In biometrics and related fields, the Cox proportional hazards model are widely used to analyze with covariate adjustment. However, when some covariates are not observed, an unbiased estimator usually cannot be obtained. Even if there are some unmeasured covariates, instrumental variable methods can be applied under some assumptions. In this paper, we propose the new instrumental variable estimator for the Cox proportional hazards model. The estimator is the similar feature as Martinez-Camblor et al., 2019, but not the same exactly; we use an idea of limited-information maximum likelihood. We show that the estimator has good theoretical properties. Also, we confirm properties of our method and previous methods through simulations datasets.
The Cox proportional hazards model, commonly used in clinical trials, assumes proportional hazards. However, it does not hold when, for example, there is a delayed onset of the treatment effect. In such a situation, an acute change in the hazard ratio function is expected to exist. This paper considers the Cox model with change-points and derives AIC-type information criteria for detecting those change-points. The change-point model does not allow for conventional statistical asymptotics due to its irregularity, thus a formal AIC that penalizes twice the number of parameters would not be analy…
Instrumental variable (IV) methods are widely used for estimating average treatment effects in the presence of unmeasured confounders. However, the capability of existing IV procedures, and most notably the two-stage residual inclusion (2SRI) procedure recommended for use in nonlinear contexts, to account for unmeasured confounders in the Cox proportional hazard model is unclear. We show that instrumenting an endogenous treatment induces an unmeasured covariate, referred to as an individual frailty in survival analysis parlance, which if not accounted for leads to bias. We propose a new proced…
Instrumental variables (IV) are a useful tool for estimating causal effects in the presence of unmeasured confounding. IV methods are well developed for uncensored outcomes, particularly for structural linear equation models, where simple two-stage estimation schemes are available. The extension of these methods to survival settings is challenging, partly because of the nonlinearity of the popular survival regression models and partly because of the complications associated with right censoring or other survival features. We develop a simple causal hazard ratio estimator in a proportional haza…
Non-proportional hazards (NPH) have been observed in confirmatory clinical trials with time to event outcomes. Under NPH, the hazard ratio does not stay constant over time and the log-rank test is no longer the most powerful test. The weighted log-rank test (WLRT) has been introduced to deal with the presence of non-proportionality. We focus our attention on the WLRT and the complementary Cox model based on the time-varying treatment effect proposed by Lin and León (2017) (doi: 10.1016/j.conctc.2017.09.004). We will investigate whether the proposed weighted hazard ratio (WHR) approach is unbia…
In this paper, we discuss causal inference on the efficacy of a treatment or medication on a time-to-event outcome with competing risks. Although the treatment group can be randomized, there can be confoundings between the compliance and the outcome. Unmeasured confoundings may exist even after adjustment for measured co- variates. Instrumental variable (IV) methods are commonly used to yield consistent estimations of causal parameters in the presence of unmeasured confoundings. Based on a semi-parametric additive hazard model for the subdistribution hazard, we pro- pose an instrumental variab…
Instrumental variable is an essential tool for addressing unmeasured confounding in observational studies. Two stage predictor substitution (2SPS) estimator and two stage residual inclusion(2SRI) are two commonly used approaches in applying instrumental variables. Recently 2SPS was studied under the additive hazards model in the presence of competing risks of time-to-events data, where linearity was assumed for the relationship between the treatment and the instrument variable. This assumption may not be the most appropriate when we have binary treatments. In this paper, we consider the 2SRI e…
MEC-Cox: Machine-Learning-Assisted Generalized Entropy Calibration for ATT Marginal Hazard-Ratio Estimation
Department of Statistics, Texas A&M University（统计学系，德克萨斯A&M大学）；Department of Mathematics, Korea Military Academy（数学系，韩国军事学院）；Department of Statistics, Iowa State University（统计学系，爱荷华州立大学）
Time-to-event analyses are often plagued by both -- possibly unmeasured -- confounding and competing risks. To deal with the former, the use of instrumental variables for effect estimation is rapidly gaining ground. We show how to make use of such variables in competing risk analyses. In particular, we show how to infer the effect of an arbitrary exposure on cause-specific hazard functions under a semi-parametric model that imposes relatively weak restrictions on the observed data distribution. The proposed approach is flexible accommodating exposures and instrumental variables of arbitrary ty…
This paper discusses endogenous treatment models with duration outcomes, competing risks and random right censoring. The endogeneity issue is solved using a discrete instrumental variable. We show that the competing risks model generates a non-parametric quantile instrumental regression problem. The cause-specific cumulative incidence, the cause-specific hazard and the subdistribution hazard can be recovered from the regression function. A distinguishing feature of the model is that censoring and competing risks prevent identification at some quantiles. We characterize the set of quantiles for…
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…
Linear transformation model provides a general framework for analyzing censored survival data with covariates. The proportional hazards and proportional odds models are special cases of the linear transformation model. In biomedical studies, covariates with measurement error may occur in survival data. In this work, we propose a method to obtain estimators of the regression coefficients in the linear transformation model when the covariates are subject to measurement error. In the proposed method, we assume that instrumental variables are available. We develop counting process based estimating…
Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial
