A key question in clinical practice is accurate prediction of patient prognosis. To this end, nowadays, physicians have at their disposal a variety of tests and biomarkers to aid them in optimizing medical care. These tests are often performed on a regular basis in order to closely follow the progression of the disease. In this setting it is of medical interest to optimally utilize the recorded information and provide medically-relevant summary measures, such as survival probabilities, that will aid in decision making. In this work we present and compare two statistical techniques that provide dynamically-updated estimates of survival probabilities, namely landmark analysis and joint models for longitudinal and time-to-event data. Special attention is given to the functional form linking the longitudinal and event time processes, and to measures of discrimination and calibration in the context of dynamic prediction.
The Cox regression model is a popular model for analyzing the relationship between a covariate and a survival endpoint. The standard Cox model assumes a constant covariate effect across the entire covariate domain. However, in many epidemiological and other applications, the covariate of main interest is subject to a threshold effect: a change in the slope at a certain point within the covariate domain. Often, the covariate of interest is subject to some degree of measurement error. In this paper, we study measurement error correction in the case where the threshold is known. Several bias corr…
Understanding the factors that explain differences in survival times is an important issue for establishing policies to improve national health systems. Motivated by breast cancer data arising from the Surveillance Epidemiology and End Results program, we propose a covariate-adjusted proportional hazards frailty model for the analysis of clustered right-censored data. Rather than incorporating exchangeable frailties in the linear predictor of commonly-used survival models, we allow the frailty distribution to flexibly change with both continuous and categorical cluster-level covariates and mod…
In this article we suggest a new statistical approach considering survival heterogeneity as a breakpoint model in an ordered sequence of time to event variables. The survival responses need to be ordered according to a numerical covariate. Our esti- mation method will aim at detecting heterogeneity that could arise through the or- dering covariate. We formally introduce our model as a constrained Hidden Markov Model (HMM) where the hidden states are the unknown segmentation (breakpoint locations) and the observed states are the survival responses. We derive an efficient Expectation-Maximizatio…
Tree methods (recursive partitioning) are a popular class of nonparametric methods for analyzing data. One extension of the basic tree methodology is the survival tree, which applies recursive partitioning to censored survival data. There are several existing survival tree methods in the literature, which are mainly designed for right-censored data. We propose two new survival trees for left-truncated and right-censored (LTRC) data, which can be seen as a generalization of the traditional survival tree for right-censored data. Further, we show that such trees can be used to analyze survival da…
The goals in clinical and cohort studies often include evaluation of the association of a time-dependent binary treatment or exposure with a survival outcome. Recently, several impactful studies targeted the association between aspirin-taking and survival following colorectal cancer diagnosis. Due to surgery, aspirin-taking value is zero at baseline and may change its value to one at some time point. Estimating this association is complicated by having only intermittent measurements on aspirin-taking. Naive, commonly-used, methods can lead to substantial bias. We present a class of calibration…
In this paper we apply survival techniques to soccer data, treating a goal scoring as the event of interest. It specifically concerns the relationship between the time of the first goal in the game and the time of the second goal. In order to do so, the relevant survival analysis concepts are readjusted to fit the problem and a Cox model is developed for the hazard function. Attributes such as time dependent covariates and a frailty term are also being considered. We also use a reliable propensity score to summarize the pre-game covariates. The conclusions derived from the results are that a f…
The analysis of randomized trials with time-to-event endpoints is nearly always plagued by the problem of censoring. As the censoring mechanism is usually unknown, analyses typically employ the assumption of non-informative censoring. While this assumption usually becomes more plausible as more baseline covariates are being adjusted for, such adjustment also raises concerns. Pre-specification of which covariates will be adjusted for (and how) is difficult, thus prompting the use of data-driven variable selection procedures, which may impede valid inferences to be drawn. The adjustment for cova…
Extended cure survival models enable to separate covariates that affect the probability of an event (or `long-term' survival) from those only affecting the event timing (or `short-term' survival). We propose to generalize the bounded cumulative hazard model to handle additive terms for time-varying (exogenous) covariates jointly impacting long- and short-term survival. The selection of the penalty parameters is a challenge in that framework. A fast algorithm based on Laplace approximations in Bayesian P-spline models is proposed. The methodology is motivated by fertility studies where women's …
