Hazard functions play a central role in survival analysis, providing insight into the underlying risk dynamics of time-to-event data, with broad applications in medicine, epidemiology, and related fields. First-order ordinary differential equation (ODE) formulations of the hazard function have been explored as extensions beyond classical parametric models. However, such approaches typically produce monotonic hazard patterns, limiting their ability to represent oscillatory behavior, nonlinear damping, or coupled growth-decay dynamics. We propose a general statistical framework for modeling and simulating hazard functions governed by higher-order ODEs, allowing the hazard to depend on both its current level, its rate of change, and time. This formulation accommodates complex temporal risk behaviors arising in a range of applications. Building on this framework, we develop a class of nonlinear and oscillatory hazard models, each associated with an interpretable dynamical mechanism and an induced survival distribution. We also present a simulation procedure for solving a system of non-linear higher-order ODEs, with failure times generated via cumulative hazard inversion. Likelihood-based Bayesian inference under right censoring is also developed, and moment generating function analysis is used to characterize tail behavior. The proposed framework is evaluated through simulation studies and illustrated using real data, demonstrating its ability to capture temporal risk patterns not well represented by standard monotone models. In contrast to existing linear ODE-based hazard models, the proposed approach accommodates nonlinear and non-equilibrium dynamics, enabling the representation of temporal risk patterns that are not well captured by first-order or linear oscillator-based formulations.
The classical approach to analyze time-to-event data, e.g. in clinical trials, is to fit Kaplan-Meier curves yielding the treatment effect as the hazard ratio between treatment groups. Afterwards commonly a log-rank test is performed in order to investigate whether there is a difference in survival, or, depending on additional covariates, a Cox proportional hazard model is used. However, in numerous trials these approaches fail due to the presence of non-proportional hazards, resulting in difficulties of interpreting the hazard ratio and a loss of power. When considering equivalence or non-inf…
Unobserved individual heterogeneity is a common challenge in population cancer survival studies. This heterogeneity is usually associated with the combination of model misspecification and the failure to record truly relevant variables. We investigate the effects of unobserved individual heterogeneity in the context of excess hazard models, one of the main tools in cancer epidemiology. We propose an individual excess hazard frailty model to account for individual heterogeneity. This represents an extension of frailty modelling to the relative survival framework. In order to facilitate the infe…
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 …
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 …
We discuss causal mediation analyses for survival data and propose a new approach based on the additive hazards model. The emphasis is on a dynamic point of view, that is, understanding how the direct and indirect effects develop over time. Hence, importantly, we allow for a time varying mediator. To define direct and indirect effects in such a longitudinal survival setting we take an interventional approach (Didelez (2018)) where treatment is separated into one aspect affecting the mediator and a different aspect affecting survival. In general, this leads to a version of the non-parametric g-…
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 …
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…
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…
The conventional nonparametric tests in survival analysis, such as the log-rank test, assess the null hypothesis that the hazards are equal at all times. However, hazards are hard to interpret causally, and other null hypotheses are more relevant in many scenarios with survival outcomes. To allow for a wider range of null hypotheses, we present a generic approach to define test statistics. This approach utilizes the fact that a wide range of common parameters in survival analysis can be expressed as solutions of differential equations. Thereby we can test hypotheses based on survival parameter…
