The Adult Changes in Thought (ACT) study is a long-running prospective study of incident all-cause dementia and Alzheimer's disease (AD). As the cohort ages, death (a terminal event) is a prominent competing risk for AD (a non-terminal event), although the reverse is not the case. As such, analyses of data from ACT can be placed within the semi-competing risks framework. Central to semi-competing risks, and in contrast to standard competing risks, is that one can learn about the dependence structure between the two events. To-date, however, most methods for semi-competing risks treat dependence as a nuisance and not a potential source of new clinical knowledge. We propose a novel regression-based framework that views the two time-to-event outcomes through the lens of a longitudinal bivariate process on a partition of the time scale. A key innovation of the framework is that dependence is represented in two distinct forms, $\textit{local}$ and $\textit{global}$ dependence, both of which have intuitive clinical interpretations. Estimation and inference are performed via penalized maximum likelihood, and can accommodate right censoring, left truncation and time-varying covariates. The framework is used to investigate the role of gender and having $\ge$1 APOE-$\epsilon4$ allele on the joint risk of AD and death.
Rheumatoid arthritis clinical trials are strategically designed to collect the disease activity score of each patient over multiple clinical visits, meanwhile a patient may drop out before their intended completion due to various reasons. The dropout terminates the longitudinal data collection on the patients activity score. In the presence of informative dropout, that is, the dropout depends on latent variables from the longitudinal process, simply applying a model to analyze the longitudinal outcomes may lead to biased results because the assumption of random dropout is violated. In this pap…
Semiparametric joint models of longitudinal and competing risks data are computationally costly and their current implementations do not scale well to massive biobank data. This paper identifies and addresses some key computational barriers in a semiparametric joint model for longitudinal and competing risks survival data. By developing and implementing customized linear scan algorithms, we reduce the computational complexities from $O(n^2)$ or $O(n^3)$ to $O(n)$ in various components including numerical integration, risk set calculation, and standard error estimation, where $n$ is the number …
The cause-specific cumulative incidence function (CIF) quantifies the subject-specific disease risk with competing risk outcome. With longitudinally collected biomarker data, it is of interest to dynamically update the predicted CIF by incorporating the most recent biomarker as well as the cumulating longitudinal history. Motivated by a longitudinal cohort study of chronic kidney disease, we propose a framework for dynamic prediction of end stage renal disease using multivariate longitudinal biomarkers, accounting for the competing risk of death. The proposed framework extends the landmark sur…
In this article, a general family of bivariate distributions is used to model competing risks data with dependent factors. The general structure of competing risks data considered here includes ties. A comprehensive inferential framework for the proposed model is presented: maximum likelihood estimation, confidence interval construction, and model selection within the bivariate family of distributions for a given dependent competing risks data. The inferential methods are very convenient to implement. Through detailed simulations, the inferential methods are observed to provide quite reasonabl…
This proposal is motivated by an analysis of the English Longitudinal Study of Ageing (ELSA), which aims to investigate the role of loneliness in explaining the negative impact of hearing loss on dementia. The methodological challenges that complicate this mediation analysis include the use of a time-to-event endpoint subject to competing risks, as well as the presence of feedback relationships between the mediator and confounders that are both repeatedly measured over time. To account for these challenges, we introduce natural effect proportional (cause-specific) hazard models. These extend m…
Joint models initially dedicated to a single longitudinal marker and a single time-to-event need to be extended to account for the rich longitudinal data of cohort studies. Multiple causes of clinical progression are indeed usually observed, and multiple longitudinal markers are collected when the true latent trait of interest is hard to capture (e.g. quality of life, functional dependency, cognitive level). These multivariate and longitudinal data also usually have nonstandard distributions (discrete, asymmetric, bounded,...). We propose a joint model based on a latent process and latent clas…
Massachusetts Institute of Technology（麻省理工学院）；Dana-Farber Cancer Institute（达纳-法伯癌症研究所）
Effective learning from electronic health records (EHR) data for prediction of clinical outcomes is often challenging because of features recorded at irregular timesteps and loss to follow-up as well as competing events such as death or disease progression. To that end, we propose a generative time-to-event model, SurvLatent ODE, which adopts an Ordinary Differential Equation-based Recurrent Neural Networks (ODE-RNN) as an encoder to effectively parameterize dynamics of latent states under irregularly sampled input data. Our model then utilizes the resulting latent embedding to flexibly estima…
Bivariate linear mixed models are useful when analyzing longitudinal data of two associated markers. In this paper, we present a bivariate linear mixed model including random effects or first-order auto-regressive process and independent measurement error for both markers. Codes and tricks to fit these models using SAS Proc MIXED are provided. Limitations of this program are discussed and an example in the field of HIV infection is shown. Despite some limitations, SAS Proc MIXED is a useful tool that may be easily extendable to multivariate response in longitudinal studies.
