Software development innovations and advances in computing have enabled more complex and less costly computations in medical research (survival analysis), engineering studies (reliability analysis), and social sciences event analysis (historical analysis). As a result, many semi-parametric modeling efforts emerged when it comes to time-to-event data analysis. In this context, this work presents a flexible Bernstein polynomial (BP) based framework for survival data modeling. This innovative approach is applied to existing families of models such as proportional hazards (PH), proportional odds (PO), and accelerated failure time (AFT) models to estimate unknown baseline functions. Along with this contribution, this work also presents new automated routines in R, taking advantage of algorithms available in Stan. The proposed computation routines are tested and explored through simulation studies based on artificial datasets. The tools implemented to fit the proposed statistical models are combined and organized in an R package. Also, the BP based proportional hazards (BPPH), proportional odds (BPPO), and accelerated failure time (BPAFT) models are illustrated in real applications related to cancer trial data using maximum likelihood (ML) estimation and Markov chain Monte Carlo (MCMC) methods.
University College London（伦敦大学学院）；LMU Munich（慕尼黑大学）
As machine learning has become increasingly popular over the last few decades, so too has the number of machine learning interfaces for implementing these models. Whilst many R libraries exist for machine learning, very few offer extended support for survival analysis. This is problematic considering its importance in fields like medicine, bioinformatics, economics, engineering, and more. mlr3proba provides a comprehensive machine learning interface for survival analysis and connects with mlr3's general model tuning and benchmarking facilities to provide a systematic infrastructure for surviva…
In this paper we present SurvLIMEpy, an open-source Python package that implements the SurvLIME algorithm. This method allows to compute local feature importance for machine learning algorithms designed for modelling Survival Analysis data. Our implementation takes advantage of the parallelisation paradigm as all computations are performed in a matrix-wise fashion which speeds up execution time. Additionally, SurvLIMEpy assists the user with visualization tools to better understand the result of the algorithm. The package supports a wide variety of survival models, from the Cox Proportional Ha…
Semi-competing risks refer to the setting where primary scientific interest lies in estimation and inference with respect to a non-terminal event, the occurrence of which is subject to a terminal event. In this paper, we present the R package SemiCompRisks that provides functions to perform the analysis of independent/clustered semi-competing risks data under the illness-death multi-state model. The package allows the user to choose the specification for model components from a range of options giving users substantial flexibility, including: accelerated failure time or proportional hazards re…
FastJM: An R Package for Efficient Implementation of Semiparametric Joint Models for Longitudinal and Survival Data
Beijing Normal–Hong Kong Baptist University（北京师范大学-香港浸会大学联合国际学院）；University of California at Riverside（加州大学河滨分校）；University of California at Los Angeles（加州大学洛杉矶分校）
Researchers are often interested in using longitudinal data to estimate the causal effects of hypothetical time-varying treatment interventions on the mean or risk of a future outcome. Standard regression/conditioning methods for confounding control generally fail to recover causal effects when time-varying confounders are themselves affected by past treatment. In such settings, estimators derived from Robins's g-formula may recover time-varying treatment effects provided sufficient covariates are measured to control confounding by unmeasured risk factors. The package gfoRmula implements in R …
The software package $\texttt{mstate}$, in articulation with the package $\texttt{survival}$, provides not only a well-established multi-state survival analysis framework in R, but also one of the most complete, as it includes point and interval estimation of relative transition hazards, cumulative transition hazards and state occupation probabilities, both under clock-forward and clock-reset models; personalised estimates, i.e. estimates for an individual with specific covariate measurements, can also be obtained with $\texttt{mstate}$ by fitting a Cox regression model. The new R package $\te…
Hundreds of millions of people live in countries that do not have complete death registration systems, meaning that most deaths are not recorded and critical quantities like life expectancy cannot be directly measured. The sibling survival method is a leading approach to estimating adult mortality in the absence of death registration. The idea is to ask a survey respondent to enumerate her siblings and to report about their survival status. In many countries and time periods, sibling survival data are the only nationally-representative source of information about adult mortality. Although a hu…
