Causal inference is best understood using potential outcomes. This use is particularly important in more complex settings, that is, observational studies or randomized experiments with complications such as noncompliance. The topic of this lecture, the issue of estimating the causal effect of a treatment on a primary outcome that is ``censored'' by death, is another such complication. For example, suppose that we wish to estimate the effect of a new drug on Quality of Life (QOL) in a randomized experiment, where some of the patients die before the time designated for their QOL to be assessed. Another example with the same structure occurs with the evaluation of an educational program designed to increase final test scores, which are not defined for those who drop out of school before taking the test. A further application is to studies of the effect of job-training programs on wages, where wages are only defined for those who are employed. The analysis of examples like these is greatly clarified using potential outcomes to define causal effects, followed by principal stratification on the intermediated outcomes (e.g., survival).
Rejoinder on Causal Inference Through Potential Outcomes and Principal Stratification: Application to Studies with ``Censoring'' Due to Death by D. B. Rubin [math.ST/0612783]
The analysis of causal effects when the outcome of interest is possibly truncated by death has a long history in statistics and causal inference. The survivor average causal effect is commonly identified with more assumptions than those guaranteed by the design of a randomized clinical trial or using sensitivity analysis. This paper demonstrates that individual level causal effects in the `always survivor' principal stratum can be identified with no stronger identification assumptions than randomization. We illustrate the practical utility of our methods using data from a clinical trial on pat…
Though they may offer valuable patient and disease information that is impossible to study in a randomized trial, clinical disease registries also require special care and attention in causal inference. Registry data may be incomplete, inconsistent, and subject to confounding. In this paper we aim to address several analytical issues in estimating treatment effects that plague clinical registries such as the Emory amyotrophic lateral sclerosis (ALS) Clinic Registry. When attempting to assess the effect of a surgical insertion of a percutaneous endoscopic gastrostomy (PEG) tube on body mass ind…
Two problems that arise in making causal inferences for non-mortality outcomes such as bronchopulmonary dysplasia (BPD) are unmeasured confounding and censoring by death, i.e., the outcome is only observed when subjects survive. In randomized experiments with noncompliance, instrumental variable methods can be used to control for the unmeasured confounding without censoring by death. But when there is censoring by death, the average causal treatment effect cannot be identified under usual assumptions, but can be studied for a specific subpopulation by using sensitivity analysis with additional…
Comment on Complex Causal Questions Require Careful Model Formulation: Discussion of Rubin on Experiments with ``Censoring'' Due to Death [math.ST/0612783]
In semicompeting risks problems, nonterminal time-to-event outcomes such as time to hospital readmission are subject to truncation by death. These settings are often modeled with illness-death models for the hazards of the terminal and nonterminal events, but evaluating causal treatment effects with hazard models is problematic due to conditioning on survival (a post-treatment outcome) that is embedded in the definition of a hazard. Extending an existing survivor average causal effect (SACE) estimand, we frame the evaluation of treatment effects in the context of semicompeting risks with princ…
Evaluating treatment effects on longitudinal outcomes with attrition due to death: Methods for a two-dimentional estimand with a case study in Quality of Life
Ghent University（根特大学）；Leiden University Medical Center（莱顿大学医学中心）；Pfizer Inc（辉瑞公司）；Oslo University Hospital（奥斯陆大学医院）；European Organisation for Research and Treatment of Cancer (EORTC) Headquarters（欧洲癌症研究与治疗组织（EORTC）总部）；University of Freiburg（弗赖堡大学）
Participants in longitudinal studies on the effects of drug treatment and criminal justice system interventions are at high risk for institutionalization (e.g., spending time in an environment where their freedom to use drugs, commit crimes, or engage in risky behavior may be circumscribed). Methods used for estimating treatment effects in the presence of institutionalization during follow-up can be highly sensitive to assumptions that are unlikely to be met in applications and thus likely to yield misleading inferences. In this paper we consider the use of principal stratification to control …
Heterogeneous Treatment Effect in Time-to-Event Outcomes: Harnessing Censored Data with Recursively Imputed Trees
Faculty of Data and Decisions Sciences, Technion - Israel Institute of Technology（数据与决策科学学院，技术ion-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）
Clinical studies sometimes encounter truncation by death, rendering outcomes undefined. Statistical analysis based solely on observed survivors may give biased results because the characteristics of survivors differ between treatment groups. By principal stratification, the survivor average causal effect was proposed as a causal estimand defined in always-survivors. However, this estimand is not identifiable when there is unmeasured confounding between the treatment assignment and survival or outcome process. In this paper, we consider the comparison between an aggressive treatment and a conse…