The coronavirus disease 2019 (COVID-19) pandemic has exerted a profound impact on patients with end-stage renal disease relying on kidney dialysis to sustain their lives. Motivated by a request by the U.S. Centers for Medicare & Medicaid Services, our analysis of their postdischarge hospital readmissions and deaths in 2020 revealed that the COVID-19 effect has varied significantly with postdischarge time and time since the onset of the pandemic. However, the complex dynamics of the COVID-19 effect trajectories cannot be characterized by existing varying coefficient models. To address this issu…
In many medical studies, patients are followed longitudinally and interest is on assessing the relationship between longitudinal measurements and time to an event. Recently, various authors have proposed joint modeling approaches for longitudinal and time-to-event data for a single longitudinal variable. These joint modeling approaches become intractable with even a few longitudinal variables. In this paper we propose a regression calibration approach for jointly modeling multiple longitudinal measurements and discrete time-to-event data. Ideally, a two-stage modeling approach could be applied…
We propose a nonparametric bivariate time-varying coefficient model for longitudinal measurements with the occurrence of a terminal event that is subject to right censoring. The time-varying coefficients capture the longitudinal trajectories of covariate effects along with both the followup time and the residual lifetime. The proposed model extends the parametric conditional approach given terminal event time in recent literature, and thus avoids potential model misspecification. We consider a kernel smoothing method for estimating regression coefficients in our model and use cross-validation …
Multi-state Models For Disease Histories Based On Longitudinal Data
Statistical Consulting Unit StaBLab, Department of Statistics, LMU Munich（慕尼黑大学统计咨询单元StaBLab，统计学系）；Department of Genetic Epidemiology, University of Regensburg（雷根斯堡大学生物遗传流行病学系）；Munich Center for Machine Learning, LMU Munich（慕尼黑机器学习中心，慕尼黑大学）；Faculty of Informatics and Data Science, University of Regensburg（雷根斯堡大学信息科学与数据科学学院）
Joint models for longitudinal and survival data have gained a lot of attention in recent years, with the development of myriad extensions to the basic model, including those which allow for multivariate longitudinal data, competing risks and recurrent events. Several software packages are now also available for their implementation. Although mathematically straightforward, the inclusion of multiple longitudinal outcomes in the joint model remains computationally difficult due to the large number of random effects required, which hampers the practical application of this extension. We present a…
In this paper, we use the method of modified signed log-likelihood ratio test for the problem of testing the equality of correlation coefficients in two independent bivariate normal distributions. We compare this method with two other %competing approaches, Fisher's Z-transform and generalized test variable, using a Monte Carlo simulation. It indicates that the proposed method is better than the other approaches, in terms of the actual sizes and powers especially when the sample sizes are unequal. We illustrate performance of the proposed approach, using a real data set.