One of the most common ways researchers compare survival outcomes across treatments when confounding is present is using Cox regression. This model is limited by its underlying assumption of proportional hazards; in some cases, substantial violations may occur. Here we present and compare approaches which attempt to address this issue, including Cox models with time-varying hazard ratios; parametric accelerated failure time models; Kaplan-Meier curves; and pseudo-observations. To adjust for differences between treatment groups, we use Inverse Probability of Treatment Weighting based on the pro…
The Hazard Ratio (HR) is often reported as the main causal effect when studying survival data. Despite its popularity, the HR suffers from an unclear causal interpretation. As already pointed out in the literature, there is a built-in selection bias in the HR, because similarly to the truncation by death problem, the HR conditions on post-treatment survival. A recently proposed alternative, inspired by the Survivor Average Causal Effect (SACE), is the causal HR, defined as the ratio between hazards across treatment groups among the study participants that would have survived regardless of thei…
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…
In two harmonized efficacy studies to prevent HIV infection through multiple infusions of the monoclonal antibody VRC01, a key objective is to evaluate whether the serum concentration of VRC01, which changes cyclically over time along with the infusion schedule, is associated with the rate of HIV infection. Simulation studies are needed in the development of such survival models. In this paper, we consider simulating event time data with a continuous time-varying covariate whose values vary with time through multiple drug administration cycles, and whose effect on survival changes differently …
The penalized Cox proportional hazard model is a popular analytical approach for survival data with a large number of covariates. Such problems are especially challenging when covariates vary over follow-up time (i.e., the covariates are time-dependent). The standard R packages for fully penalized Cox models cannot currently incorporate time-dependent covariates. To address this gap, we implement a variant of gradient descent algorithm (proximal gradient descent) for fitting penalized Cox models. We apply our implementation to real and simulated data sets.
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…
Variable selection in high dimensional space has challenged many contemporary statistical problems from many frontiers of scientific disciplines. Recent technology advance has made it possible to collect a huge amount of covariate information such as microarray, proteomic and SNP data via bioimaging technology while observing survival information on patients in clinical studies. Thus, the same challenge applies to the survival analysis in order to understand the association between genomics information and clinical information about the survival time. In this work, we extend the sure screening…
While analysing time-to-event data, it is possible that a certain fraction of subjects will never experience the event of interest and they are said to be cured. When this feature of survival models is taken into account, the models are commonly referred to as cure models. In the presence of covariates, the conditional survival function of the population can be modelled by using cure model which depends on the probability of being uncured (incidence) and the conditional survival function of the uncured subjects (latency), and a combination of logistic regression and Cox proportional hazards (P…
Polygenic hazard score (PHS) models designed for European ancestry (EUR) individuals provide ample information regarding survival risk discrimination. Incorporating such information can improve the performance of risk discrimination in an internal small-sized non-EUR cohort. However, given that external EUR-based model and internal individual-level data come from different populations, ignoring population heterogeneity can introduce substantial bias. In this paper, we develop a Kullback-Leibler-based Cox model (CoxKL) to integrate internal individual-level time-to-event data with external risk…
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…
Cox's proportional hazards model is one of the most popular statistical models to evaluate associations of exposure with a censored failure time outcome. When confounding factors are not fully observed, the exposure hazard ratio estimated using a Cox model is subject to unmeasured confounding bias. To address this, we propose a novel approach for the identification and estimation of the causal hazard ratio in the presence of unmeasured confounding factors. Our approach is based on a binary instrumental variable, and an additional no-interaction assumption in a first stage regression of the tre…
In Cox regression it is sometimes of interest to study time-varying effects (TVE) of exposures and to test the proportional hazards assumption. TVEs can be investigated with log hazard ratios modelled as a function of time. Missing data on exposures are common and multiple imputation (MI) is a popular approach to handling this, to avoid the potential bias and loss of efficiency resulting from a 'complete-case' analysis. Two MI methods have been proposed for when the substantive model is a Cox proportional hazards regression: an approximate method (White and Royston, Statist. Med. 2009;28:1982-…
The ratio of the hazard functions of two populations or two strata of a single population plays an important role in time-to-event analysis. Cox regression is commonly used to estimate the hazard ratio under the assumption that it is constant in time, which is known as the proportional hazards assumption. However, this assumption is often violated in practice, and when it is violated, the parameter estimated by Cox regression is difficult to interpret. The hazard ratio can be estimated in a nonparametric manner using smoothing, but smoothing-based estimators are sensitive to the selection of t…
We propose new resampling-based approaches to construct asymptotically valid time simultaneous confidence bands for cumulative hazard functions in multi-state Cox models. In particular, we exemplify the methodology in detail for the simple Cox model with time dependent covariates, where the data may be subject to independent right-censoring or left-truncation. In extensive simulations we investigate their finite sample behaviour. Finally, the methods are utilized to analyze an empirical example.