The R package merlin performs flexible joint modelling of hierarchical multi-outcome data. Increasingly, multiple longitudinal biomarker measurements, possibly censored time-to-event outcomes and baseline characteristics are available. However, there is limited software that allows all of this information to be incorporated into one model. In this paper, we present merlin which allows for the estimation of models with unlimited numbers of continuous, binary, count and time-to-event outcomes, with unlimited levels of nested random effects. A wide variety of link functions, including the expecte…
Extensions in the field of joint modeling of correlated data and dynamic predictions improve the development of prognosis research. The R package frailtypack provides estimations of various joint models for longitudinal data and survival events. In particular, it fits models for recurrent events and a terminal event (frailtyPenal), models for two survival outcomes for clustered data (frailtyPenal), models for two types of recurrent events and a terminal event (multivPenal), models for a longitudinal biomarker and a terminal event (longiPenal) and models for a longitudinal biomarker, recurrent …
Random double truncation refers a situation in which the variable of interest is observed only when it falls within two random limits. Such phenomenon occurs in many applications of Survival Analysis and Epidemiology, among many other fields. There exist several R packages to analyze doubly truncated data which implement, for instance, estimators for the cumulative distribution, the cumulative incidences of competing risks, or the regression coefficients in the Cox model. In this paper the main features of these packages are reviewed. The relative merits of the libraries are illustrated throug…
Emergency Medical Systems (EMS) provide crucial pre-hospital care and transportation. Faster EMS response time provides quicker pre-hospital care and thus increases survival rate. We reduce response time by providing optimal ambulance stationing and routing decisions by solving two stage stochastic and robust linear programs. Although operational research on ambulance systems is decades old, there is little open-source code and consistency in simulations. We begin to bridge this gap by publishing OpenEMS, in collaboration with the Austin-Travis County EMS (ATCEMS) in Texas, an end-to-end pipel…
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…
The statistically equivalent signature (SES) algorithm is a method for feature selection inspired by the principles of constrained-based learning of Bayesian Networks. Most of the currently available feature-selection methods return only a single subset of features, supposedly the one with the highest predictive power. We argue that in several domains multiple subsets can achieve close to maximal predictive accuracy, and that arbitrarily providing only one has several drawbacks. The SES method attempts to identify multiple, predictive feature subsets whose performances are statistically equiva…
Efficient variable selection in high-dimensional cancer genomic studies is critical for discovering genes associated with specific cancer types and for predicting response to treatment. Censored survival data is prevalent in such studies. In this article we introduce a Bayesian variable selection procedure that uses a mixture prior composed of a point mass at zero and an inverse moment prior in conjunction with the partial likelihood defined by the Cox proportional hazard model. The procedure is implemented in the R package BVSNLP, which supports parallel computing and uses a stochastic search…
Objective: To provide guidance for the use of the main functions available in R for performing post hoc Bayesian analysis of a randomized clinical trial with a survival endpoint using proportional hazard models. Study Design and Setting: Data derived from the ALLOZITHRO trial, conducted with 465 patients after allograft to prevent pulmonary complications and allocated between azithromycin and placebo; airflow decline-free survival at 2 years after randomization was the main endpoint. Results: Despite heterogeneity in modeling assumptions, in particular for the baseline hazard (parametric or no…
We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Comput…
This paper considers the problem of semi-parametric proportional hazards model fitting for interval, left and right censored survival times. We adopt a more versatile penalized likelihood method to estimate the baseline hazard and the regression coefficients simultaneously, where the penalty is introduced in order to regularize the baseline hazard estimate. We present asymptotic properties of our estimate, allowing for the possibility that it may lie on the boundary of the parameter space. We also provide a computational method based on marginal likelihood, which allows the regularization para…
We present methodological advances in understanding the effectiveness of personalized medicine models and supply easy-to-use open-source software. Personalized medicine involves the systematic use of individual patient characteristics to determine which treatment option is most likely to result in a better outcome for the patient on average. Why is personalized medicine not done more in practice? One of many reasons is because practitioners do not have any easy way to holistically evaluate whether their personalization procedure does better than the standard of care. Our software, "Personalize…
