Comparative effectiveness research often involves evaluating the differences in the risks of an event of interest between two or more treatments using observational data. Often, the post-treatment outcome of interest is whether the event happens within a pre-specified time window, which leads to a binary outcome. One source of bias for estimating the causal treatment effect is the presence of confounders, which are usually controlled using propensity score-based methods. An additional source of bias is right-censoring, which occurs when the information on the outcome of interest is not completely available due to dropout, study termination, or treatment switch before the event of interest. We propose an inverse probability weighted regression-based estimator that can simultaneously handle both confounding and right-censoring, calling the method CIPWR, with the letter C highlighting the censoring component. CIPWR estimates the average treatment effects by averaging the predicted outcomes obtained from a logistic regression model that is fitted using a weighted score function. The CIPWR estimator has a double robustness property such that estimation consistency can be achieved when either the model for the outcome or the models for both treatment and censoring are correctly specified. We establish the asymptotic properties of the CIPWR estimator for conducting inference, and compare its finite sample performance with that of several alternatives through simulation studies. The methods under comparison are applied to a cohort of prostate cancer patients from an insurance claims database for comparing the adverse effects of four candidate drugs for advanced stage prostate cancer.
Interference occurs between individuals when the treatment (or exposure) of one individual affects the outcome of another individual. Previous work on causal inference methods in the presence of interference has focused on the setting where a priori it is assumed there is 'partial interference,' in the sense that individuals can be partitioned into groups wherein there is no interference between individuals in different groups. Bowers, Fredrickson, and Panagopoulos (2012) and Bowers, Fredrickson, and Aronow (2016) consider randomization-based inferential methods that allow for more general int…
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…
Recent advances in causal mediation analysis have formalized conditions for estimating direct and indirect effects in various contexts. These approaches have been extended to a number of models for survival outcomes including accelerated failure time (AFT) models which are widely used in a broad range of health applications given their intuitive interpretation. In this setting, it has been suggested that under standard assumptions, the "difference" and "product" methods produce equivalent estimates of the indirect effect of exposure on the survival outcome. We formally show that these two meth…
Marginal structural models (MSMs) with inverse probability weighting offer an approach to estimating causal effects of treatment sequences on repeated outcome measures in the presence of time-varying confounding and dependent censoring. However, when weights are estimated by maximum likelihood, inverse probability weighted estimators (IPWEs) can be inefficient and unstable in practice. We propose a joint calibration approach for inverse probability of treatment and censoring weights to improve the efficiency and robustness of the IPWEs for MSMs with time-varying treatments of arbitrary (i.e., …
Estimating population-level effects of a vaccine is challenging because there may be interference, i.e., the outcome of one individual may depend on the vaccination status of another individual. Partial interference occurs when individuals can be partitioned into groups such that interference occurs only within groups. In the absence of interference, inverse probability weighted (IPW) estimators are commonly used to draw inference about causal effects of an exposure or treatment. Tchetgen Tchetgen and VanderWeele (2012) proposed a modified IPW estimator for causal effects in the presence of pa…
Structural Nested Mean Models (SNMMs) are useful for causal inference of treatment effects in longitudinal observational studies. Most existing works assume that the data are collected at pre-fixed time points for all subjects, which, however, is restrictive in practice. To deal with irregularly spaced observations, we assume a class of continuous-time SNMMs and a martingale condition of no unmeasured confounding (NUC) to identify the causal parameters. We develop the first semiparametric efficiency theory and locally efficient estimators for continuous-time SNMMs. This task is non-trivial due…
