Flexible parametric copula modeling approaches for clustered survival data.

Copula-based survival regression models, which consist of a copula function and marginal distribution (i.e., marginal survival function), have been widely used for analyzing clustered multivariate survival data. Archimedean copula functions are useful for modeling such dependence. For the likelihood inference, one-stage and two-stage estimation methods have been usually used. The two-stage procedure can give inefficient estimation results because of separate estimation of the marginal and copula's dependence parameters. The more efficient one-stage procedure has been mainly developed under a restrictive parametric assumption of marginal distribution due to complexity of the full likelihood with unknown marginal baseline hazard functions. In this paper, we propose a flexible parametric Archimedean copula modeling approach using a one-stage likelihood procedure. In order to reduce the complexity of the full likelihood, the unknown marginal baseline hazards are modeled based on a cubic M-spline basis function that does not require a specific parametric form. Simulation results demonstrate that the proposed one-stage estimation method gives a consistent estimator and also provides more efficient results over existing one- and two-stage methods. The new method is illustrated with three clinical data sets. The Appendix provides an R function so that the proposed method becomes directly accessible to interested readers.

Dynamic Risk Prediction via a Joint Frailty-Copula Model and IPD Meta-Analysis: Building Web Applications.

Clinical risk prediction formulas for cancer patients can be improved by dynamically updating the formulas by intermediate events, such as tumor progression. The increased accessibility of individual patient data (IPD) from multiple studies has motivated the development of dynamic prediction formulas accounting for between-study heterogeneity. A joint frailty-copula model for overall survival and time to tumor progression has the potential to develop a dynamic prediction formula of death from heterogenous studies. However, the process of developing, validating, and publishing the prediction formula is complex, which has not been sufficiently described in the literature. In this article, we provide a tutorial in order to build a web-based application for dynamic risk prediction for cancer patients on the basis of the R packages joint.Cox and Shiny. We demonstrate the proposed methods using a dataset of breast cancer patients from multiple clinical studies. Following this tutorial, we demonstrate how one can publish web applications available online, which can be manipulated by any user through a smartphone or personal computer. After learning this tutorial, developers acquire the ability to build an online web application using their own datasets.

A joint frailty-copula model for meta-analytic validation of failure time surrogate endpoints in clinical trials.

In a meta-analysis framework, the classical approach for the validation of time-to-event surrogate endpoint is based on a two-step analysis. This approach often raises estimation issues. Recently, we proposed a one-step validation approach based on a joint frailty model. This approach was quite time consuming, despite parallel computing, due to individual-level frailties used to take into account heterogeneity in the data at the individual level. We now propose an alternative one-step approach for evaluating surrogacy, using a joint frailty-copula model. The model includes two correlated random effects treatment-by-trial interaction and a shared random effect associated with the baseline risks. At the individual level, the joint survivor functions of time-to-event endpoints are linked using copula functions. We used splines for the baseline hazard functions. We estimated parameters and hazard function using a semiparametric penalized marginal likelihood method, considering various numerical integration methods. Both individual-level and trial-level surrogacy were evaluated using Kendall's tau and coefficient of determination. The performance of the estimators was evaluated using simulation studies. The model was applied to individual patient data meta-analyses in advanced ovarian cancer to assess progression-free survival as a surrogate for overall survival, as part of the evaluation of new therapy. The model showed good performance and was quite robust regarding the integration methods and data variation, regardless of the surrogacy evaluation criteria. Kendall's Tau was better estimated using the Clayton copula model compared to the joint frailty model. The proposed model reduces the convergence and model estimation issues encountered in the two-step approach.

One-step validation method for surrogate endpoints using data from multiple randomized cancer clinical trials with failure-time endpoints.

