Proportional hazards (PH), proportional odds (PO) and accelerated failure time (AFT) models have been widely used to deal with survival data in different fields of knowledge. Despite their popularity, such models are not suitable to handle survival data with crossing survival curves. Yang and Prentice (2005) proposed a semiparametric two-sample approach, denoted here as the YP model, allowing the analysis of crossing survival curves and including the PH and PO configurations as particular cases. In a general regression setting, the present work proposes a fully likelihood-based approach to fit the YP model. The main idea is to model the baseline hazard via the piecewise exponential (PE) distribution. The approach shares the flexibility of the semiparametric models and the tractability of the parametric representations. An extensive simulation study is developed to evaluate the performance of the proposed model. In addition, we demonstrate how useful is the new method through the analysis of survival times related to patients enrolled in a cancer clinical trial. The simulation results indicate that our model performs well for moderate sample sizes in the general regression setting. A superior performance is also observed with respect to the original YP model designed for the two-sample scenario.
The proportional hazards (PH), proportional odds (PO) and accelerated failure time (AFT) models have been widely used in different applications of survival analysis. Despite their popularity, these models are not suitable to handle lifetime data with crossing survival curves. In 2005, Yang and Prentice proposed a semiparametric two-sample strategy (YP model), including the PH and PO frameworks as particular cases, to deal with this type of data. Assuming a general regression setting, the present paper proposes an unified approach to fit the YP model by employing Bernstein polynomials to manage…
Crossing survival curves complicate how we interpret results from a clinical trial's primary endpoint. We find the function to determine a crossing point's location depends exponentially on individual survival curves. This exponential relationship between survival curves and the crossing point transforms small survival curve errors into large crossing point errors. In most cases, crossing points are sensitive to individual survival errors and may make accurately locating a crossing point unsuccessful. We argue more complicated analyses for mitigating crossing points should be reserved only aft…
Current Targeted Maximum Likelihood Estimation (TMLE) methods used to analyze time-to-event data estimate the survival probability for each time point separately, which result in estimates that are not necessarily monotone. In this paper, we present an extension of TMLE for observational time-to-event data, the one-step Targeted Maximum Likelihood Estimator for the treatment-rule specific survival curve. We construct a one-dimensional universal least favorable submodel that targets the entire survival curve, and thereby requires minimal extra fitting with data to achieve its goal of solving th…
In comparative research on time-to-event data for two groups, when two survival curves cross each other, it may be difficult to use the log-rank test and hazard ratio (HR) to properly assess the treatment benefit. Our aim was to identify a method for evaluating the treatment benefits for two groups in the above situation. We quantified treatment benefits based on an intuitive measure called the area between two survival curves (ABS), which is a robust measure of treatment benefits in clinical trials regardless of whether the proportional hazards assumption is violated or two survival curves cr…
In survival studies it is important to record the values of key longitudinal covariates until the occurrence of event of a subject. For this reason, it is essential to study the association between longitudinal and time-to-event outcomes using the joint model. In this paper, profile likelihood approach has been used to estimate the cumulative hazard and regression parameters from the joint model of survival and longitudinal data. Moreover, we show the asymptotic normality of the profile likelihood estimator via asymptotic expansion of the profile likelihood and obtain the explicit form of the …
Nonparametric and semiparametric methods are commonly used in survival analysis to mitigate the bias due to model misspecification. However, such methods often cannot estimate upper-tail survival quantiles when a sizable proportion of the data are censored, in which case parametric likelihood-based estimators present a viable alternative. In this article, we extend a popular family of parametric survival models which make the Accelerated Failure Time (AFT) assumption to account for heteroscedasticity in the survival times. The conditional variances can depend on arbitrary covariates, thus addi…
While there are many well-developed data science methods for classification and regression, there are relatively few methods for working with right-censored data. Here, we present "survival stacking": a method for casting survival analysis problems as classification problems, thereby allowing the use of general classification methods and software in a survival setting. Inspired by the Cox partial likelihood, survival stacking collects features and outcomes of survival data in a large data frame with a binary outcome. We show that survival stacking with logistic regression is approximately equi…
We develop flexible multi-parameter regression survival models for interval censored survival data arising in longitudinal prospective studies and longitudinal randomised controlled clinical trials. A multi-parameter Weibull regression survival model, which is wholly parametric, and has non-proportional hazards, is the main focus of the paper. We describe the basic model, develop the interval-censored likelihood and extend the model to include gamma frailty and a dispersion model. We evaluate the models by means of a simulation study and a detailed re-analysis of data from the Signal Tandmobie…
Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative and absolute, may be used to fully elucidate study results. Restricted mean survival time differences between groups have been advocated as useful measures of association. Recent work focused on model-free estimates of the difference in restricted mean survival for all follow-up times instead of focusing on a single time horizon. In this work a model-based alternative is proposed with estimation u…
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…
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
J- and MJ-Type Tests for Non-Nested Parametric Survival Models with a Cure Fraction: A Score Test Approach
Institute of Mathematics and Statistics, Federal University of Goiás（戈亚斯联邦大学数学与统计学院）；Department of Statistics, Federal University of Paraíba（帕拉伊巴联邦大学统计学系）；Department of Statistics, Federal University of Pernambuco（伯南布哥联邦大学统计学系）
Maximum approximate Bernstein likelihood estimates of the baseline density function and the regression coefficients in the proportional hazard regression models based on interval-censored event time data are proposed. This results in not only a smooth estimate of the survival function which enjoys faster convergence rate but also improved estimates of the regression coefficients. Simulation shows that the finite sample performance of the proposed method is better than the existing ones. The proposed method is illustrated by real data applications.