Instrumental variable (IV) methods allow us the opportunity to address unmeasured confounding in causal inference. However, most IV methods are only applicable to discrete or continuous outcomes with very few IV methods for censored survival outcomes. In this work we propose nonparametric estimators for the local average treatment effect on survival probabilities under both nonignorable and ignorable censoring. We provide an efficient influence function-based estimator and a simple estimation procedure when the IV is either binary or continuous. The proposed estimators possess double-robustnes…
Bayesian hierarchical bootstrap framework for causal subgroup estimation with a time-to-event outcome
Dalla Lana School of Public Health, University of Toronto（多伦多大学达拉·兰纳公共卫生学院）；Division of Gastroenterology, Hepatology Nutrition, The Hospital for Sick Children（多伦多加急儿童医院胃肠病、肝病与营养科）；University of Utah and Intermountain Healthcare Primary Children’s Hospital（犹他大学和盐湖城初级儿童医院）；Institute of Health Policy, Management and Evaluation, University of Toronto（多伦多大学卫生政策、管理与评估研究所）
Illustrating implications of misaligned causal questions and statistics in settings with competing events and interest in treatment mechanisms
Harvard Medical School（哈佛医学院）；Harvard Pilgrim Health Care Institute（哈佛皮尔格林健康保健研究所）；The University of Tokyo Hospital（东京大学医院）；Yale School of Public Health（耶鲁大学公共卫生学院）；Harvard T. H. Chan School of Public Health（哈佛陈曾熙公共卫生学院）
Propensity score methods are increasingly being used to reduce estimation bias of treatment effects for observational studies. Previous research has shown that propensity score methods consistently estimate the marginal hazard ratio for time to event data. However, recurrent data frequently arise in the biomedical literature and there is a paucity of research into the use of propensity score methods when data are recurrent in nature. The objective of this paper is to extend the existing propensity score methods to recurrent data setting. We illustrate our methods through a series of Monte Carl…
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…
Nonparametric efficient causal estimation of the intervention-specific expected number of recurrent events with continuous-time targeted maximum likelihood and highly adaptive lasso estimation
Propensity scores are commonly used to reduce the confounding bias in non-randomized observational studies for estimating the average treatment effect. An important assumption underlying this approach is that all confounders that are associated with both the treatment and the outcome of interest are measured and included in the propensity score model. In the absence of strong prior knowledge about potential confounders, researchers may agnostically want to adjust for a high-dimensional set of pre-treatment variables. As such, variable selection procedure is needed for propensity score estimati…
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…
When engagement with a randomized trial is driven by factors that affect the outcome or when trial engagement directly affects the outcome independent of treatment, the average treatment effect among trial participants is unlikely to generalize to a target population. In this paper, we use counterfactual and graphical causal models to examine under what conditions we can generalize causal inferences from a randomized trial to the target population of trial-eligible individuals. We offer an interpretation of generalizability analyses using the notion of a hypothetical intervention to "scale-up"…
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…
Causal inference on multiple non-independent outcomes raises serious challenges, because multivariate techniques that properly account for the outcome's dependence structure need to be considered. We focus on the case of binary outcomes framing our discussion in the potential outcome approach to causal inference. We define causal effects of treatment on joint outcomes introducing the notion of product outcomes. We also discuss a decomposition of the causal effect on product outcomes into intrinsic and extrinsic causal effects, which respectively provide information on treatment effect on the i…
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. …
The literature for count modeling provides useful tools to conduct causal inference when outcomes take non-negative integer values. Applied to the potential outcomes framework, we link the Bayesian causal inference literature to statistical models for count data. We discuss the general architectural considerations for constructing the predictive posterior of the missing potential outcomes. Special considerations for estimating average treatment effects are discussed, some generalizing certain relationships and some not yet encountered in the causal inference literature.
