Statistical inference after variable selection in Cox models: A simulation study
Mathematical Statistics and Artificial Intelligence in Medicine, University of Augsburg（医学中的数学统计与人工智能，乌尔姆大学）；Center for Advanced Analytics and Predictive Sciences (CAAPS), University of Augsburg（高级分析与预测科学中心（CAAPS），乌尔姆大学）
Choosing relevant predictors is central to the analysis of biomedical time-to-event data. Classical frequentist inference, however, presumes that the set of covariates is fixed in advance and does not account for data-driven variable selection. As a consequence, naive post-selection inference may be biased and misleading. In right-censored survival settings, these issues may be further exacerbated by the additional uncertainty induced by censoring. We investigate several inference procedures applied after variable selection for the coefficients of the Lasso and its extension, the adaptive Lasso, in the context of the Cox model. The methods considered include sample splitting, exact post-selection inference, and the debiased Lasso. Their performance is examined in a neutral simulation study reflecting realistic covariate structures and censoring rates commonly encountered in biomedical applications. To complement the simulation results, we illustrate the practical behavior of these procedures in an applied example using a publicly available survival dataset.
Variable selection problem for the nonlinear Cox regression model is considered. In survival analysis, one main objective is to identify the covariates that are associated with the risk of experiencing the event of interest. The Cox proportional hazard model is being used extensively in survival analysis in studying the relationship between survival times and covariates, where the model assumes that the covariate has a log-linear effect on the hazard function. However, this linearity assumption may not be satisfied in practice. In order to extract a representative subset of features, various v…
Cox proportional hazards model is one of the most popular models in biomedical data analysis. There have been continuing efforts to improve the flexibility of such models for complex signal detection, for example, via additive functions. Nevertheless, the task to extend Cox additive models to accommodate high-dimensional data is nontrivial. When estimating additive functions, commonly used group sparse regularization may introduce excess smoothing shrinkage on additive functions, damaging predictive performance. Moreover, an "all-in-all-out" approach makes functional selection challenging to a…
Variable selection has become a pivotal choice in data analyses that impacts subsequent inference and prediction. In linear models, variable selection using Second-Generation P-Values (SGPV) has been shown to be as good as any other algorithm available to researchers. Here we extend the idea of Penalized Regression with Second-Generation P-Values (ProSGPV) to the generalized linear model (GLM) and Cox regression settings. The proposed ProSGPV extension is largely free of tuning parameters, adaptable to various regularization schemes and null bound specifications, and is computationally fast. L…
In the analysis of survival outcome supplemented with both clinical information and high-dimensional gene expression data, use of the traditional Cox proportional hazards model (1972) fails to meet some emerging needs in biomedical research. First, the number of covariates is generally much larger the sample size. Secondly, predicting an outcome based on individual gene expression is inadequate because multiple biological processes and functional pathways regulate the expression associated with a gene. Another challenge is that the Cox model assumes that populations are homogenous, implying th…
We consider varying coefficient Cox models with high-dimensional covariates. We apply the group Lasso method to these models and propose a variable selection procedure. Our procedure copes with variable selection and structure identification from a high dimensional varying coefficient model to a semivarying coefficient model simultaneously. We derive an oracle inequality and closely examine restrictive eigenvalue conditions, too. In this paper, we give the details for Cox models with time-varying coefficients. The theoretical results on variable selection can be easily extended to some other i…
Important objectives in cancer research are the prediction of a patient's risk based on molecular measurements such as gene expression data and the identification of new prognostic biomarkers (e.g. genes). In clinical practice, this is often challenging because patient cohorts are typically small and can be heterogeneous. In classical subgroup analysis, a separate prediction model is fitted using only the data of one specific cohort. However, this can lead to a loss of power when the sample size is small. Simple pooling of all cohorts, on the other hand, can lead to biased results, especially …
In this paper, we describe an R package named coxphMIC, which implements the sparse estimation method for Cox proportional hazards models via approximated information criterion (Su et al., 2016 Biometrics). The developed methodology is named MIC which stands for "Minimizing approximated Information Criteria". A reparameterization step is introduced to enforce sparsity while at the same time keeping the objective function smooth. As a result, MIC is computationally fast with a superior performance in sparse estimation. Furthermore, the reparameterization tactic yields an additional advantage in…
In this work a method to regularize Cox frailty models is proposed that accommodates time-varying covariates and time-varying coefficients and is based on the full instead of the partial likelihood. A particular advantage in this framework is that the baseline hazard can be explicitly modeled in a smooth, semi-parametric way, e.g. via P-splines. Regularization for variable selection is performed via a lasso penalty and via group lasso for categorical variables while a second penalty regularizes wiggliness of smooth estimates of time-varying coefficients and the baseline hazard. Additionally, a…
This paper deals with the proportional hazards model proposed by D. R. Cox in a high-dimensional and sparse setting for a regression parameter. To estimate the regression parameter, the Dantzig selector is applied. The variable selection consistency of the Dantzig selector for the model will be proved. This property enables us to reduce the dimension of the parameter and to construct asymptotically normal estimators for the regression parameter and the cumulative baseline hazard function.