The restricted mean survival time is a clinically easy-to-interpret measure that does not require any assumption of proportional hazards. We focus on two ways to directly model the survival time and adjust the covariates. One is to calculate the pseudo-survival time for each subject using leave-one-out, and then perform a model analysis using all pseudo-values to adjust for covariates. The pseudo-survival time is used to reflect information of censored subjects in the model analysis. The other method adjusts for covariates using subjects for whom the time-to-event was observed while adjusting …
One goal in survival analysis of right-censored data is to estimate the marginal survival function in the presence of dependent censoring. When many auxiliary covariates are sufficient to explain the dependent censoring, estimation based on either a semiparametric model or a nonparametric model of the conditional survival function can be problematic due to the high dimensionality of the auxiliary information. In this paper, we use two working models to condense these high-dimensional covariates in dimension reduction; then an estimate of the marginal survival function can be derived nonparamet…
Most papers implicitly assume competing risks to be induced by residual cohort heterogeneity, i.e. heterogeneity that is not captured by the recorded covariates. Based on this observation we develop a generic statistical description of competing risks that unifies the main schools of thought. Assuming heterogeneity-induced competing risks is much weaker than assuming risk independence. However, we show that it still imposes sufficient constraints to solve the competing risk problem, and derive exact formulae for decontaminated primary risk hazard rates and cause-specific survival functions. Th…
There is a surge in medical follow-up studies that include longitudinal covariates in the modeling of survival data. So far, the focus has been largely on right-censored survival data. We consider survival data that are subject to both left truncation and right censoring. Left truncation is well known to produce biased sample. The sampling bias issue has been resolved in the literature for the case which involves baseline or time-varying covariates that are observable. The problem remains open, however, for the important case where longitudinal covariates are present in survival models. A join…
Covariate-adaptive randomization is popular in clinical trials with sequentially arrived patients for balancing treatment assignments across prognostic factors which may have influence on the response. However, existing theory on tests for treatment effect under covariate-adaptive randomization is limited to tests under linear or generalized linear models, although covariate-adaptive randomization has been used in survival analysis for a long time and its main application is in survival analysis. Often times, practitioners would simply adopt a conventional test such as the log-rank test or sco…
We use recurrent-events survival analysis techniques and methods to analyze the duration of Olympic records. The Kaplan-Meier estimator is used to perform preliminary tests and recurrent event survivor function estimators proposed by Wang & Chang (1999) and Pena et al. (2001) are used to estimate survival curves. Extensions of the Cox Proportional Hazards model are employed as well as a discrete-time logistic model for repeated events to estimate models and quantify parameter significance. The logistic model was the best fit to the data according to the Akaike Information Criterion (AIC). We d…
In survival analysis, the hazard function often depends on a set of covariates. Martingale and deviance residual are most widely used for examining the validity of the function form of covariates by checking whether there is a discernible trend in their scatterplot against continuous covariates. However, visual inspection of martingale and deviance residuals is often subjective. In addition, these residuals lack a reference distribution due to censoring. It is therefore challenging to derive numerical statistical tests based on martingale or deviance residuals. In this paper, we extend the ide…
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 …
We introduce a general, flexible, parametric survival modelling framework which encompasses key shapes of hazard function (constant, increasing, decreasing, up-then-down, down-then-up), various common survival distributions (log-logistic, Burr type XII, Weibull, Gompertz), and includes defective distributions (i.e., cure models). This generality is achieved using four basic distributional parameters: two scale-type parameters and two shape parameters. Generalising to covariate dependence, the scale-type regression components correspond to accelerated failure time (AFT) and proportional hazards…
Predicting patient survival probabilities based on observed covariates is an important assessment in clinical practice. These patient-specific covariates are often measured over multiple follow-up appointments. It is then of interest to predict survival based on the history of these longitudinal measurements, and to update predictions as more observations become available. The standard approaches to these so-called `dynamic prediction' assessments are joint models and landmark analysis. Joint models involve high-dimensional parametrisations, and their computational complexity often prohibits i…