A Novel Stratified Analysis Method for Testing and Estimating Overall Treatment Effects on Time-to-Event Outcomes Using Average Hazard with Survival Weight
In statistics, time-to-event analysis methods traditionally focus on the estimation of hazards. In recent years, machine learning methods have been proposed to directly predict the event times. We propose a method based on vine copula models to make point and interval predictions for a right-censored response variable given mixed discrete-continuous explanatory variables. Extensive experiments on simulated and real datasets show that our proposed vine copula approach provides a decent approximation to other time-to-event analysis models including Cox proportional hazards and Accelerate Failure…
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…
High throughput genetic sequencing arrays with thousands of measurements per sample and a great amount of related censored clinical data have increased demanding need for better measurement specific model selection. In this paper we establish strong oracle properties of nonconcave penalized methods for nonpolynomial (NP) dimensional data with censoring in the framework of Cox's proportional hazards model. A class of folded-concave penalties are employed and both LASSO and SCAD are discussed specifically. We unveil the question under which dimensionality and correlation restrictions can an orac…
Latent class analysis (LCA) is a useful tool to investigate the heterogeneity of a disease population with time-to-event data. We propose a new method based on non-parametric maximum likelihood estimator (NPMLE), which facilitates theoretically validated inference procedure for covariate effects and cumulative hazard functions. We assess the proposed method via extensive simulation studies and demonstrate improved predictive performance over standard Cox regression model. We further illustrate the practical utility of the proposed method through an application to a mild cognitive impairment (M…
We consider the Cox regression model and study the asymptotic global behavior of the Grenander-type estimator for a monotone baseline hazard function. This model is not included in the general setting of Durot (2007). However, we show that a similar central limit theorem holds for $L_p$-error of the Grenander-type estimator. We also propose a test procedure for a Weibull baseline distribution, based on the $L_p$-distance between the Grenander estimator and a parametric estimator of the baseline hazard. Simulation studies are performed to investigate the performance of this test.
The additive hazards model specifies the effect of covariates on the hazard in an additive way, in contrast to the popular Cox model, in which it is multiplicative. As non-parametric model, it offers a very flexible way of modeling time-varying covariate effects. It is most commonly estimated by ordinary least squares. In this paper we consider the case where covariates are bounded, and derive the maximum likelihood estimator under the constraint that the hazard is non-negative for all covariate values in their domain. We describe an efficient algorithm to find the maximum likelihood estimator…
The Cox regression model and its associated hazard ratio (HR) are frequently used for summarizing the effect of treatments on time to event outcomes. However, the HR's interpretation strongly depends on the assumed underlying survival model. The challenge of interpreting the HR has been the focus of a number of recent works. Besides, several alternative measures have been proposed in order to deal with these concerns. The marginal Cox regression models include an identifiable hazard ratio without individual but populational causal interpretation. In this work, we study the properties of one pa…
From an optimizer's perspective, achieving the global optimum for a general nonconvex problem is often provably NP-hard using the classical worst-case analysis. In the case of Cox's proportional hazards model, by taking its statistical model structures into account, we identify local strong convexity near the global optimum, motivated by which we propose to use two convex programs to optimize the folded-concave penalized Cox's proportional hazards regression. Theoretically, we investigate the statistical and computational tradeoffs of the proposed algorithm and establish the strong oracle prop…