Background: The development of classification methods for personalized medicine is highly dependent on the identification of predictive genetic markers. In survival analysis it is often necessary to discriminate between influential and non-influential markers. Usually, the first step is to perform a univariate screening step that ranks the markers according to their associations with the outcome. It is common to perform screening using Cox scores, which quantify the associations between survival and each of the markers individually. Since Cox scores do not account for dependencies between the …
We consider high-dimensional inference for potentially misspecified Cox proportional hazard models based on low dimensional results by Lin and Wei [1989]. A de-sparsified Lasso estimator is proposed based on the log partial likelihood function and shown to converge to a pseudo-true parameter vector. Interestingly, the sparsity of the true parameter can be inferred from that of the above limiting parameter. Moreover, each component of the above (non-sparse) estimator is shown to be asymptotically normal with a variance that can be consistently estimated even under model misspecifications. In so…
Variable selection is an important problem in statistics and machine learning. Copula Entropy (CE) is a mathematical concept for measuring statistical independence and has been applied to variable selection recently. In this paper we propose to apply the CE-based method for variable selection to survival analysis. The idea is to measure the correlation between variables and time-to-event with CE and then select variables according to their CE value. Experiments on simulated data and two real cancer data were conducted to compare the proposed method with two related methods: random survival for…
The most popular approach for analyzing survival data is the Cox regression model. The Cox model may, however, be misspecified, and its proportionality assumption may not always be fulfilled. An alternative approach for survival prediction is random forests for survival outcomes. The standard split criterion for random survival forests is the log-rank test statistics, which favors splitting variables with many possible split points. Conditional inference forests avoid this split variable selection bias. However, linear rank statistics are utilized by default in conditional inference forests to…
Efficient variable selection in high-dimensional cancer genomic studies is critical for discovering genes associated with specific cancer types and for predicting response to treatment. Censored survival data is prevalent in such studies. In this article we introduce a Bayesian variable selection procedure that uses a mixture prior composed of a point mass at zero and an inverse moment prior in conjunction with the partial likelihood defined by the Cox proportional hazard model. The procedure is implemented in the R package BVSNLP, which supports parallel computing and uses a stochastic search…
In this paper we utilize a survival analysis methodology incorporating Bayesian additive regression trees to account for nonlinear and additive covariate effects. We compare the performance of Bayesian additive regression trees, Cox proportional hazards and random survival forests models for censored survival data, using simulation studies and survival analysis for breast cancer with U.S. SEER database for the year 2005. In simulation studies, we compare the three models across varying sample sizes and censoring rates on the basis of bias and prediction accuracy. In survival analysis for breas…
We propose a novel approach to estimate the Cox model with temporal covariates. Our new approach treats the temporal covariates as arising from a longitudinal process which is modeled jointly with the event time. Different from the literature, the longitudinal process in our model is specified as a bounded variational process and determined by a family of Initial Value Problems associated with an Ordinary Differential Equation. Our specification has the advantage that only the observation of the temporal covariates at the time to event and the time to event itself are required to fit the model…
IMPORTANCE: Time-to-event outcomes are commonly used in clinical trials and biomarker discovery studies and have been primarily analyzed using Cox proportional hazards models. But it's unclear which statistical models should be recommended for feature selection tasks when time-to-event outcomes are of the primary interest. OBJECTIVE: To explore if Gaussian regression of log-transformed survival time could outperform Cox proportional hazards models in feature selection. DESIGN: In this simulation study, the true models are multivariate Cox proportional hazards models with 10 covariates. For all…
We discuss the role of misspecification and censoring on Bayesian model selection in the contexts of right-censored survival and concave log-likelihood regression. Misspecification includes wrongly assuming the censoring mechanism to be non-informative. Emphasis is placed on additive accelerated failure time, Cox proportional hazards and probit models. We offer a theoretical treatment that includes local and non-local priors, and a general non-linear effect decomposition to improve power-sparsity trade-offs. We discuss a fundamental question: what solution can one hope to obtain when (inevitab…
This paper considers errors-in-variables models in a high-dimensional setting where the number of covariates can be much larger than the sample size, and there are only a small number of non-zero covariates. The presence of measurement error in the covariates can result in severely biased parameter estimates, and also affects the ability of penalized methods such as the lasso to recover the true sparsity pattern. A new estimation procedure called SIMSELEX (SIMulation-SELection-EXtrapolation) is proposed. This procedure augments the traditional SIMEX approach with a variable selection step base…
Recently the shape-restricted inference has gained popularity in statistical and econometric literature in order to relax the linear or quadratic covariate effect in regression analyses. The typical shape-restricted covariate effect includes monotonic increasing, decreasing, convexity or concavity. In this paper, we introduce the shape-restricted inference to the celebrated Cox regression model (SR-Cox), in which the covariate response is modeled as shape-restricted additive functions. The SR-Cox regression approximates the shape-restricted functions using a spline basis expansion with data dr…
Statistical inference for highly multivariate point pattern data is challenging due to complex models with large numbers of parameters. In this paper, we develop numerically stable and efficient parameter estimation and model selection algorithms for a class of multivariate log Gaussian Cox processes. The methodology is applied to a highly multivariate point pattern data set from tropical rain forest ecology.