Stanford University（斯坦福大学）；Université Paris 1 Panthéon-Sorbonne（巴黎第一大学先贤祠-索邦大学）；University of Toronto（多伦多大学）；Northwestern University（西北大学）
The Cox proportional hazards model is a canonical method in survival analysis for prediction of the life expectancy of a patient given clinical or genetic covariates -- it is a linear model in its original form. In recent years, several methods have been proposed to generalize the Cox model to neural networks, but none of these are both numerically correct and computationally efficient. We propose FastCPH, a new method that runs in linear time and supports both the standard Breslow and Efron methods for tied events. We also demonstrate the performance of FastCPH combined with LassoNet, a neura…
In the process of clinical diagnosis and treatment, the restricted mean survival time (RMST), which reflects the life expectancy of patients up to a specified time, can be used as an appropriate outcome measure. However, the RMST only calculates the mean survival time of patients within a period of time after the start of follow-up and may not accurately portray the change in a patient's life expectancy over time. The life expectancy can be adjusted for the time the patient has already survived and defined as the conditional restricted mean survival time (cRMST). A dynamic RMST model based on …
Spatial survival analysis has received a great deal of attention over the last 20 years due to the important role that geographical information can play in predicting survival. This paper provides an introduction to a set of programs for implementing some Bayesian spatial survival models in R using the package spBayesSurv. The function survregbayes includes the three most commonly-used semiparametric models: proportional hazards, proportional odds, and accelerated failure time. All manner of censored survival times are simultaneously accommodated including uncensored, interval censored, curren…
We are interested in survival analysis of hemodialysis patients for whom several biomarkers are recorded over time. Motivated by this challenging problem, we propose a general framework for multivariate joint longitudinal-survival modeling that can be used to examine the association between several longitudinally recorded covariates and a time-to-event endpoint. Our method allows for simultaneous modeling of longitudinal covariates by taking their correlation into account. This leads to a more efficient method for modeling their trajectories over time, and hence, it can better capture their re…
McCombs School of Business（麦克库姆斯商学院）；The University of Texas at Austin（德克萨斯大学奥斯汀分校）
We propose Lomax delegate racing (LDR) to explicitly model the mechanism of survival under competing risks and to interpret how the covariates accelerate or decelerate the time to event. LDR explains non-monotonic covariate effects by racing a potentially infinite number of sub-risks, and consequently relaxes the ubiquitous proportional-hazards assumption which may be too restrictive. Moreover, LDR is naturally able to model not only censoring, but also missing event times or event types. For inference, we develop a Gibbs sampler under data augmentation for moderately sized data, along with a …
Survival analysis of right censored data arises often in many areas of research including medical research. Effect of covariates (and their interactions) on survival distribution can be studied through existing methods which requires to pre-specify the functional form of the covariates including their interactions. Survival trees offer relatively flexible approach when the form of covariates' effects is unknown. Most of the currently available survival tree construction techniques are not based on a formal test of significance; however, recently proposed ctree algorithm (Hothorn et al., 2006) …
Semi-parametric survival analysis methods like the Cox Proportional Hazards (CPH) regression (Cox, 1972) are a popular approach for survival analysis. These methods involve fitting of the log-proportional hazard as a function of the covariates and are convenient as they do not require estimation of the baseline hazard rate. Recent approaches have involved learning non-linear representations of the input covariates and demonstrate improved performance. In this paper we argue against such deep parameterizations for survival analysis and experimentally demonstrate that more interpretable semi-par…
This article considers ultrahigh-dimensional forecasting problems with survival response variables. We propose a two-step model averaging procedure for improving the forecasting accuracy of the true conditional mean of a survival response variable. The first step is to construct a class of candidate models, each with low-dimensional covariates. For this, a feature screening procedure is developed to separate the active and inactive predictors through a marginal BuckleyCJames index, and to group covariates with a similar index size together to form regression models with survival response varia…
Randomized clinical trials are often designed to assess whether a test treatment prolongs survival relative to a control treatment. Increased patient heterogeneity, while desirable for generalizability of results, can weaken the ability of common statistical approaches to detect treatment differences, potentially hampering the regulatory approval of safe and efficacious therapies. A novel solution to this problem is proposed. A list of baseline covariates that have the potential to be prognostic for survival under either treatment is pre-specified in the analysis plan. At the analysis stage, u…