Repeated measures of biomarkers have the potential of explaining hazards of survival outcomes. In practice, these measurements are intermittently measured and are known to be subject to substantial measurement error. Joint modelling of longitudinal and survival data enables us to associate intermittently measured error-prone biomarkers with risks of survival outcomes. Most of the joint models available in the literature have been built on the Gaussian assumption. This makes them sensitive to outliers. In this work, we study a range of robust models to address this issue. For medical data, it h…
Not-at-random missingness presents a challenge in addressing missing data in many health research applications. In this paper, we propose a new approach to account for not-at-random missingness after multiple imputation through weighted analysis of stacked multiple imputations. The weights are easily calculated as a function of the imputed data and assumptions about the not-at-random missingness. We demonstrate through simulation that the proposed method has excellent performance when the missingness model is correctly specified. In practice, the missingness mechanism will not be known. We sho…
In medical research, it is often needed to obtain subgroups with heterogeneous survivals, which have been predicted from a prognostic factor. For this purpose, a binary split has often been used once or recursively; however, binary partitioning may not provide an optimal set of well separated subgroups. We propose a multi-way partitioning algorithm, which divides the data into K heterogeneous subgroups based on the information from a prognostic factor. The resulting subgroups show significant differences in survival. Such a multi-way partition is found by maximizing the minimum of the subgroup…
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…
A comprehensive, unified approach to modeling arbitrarily censored spatial survival data is presented for the three most commonly-used semiparametric models: proportional hazards, proportional odds, and accelerated failure time. Unlike many other approaches, all manner of censored survival times are simultaneously accommodated including uncensored, interval censored, current-status, left and right censored, and mixtures of these. Left-truncated data are also accommodated leading to models for time-dependent covariates. Both georeferenced (location exactly observed) and areally observed (locati…
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 many applications of survival data analysis, the individuals are treated in different medical centres or belong to different clusters defined by geographical or administrative regions. The analysis of such data requires accounting for between-cluster variability. Ignoring such variability would impose unrealistic assumptions in the analysis and could affect the inference on the statistical models. We develop a novel parametric mixed-effects general hazard (MEGH) model that is particularly suitable for the analysis of clustered survival data. The proposed structure generalises the mixed-effe…
Predictive modeling from high-dimensional genomic data is often preceded by a dimension reduction step, such as principal components analysis (PCA). However, the application of PCA is not straightforward for multi-source data, wherein multiple sources of 'omics data measure different but related biological components. In this article we utilize recent advances in the dimension reduction of multi-source data for predictive modeling. In particular, we apply exploratory results from Joint and Individual Variation Explained (JIVE), an extension of PCA for multi-source data, for prediction of diffe…
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…
We propose a class of two-sample statistics for testing the equality of proportions and the equality of survival functions. We build our proposal on a weighted combination of a score test for the difference in proportions and a Weighted Kaplan-Meier statistic-based test for the difference of survival functions. The proposed statistics are fully non-parametric and do not rely on the proportional hazards assumption for the survival outcome. We present the asymptotic distribution of these statistics, propose a variance estimator and show their asymptotic properties under fixed and local alternati…
A new method for clustered survival data]{A new method for clustered survival data: Estimation of treatment effect heterogeneity and variable selection
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…
The computational prediction algorithm of neural network, or deep learning, has drawn much attention recently in statistics as well as in image recognition and natural language processing. Particularly in statistical application for censored survival data, the loss function used for optimization has been mainly based on the partial likelihood from Cox's model and its variations to utilize existing neural network library such as Keras, which was built upon the open source library of TensorFlow. This paper presents a novel application of the neural network to the quantile regression for survival…
A Guide to Estimating Conditional Average Treatment Effects in Competing Risks Settings
Department of Statistics, TU Dortmund University（图恩-多特蒙德大学统计学系）；Research Center Trustworthy Data Science and Security, University Alliance Ruhr (UA Ruhr)（鲁尔大学联盟可信数据科学与安全研究中心）；Institute for Mathematics, University of Augsburg（艾希施泰特大学数学研究所）