A surrogate endpoint can be used instead of the most relevant clinical endpoint to assess the efficiency of a new treatment. Before being used, a surrogate endpoint must be validated based on appropriate methods. Numerous validation approaches have been proposed with the most popular used in a context of meta-analysis, based on a two-step analysis strategy. For two failure-time endpoints, two association measurements are usually used, Kendall's τ at the individual level and the adjusted coefficient of determination ( Rtrial,adj2 ) at the trial level. However, Rtrial,adj2 is not always available due to model estimation constraints. We propose a one-step validation approach based on a joint frailty model, including both individual-level and trial-level random effects. Parameters have been estimated using a semiparametric penalized marginal log-likelihood method, and various numerical integration approaches were considered. Both individual- and trial-level surrogacy were evaluated using a new definition of Kendall's τ and the coefficient of determination. Estimators' performances were evaluated using simulation studies and satisfactory results were found. The model was applied to individual patient data meta-analyses in gastric cancer to assess disease-free survival as a surrogate for overall survival, as part of the evaluation of adjuvant therapy.

Statistical inference based on the nonparametric maximum likelihood estimator under double-truncation.

Doubly truncated data consist of samples whose observed values fall between the right- and left- truncation limits. With such samples, the distribution function of interest is estimated using the nonparametric maximum likelihood estimator (NPMLE) that is obtained through a self-consistency algorithm. Owing to the complicated asymptotic distribution of the NPMLE, the bootstrap method has been suggested for statistical inference. This paper proposes a closed-form estimator for the asymptotic covariance function of the NPMLE, which is computationally attractive alternative to bootstrapping. Furthermore, we develop various statistical inference procedures, such as confidence interval, goodness-of-fit tests, and confidence bands to demonstrate the usefulness of the proposed covariance estimator. Simulations are performed to compare the proposed method with both the bootstrap and jackknife methods. The methods are illustrated using the childhood cancer dataset.

Factorial survival analysis for treatment effects under dependent censoring.

Factorial analyses offer a powerful nonparametric means to detect main or interaction effects among multiple treatments. For survival outcomes, for example, from clinical trials, such techniques can be adopted for comparing reasonable quantifications of treatment effects. The key difficulty to solve in survival analysis concerns the proper handling of censoring. So far, all existing factorial analyses for survival data have been developed under the independent censoring assumption, which is too strong for many applications. As a solution, the central aim of this article is to develop new methods for factorial survival analyses under quite general dependent censoring regimes. This will be accomplished by combining existing nonparametric methods for factorial survival analyses with techniques developed for survival copula models. As a result, we will present an appealing F-test that exhibits sound performance in our simulation study. The new methods are illustrated in a real data analysis. We implement the proposed method in an R function surv.factorial(.) in the R package compound.Cox.

Sensitivity Analysis for Survival Prognostic Prediction with Gene Selection: A Copula Method for Dependent Censoring.

Prognostic analysis for patient survival often employs gene expressions obtained from high-throughput screening for tumor tissues from patients. When dealing with survival data, a dependent censoring phenomenon arises, and thus the traditional Cox model may not correctly identify the effect of each gene. A copula-based gene selection model can effectively adjust for dependent censoring, yielding a multi-gene predictor for survival prognosis. However, methods to assess the impact of various types of dependent censoring on the multi-gene predictor have not been developed. In this article, we propose a sensitivity analysis method using the copula-graphic estimator under dependent censoring, and implement relevant methods in the R package "compound.Cox". The purpose of the proposed method is to investigate the sensitivity of the multi-gene predictor to a variety of dependent censoring mechanisms. In order to make the proposed sensitivity analysis practical, we develop a web application. We apply the proposed method and the web application to a lung cancer dataset. We provide a template file so that developers can modify the template to establish their own web applications.

A survival tree based on stabilized score tests for high-dimensional covariates.

