Interval-censored Survival Data Research Articles

Additive Hazards Regression Analysis of Massive Interval-Censored Data via Data Splitting

With the rapid development of data acquisition and storage space, massive data sets exhibited with large sample size emerge increasingly and make more advanced statistical tools urgently need. To accommodate such big volume in the analysis, a variety of methods have been proposed in the circumstances of complete or right censored survival data. However, existing development of big data methodology has not attended to interval-censored outcomes, which are ubiquitous in cross-sectional or periodical follow-up studies. In this work, we propose an easily implemented divide-and-combine approach for analyzing massive interval-censored survival data under the additive hazards model. We establish the asymptotic properties of the proposed estimator, including the consistency and asymptotic normality. In addition, the divide-and-combine estimator is shown to be asymptotically equivalent to the full-data-based estimator obtained from analyzing all data together. Simulation studies suggest that, relative to the full-data-based approach, the proposed divide-and-combine approach has desirable advantage in terms of computation time, making it more applicable to large-scale data analysis. An application to a set of interval-censored data also demonstrates the practical utility of the proposed method.

Interval-Censored Linear Quantile Regression

Censored quantile regression has emerged as a prominent alternative to classical Cox’s proportional hazards model or accelerated failure time model in both theoretical and applied statistics. While quantile regression has been extensively studied for right-censored survival data, methodologies for analyzing interval-censored data remain limited in the survival analysis literature. This article introduces a novel local weighting approach for estimating linear censored quantile regression, specifically tailored to handle diverse forms of interval-censored survival data. The estimation equation and the corresponding convex objective function for the regression parameter can be constructed as a weighted average of quantile loss contributions at two interval endpoints. The weighting components are nonparametrically estimated using local kernel smoothing or ensemble machine learning techniques. To estimate the nonparametric distribution mass for interval-censored data, a modified EM algorithm for nonparametric maximum likelihood estimation is employed by introducing subject-specific latent Poisson variables. The proposed method’s empirical performance is demonstrated through extensive simulation studies and real data analyses of two HIV/AIDS datasets. Supplementary materials for this article are available online.

A Bayesian semiparametric mixed effects proportional hazards model for clustered partly interval-censored data

Clustered partly interval-censored survival data naturally arise from many medical and epidemiological studies. We propose a Bayesian semiparametric approach for fitting a mixed effects proportional hazards (PH) model to clustered partly interval-censored data. The proposed method allows for not only a random intercept as most frailty models do for clustered survival data, but also random effects of covariates. We assume a normal prior for each random intercept/random effect, seeing the instability of a gamma prior for a frailty in this situation. Simulation studies with data generated from both mixed effects PH model and mixed effects accelerated failure times model are conducted, to evaluate the performance of the proposed method and compare it with the three methods currently available in the literature. The application of the proposed approach is illustrated through analyzing the progression-free survival data derived from a phase III metastatic colorectal cancer clinical trial.

Analysis of length-biased and partly interval-censored survival data with mismeasured covariates.

In this paper, we analyze the length-biased and partly interval-censored data, whose challenges primarily come from biased sampling and interfere induced by interval censoring. Unlike existing methods that focus on low-dimensional data and assume the covariates to be precisely measured, sometimes researchers may encounter high-dimensional data subject to measurement error, which are ubiquitous in applications and make estimation unreliable. To address those challenges, we explore a valid inference method for handling high-dimensional length-biased and interval-censored survival data with measurement error in covariates under the accelerated failure time model. We primarily employ the SIMEX method to correct for measurement error effects and propose the boosting procedure to do variable selection and estimation. The proposed method is able to handle the case that the dimension of covariates is larger than the sample size and enjoys appealing features that the distributions of the covariates are leftunspecified.

The generalized odd log-logistic-G regression with interval-censored survival data

The article proposes a new regression based on the generalized odd log-logistic family for interval-censored data. The survival times are not observed for this type of data, and the event of interest occurs at some random interval. This family can be used in interval modeling since it generalizes some popular lifetime distributions in addition to its ability to present various forms of the risk function. The estimation of the parameters is addressed by the classical and Bayesian methods. We examine the behavior of the estimates for some sample sizes and censorship percentages. Selection criteria, likelihood ratio tests, residual analysis, and graphical techniques assess the goodness of fit of the fitted models. The usefulness of the proposed models is red shown by means of two real data sets.