Studies to compare the survival of two or more groups using time-to-event data are of high importance in medical research. The gold standard is the log-rank test, which is optimal under proportional hazards. As the latter is no simple regularity assumption, we are interested in evaluating the power of various statistical tests under different settings including proportional and non-proportional hazards with a special emphasize on crossing hazards. This challenge has been going on for many years now and multiple methods have already been investigated in extensive simulation studies. However, in…
The Cox model, which remains as the first choice in analyzing time-to-event data even for large datasets, relies on the proportional hazards (PH) assumption. When survival data arrive sequentially in chunks, a fast and minimally storage intensive approach to test the PH assumption is desirable. We propose an online updating approach that updates the standard test statistic as each new block of data becomes available, and greatly lightens the computational burden. Under the null hypothesis of PH, the proposed statistic is shown to have the same asymptotic distribution as the standard version co…
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 the analysis of survival data, it is usually assumed that any unit will experience the event of interest if it is observed for a sufficient long time. However, one can explicitly assume that an unknown proportion of the population under study will never experience the monitored event. The promotion time model, which has a biological motivation, is one of the survival models taking this feature into account. The promotion time model assumes that the failure time of each subject is generated by the minimum of N latent event times which are independent with a common distribution independent of…
NAVER R&D Center（NAVER研发中心）；NAVER CLOVA；NAVER AI LAB（NAVER人工智能实验室）
Survival analysis appears in various fields such as medicine, economics, engineering, and business. Recent studies showed that the Ordinary Differential Equation (ODE) modeling framework unifies many existing survival models while the framework is flexible and widely applicable. However, naively applying the ODE framework to survival analysis problems may model fiercely changing density function which may worsen the model's performance. Though we can apply L1 or L2 regularizers to the ODE model, their effect on the ODE modeling framework is barely known. In this paper, we propose hazard gradie…
For many diseases it is reasonable to assume that the hazard rate is not constant across time, but also that it changes in different time intervals. To capture this, we work here with a piecewise survival model. One of the major problems in such piecewise models is to determine the time points of change of the hazard rate. From the practical point of view this can provide very important information as it may reflect changes in the progress of a disease. We present piecewise Weibull regression models with covariates. The time points where change occurs are assumed unknown and need to be estimat…
In heterogeneous cohorts and those where censoring by non-primary risks is informative many conventional survival analysis methods are not applicable; the proportional hazards assumption is usually violated at population level and the observed crude hazard rates are no longer estimators of what they would have been in the absence of other risks. In this paper, we develop a fully Bayesian survival analysis to determine the probabilistically optimal description of a heterogeneous cohort and we propose a novel means of recovering hazard rates and survival functions `decontaminated' of the effects…
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…
We present a general approach to synthesizing evidence of time-to-event endpoints in meta-analyses of aggregate data (AD). Our work goes beyond most previous meta-analytic research by using reconstructed survival data as a source of information. A Bayesian multilevel regression model, called the "meta-analysis of reconstructed survival data" (MARS), is introduced, by modeling and integrating reconstructed survival information with other types of summary data, to estimate the hazard ratio function and survival probabilities. The method attempts to reduce selection bias, and relaxes the presumpt…
A survival model is derived from the exponential function using the concept of fractional differentiation. The hazard function of the proposed model generates various shapes of curves including increasing, increasing-constant-increasing, increasing-decreasing-increasing, and so-called bathtub hazard curve. The model also contains a parameter that is the maximum of the survival time.
