Kernel survival analysis methods predict subject-specific survival curves and times using information about which training subjects are most similar to a test subject. These most similar training subjects could serve as forecast evidence. How similar any two subjects are is given by the kernel function. In this paper, we present the first neural network framework that learns which kernel functions to use in kernel survival analysis. We also show how to use kernel functions to construct prediction intervals of survival time estimates that are statistically valid for individuals similar to a test subject. These prediction intervals can use any kernel function, such as ones learned using our neural kernel learning framework or using random survival forests. Our experiments show that our neural kernel survival estimators are competitive with a variety of existing survival analysis methods, and that our prediction intervals can help compare different methods' uncertainties, even for estimators that do not use kernels. In particular, these prediction interval widths can be used as a new performance metric for survival analysis methods.
Accurate models of patient survival probabilities provide important information to clinicians prescribing care for life-threatening and terminal ailments. A recently developed class of models - known as individual survival distributions (ISDs) - produces patient-specific survival functions that offer greater descriptive power of patient outcomes than was previously possible. Unfortunately, at the time of writing, ISD models almost universally lack uncertainty quantification. In this paper, we demonstrate that an existing method for estimating simultaneous prediction intervals from samples can …
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…
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…
Neural Topic Models with Survival Supervision: Jointly Predicting Time-to-Event Outcomes and Learning How Clinical Features Relate
Heinz College of Information Systems and Public Policy, Carnegie Mellon University（卡内基梅隆大学信息系统与公共政策学院）；McKinsey & Company（麦肯锡公司）；Cornerstone Research（基石研究公司）；Microsoft Research（微软研究院）；National Library of Medicine, National Institutes of Health（美国国立卫生研究院国家医学图书馆）
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…
University of Michigan（密歇根大学）；Merck Research Laboratories（默克研究实验室）
There has been increasing interest in modelling survival data using deep learning methods in medical research. Current approaches have focused on designing special cost functions to handle censored survival data. We propose a very different method with two steps. In the first step, we transform each subject's survival time into a series of jackknife pseudo conditional survival probabilities and then use these pseudo probabilities as a quantitative response variable in the deep neural network model. By using the pseudo values, we reduce a complex survival analysis to a standard regression probl…
Interval-censored data analysis is important in biomedical statistics for any type of time-to-event response where the time of response is not known exactly, but rather only known to occur between two assessment times. Many clinical trials and longitudinal studies generate interval-censored data; one common example occurs in medical studies that entail periodic follow-up. In this paper we propose a survival forest method for interval-censored data based on the conditional inference framework. We describe how this framework can be adapted to the situation of interval-censored data. We show that…
PyDTS: A Python Package for Discrete-Time Survival Analysis with Competing Risks and Optional Penalization
Faculty of Data and Decision Sciences, Technion - Israel Institute of Technology（数据与决策科学学院，技术离子-以色列理工学院）；Department of Statistics and Operations Research, Tel Aviv University（统计与运筹学系，特拉维夫大学）
Conventional survival analysis approaches estimate risk scores or individualized time-to-event distributions conditioned on covariates. In practice, there is often great population-level phenotypic heterogeneity, resulting from (unknown) subpopulations with diverse risk profiles or survival distributions. As a result, there is an unmet need in survival analysis for identifying subpopulations with distinct risk profiles, while jointly accounting for accurate individualized time-to-event predictions. An approach that addresses this need is likely to improve characterization of individual outcome…
Politecnico di Torino（都灵理工大学）；IEIIT CNR（意大利国家研究委员会电子与信息工程研究所）；Eurostep Digital AS（Eurostep数字公司）
Within the Private Equity (PE) market, the event of a private company undertaking an Initial Public Offering (IPO) is usually a very high-return one for the investors in the company. For this reason, an effective predictive model for the IPO event is considered as a valuable tool in the PE market, an endeavor in which publicly available quantitative information is generally scarce. In this paper, we describe a data-analytic procedure for predicting the probability with which a company will go public in a given forward period of time. The proposed method is based on the interplay of a neural ne…
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 …