An augmented likelihood approach for the Cox proportional hazards model with interval-censored auxiliary and validated outcome data-with application to the Hispanic Community Health Study/Study of Latinos.

In large epidemiologic studies, it is typical for an inexpensive, non-invasive procedure to be used to record disease status during regular follow-up visits, with less frequent assessment by a gold standard test. Inexpensive outcome measures like self-reported disease status are practical to obtain, but can be error-prone. Association analysis reliant on error-prone outcomes may lead to biased results; however, restricting analyses to only data from the less frequently observed error-free outcome could be inefficient. We have developed an augmented likelihood that incorporates data from both error-prone outcomes and a gold standard assessment. We conduct a numerical study to show how we can improve statistical efficiency by using the proposed method over standard approaches for interval-censored survival data that do not leverage auxiliary data. We extend this method for the complex survey design setting so that it can be applied in our motivating data example. Our method is applied to data from the Hispanic Community Health Study/Study of Latinos to assess the association between energy and protein intake and the risk of incident diabetes. In our application, we demonstrate how our method can be used in combination with regression calibration to additionally address the covariate measurement error in self-reported diet.

범주형 전환문항을 포함하는 항목 무응답 대체 방법 비교

In social surveys, unfolding bracket questions are used as a technique to reduce the loss of information due to nonresponse when item nonresponses occur. Item nonresponse, including unfolding bracket questions, has a similar structure to interval censored survival data. However, imputation methods to handle item nonresponses including unfolding bracket questions are limited. In this study, we examine performance of imputation with and without unfolding bracket questions. Also we compare three imputation methods to handle unfolding bracket questions. The First method is a linear regression-based nearest neighbor hotdeck imputation. Secondly, it is possible to consider a uniform distribution that selects a value with the same probability within the section for each individual. The third is an imputation method using the survival function estimated by the nonparametric maximum likelihood estimation method. Hotdeck imputation was considered as an imputation for not using unfolding bracket questions. The performance of these imputation methods was evaluated through simulation and the KLoSA study is used to provide examples of the application of these methods to real data. Imputation methods using unfolding bracket questions showed better performance than the method without unfolding bracket questions. The performance of the imputation method using the survival function estimated by the nonparametric maximum likelihood estimation method was better when the nonresponse rate was low and when the nonresponse rate is large in terms of root mean square error. When the non-response rate is large, the linear regression-based nearest neighbor hotdeck imputation method showed better results in terms of mean bias.

Estimation and testing for clustered interval-censored bivariate survival data with application using the semi-parametric version of the Clayton-Oakes model.

The Kaplan-Meier estimator is ubiquitously used to estimate survival probabilities for time-to-event data. It is nonparametric, and thus does not require specification of a survival distribution, but it does assume that the risk set at any time t consists of independent observations. This assumption does not hold for data from paired organ systems such as occur in ophthalmology (eyes) or otolaryngology (ears), or for other types of clustered data. In this article, we estimate marginal survival probabilities in the setting of clustered data, and provide confidence limits for these estimates with intra-cluster correlation accounted for by an interval-censored version of the Clayton-Oakes model. We develop a goodness-of-fit test for general bivariate interval-censored data and apply it to the proposed interval-censored version of the Clayton-Oakes model. We also propose a likelihood ratio test for the comparison of survival distributions between two groups in the setting of clustered data under the assumption of a constant between-group hazard ratio. This methodology can be used both for balanced and unbalanced cluster sizes, and also when the cluster size is informative. We compare our test to the ordinary log rank test and the Lin-Wei (LW) test based on the marginal Cox proportional Hazards model with robust standard errors obtained from the sandwich estimator. Simulation results indicate that the ordinary log rank test over-inflates type I error, while the proposed unconditional likelihood ratio test has appropriate type I error and higher power than the LW test. The method is demonstrated in real examples from the Sorbinil Retinopathy Trial, and the Age-Related Macular Degeneration Study. Raw data from these two trials are provided.