A survival tree can classify subjects into different survival prognostic groups. However, when data contains high-dimensional covariates, the two popular classification trees exhibit fatal drawbacks. The logrank tree is unstable and tends to have false nodes; the conditional inference tree is difficult to interpret the adjusted P-value for high-dimensional tests. Motivated by these problems, we propose a new survival tree based on the stabilized score tests. We propose a novel matrix-based algorithm in order to tests a number of nodes simultaneously via stabilized score tests. We propose a recursive partitioning algorithm to construct a survival tree and develop our original R package uni.survival.tree (https://cran.r-project.org/package=uni.survival.tree) for implementation. Simulations are performed to demonstrate the superiority of the proposed method over the existing methods. The lung cancer data analysis demonstrates the usefulness of the proposed method.

Conditional copula models for correlated survival endpoints: Individual patient data meta-analysis of randomized controlled trials.

Correlations among survival endpoints are important for exploring surrogate endpoints of the true endpoint. With a valid surrogate endpoint tightly correlated with the true endpoint, the efficacy of a new drug/treatment can be measurable on it. However, the existing methods for measuring correlation between two endpoints impose an invalid assumption: correlation structure is constant across different treatment arms. In this article, we reconsider the definition of Kendall's concordance measure (tau) in the context of individual patient data meta-analyses of randomized controlled trials. According to our new definition of Kendall's tau, its value depends on the treatment arms. We then suggest extending the existing copula (and frailty) models so that their Kendall's tau can vary across treatment arms. Our newly proposed model, a joint frailty-conditional copula model, is the implementation of the new definition of Kendall's tau in meta-analyses. In order to facilitate our approach, we develop an original R function condCox.reg(.) and make it available in the R package joint.Cox (https://CRAN.R-project.org/package=joint.Cox). We apply the proposed method to a gastric cancer dataset (3288 patients in 14 randomized trials from the GASTRIC group). This data analysis concludes that Kendall's tau has different values between the surgical treatment arm and the adjuvant chemotherapy arm (p-value<0.001), whereas disease-free survival remains a valid surrogate at individual level for overall survival in these trials.

Comparison of the marginal hazard model and the sub-distribution hazard model for competing risks under an assumed copula.

For the analysis of competing risks data, three different types of hazard functions have been considered in the literature, namely the cause-specific hazard, the sub-distribution hazard, and the marginal hazard function. Accordingly, medical researchers can fit three different types of the Cox model to estimate the effect of covariates on each of the hazard function. While the relationship between the cause-specific hazard and the sub-distribution hazard has been extensively studied, the relationship to the marginal hazard function has not yet been analyzed due to the difficulties related to non-identifiability. In this paper, we adopt an assumed copula model to deal with the model identifiability issue, making it possible to establish a relationship between the sub-distribution hazard and the marginal hazard function. We then compare the two methods of fitting the Cox model to competing risks data. We also extend our comparative analysis to clustered competing risks data that are frequently used in medical studies. To facilitate the numerical comparison, we implement the computing algorithm for marginal Cox regression with clustered competing risks data in the R joint.Cox package and check its performance via simulations. For illustration, we analyze two survival datasets from lung cancer and bladder cancer patients.

compound.Cox: Univariate feature selection and compound covariate for predicting survival.

BACKGROUND AND OBJECTIVE: Univariate feature selection is one of the simplest and most commonly used techniques to develop a multigene predictor for survival. Presently, there is no software tailored to perform univariate feature selection and predictor construction. METHODS: We develop the compound.Cox R package that implements univariate significance tests (via the Wald tests or score tests) for feature selection. We provide a cross-validation algorithm to measure predictive capability of selected genes and a permutation algorithm to assess the false discovery rate. We also provide three algorithms for constructing a multigene predictor (compound covariate, compound shrinkage, and copula-based methods), which are tailored to the subset of genes obtained from univariate feature selection. We demonstrate our package using survival data on the lung cancer patients. We examine the predictive capability of the developed algorithms by the lung cancer data and simulated data. RESULTS: The developed R package, compound.Cox, is available on the CRAN repository. The statistical tools in compound.Cox allow researchers to determine an optimal significance level of the tests, thus providing researchers an optimal subset of genes for prediction. The package also allows researchers to compute the false discovery rate and various prediction algorithms.