In failure-time settings, a competing risk event is any event that makes it impossible for the event of interest to occur. For example, cardiovascular disease death is a competing event for prostate cancer death because an individual cannot die of prostate cancer once he has died of cardiovascular disease. Various statistical estimands have been defined as possible targets of inference in the classical competing risks literature. Many reviews have described these statistical estimands and their estimating procedures with recommendations about their use. However, this previous work has not used…
Even in a carefully designed randomized trial, outcomes for some study participants can be missing, or more precisely, ill-defined, because participants had died prior to date of outcome collection. This problem, known as truncation by death, means that the treated and untreated are no longer balanced with respect to covariates determining survival. Therefore, researchers often utilize principal stratification and focus on the Survivor Average Causal Effect (SACE). The SACE is the average causal effect among the subpopulation that will survive regardless of treatment status. In this paper, we …
Pre-treatment selection or censoring (`selection on treatment') can occur when two treatment levels are compared ignoring the third option of neither treatment, in `censoring by death' settings where treatment is only defined for those who survive long enough to receive it, or in general in studies where the treatment is only defined for a subset of the population. Unfortunately, the standard instrumental variable (IV) estimand is not defined in the presence of such selection, so we consider estimating a new survivor-complier causal effect. Although this effect is generally not identified unde…
In observational studies of survival time featuring a binary time-dependent treatment, the hazard ratio (an instantaneous measure) is often used to represent the treatment effect. However, investigators are often more interested in the difference in survival functions. We propose semiparametric methods to estimate the causal effect of treatment among the treated with respect to survival probability. The objective is to compare post-treatment survival with the survival function that would have been observed in the absence of treatment. For each patient, we compute a prognostic score (based on t…
Studies involving both randomized experiments as well as observational data typically involve time-to-event outcomes such as time-to-failure, death or onset of an adverse condition. Such outcomes are typically subject to censoring due to loss of follow-up and established statistical practice involves comparing treatment efficacy in terms of hazard ratios between the treated and control groups. In this paper we propose a statistical approach to recovering sparse phenogroups (or subtypes) that demonstrate differential treatment effects as compared to the study population. Our approach involves m…
The Hazard Ratio (HR) is often reported as the main causal effect when studying survival data. Despite its popularity, the HR suffers from an unclear causal interpretation. As already pointed out in the literature, there is a built-in selection bias in the HR, because similarly to the truncation by death problem, the HR conditions on post-treatment survival. A recently proposed alternative, inspired by the Survivor Average Causal Effect (SACE), is the causal HR, defined as the ratio between hazards across treatment groups among the study participants that would have survived regardless of thei…
An emerging challenge for time-to-event data is studying semi-competing risks, namely when two event times are of interest: a non-terminal event time (e.g. age at disease diagnosis), and a terminal event time (e.g. age at death). The non-terminal event is observed only if it precedes the terminal event, which may occur before or after the non-terminal event. Studying treatment or intervention effects on the dual event times is complicated because for some units, the non-terminal event may occur under one treatment value but not under the other. Until recently, existing approaches (e.g., the su…
Marginal structural models (MSMs) estimate the causal effect of a time-varying treatment in the presence of time-dependent confounding via weighted regression. The standard approach of using inverse probability of treatment weighting (IPTW) can lead to high-variance estimates due to extreme weights and be sensitive to model misspecification. Various methods have been proposed to partially address this, including truncation and stabilized-IPTW to temper extreme weights and covariate balancing propensity score (CBPS) to address treatment model misspecification. In this paper, we present Kernel O…
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）
University of Florida（佛罗里达大学）；Emerging Pathogens Institute（新兴病原体研究所）
Bacterial infections are responsible for high mortality worldwide. Antimicrobial resistance underlying the infection, and multifaceted patient's clinical status can hamper the correct choice of antibiotic treatment. Randomized clinical trials provide average treatment effect estimates but are not ideal for risk stratification and optimization of therapeutic choice, i.e., individualized treatment effects (ITE). Here, we leverage large-scale electronic health record data, collected from Southern US academic clinics, to emulate a clinical trial, i.e., 'target trial', and develop a machine learnin…
The principal stratification has become a popular tool to address a broad class of causal inference questions, particularly in dealing with non-compliance and truncation-by-death problems. The causal effects within principal strata which are determined by joint potential values of the intermediate variable, also known as the principal causal effects, are often of interest in these studies. Analyses of principal causal effects from observed data in the literature mostly rely on ignorability of the treatment assignment, which requires practitioners to accurately measure as many as covariates so …