Statistical methodologies for evaluation of the rate of persistence of Ebola virus in semen of male survivors in Sierra Leone.

The 2013-2016 Ebola virus (EBOV) outbreak in West Africa was the largest and most complex outbreak ever, with a total number of cases and deaths higher than in all previous EBOV outbreaks combined. The outbreak was characterized by rapid spread of the infection in nations that were weakly prepared to handle it. EBOV ribonucleic acid (RNA) is known to persist in body fluids following disease recovery, and studying this persistence is crucial for controlling such epidemics. Observational cohort studies investigating EBOV persistence in semen require following up recently recovered survivors of Ebola virus disease (EVD), from recruitment to the time when their semen tests negative for EBOV, the endpoint being time-to-event. Because recruitment of EVD survivors takes place weeks or months following disease recovery, the event of interest may have already occurred. Survival analysis methods are the best suited for the estimation of the virus persistence in body fluids but must account for left- and interval-censoring present in the data, which is a more complex problem than that of presence of right censoring alone. Using the Sierra Leone Ebola Virus Persistence Study, we discuss study design issues, endpoint of interest and statistical methodologies for interval- and right-censored non-parametric and parametric survival modelling. Using the data from 203 EVD recruited survivors, we illustrate the performance of five different survival models for estimation of persistence of EBOV in semen. The interval censored survival analytic methods produced more precise estimates of EBOV persistence in semen and were more representative of the source population than the right censored ones. The potential to apply these methods is enhanced by increased availability of statistical software to handle interval censored survival data. These methods may be applicable to diseases of a similar nature where persistence estimation of pathogens is of interest.

Median regression models for clustered, interval-censored survival data - An application to prostate surgery study.

Genitourinary surgeons and oncologists are particularly interested in whether a robotic surgery improves times to Prostate Specific Antigen (PSA) recurrence compared to a non-robotic surgery for removing the cancerous prostate. Time to PSA recurrence is an example of a survival time that is typically interval-censored between two consecutive clinical inspections with opposite test results. In addition, success of medical devices and technologies often depends on factors such as experience and skill level of the medical service providers, thus leading to clustering of these survival times. For analyzing the effects of surgery types and other covariates on median of clustered interval-censored time to post-surgery PSA recurrence, we present three competing novel models and associated frequentist and Bayesian analyses. The first model is based on a transform-both-sides of survival time with Gaussian random effects to account for the within-cluster association. Our second model assumes an approximate marginal Laplace distribution for the transformed log-survival times with a Gaussian copula to accommodate clustering. Our third model is a special case of the second model with Laplace distribution for the marginal log-survival times and Gaussian copula for the within-cluster association. Simulation studies establish the second model to be highly robust against extreme observations while estimating median regression coefficients. We provide a comprehensive comparison among these three competing models based on the model properties and the computational ease of their Frequentist and Bayesian analysis. We also illustrate the practical implementations and uses of these methods via analysis of a simulated clustered interval-censored data-set similar in design to a post-surgery PSA recurrence study.

A spline-based nonparametric analysis for interval-censored bivariate survival data.

In this manuscript we propose a spline-based sieve nonparametric maximum likelihood estimation method for joint distribution function with bivariate interval-censored data. We study the asymptotic behavior of the proposed estimator by proving the consistency and deriving the rate of convergence. Based on the sieve estimate of the joint distribution, we also develop an efficient nonparametric test for making inference about the dependence between two interval-censored event times and establish its asymptotic normality. We conduct simulation studies to examine the finite sample performance of the proposed methodology. Finally we apply the method to assess the association between two subtypes of mild cognitive impairment (MCI): amnestic MCI and non-amnestic MCI, for Huntington disease (HD) using data from a 12-year observational cohort study on premanifest HD individuals, PREDICT-HD.

Interval Censored Recursive Forests

We propose interval censored recursive forests (ICRF), an iterative tree ensemble method for interval censored survival data. This nonparametric regression estimator addresses the splitting bias problem of existing tree-based methods and iteratively updates survival estimates in a self-consistent manner. Consistent splitting rules are developed for interval censored data, convergence is monitored using out-of-bag samples, and kernel-smoothing is applied. The ICRF is uniformly consistent and displays high prediction accuracy in both simulations and applications to avalanche and national mortality data. An R package icrf is available on CRAN. Supplementary files for this article are available online.