Methods for the evaluation of the predictive accuracy of biomarkers with respect to survival outcomes subject to right censoring have been discussed extensively in the literature. In cancer and other diseases, survival outcomes are commonly subject to interval censoring by design or due to the follow up schema. In this paper, we present an estimator for the area under the time-dependent receiver operating characteristic ROC curve for interval censored data based on a nonparametric sieve maximum likelihood approach. We establish the asymptotic properties of the proposed estimator, and illustrat…
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…
In a survival analysis context we suggest a new method to estimate the piecewise constant hazard rate model. The method provides an automatic procedure to find the number and location of cut points and to estimate the hazard on each cut interval. Estimation is performed through a penalized likelihood using an adaptive ridge procedure. A bootstrap procedure is proposed in order to derive valid statistical inference taking both into account the variability of the estimate and the variability in the choice of the cut points. The new method is applied both to simulated data and to the Mayo Clinic …
The primary endpoint in oncology is usually overall survival, where differences between therapies may only be observable after many years. To avoid withholding of a promising therapy, preliminary approval based on a surrogate endpoint is possible. The approval can be confirmed later by assessing overall survival within the same study. In these trials, the correlation between surrogate endpoint and overall survival has to be taken into account for sample size calculation and analysis. For a binary surrogate endpoint, this relation can be modeled by means of the responder stratified exponential …
In this work we provide a simple estimation procedure for a general frailty model for analysis of prospective correlated failure times. Rigorous large-sample theory for the proposed estimators of both the regression coefficient vector and the dependence parameter is given, including consistent variance estimators. In a simulation study under the widely used gamma frailty model, our proposed approach was found to have essentially the same efficiency as the EM-based estimator considered by other authors, with negligible difference between the standard errors of the two estimators. The proposed a…
On a penalised likelihood approach for joint modelling of longitudinal covariates and partly interval-censored data -- an application to the Anti-PD1 brain collaboration trial
We consider a parametric modelling approach for survival data where covariates are allowed to enter the model through multiple distributional parameters, i.e., scale and shape. This is in contrast with the standard convention of having a single covariate-dependent parameter, typically the scale. Taking what is referred to as a multi-parameter regression (MPR) approach to modelling has been shown to produce flexible and robust models with relatively low model complexity cost. However, it is very common to have clustered data arising from survival analysis studies, and this is something that is …
A bivariate cure copula model with zero-inflated gamma frailty for right-censored data
Graduate Institute for Advanced Studies, SOKENDAI（SOKENDAI 高级研究研究生院）；Institute of Statistical Mathematics（统计数学研究所）；School of Informatics and Data Science, Hiroshima University（广岛大学信息科学与数据科学学院）
Tree-based methods for length-biased survival data
National Cancer Center（韩国国立癌症中心）；Yonsei University（延世大学）；Seoul National University College of Medicine（首尔大学医学院）；Seoul Metropolitan Government-Seoul National University Boramae Medical Center（首尔市政府-首尔大学八良医疗中心）；Ewha Womans University（梨花女子大学）
University Paris Descartes（巴黎笛卡尔大学）；Institut Hypercube（超立方体研究所）；Montreal Institute for Learning Algorithms（蒙特利尔学习算法研究所）；École Polytechnique de Montréal（蒙特利尔理工学院）
An accurate model of patient-specific kidney graft survival distributions can help to improve shared-decision making in the treatment and care of patients. In this paper, we propose a deep learning method that directly models the survival function instead of estimating the hazard function to predict survival times for graft patients based on the principle of multi-task learning. By learning to jointly predict the time of the event, and its rank in the cox partial log likelihood framework, our deep learning approach outperforms, in terms of survival time prediction quality and concordance index…
Value-Monotonicity Matters: A Concordance Loss for Deep Survival Prediction
Department of Radiation Oncology, University of Colorado School of Medicine（科罗拉多大学医学院放射肿瘤学系）；Department of Radiation Oncology, University of Texas Southwestern Medical Center（德克萨斯大学西南医学中心放射肿瘤学系）
We propose inference procedures for general nonparametric factorial survival designs with possibly right-censored data. Similar to additive Aalen models, null hypotheses are formulated in terms of cumulative hazards. Thereby, deviations are measured in terms of quadratic forms in Nelson-Aalen-type integrals. Different to existing approaches this allows to work without restrictive model assumptions as proportional hazards. In particular, crossing survival or hazard curves can be detected without a significant loss of power. For a distribution-free application of the method, a permutation strate…
