling approach for smoothing mortality (or incidence) risks in high-dimensional data, that is, when the number of small areas is very large. The method is implemented in the R add-on package bigDM. Model fitting and inference is based on the idea of "divide and conquer" and use integrated nested Laplace approximations and numerical integration. We …
Various computational challenges arise when applying Bayesian inference approaches to complex hierarchical models. Sampling-based inference methods, such as Markov Chain Monte Carlo strategies, are renowned for providing accurate results but with high computational costs and slow or questionable convergence. On the contrary, approximate methods like the Integrated Nested Laplace Approximation (INLA) construct a deterministic approximation to the univariate posteriors through nested Laplace Approximations. This method enables fast inference performance in Latent Gaussian Models, which encode a …
The key operation in Bayesian inference, is to compute high-dimensional integrals. An old approximate technique is the Laplace method or approximation, which dates back to Pierre- Simon Laplace (1774). This simple idea approximates the integrand with a second order Taylor expansion around the mode and computes the integral analytically. By developing a nested version of this classical idea, combined with modern numerical techniques for sparse matrices, we obtain the approach of Integrated Nested Laplace Approximations (INLA) to do approximate Bayesian inference for latent Gaussian models (LGMs…
The mixture cure model for analyzing survival data is characterized by the assumption that the population under study is divided into a group of subjects who will experience the event of interest over some finite time horizon and another group of cured subjects who will never experience the event irrespective of the duration of follow-up. When using the Bayesian paradigm for inference in survival models with a cure fraction, it is common practice to rely on Markov chain Monte Carlo (MCMC) methods to sample from posterior distributions. Although computationally feasible, the iterative nature of…
Survival models are used to analyze time-to-event data in a variety of disciplines. Proportional hazard models provide interpretable parameter estimates, but proportional hazards assumptions are not always appropriate. Non-parametric models are more flexible but often lack a clear inferential framework. We propose a Bayesian tree partition model which is both flexible and inferential. Inference is obtained through the posterior tree structure and flexibility is preserved by modeling the the hazard function in each partition using a latent exponentiated Gaussian process. An efficient reversible…
We define a novel class of additive models, called Extended Latent Gaussian Models, that allow for a wide range of response distributions and flexible relationships between the additive predictor and mean response. The new class covers a broad range of interesting models including multi-resolution spatial processes, partial likelihood-based survival models, and multivariate measurement error models. Because computation of the exact posterior distribution is infeasible, we develop a fast, scalable approximate Bayesian inference methodology for this class based on nested Gaussian, Laplace, and a…
Bayesian joint modelling of longitudinal biomarkers to enable extrapolation of overall survival: an application using larotrectinib trial clinical data
The R package merlin performs flexible joint modelling of hierarchical multi-outcome data. Increasingly, multiple longitudinal biomarker measurements, possibly censored time-to-event outcomes and baseline characteristics are available. However, there is limited software that allows all of this information to be incorporated into one model. In this paper, we present merlin which allows for the estimation of models with unlimited numbers of continuous, binary, count and time-to-event outcomes, with unlimited levels of nested random effects. A wide variety of link functions, including the expecte…
In this paper we describe fast Bayesian statistical analysis of vector positive-valued time series, with application to interesting financial data streams. We discuss a flexible level correlated model (LCM) framework for building hierarchical models for vector positive-valued time series. The LCM allows us to combine marginal gamma distributions for the positive-valued component responses, while accounting for association among the components at a latent level. We use integrated nested Laplace approximation (INLA) for fast approximate Bayesian modeling via the R-INLA package, building custom f…
We introduce a new copula-based correction for generalized linear mixed models (GLMMs) within the integrated nested Laplace approximation (INLA) approach for approximate Bayesian inference for latent Gaussian models. While INLA is usually very accurate, some (rather extreme) cases of GLMMs with e.g. binomial or Poisson data have been seen to be problematic. Inaccuracies can occur when there is a very low degree of smoothing or "borrowing strength" within the model, and we have therefore developed a correction aiming to push the boundaries of the applicability of INLA. Our new correction has be…
The comparison of local characteristics of two random processes can shed light on periods of time or space at which the processes differ the most. This paper proposes a method that learns about regions with a certain volume, where the marginal attributes of two processes are less similar. The proposed methods are devised in full generality for the setting where the data of interest are themselves stochastic processes, and thus the proposed method can be used for pointing out the regions of maximum dissimilarity with a certain volume, in the contexts of functional data, time series, and point p…
Many of the data, particularly in medicine and disease mapping are count. Indeed, the under or overdispersion problem in count data distrusts the performance of the classical Poisson model. For taking into account this problem, in this paper, we introduce a new Bayesian structured additive regression model, called gamma count, with enough flexibility in modeling dispersion. Setting convenient prior distributions on the model parameters is a momentous issue in Bayesian statistics that characterize the nature of our uncertainty parameters. Relying on a recently proposed class of penalized comple…
Bayesian hierarchical models are increasingly popular for realistic modelling and analysis of complex data. This trend is accompanied by the need for flexible, general, and computationally efficient methods for model criticism and conflict detection. Usually, a Bayesian hierarchical model incorporates a grouping of the individual data points, for example individuals in repeated measurement data. In such cases, the following question arises: Are any of the groups "outliers", or in conflict with the remaining groups? Existing general approaches aiming to answer such questions tend to be extremel…
This paper presents the development of a spatial block-Nearest Neighbor Gaussian process (block-NNGP) for location-referenced large spatial data. The key idea behind this approach is to divide the spatial domain into several blocks which are dependent under some constraints. The cross-blocks capture the large-scale spatial dependence, while each block captures the small-scale spatial dependence. The resulting block-NNGP enjoys Markov properties reflected on its sparse precision matrix. It is embedded as a prior within the class of latent Gaussian models, thus Bayesian inference is obtained usi…
In employing spatial regression models for counts, we usually meet two issues. First, ignoring the inherent collinearity between covariates and the spatial effect would lead to causal inferences. Second, real count data usually reveal over or under-dispersion where the classical Poisson model is not appropriate to use. We propose a flexible Bayesian hierarchical modeling approach by joining non-confounding spatial methodology and a newly reconsidered dispersed count modeling from the renewal theory to control the issues. Specifically, we extend the methodology for analyzing spatial count data …
The integrated nested Laplace approximation (INLA) is a well-known and popular technique for spatial modeling with a user-friendly interface in the R-INLA package. Unfortunately, only a certain class of latent Gaussian models are amenable to fitting with INLA. In this paper we describe Template Model Builder (TMB), an existing technique which is well-suited to fitting complex spatio-temporal models. TMB is relatively unknown to the spatial statistics community, but is a highly flexible random effects modeling tool which allows users to define complex random effects models through simple C++ te…
Current implementations of multiresolution methods are limited in terms of possible types of responses and approaches to inference. We provide a multiresolution approach for spatial analysis of non-Gaussian responses using latent Gaussian models and Bayesian inference via integrated nested Laplace approximation (INLA). The approach builds on `LatticeKrig', but uses a reparameterization of the model parameters that is intuitive and interpretable so that modeling and prior selection can be guided by expert knowledge about the different spatial scales at which dependence acts. The priors can be u…
