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, adaptive weights are included to stabilize the estimation. The method is implemented in R as coxlasso and will be compared to other packages for regularized Cox regression. Existing packages, however, do not allow for the combination of different effects that are accommodated in coxlasso.
The Scientific Registry of Transplant Recipients (SRTR) system has become a rich resource for understanding the complex mechanisms of graft failure after kidney transplant, a crucial step for allocating organs effectively and implementing appropriate care. As transplant centers that treated patients might strongly confound graft failures, Cox models stratified by centers can eliminate their confounding effects. Also, since recipient age is a proven non-modifiable risk factor, a common practice is to fit models separately by recipient age groups. The moderate sample sizes, relative to the numbe…
The Cox regression, a semi-parametric method of survival analysis, is extremely popular in biomedical applications. The proportional hazards assumption is a key requirement in the Cox model. To accommodate non-proportional hazards, we propose to parameterise the shape parameter of the baseline hazard function using the additional, separate Cox-regression term which depends on the vector of the covariates. We call this model the double-Cox model. The R programs for fitting the double-Cox model are available on Github. We formally introduce the double-Cox model with shared frailty and investigat…
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）
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 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…
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…
Dependent survival data arise in many contexts. One context is clustered survival data, where survival data are collected on clusters such as families or medical centers. Dependent survival data also arise when multiple survival times are recorded for each individual. Frailty models is one common approach to handle such data. In frailty models, the dependence is expressed in terms of a random effect, called the frailty. Frailty models have been used with both Cox proportional hazards model and the accelerated failure time model. This paper reviews recent developments in the area of frailty mod…
Frailty models are often the model of choice for heterogeneous survival data. A frailty model contains both random effects and fixed effects, with the random effects accommodating for the correlation in the data. Different estimation procedures have been proposed for the fixed effects and the variances of and covariances between the random effects. Especially with an unspecified baseline hazard, i.e., the Cox model, the few available methods deal only with a specific correlation structure. In this paper, an estimation procedure, based on the integrated partial likelihood, is introduced, which …
Survival models incorporating random effects to account for unmeasured heterogeneity are being increasingly used in biostatistical and applied research. Specifically, unmeasured covariates whose lack of inclusion in the model would lead to biased, inefficient results are commonly modelled by including a subject-specific (or cluster-specific) frailty term that follows a given distribution (e.g. Gamma or log-Normal). Despite that, in the context of parametric frailty models little is known about the impact of misspecifying the baseline hazard, the frailty distribution, or both. Therefore, our ai…
Spatial scan statistics are well known and widely used methods for the detection of spatial clusters of events. In the field of spatial analysis of time-to-event data, several models of scan statistics have been proposed. However, these models do not take into account the potential intra-unit spatial correlation of individuals nor a potential correlation between spatial units. To overcome this problem, we propose here a scan statistic based on a Cox model with shared frailty that takes into account the spatial correlation between spatial units. In simulation studies, we have shown that (i) cla…
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…
Identification of biomarkers is an emerging area in Oncology. In this article, we develop an efficient statistical procedure for classification of protein markers according to their effect on cancer progression. A high-dimensional time-course dataset of protein markers for 80 patients motivates us for developing the model. We obtain the optimal threshold values for markers using Cox proportional hazard model. The optimal threshold value is defined as a level of a marker having maximum impact on cancer progression. The classification was validated by comparing random components using both propo…
This commentary regards a recent simulation study conducted by Aouni, Gaudel-Dedieu and Sebastien, evaluating the performance of different versions of matching-adjusted indirect comparison (MAIC) in an anchored scenario with a common comparator. The simulation study uses survival outcomes and the Cox proportional hazards regression as the outcome model. It concludes that using the LASSO for variable selection is preferable to balancing a maximal set of covariates. However, there are no treatment effect modifiers in imbalance in the study. The LASSO is more efficient because it selects a subset…
