A treatment regime is a deterministic function that dictates personalized treatment based on patients' individual prognostic information. There is a fast-growing interest in finding optimal treatment regimes to maximize expected long-term clinical outcomes of patients for complex diseases, such as cancer and AIDS. For many clinical studies with survival time as a primary endpoint, a main goal is to maximize patients' survival probabilities given treatments. In this article, we first propose two nonparametric estimators for survival function of patients following a given treatment regime. Then, we derive the estimation of the optimal treatment regime based on a value-based searching algorithm within a set of treatment regimes indexed by parameters. The asymptotic properties of the proposed estimators for survival probabilities under derived optimal treatment regimes are established under suitable regularity conditions. Simulations are conducted to evaluate the numerical performance of the proposed estimators under various scenarios. An application to an AIDS clinical trial data is also given to illustrate the methods.
Factorial analyses offer a powerful nonparametric means to detect main or interaction effects among multiple treatments. For survival outcomes, e.g. from clinical trials, such techniques can be adopted for comparing reasonable quantifications of treatment effects. The key difficulty to solve in survival analysis concerns the proper handling of censoring. So far, all existing factorial analyses for survival data were developed under the independent censoring assumption, which is too strong for many applications. As a solution, the central aim of this article is to develop new methods in factori…
Zhejiang University（浙江大学）；Tsinghua University（清华大学）；National University of Singapore（新加坡国立大学）；George Washington University（乔治华盛顿大学）；New York University（纽约大学）
In the absence of data from a randomized trial, researchers often aim to use observational data to draw causal inference about the effect of a treatment on a time-to-event outcome. In this context, interest often focuses on the treatment-specific survival curves; that is, the survival curves were the entire population under study to be assigned to receive the treatment or not. Under certain causal conditions, including that all confounders of the treatment-outcome relationship are observed, the treatment-specific survival can be identified with a covariate-adjusted survival function. Several e…
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 …
Covariate-adaptive randomization is popular in clinical trials with sequentially arrived patients for balancing treatment assignments across prognostic factors which may have influence on the response. However, existing theory on tests for treatment effect under covariate-adaptive randomization is limited to tests under linear or generalized linear models, although covariate-adaptive randomization has been used in survival analysis for a long time and its main application is in survival analysis. Often times, practitioners would simply adopt a conventional test such as the log-rank test or sco…
Estimating individualized treatment rules is a central task for personalized medicine. [zhao2012estimating] and [zhang2012robust] proposed outcome weighted learning to estimate individualized treatment rules directly through maximizing the expected outcome without modeling the response directly. In this paper, we extend the outcome weighted learning to right censored survival data without requiring either an inverse probability of censoring weighting or a semiparametric modeling of the censoring and failure times as done in [zhao2015doubly]. To accomplish this, we take advantage of the tree ba…
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 generalized g-formula can be used to estimate the probability of survival under a sustained treatment strategy. When treatment strategies are deterministic, estimators derived from the so-called efficient influence function (EIF) for the g-formula will be doubly robust to model misspecification. In recent years, several practical applications have motivated estimation of the g-formula under non-deterministic treatment strategies where treatment assignment at each time point depends on the observed treatment process. In this case, EIF-based estimators may or may not be doubly robust. In thi…
Medical practitioners use survival models to explore and understand the relationships between patients' covariates (e.g. clinical and genetic features) and the effectiveness of various treatment options. Standard survival models like the linear Cox proportional hazards model require extensive feature engineering or prior medical knowledge to model treatment interaction at an individual level. While nonlinear survival methods, such as neural networks and survival forests, can inherently model these high-level interaction terms, they have yet to be shown as effective treatment recommender system…
Survival analysis has been developed and applied in the number of areas including manufacturing, finance, economics and healthcare. In healthcare domain, usually clinical data are high-dimensional, sparse and complex and sometimes there exists few amount of time-to-event (labeled) instances. Therefore building an accurate survival model from electronic health records is challenging. With this motivation, we address this issue and provide a new survival analysis framework using deep learning and active learning with a novel sampling strategy. First, our approach provides better representation w…
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…
SurvHTE-Bench: A Benchmark for Heterogeneous Treatment Effect Estimation in Survival Analysis
Machine Learning Department & Heinz College Carnegie Mellon University（机器学习系及卡内基梅隆大学海因兹学院）；Heinz College Carnegie Mellon University（卡内基梅隆大学海因兹学院）；National Library of Medicine National Institutes of Health（国家医学图书馆国立卫生研究院）
An optimal dynamic treatment regime (DTR) consists of a sequence of decision rules in maximizing long-term benefits, which is applicable for chronic diseases such as HIV infection or cancer. In this paper, we develop a novel angle-based approach to search the optimal DTR under a multicategory treatment framework for survival data. The proposed method targets maximization the conditional survival function of patients following a DTR. In contrast to most existing approaches which are designed to maximize the expected survival time under a binary treatment framework, the proposed method solves th…
Restricted mean survival time (RMST) is gaining attention as a measure to quantify the treatment effect on survival outcomes in randomized clinical trials. Several methods to determine sample size based on the RMST-based tests have been proposed. However, to the best of our knowledge, there is no discussion about the power and sample size regarding the augmented version of RMST-based tests, which utilize baseline covariates for a gain in estimation efficiency and in power for testing the no treatment effect. The conventional event-driven study design based on the log-rank test allows us to cal…