Personalized dynamic prediction of death according to tumour progression and high-dimensional genetic factors: Meta-analysis with a joint model.

Developing a personalized risk prediction model of death is fundamental for improving patient care and touches on the realm of personalized medicine. The increasing availability of genomic information and large-scale meta-analytic data sets for clinicians has motivated the extension of traditional survival prediction based on the Cox proportional hazards model. The aim of our paper is to develop a personalized risk prediction formula for death according to genetic factors and dynamic tumour progression status based on meta-analytic data. To this end, we extend the existing joint frailty-copula model to a model allowing for high-dimensional genetic factors. In addition, we propose a dynamic prediction formula to predict death given tumour progression events possibly occurring after treatment or surgery. For clinical use, we implement the computation software of the prediction formula in the joint.Cox R package. We also develop a tool to validate the performance of the prediction formula by assessing the prediction error. We illustrate the method with the meta-analysis of individual patient data on ovarian cancer patients.

A joint frailty-copula model between tumour progression and death for meta-analysis.

Dependent censoring often arises in biomedical studies when time to tumour progression (e.g., relapse of cancer) is censored by an informative terminal event (e.g., death). For meta-analysis combining existing studies, a joint survival model between tumour progression and death has been considered under semicompeting risks, which induces dependence through the study-specific frailty. Our paper here utilizes copulas to generalize the joint frailty model by introducing additional source of dependence arising from intra-subject association between tumour progression and death. The practical value of the new model is particularly evident for meta-analyses in which only a few covariates are consistently measured across studies and hence there exist residual dependence. The covariate effects are formulated through the Cox proportional hazards model, and the baseline hazards are nonparametrically modeled on a basis of splines. The estimator is then obtained by maximizing a penalized log-likelihood function. We also show that the present methodologies are easily modified for the competing risks or recurrent event data, and are generalized to accommodate left-truncation. Simulations are performed to examine the performance of the proposed estimator. The method is applied to a meta-analysis for assessing a recently suggested biomarker CXCL12 for survival in ovarian cancer patients. We implement our proposed methods in R joint.Cox package.

Gene selection for survival data under dependent censoring: A copula-based approach.

Dependent censoring arises in biomedical studies when the survival outcome of interest is censored by competing risks. In survival data with microarray gene expressions, gene selection based on the univariate Cox regression analyses has been used extensively in medical research, which however, is only valid under the independent censoring assumption. In this paper, we first consider a copula-based framework to investigate the bias caused by dependent censoring on gene selection. Then, we utilize the copula-based dependence model to develop an alternative gene selection procedure. Simulations show that the proposed procedure adjusts for the effect of dependent censoring and thus outperforms the existing method when dependent censoring is indeed present. The non-small-cell lung cancer data are analyzed to demonstrate the usefulness of our proposal. We implemented the proposed method in an R "compound.Cox" package.

Survival prediction based on compound covariate under Cox proportional hazard models.

Survival prediction from a large number of covariates is a current focus of statistical and medical research. In this paper, we study a methodology known as the compound covariate prediction performed under univariate Cox proportional hazard models. We demonstrate via simulations and real data analysis that the compound covariate method generally competes well with ridge regression and Lasso methods, both already well-studied methods for predicting survival outcomes with a large number of covariates. Furthermore, we develop a refinement of the compound covariate method by incorporating likelihood information from multivariate Cox models. The new proposal is an adaptive method that borrows information contained in both the univariate and multivariate Cox regression estimators. We show that the new proposal has a theoretical justification from a statistical large sample theory and is naturally interpreted as a shrinkage-type estimator, a popular class of estimators in statistical literature. Two datasets, the primary biliary cirrhosis of the liver data and the non-small-cell lung cancer data, are used for illustration. The proposed method is implemented in R package "compound.Cox" available in CRAN at http://cran.r-project.org/.