In this paper, we consider a novel framework of positive-unlabeled data in which as positive data survival times are observed for subjects who have events during the observation time as positive data and as unlabeled data censoring times are observed but whether the event occurs or not are unknown for some subjects. We consider two cases: (1) when censoring time is observed in positive data, and (2) when it is not observed. For both cases, we developed parametric models, nonparametric models, and machine learning models and the estimation strategies for these models. Simulation studies show th…
In survival analysis it often happens that some subjects under study do not experience the event of interest; they are considered to be `cured'. The population is thus a mixture of two subpopulations: the one of cured subjects, and the one of `susceptible' subjects. When covariates are present, a so-called mixture cure model can be used to model the conditional survival function of the population. It depends on two components: the probability of being cured and the conditional survival function of the susceptible subjects. In this paper we propose a novel approach to estimate a mixture cure mo…
ICODEN: Ordinary Differential Equation Neural Networks for Interval-Censored Data
Department of Biostatistics and Health Data Science, University of Pittsburgh, PA, USA（匹兹堡大学生物统计与健康数据科学系）；Center for Applied Statistics and School of Statistics, Renmin University of China, Beijing, China（中国人民大学应用统计中心与统计学院）；Department of Applied Statistics, Konkuk University, Seoul, Republic of Korea（韩国康国民大学应用统计系）
Survival analysis, or time-to-event modelling, is a classical statistical problem that has garnered a lot of interest for its practical use in epidemiology, demographics or actuarial sciences. Recent advances on the subject from the point of view of machine learning have been concerned with precise per-individual predictions instead of population studies, driven by the rise of individualized medicine. We introduce here a conditional normalizing flow based estimate of the time-to-event density as a way to model highly flexible and individualized conditional survival distributions. We use a nove…
We propose the interval censored recursive forests (ICRF) which is an iterative tree ensemble method for interval censored survival data. This nonparametric regression estimator makes the best use of censored information by iteratively updating the survival estimate, and can be viewed as a self-consistent estimator with convergence monitored using out-of-bag samples. Splitting rules optimized for interval censored data are developed and kernel-smoothing is applied. The ICRF displays the highest prediction accuracy among competing nonparametric methods in most of the simulations and in an appli…
University of Maryland, Baltimore County（马里兰大学巴尔的摩县分校）
Multi-state survival analysis (MSA) uses multi-state models for the analysis of time-to-event data. In medical applications, MSA can provide insights about the complex disease progression in patients. A key challenge in MSA is the accurate subject-specific prediction of multi-state model quantities such as transition probability and state occupation probability in the presence of censoring. Traditional multi-state methods such as Aalen-Johansen (AJ) estimators and Cox-based methods are respectively limited by Markov and proportional hazards assumptions and are infeasible for making subject-spe…
Applications of machine learning in healthcare often require working with time-to-event prediction tasks including prognostication of an adverse event, re-hospitalization or death. Such outcomes are typically subject to censoring due to loss of follow up. Standard machine learning methods cannot be applied in a straightforward manner to datasets with censored outcomes. In this paper, we present auton-survival, an open-source repository of tools to streamline working with censored time-to-event or survival data. auton-survival includes tools for survival regression, adjustment in the presence o…
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 …
In this paper, we expand the methodology presented in Mertens et. al (2020, Biometrical Journal) to the study of life-time (survival) outcome which is subject to censoring and when imputation is used to account for missing values. We consider the problem where missing values can occur in both the calibration data as well as newly - to-be-predicted - observations (validation). We focus on the Cox model. Methods are described to combine imputation with predictive calibration in survival modeling subject to censoring. Application to cross-validation is discussed. We demonstrate how conclusions br…
We propose a flexible joint longitudinal-survival framework to examine the association between longitudinally collected biomarkers and a time-to-event endpoint. More specifically, we use our method for analyzing the survival outcome of end-stage renal disease patients with time-varying serum albumin measurements. Our proposed method is robust to common parametric assumptions in that it avoids explicit distributional assumptions on longitudinal measures and allows for subject-specific baseline hazard in the survival component. Fully joint estimation is performed to account for the uncertainty i…