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…
A Novel Stratified Analysis Method for Testing and Estimating Overall Treatment Effects on Time-to-Event Outcomes Using Average Hazard with Survival Weight
When it comes to clinical survival trials, regulatory restrictions usually require the application of methods that solely utilize baseline covariates and the intention-to-treat principle. Thereby a lot of potentially useful information is lost, as collection of time-to-event data often goes hand in hand with collection of information on biomarkers and other internal time-dependent covariates. However, there are tools to incorporate information from repeated measurements in a useful manner that can help to shed more light on the underlying treatment mechanisms. We consider dynamic path analysis…
When choosing estimands and estimators in randomized clinical trials, caution is warranted as intercurrent events, such as - due to patients who switch treatment after disease progression, are often extreme. Statistical analyses may then easily lure one into making large implicit extrapolations, which often go unnoticed. We will illustrate this problem of implicit extrapolations using a real oncology case study, with a right-censored time-to-event endpoint, in which patients can cross over from the control to the experimental treatment after disease progression, for ethical reasons. We resolve…
Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial d…
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…
Patient-level health economic data collected alongside clinical trials are an important component of the process of technology appraisal, with a view to informing resource allocation decisions. For end of life treatments, such as cancer treatments, modelling of cost-effectiveness/utility data may involve some form of partitioned survival analysis, where measures of health-related quality of life and survival time for both pre- and post-progression periods are combined to generate some aggregate measure of clinical benefits (e.g. quality-adjusted survival). In addition, resource use data are of…
Medical investigations focusing on patient survival often generate not only a failure time for each patient but also a sequence of measurements on patient health at annual or semi-annual check-ups while the patient remains alive. Such a sequence of random length accompanied by a survival time is called a survival process. Ordinarily robust health is associated with longer survival, so the two parts of a survival process cannot be assumed independent. This paper is concerned with a general technique---time reversal---for constructing statistical models for survival processes. A revival model is…
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…
We analyse an issue when comparing survival curves between two subgroups. We show that there is a direct relationship between estimates of subgroups' survival at a time point and positive and negative predictive values in the binary classification settings. Our findings present a case where current methods of comparing survival curves between subgroups may be misleading. We think that this ought to be taken into account during the validation of prognostic diagnostic tests that predict two prognostic subgroups for a given disease or treatment, when the validation data set consists of censored d…
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…
Balanced representation learning methods have been applied successfully to counterfactual inference from observational data. However, approaches that account for survival outcomes are relatively limited. Survival data are frequently encountered across diverse medical applications, i.e., drug development, risk profiling, and clinical trials, and such data are also relevant in fields like manufacturing (e.g., for equipment monitoring). When the outcome of interest is a time-to-event, special precautions for handling censored events need to be taken, as ignoring censored outcomes may lead to bias…
Due to the heterogeneity of the randomized controlled trial (RCT) and external target populations, the estimated treatment effect from the RCT is not directly applicable to the target population. For example, the patient characteristics of the ACTG 175 HIV trial are significantly different from that of the three external target populations of interest: US early-stage HIV patients, Thailand HIV patients, and southern Ethiopia HIV patients. This paper considers several methods to transport the treatment effect from the ACTG 175 HIV trial to the target populations beyond the trial population. Mos…
Survival analysis is the branch of statistics that studies the relation between the characteristics of living entities and their respective survival times, taking into account the partial information held by censored cases. A good analysis can, for example, determine whether one medical treatment for a group of patients is better than another. With the rise of machine learning, survival analysis can be modeled as learning a function that maps studied patients to their survival times. To succeed with that, there are three crucial issues to be tackled. First, some patient data is censored: we do…
Indian Institute of Technology Kharagpur（印度理工学院卡拉格普尔分校）；Tata Medical Center（塔塔医学中心）；Arden Cancer Centre（雅顿癌症中心）；University Hospitals Coventry and Warwickshire（考文垂与沃里克郡大学医院）
Prediction of survivability in a patient for tumor progression is useful to estimate the effectiveness of a treatment protocol. In our work, we present a model to take into account the heterogeneous nature of a tumor to predict survival. The tumor heterogeneity is measured in terms of its mass by combining information regarding the radiodensity obtained in images with the gross tumor volume (GTV). We propose a novel feature called Tumor Mass within a GTV (TMG), that improves the prediction of survivability, compared to existing models which use GTV. Weekly variation in TMG of a patient is comp…
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…
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…
This paper introduces new effect parameters for factorial survival designs with possibly right-censored time-to-event data. In the special case of a two-sample design it coincides with the concordance or Wilcoxon parameter in survival analysis. More generally, the new parameters describe treatment or interaction effects and we develop estimates and tests to infer their presence. We rigorously study the asymptotic properties by means of empirical process techniques and additionally suggest wild bootstrapping for a consistent and distribution-free application of the inference procedures. The sma…