Exposure assessment for Cox proportional hazards cure models with interval-censored survival data.

Mixture cure models have been developed as an effective tool to analyze failure time data with a cure fraction. Used in conjunction with the logistic regression model, this model allows covariate-adjusted inference of an exposure effect on the cured probability and the hazard of failure for the uncured subjects. However, the covariate-adjusted inference for the overall exposure effect is not directly provided. In this paper, we describe a Cox proportional hazards cure model to analyze interval-censored survival data in the presence of a cured fraction and then apply a post-estimation approach by using model-predicted estimates difference to assess the overall exposure effect on the restricted mean survival time scale. For baseline hazard/survival function estimation, simple parametric models as fractional polynomials or restricted cubic splines are utilized to approximate the baseline logarithm cumulative hazard function, or, alternatively, the full likelihood is specified through a piecewise linear approximation for the cumulative baseline hazard function. Simulation studies were conducted to demonstrate the unbiasedness of both estimation methods for the overall exposure effect estimates over various baseline hazard distribution shapes. The methods are applied to analyze the interval-censored relapse time data from a smoking cessation study.

Semiparametric analysis of clustered interval-censored survival data using soft Bayesian additive regression trees (SBART).

Popular parametric and semiparametric hazards regression models for clustered survival data are inappropriate and inadequate when the unknown effects of different covariates and clustering are complex. This calls for a flexible modeling framework to yield efficient survival prediction. Moreover, for some survival studies involving time to occurrence of some asymptomatic events, survival times are typically interval censored between consecutive clinical inspections. In this article, we propose a robust semiparametric model for clustered interval-censored survival data under a paradigm of Bayesian ensemble learning, called soft Bayesian additive regression trees or SBART (Linero and Yang, 2018), which combines multiple sparse (soft) decision trees to attain excellent predictive accuracy. We develop a novel semiparametric hazards regression model by modeling the hazard function as a product of a parametric baseline hazard function and a nonparametric component that uses SBART to incorporate clustering, unknown functional forms of the main effects, and interaction effects of various covariates. In addition to being applicable for left-censored, right-censored, and interval-censored survival data, our methodology is implemented using a data augmentation scheme which allows for existing Bayesian backfitting algorithms to be used. We illustrate the practical implementation and advantages of our method via simulation studies and an analysis of a prostate cancer surgery study where dependence on the experience and skill level of the physicians leads to clustering of survival times. We conclude by discussing our method's applicability in studies involving high-dimensional data with complex underlyingassociations.

An Interval-Censored Proportional Hazards Model

We fit a Cox proportional hazards (PH) model to interval-censored survival data by first subdividing each individual's failure interval into nonoverlapping sub-intervals. Using the set of all interval endpoints in the data set, those that fall into the individual's interval are then used as the cut points for the sub-intervals. Each sub-interval has an accompanying weight calculated from a parametric Weibull model based on the current parameter estimates. A weighted PH model is then fit with multiple lines of observations corresponding to the sub-intervals for each individual, where the lower end of each sub-interval is used as the observed failure time with the accompanying weights incorporated. Right-censored observations are handled in the usual manner. We iterate between estimating the baseline Weibull distribution and fitting the weighted PH model until the regression parameters of interest converge. The regression parameter estimates are fixed as an offset when we update the estimates of the Weibull distribution and recalculate the weights. Our approach is similar to Satten et al.'s (1998) method for interval-censored survival analysis that used imputed failure times generated from a parametric model in a PH model. Simulation results demonstrate apparently unbiased parameter estimation for the correctly specified Weibull model and little to no bias for a mis-specified log-logistic model. Breast cosmetic deterioration data and ICU hyperlactemia data are analyzed.