Several approaches to causal inference from observational studies have been proposed. Since the proposal of Rubin (1974) many works have developed a counterfactual approach to causality, statistically formalized by potential outcomes. Pearl (2000) has put forward a theory of structural causal models which gives an important role to graphical models and do not necessarily use potential outcomes. On the other hand, several authors have developed a dynamical approach in line with Granger (1969). We analyze prospective and retrospective causal questions and their different modalities. Following Da…
Assessing the causal effects of interventions on ordinal outcomes is an important objective of many educational and behavioral studies. Under the potential outcomes framework, we can define causal effects as comparisons between the potential outcomes under treatment and control. However, unfortunately, the average causal effect, often the parameter of interest, is difficult to interpret for ordinal outcomes. To address this challenge, we propose to use two causal parameters, which are defined as the probabilities that the treatment is beneficial and strictly beneficial for the experimental uni…
Many outcomes of interest in the social and health sciences, as well as in modern applications in computational social science and experimentation on social media platforms, are ordinal and do not have a meaningful scale. Causal analyses that leverage this type of data, termed ordinal non-numeric, require careful treatment, as much of the classical potential outcomes literature is concerned with estimation and hypothesis testing for outcomes whose relative magnitudes are well defined. Here, we propose a class of finite population causal estimands that depend on conditional distributions of the…
Unobserved confounding presents a major threat to causal inference from observational studies. Recently, several authors suggest that this problem may be overcome in a shared confounding setting where multiple treatments are independent given a common latent confounder. It has been shown that under a linear Gaussian model for the treatments, the causal effect is not identifiable without parametric assumptions on the outcome model. In this paper, we show that the causal effect is indeed identifiable if we assume a general binary choice model for the outcome with a non-probit link. Our identific…
Analyses of biomedical studies often necessitate modeling longitudinal causal effects. The current focus on personalized medicine and effect heterogeneity makes this task even more challenging. Towards this end, structural nested mean models (SNMMs) are fundamental tools for studying heterogeneous treatment effects in longitudinal studies. However, when outcomes are binary, current methods for estimating multiplicative and additive SNMM parameters suffer from variation dependence between the causal parameters and the non-causal nuisance parameters. This leads to a series of difficulties in int…
Instrumental variable methods are widely used for inferring the causal effect in the presence of unmeasured confounders. Existing instrumental variable methods for nonlinear outcome models require stringent identifiability conditions. This paper considers a flexible semi-parametric potential outcome model that allows for possibly invalid instruments. We propose new identifiability conditions to identify the causal parameters when the majority of the instrumental variables are valid. We devise a novel inference procedure for a new average structural function and the conditional average treatmen…
In this paper we propose a new template for empirical studies intended to assess causal effects: the outcome-wide longitudinal design. The approach is an extension of what is often done to assess the causal effects of a treatment or exposure using confounding control, but now, over numerous outcomes. We discuss the temporal and confounding control principles for such outcome-wide studies, metrics to evaluate robustness or sensitivity to potential unmeasured confounding for each outcome, and approaches to handle multiple testing. We argue that the outcome-wide longitudinal design has numerous a…
Noncompliance and missing data often occur in randomized trials, which complicate the inference of causal effects. When both noncompliance and missing data are present, previous papers proposed moment and maximum likelihood estimators for binary and normally distributed continuous outcomes under the latent ignorable missing data mechanism. However, the latent ignorable missing data mechanism may be violated in practice, because the missing data mechanism may depend directly on the missing outcome itself. Under noncompliance and an outcome-dependent nonignorable missing data mechanism, previous…
A parametric expression for causal natural direct and indirect effects is derived for the setting of a binary outcome with a binary mediator. The proposed effect decomposition does not require the outcome to be rare and generalizes the existing ones, allowing for interactions between both the exposure and the mediator and confounding covariates. Further, it outlines the relationship between the causal effects and the correspondent pathway-specific logistic regression parameters, in parallel with results derived under the rare outcome assumption. Formulae for standard errors, obtained via the d…
Relationship between two popular modeling frameworks of causal inference from observational data, namely, causal graphical model and potential outcome causal model is discussed. How some popular causal effect estimators found in applications of the potential outcome causal model, such as inverse probability of treatment weighted estimator and doubly robust estimator can be obtained by using the causal graphical model is shown. We confine to the simple case of binary outcome and treatment variables with discrete confounders and it is shown how to generalize results to cases of continuous variab…