School of Electrical and Computer Engineering, Purdue University（普渡大学电气与计算机工程学院）；Department of Medicine, Indiana University School of Medicine（印第安纳大学医学院医学系）；School of Electrical and Computer Engineering, Indiana University - Purdue University Indianapolis（印第安纳大学-普渡大学印第安纳波利斯分校电气与计算机工程学院）
One of the central goals in precision health is the understanding and interpretation of high-dimensional biological data to identify genes and markers associated with disease initiation, development, and outcomes. Though significant effort has been committed to harness gene expression data for multiple analyses while accounting for time-to-event modeling by including survival times, many traditional analyses have focused separately on non-negative matrix factorization (NMF) of the gene expression data matrix and survival regression with Cox proportional hazards model. In this work, Cox proport…
A Novel Stratified Analysis Method for Testing and Estimating Overall Treatment Effects on Time-to-Event Outcomes Using Average Hazard with Survival Weight
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…
Antibodies, an essential part of our immune system, develop through an intricate process to bind a wide array of pathogens. This process involves randomly mutating DNA sequences encoding these antibodies to find variants with improved binding, though mutations are not distributed uniformly across sequence sites. Immunologists observe this nonuniformity to be consistent with "mutation motifs", which are short DNA subsequences that affect how likely a given site is to experience a mutation. Quantifying the effect of motifs on mutation rates is challenging: a large number of possible motifs makes…
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…
We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the …
In this paper, we explore a method for treating survival analysis as a classification problem. The method uses a "stacking" idea that collects the features and outcomes of the survival data in a large data frame, and then treats it as a classification problem. In this framework, various statistical learning algorithms (including logistic regression, random forests, gradient boosting machines and neural networks) can be applied to estimate the parameters and make predictions. For stacking with logistic regression, we show that this approach is approximately equivalent to the Cox proportional ha…
Comparison of the Cox proportional hazards model and Random Survival Forest algorithm for predicting patient-specific survival probabilities in clinical trial data
University of Augsburg（奥格斯堡大学）；University of Reading（雷丁大学）
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…
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…
Stochastic volatility often implies increasing risks that are difficult to capture given the dynamic nature of real-world applications. We propose using arc length, a mathematical concept, to quantify cumulative variations (the total variability over time) to more fully characterize stochastic volatility. The hazard rate, as defined by the Cox proportional hazards model in survival analysis, is assumed to be impacted by the instantaneous value of a longitudinal variable. However, when cumulative variations pose a significant impact on the hazard, this assumption is questionable. Our proposed B…
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…
Non-proportional hazards (NPH) have been observed recently in many immuno-oncology clinical trials. Weighted log-rank tests (WLRT) with suitably chosen weights can be used to improve the power of detecting the difference of the two survival curves in the presence of NPH. However, it is not easy to choose a proper WLRT in practice when both robustness and efficiency are considered. A versatile maxcombo test was proposed to achieve the balance of robustness and efficiency and has received increasing attentions in both methodology development and application. However, survival trials often warran…
Marginal structural models (MSMs) allow for causal analysis of longitudinal data. The MSMs were originally developed as discrete time models. Recently, continuous-time MSMs were presented as a conceptually appealing alternative for survival analysis. In applied analyses, it is often assumed that the theoretical treatment weights are known, but these weights are usually unknown and must be estimated from the data. Here we provide a sufficient condition for a class of continuous-time MSMs to be consistent even when the weights are estimated, and we show how additive hazard models can be used to …
Survival analysis (SA) is an active field of research that is concerned with time-to-event outcomes and is prevalent in many domains, particularly biomedical applications. Despite its importance, SA remains challenging due to small-scale data sets and complex outcome distributions, concealed by truncation and censoring processes. The piecewise exponential additive mixed model (PAMM) is a model class addressing many of these challenges, yet PAMMs are not applicable in high-dimensional feature settings or in the case of unstructured or multimodal data. We unify existing approaches by proposing D…
In survival analysis, Cox model is widely used for most clinical trial data. Alternatives include the additive hazard model, the accelerated failure time (AFT) model and a more general transformation model. All these models assume that the effects for all covariates are on the same scale. However, it is possible that for different covariates, the effects are on different scales. In this paper, we propose a shape-invariant hazard regression model that allows us to estimate the multiplicative treatment effect with adjustment of covariates that have non-multiplicative effects. We propose moment-b…
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…
Peter the Great St.Petersburg Polytechnic University（彼得大帝圣彼得堡理工大学）
A new robust algorithm based of the explanation method SurvLIME called SurvLIME-KS is proposed for explaining machine learning survival models. The algorithm is developed to ensure robustness to cases of a small amount of training data or outliers of survival data. The first idea behind SurvLIME-KS is to apply the Cox proportional hazards model to approximate the black-box survival model at the local area around a test example due to the linear relationship of covariates in the model. The second idea is to incorporate the well-known Kolmogorov-Smirnov bounds for constructing sets of predicted …