The methodological advancements made in the field of joint models are numerous. None the less, the case of competing risks joint models have largely been neglected, especially from a practitioner's point of view. In the relevant works on competing risks joint models, the assumptions of Gaussian linear longitudinal series and proportional cause-specific hazard functions, amongst others, have remained unchallenged. In this paper, we provide a framework based on R-INLA to apply competing risks joint models in a unifying way such that non-Gaussian longitudinal data, spatial structures, time depend…
A Bayesian joint model of multiple nonlinear longitudinal and competing risks outcomes for dynamic prediction in multiple myeloma: joint estimation and corrected two-stage approaches
Toward Joint Prediction of a Longitudinal Marker and a Terminal Event: A bivariate discrete-time framework
Harvard T.H. Chan School of Public Health（哈佛陈曾熙公共卫生学院）；Richard A. and Susan F. Smith Center for Outcomes Research, Beth Israel Deaconess Medical Center（贝斯以色列女执事医疗中心理查德·A和苏珊·F史密斯结果研究中心）；Massachusetts General Hospital（麻省总医院）；Harvard Medical School（哈佛医学院）
Analysis of competing risks data plays an important role in the lifetime data analysis. Recently Feizjavadian and Hashemi (Computational Statistics and Data Analysis, vol. 82, 19-34, 2015) provided a classical inference of a competing risks data set using four-parameter Marshall-Olkin bivariate Weibull distribution when the failure of an unit at a particular time point can happen due to more than one cause. The aim of this paper is to provide the Bayesian analysis of the same model based on a very flexible Gamma-Dirichlet prior on the scale parameters. It is observed that the Bayesian inferenc…
Joint models are used in ageing studies to investigate the association between longitudinal markers and a time-to-event, and have been extended to multiple markers and/or competing risks. The competing risk of death must be considered in the elderly because death and dementia have common risk factors. Moreover, in cohort studies, time-to-dementia is interval-censored because dementia is only assessed intermittently. So subjects can become demented and die between two follow-up visits without being diagnosed. To study pre-dementia cognitive decline, we propose a joint latent class model combini…
We propose a fast bivariate smoothing approach for symmetric surfaces that has a wide range of applications. We show how it can be applied to estimate the covariance function in longitudinal data as well as multiple additive covariances in functional data with complex correlation structures. Our symmetric smoother can handle (possibly noisy) data sampled on a common, dense grid as well as irregularly or sparsely sampled data. Estimation is based on bivariate penalized spline smoothing using a mixed model representation and the symmetry is used to reduce computation time compared to the usual n…
A joint model for (un)bounded longitudinal markers, competing risks, and recurrent events using patient registry data
Erasmus University Medical Center（伊拉斯姆斯大学医学中心）；Duke University（杜克大学）；Cincinnati Children’s Hospital Medical Center（辛辛那提儿童医院医疗中心）；University of Cincinnati（辛辛那提大学）
Inferring nonlinear and asymmetric causal relationships between multivariate longitudinal data is a challenging task with wide-ranging application areas including clinical medicine, mathematical biology, economics and environmental research. A number of methods for inferring causal relationships within complex dynamic and stochastic systems have been proposed but there is not a unified consistent definition of causality in this context. We evaluate the performance of ten prominent bivariate causality indices for time series data, across four simulated model systems that have different coupling…
Inference over tails is performed by applying only the results of extreme value theory. Whilst such theory is well defined and flexible enough in the univariate case, multivariate inferential methods often require the imposition of arbitrary constraints not fully justifed by the underlying theory. In contrast, our approach uses only the constraints imposed by theory. We build on previous, theoretically justified work for marginal exceedances over a high, unknown threshold, by combining it with flexible, semiparametric copulae specifications to investigate extreme dependence. Whilst giving prob…
Smoothing of noisy sample covariances is an important component in functional data analysis. We propose a novel covariance smoothing method based on penalized splines and associated software. The proposed method is a bivariate spline smoother that is designed for covariance smoothing and can be used for sparse functional or longitudinal data. We propose a fast algorithm for covariance smoothing using leave-one-subject-out cross validation. Our simulations show that the proposed method compares favorably against several commonly used methods. The method is applied to a study of child growth led…
A Bayesian semi-parametric approach to causal mediation for longitudinal mediators and time-to-event outcomes with application to a cardiovascular disease cohort study