Non-parametric Analysis of Interval-Censored Survival Data with Application to a Phase III Metastatic Colorectal Cancer Clinical Trial

In oncology clinical trials, the exact time of event occurrence such as tumor progression is usually unknown but the time interval within which the event occurs is known. The determination of such survival time can be subject to measurement error and influenced by the timing of scheduled assessment. Ignoring interval-censored survival time could lead to serious estimation bias. In addition, a crucial characteristic of interval-censored data is how frequently the measurement interval is taken, which directly determine the efficiency of statistical inference. Therefore, it is highly desirable to find statistical methods that are robust to different assessment frequencies. We compare conventional imputation-based approach with non-parametric approaches to handle interval-censored survival data. We apply these approaches to both hypothesis test and the estimations of hazard and survival functions. Empirical performance of these methods are assessed through extensive simulation studies with various sample sizes. A phase III randomized clinical trial on metastatic colorectal cancer is analyzed by using conventional approaches and non-parametric interval-censored analysis approaches. Out findings suggest that the phase III colorectal cancer clinical trial failed to show a clinical benefit of adding bevacizumab (B) to standard chemotherapy (CT), and the proposed non-parametric interval-censored analysis approaches outperforms the conventional approach for routine applications to oncology clinical trials to analyze interval-censored survival data.

Joint analysis of multivariate interval-censored survival data and a time-dependent covariate.

We develop a joint modeling method for multivariate interval-censored survival data and a time-dependent covariate that is intermittently measured with error. The joint model is estimated using nonparametric maximum likelihood estimation, which is carried out via an expectation-maximization algorithm, and the inference for finite-dimensional parameters is performed using bootstrap. We also develop a similar joint modeling method for univariate interval-censored survival data and a time-dependent covariate, which excels the existing methods in terms of model flexibility and interpretation. Simulation studies show that the model fitting and inference approaches perform very well under realistic sample sizes. We apply the method to a longitudinal study of dental caries in African-American children from low-income families in the city of Detroit, Michigan.

A gamma-frailty model for interval-censored data with dependent examination times: a computationally efficient approach

Interval-censored survival data arise naturally in many fields such as medical follow-up studies, in which the event or failure is not observed exactly but only known to occur within a time interval. Most existing approaches for analyzing interval-censored failure time data assume that the examination times and the failure time are independent or conditionally independent given covariates. While this assumption offers considerable simplification, it is not plausible in some situations, e.g., the visiting rate can be positively or negatively correlated with the risk of failure due to unobservable health status even after adjusting for observable covariates. In this article, we consider dependent interval-censored data, where there exists dependence between the failure time and the entire visiting process. A shared frailty is used to characterize the dependence of hazard function of failure time and intensity function of visiting process. Moreover, the joint model could describe the possible none, positive or negative association between failure time and visiting process. We propose the semiparametric maximum likelihood estimators and develop an EM algorithm based on a Poisson data augmentation. The performance of the proposed method is examined through extensive simulation studies and an application to a bladder cancer dataset is presented.

A Bayesian approach for analyzing partly interval-censored data under the proportional hazards model.

Partly interval-censored time-to-event data often occur in biomedical studies of diseases where periodic medical examinations for symptoms of interest are necessary. Recent decades have seen blooming methods and R packages for interval-censored data; however, the research effort for partly interval-censored data is limited. We propose an efficient and easy-to-implement Bayesian semiparametric method for analyzing partly interval-censored data under the proportional hazards model. Two simulation studies are conducted to compare the performance of the proposed method with two main Bayesian methods currently available in the literature and the classic Cox proportional hazards model. The proposed method is applied to a partly interval-censored progression-free survival data from a metastatic colorectal cancer trial.

A multiparameter regression model for interval-censored survival data.

We develop flexible multiparameter regression (MPR) survival models for interval-censored survival data arising in longitudinal prospective studies and longitudinal randomised controlled clinical trials. A multiparameter Weibull regression survival model, which is wholly parametric, and has nonproportional hazards, is the main focus of the article. We describe the basic model, develop the interval-censored likelihood, and extend the model to include gamma frailty and a dispersion model. We evaluate the models by means of a simulation study and a detailed reanalysis of data from the Signal Tandmobiel study. The results demonstrate that the MPR model with frailty is computationally efficient and provides an excellent fit to the data.