We consider a class of Cox models with time-dependent effects that may be zero over certain unknown time regions or, in short, sparse time-varying effects. The model is particularly useful for biomedical studies as it conveniently depicts the gradual evolution of effects of risk factors on survival. Statistically, estimating and drawing inference on infinite dimensional functional parameters with sparsity (e.g., time-varying effects with zero-effect time intervals) present enormous challenges. To address them, we propose a new soft-thresholding operator for modeling sparse, piecewise smooth an…
Maximizing product use is a central goal of many businesses, which makes retention and monetization two central analytics metrics in games. Player retention may refer to various duration variables quantifying product use: total playtime or session playtime are popular research targets, and active playtime is well-suited for subscription games. Such research often has the goal of increasing player retention or conversely decreasing player churn. Survival analysis is a framework of powerful tools well suited for retention type data. This paper contributes new methods to game analytics on how pla…
Kaplan-Meier survival analysis represents the most objective measure of treatment efficacy in oncology, though subjected to potential bias, which is worrisome in an era of precision medicine. Independent of the bias inherent to the design and execution of clinical trials, bias may be the result of patient censoring, or incomplete observation. Unlike disease/progression free survival, overall survival is based on a well defined time point and thus avoids interval censoring, but right-censoring, due to incomplete follow-up, may still be a source of bias. We study three mechanisms of right-censor…
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…
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 …
Survival prediction with small sets of features is a highly relevant topic for decision-making in clinical practice. I describe a method for predicting survival of amyotrophic lateral sclerosis (ALS) patients that was developed as a submission to the DREAM ALS Stratification Prize4Life Challenge held in summer 2015 to find the most accurate prediction of ALS progression and survival. ALS is a neurodegenerative disease with very heterogeneous survival times. Based on patient data from two national registries, solvers were asked to predict survival for three different time intervals, which was t…
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…
Recent observations, especially in cancer immunotherapy clinical trials with time-to-event outcomes, show that the commonly used proportial hazard assumption is often not justifiable, hampering an appropriate analyse of the data by hazard ratios. An attractive alternative advocated is given by the restricted mean survival time (RMST), which does not rely on any model assumption and can always be interpreted intuitively. As pointed out recently by Horiguchi and Uno (2020), methods for the RMST based on asymptotic theory suffer from inflated type-I error under small sample sizes. To overcome thi…
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.
The approximate Bernstein polynomial model, a mixture of beta distributions, is applied to obtain maximum likelihood estimates of the regression coefficients, and the baseline density and survival functions in an accelerated failure time model based on interval censored data including current status data. The rate of convergence of the proposed estimates are given under some conditions for uncensored and interval censored data. Simulation shows that the proposed method is better than its competitors. The proposed method is illustrated by fitting the Breast Cosmetic Data using the accelerated f…
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 …
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…
Truncation is a statistical phenomenon that occurs in many time to event studies. For example, autopsy-confirmed studies of neurodegenerative diseases are subject to an inherent left and right truncation, also known as double truncation. When the goal is to study the effect of risk factors on survival, the standard Cox regression model cannot be used when the data is subject to truncation. Existing methods which adjust for both left and right truncation in the Cox regression model require independence between the survival times and truncation times, which may not be a reasonable assumption in …
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…
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 …
We present a new backfitting algorithm estimating the complex structured non-parametric survival model of Scheike (2001) without having to use smoothing. The considered model is a non-parametric survival model with two time-scales that are equivalent up to a constant that varies over the subjects. Covariate effects are modelled linearly on each time scale by additive Aalen models. Estimators of the cumulative intensities on the two time-scales are suggested by solving local estimating equations jointly on the two time-scales. We are able to estimate the cumulative intensities solving backfitti…
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