IMPORTANCE: Feature selection with respect to time-to-event outcomes is one of the fundamental problems in clinical trials and biomarker discovery studies. But it's unclear which statistical methods should be used when sample size is small or some of the key covariates are not measured. DESIGN: In this simulation study, the true models are multivariate Cox proportional hazards models with 10 covariates. It's assumed that only 5 out the 10 true features are observed/measured for all model fitting, along with 5 random noise features. Each sample size scenario is explored using 10,000 simulation …
For statistical inference on regression models with a diverging number of covariates, the existing literature typically makes sparsity assumptions on the inverse of the Fisher information matrix. Such assumptions, however, are often violated under Cox proportion hazards models, leading to biased estimates with under-coverage confidence intervals. We propose a modified debiased lasso approach, which solves a series of quadratic programming problems to approximate the inverse information matrix without posing sparse matrix assumptions. We establish asymptotic results for the estimated regression…
This paper develops a new scalable sparse Cox regression tool for sparse high-dimensional massive sample size (sHDMSS) survival data. The method is a local $L_0$-penalized Cox regression via repeatedly performing reweighted $L_2$-penalized Cox regression. We show that the resulting estimator enjoys the best of $L_0$- and $L_2$-penalized Cox regressions while overcoming their limitations. Specifically, the estimator is selection consistent, oracle for parameter estimation, and possesses a grouping property for highly correlated covariates. Simulation results suggest that when the sample size is…
A prevalent feature of high-dimensional data is the dependence among covariates, and model selection is known to be challenging when covariates are highly correlated. To perform model selection for the high-dimensional Cox proportional hazards model in presence of correlated covariates with factor structure, we propose a new model, Factor-Augmented Regularized Model for Hazard Regression (FarmHazard), which builds upon latent factors that drive covariate dependence and extends Cox's model. This new model generates procedures that operate in two steps by learning factors and idiosyncratic compo…
An important task in clinical medicine is the construction of risk prediction models for specific subgroups of patients based on high-dimensional molecular measurements such as gene expression data. Major objectives in modeling high-dimensional data are good prediction performance and feature selection to find a subset of predictors that are truly associated with a clinical outcome such as a time-to-event endpoint. In clinical practice, this task is challenging since patient cohorts are typically small and can be heterogeneous with regard to their relationship between predictors and outcome. W…
Institute for Mathematical and Molecular Biomedicine, King’s College London（伦敦国王学院数学与分子生物医学研究所）；King’s College London（伦敦国王学院）；Saddle Point Science Ltd（鞍点科学有限公司）
The Cox proportional hazards model is ubiquitous in the analysis of time-to-event data. However, when the data dimension p is comparable to the sample size $N$, maximum likelihood estimates for its regression parameters are known to be biased or break down entirely due to overfitting. This prompted the introduction of the so-called regularized Cox model. In this paper we use the replica method from statistical physics to investigate the relationship between the true and inferred regression parameters in regularized multivariate Cox regression with L2 regularization, in the regime where both p …
In this paper, we expand the methodology presented in Mertens et. al (2020, Biometrical Journal) to the study of life-time (survival) outcome which is subject to censoring and when imputation is used to account for missing values. We consider the problem where missing values can occur in both the calibration data as well as newly - to-be-predicted - observations (validation). We focus on the Cox model. Methods are described to combine imputation with predictive calibration in survival modeling subject to censoring. Application to cross-validation is discussed. We demonstrate how conclusions br…
We present a new method for post-selection inference for L1 (lasso)-penalized likelihood models, including generalized regression models. Our approach generalizes the post-selection framework presented in Lee et al (2014). The method provides p-values and confidence intervals that are asymptotically valid, conditional on the inherent selection done by the lasso. We present applications of this work to (regularized) logistic regression, Cox's proportional hazards model and the graphical lasso.
Functional covariates are common in many medical, biodemographic, and neuroimaging studies. The aim of this paper is to study functional Cox models with right-censored data in the presence of both functional and scalar covariates. We study the asymptotic properties of the maximum partial likelihood estimator and establish the asymptotic normality and efficiency of the estimator of the finite-dimensional estimator. Under the framework of reproducing kernel Hilbert space, the estimator of the coefficient function for a functional covariate achieves the minimax optimal rate of convergence under a…