Joint modelling of longitudinal and time-to-event data is usually described by a joint model which uses shared or correlated latent effects to capture associations between the two processes. Under this framework, the joint distribution of the two processes can be derived straightforwardly by assuming conditional independence given the random effects. Alternative approaches to induce interdependency into sub-models have also been considered in the literature and one such approach is using copulas to introduce non-linear correlation between the marginal distributions of the longitudinal and time…
Deep models trained through maximum likelihood have achieved state-of-the-art results for survival analysis. Despite this training scheme, practitioners evaluate models under other criteria, such as binary classification losses at a chosen set of time horizons, e.g. Brier score (BS) and Bernoulli log likelihood (BLL). Models trained with maximum likelihood may have poor BS or BLL since maximum likelihood does not directly optimize these criteria. Directly optimizing criteria like BS requires inverse-weighting by the censoring distribution. However, estimating the censoring model under these me…
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…
In this work we deal with correlated failure time (age at onset) data arising from population-based case-control studies, where case and control probands are selected by population-based sampling and an array of risk factor measures is collected for both cases and controls and their relatives. Parameters of interest are effects of risk factors on the hazard function of failure times and within-family dependencies of failure times after adjusting for the risk factors. Due to the retrospective nature of sampling, a large sample theory for existing methods has not been established. We develop a n…
Clinical trials involving novel immuno-oncology (IO) therapies frequently exhibit survival profiles which violate the proportional hazards assumption due to a delay in treatment effect, and in such settings, the survival curves in the two treatment arms may have a crossing before the two curves eventually separate. To flexibly model such scenarios, we describe a nonparametric approach for estimating the treatment arm-specific survival functions which constrains these two survival functions to cross at most once without making any additional assumptions about how the survival curves are related…
This paper studies Cox's regression hazard model with an unobservable random frailty where no specific distribution is postulated for the frailty variable, and the marginal lifetime distribution allows both parametric and non-parametric models. Laplace's approximation method and gradient search on smooth manifolds embedded in Euclidean space are applied, and a non-iterative profile likelihood optimization method is proposed for estimating the regression coefficients. The proposed method is compared with the Expected-Maximization method developed based on a gamma frailty assumption, and also in…
The call for patient-focused drug development is loud and clear, as expressed in the 21st Century Cures Act and in recent guidelines and initiatives of regulatory agencies. Among the factors contributing to modernized drug development and improved health-care activities are easily interpretable measures of clinical benefit. In addition, special care is needed for cancer trials with time-to-event endpoints if the treatment effect is not constant over time. We propose the predictive individual effect which is a patient-centric and tangible measure of clinical benefit under a wide variety of scen…
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…
New York University（纽约大学）；Columbia University（哥伦比亚大学）
Survival analysis models the distribution of time until an event of interest, such as discharge from the hospital or admission to the ICU. When a model's predicted number of events within any time interval is similar to the observed number, it is called well-calibrated. A survival model's calibration can be measured using, for instance, distributional calibration (D-CALIBRATION) [Haider et al., 2020] which computes the squared difference between the observed and predicted number of events within different time intervals. Classically, calibration is addressed in post-training analysis. We devel…
Survival data is encountered in a range of disciplines, most notably health and medical research. Although Bayesian approaches to the analysis of survival data can provide a number of benefits, they are less widely used than classical (e.g. likelihood-based) approaches. This may be in part due to a relative absence of user-friendly implementations of Bayesian survival models. In this article we describe how the rstanarm R package can be used to fit a wide range of Bayesian survival models. The rstanarm package facilitates Bayesian regression modelling by providing a user-friendly interface (us…