Restricted mean survival time (RMST) is gaining attention as a measure to quantify the treatment effect on survival outcomes in randomized clinical trials. Several methods to determine sample size based on the RMST-based tests have been proposed. However, to the best of our knowledge, there is no discussion about the power and sample size regarding the augmented version of RMST-based tests, which utilize baseline covariates for a gain in estimation efficiency and in power for testing the no treatment effect. The conventional event-driven study design based on the log-rank test allows us to cal…
Bayes linear kinematics and Bayes linear Bayes graphical models provide an extension of Bayes linear methods so that full conditional updates may be combined with Bayes linear belief adjustment. In this paper we investigate the application of this approach to a more complicated problem: namely survival analysis with time-dependent covariate effects. We use a piecewise-constant hazard function with a prior in which covariate effects are correlated over time. The need for computationally intensive methods is avoided and the relatively simple structure facilitates interpretation. Our approach eli…
Multilevel network meta-regression for multistate models: Population-adjusted joint synthesis of progression and survival data from individual and aggregate evidence
University of California, San Francisco（旧金山加利福尼亚大学）；UCSF Helen Diller Family Comprehensive Cancer Center（UCSF海伦·迪勒家族综合癌症中心）；The Philip R. Lee Institute for Health Policy Studies（菲利普·李健康政策研究所）；Precision AQ
Peter the Great St.Petersburg Polytechnic University (SPbPU)（圣彼得堡彼得大帝理工大学）
A new method called SurvLIME for explaining machine learning survival models is proposed. It can be viewed as an extension or modification of the well-known method LIME. The main idea behind the proposed method is to apply the Cox proportional hazards model to approximate the survival model at the local area around a test example. The Cox model is used because it considers a linear combination of the example covariates such that coefficients of the covariates can be regarded as quantitative impacts on the prediction. Another idea is to approximate cumulative hazard functions of the explained m…
We describe a new approach to estimating relative risks in time-to-event prediction problems with censored data in a fully parametric manner. Our approach does not require making strong assumptions of constant proportional hazard of the underlying survival distribution, as required by the Cox-proportional hazard model. By jointly learning deep nonlinear representations of the input covariates, we demonstrate the benefits of our approach when used to estimate survival risks through extensive experimentation on multiple real world datasets with different levels of censoring. We further demonstra…
Longitudinal and high-dimensional measurements have become increasingly common in biomedical research. However, methods to predict survival outcomes using covariates that are both longitudinal and high-dimensional are currently missing. In this article, we propose penalized regression calibration (PRC), a method that can be employed to predict survival in such situations. PRC comprises three modeling steps: First, the trajectories described by the longitudinal predictors are flexibly modeled through the specification of multivariate mixed effects models. Second, subject-specific summaries of t…
Feature screening is an important method to reduce the dimension and capture informative variables in ultrahigh-dimensional data analysis. Many methods have been developed for feature screening. These methods, however, are challenged by complex features pertinent to the data collection as well as the nature of the data themselves. Typically, incomplete response caused by right-censoring and covariates measurement error are often accompanying with survival analysis. Even though there are many methods have been proposed for censored data, little work has been available when both incomplete respo…
Medical practitioners use survival models to explore and understand the relationships between patients' covariates (e.g. clinical and genetic features) and the effectiveness of various treatment options. Standard survival models like the linear Cox proportional hazards model require extensive feature engineering or prior medical knowledge to model treatment interaction at an individual level. While nonlinear survival methods, such as neural networks and survival forests, can inherently model these high-level interaction terms, they have yet to be shown as effective treatment recommender system…
When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention-to-treat principle. Thereby a lot of potentially useful information is lost, as collection of time-to-event data often goes hand in hand with collection of information on biomarkers and other internal time-dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis…
Assuming some regression model, it is common to study the conditional distribution of survival given covariates. Here, we consider the impact of further conditioning, specifically conditioning on a marginal survival function, known or estimated. We investigate to what purposes any such information can be used in a proportional or non-proportional hazards regression analysis of time on the covariates. It does not lead to any improvement in efficiency when the form of the assumed proportional hazards model is valid. However, when the proportional hazards model is not valid, the usual partial lik…