A class of multivariate mixed survival models for continuous and discrete time with a complex covariance structure is introduced in a context of quantitative genetic applications. The methods introduced can be used in many applications in quantitative genetics although the discussion presented concentrates on longevity studies. The framework presented allows to combine models based on continuous time with models based on discrete time in a joint analysis. The continuous time models are approximations of the frailty model in which the hazard function will be assumed to be piece-wise constant. T…
In this paper, we propose a flexible model for survival analysis using neural networks along with scalable optimization algorithms. One key technical challenge for directly applying maximum likelihood estimation (MLE) to censored data is that evaluating the objective function and its gradients with respect to model parameters requires the calculation of integrals. To address this challenge, we recognize that the MLE for censored data can be viewed as a differential-equation constrained optimization problem, a novel perspective. Following this connection, we model the distribution of event time…
We present a new method for analyzing stochastic epidemic models under minimal assumptions. The method, dubbed DSA, is based on a simple yet powerful observation, namely that population-level mean-field trajectories described by a system of PDE may also approximate individual-level times of infection and recovery. This idea gives rise to a certain non-Markovian agent-based model and provides an agent-level likelihood function for a random sample of infection and/or recovery times. Extensive numerical analyses on both synthetic and real epidemic data from the FMD in the United Kingdom and the C…
In decision modelling with time to event data, there are a variety of parametric models which could be used to extrapolate the survivor function. Each of these implies a different hazard function and in situations where there is moderate censoring, they can result in quite different extrapolations. Expert opinion on the long-term survival or other quantities could reduce model uncertainty. We present a general and easily implementable approach for including a variety of types of expert opinions. Expert opinion is incorporated by penalizing the likelihood function. Inference is performed in a B…
With known cause of death (CoD), competing risk survival methods are applicable in estimating disease-specific survival. Relative survival analysis may be used to estimate disease-specific survival when cause of death is either unknown or subject to misspecification and not reliable for practical usage. This method is popular for population-based cancer survival studies using registry data and does not require CoD information. The standard estimator is the ratio of all-cause survival in the cancer cohort group to the known expected survival from a general reference population. Disease-specific…
We consider a non-proportional hazards model where the regression coefficient is not constant but piecewise constant. Following Andersen and Gill (1982), we know that a knowledge of the changepoint leads to a relatively straightforward estimation of the regression coefficients on either side of the changepoint. Between adjacent changepoints, we place ourselves under the proportional hazards model. We can then maximize the partial likelihood to obtain a consistent estimation of the regression coefficients. Difficulties occur when we want to estimate these changepoints. We obtain a confidence re…
The time-varying effects model is a flexible and powerful tool for modeling the dynamic changes of covariate effects. However, in survival analysis, its computational burden increases quickly as the number of sample sizes or predictors grows. Traditional methods that perform well for moderate sample sizes and low-dimensional data do not scale to massive data. Analysis of national kidney transplant data with a massive sample size and large number of predictors defy any existing statistical methods and software. In view of these difficulties, we propose a Minorization-Maximization-based steepest…
Survival analysis, the art of time-to-event modeling, plays an important role in clinical treatment decisions. Recently, continuous time models built from neural ODEs have been proposed for survival analysis. However, the training of neural ODEs is slow due to the high computational complexity of neural ODE solvers. Here, we propose an efficient alternative for flexible continuous time models, called Survival Mixture Density Networks (Survival MDNs). Survival MDN applies an invertible positive function to the output of Mixture Density Networks (MDNs). While MDNs produce flexible real-valued di…
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…
Credit scoring plays a vital role in the field of consumer finance. Survival analysis provides an advanced solution to the credit-scoring problem by quantifying the probability of survival time. In order to deal with highly heterogeneous industrial data collected in Chinese market of consumer finance, we propose a nonparametric ensemble tree model called gradient boosting survival tree (GBST) that extends the survival tree models with a gradient boosting algorithm. The survival tree ensemble is learned by minimizing the negative log-likelihood in an additive manner. The proposed model optimize…
