Hazard serves as a pivotal estimand in both practical applications and methodological frameworks. However, its causal interpretation poses notable challenges, including inherent selection biases and ill-defined populations to be compared between different treatment groups. In response, we propose a novel definition of counterfactual hazard within the framework of possible worlds. Instead of conditioning on prior survival status as a conditional probability, our new definition involves intervening in the prior status, treating it as a marginal probability. Using single-world intervention graphs, we demonstrate that the proposed counterfactual hazard is a type of controlled direct effect. Conceptually, intervening in survival status at each time point generates a new possible world, where the proposed hazards across time points represent risks in these hypothetical scenarios, forming a "multiverse of hazard." The cumulative and average counterfactual hazards correspond to the sum and average of risks across this multiverse, respectively, with the actual world's risk lying between the two. This conceptual shift reframes hazards in the actual world as a collection of risks across possible worlds, marking a significant advancement in the causal interpretation of hazards.
It is emphasised that for epidemiological studies where disease incidence is rare, results from conventional proportional hazards models can often correctly estimate causal associations. The well-known "backdoor criteria" from causal-inference is applied to the common epidemiological study of rare diseases with a proportional hazards model, providing an example of when and how estimates from conventional proportional hazards studies can be used. A similar study with the "frontdoor criteria", that allows studies with unmeasured confounders, finds similar results to conventional mediation analys…
Instrumental variables (IV) are a useful tool for estimating causal effects in the presence of unmeasured confounding. IV methods are well developed for uncensored outcomes, particularly for structural linear equation models, where simple two-stage estimation schemes are available. The extension of these methods to survival settings is challenging, partly because of the nonlinearity of the popular survival regression models and partly because of the complications associated with right censoring or other survival features. We develop a simple causal hazard ratio estimator in a proportional haza…
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…
Hazard ratios are prone to selection bias, compromising their use as causal estimands. On the other hand, the hazard difference has been shown to remain unaffected by the selection of frailty factors over time. Therefore, observed hazard differences can be used as an unbiased estimator for the causal hazard differences in the absence of confounding. However, in the presence of effect (on the hazard) heterogeneity, the hazard difference is also affected by selection. In this work, we formalize how the observed hazard difference (from a randomized controlled trial) evolves by selecting favourabl…
Observational longitudinal data on treatments and covariates are increasingly used to investigate treatment effects, but are often subject to time-dependent confounding. Marginal structural models (MSMs), estimated using inverse probability of treatment weighting or the g-formula, are popular for handling this problem. With increasing development of advanced causal inference methods, it is important to be able to assess their performance in different scenarios to guide their application. Simulation studies are a key tool for this, but their use to evaluate causal inference methods has been lim…
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…
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…
It is known that the hazard ratio lacks a useful causal interpretation. Even for data from a randomized controlled trial, the hazard ratio suffers from built-in selection bias as, over time, the individuals at risk in the exposed and unexposed are no longer exchangeable. In this work, we formalize how the observed hazard ratio evolves and deviates from the causal hazard ratio of interest in the presence of heterogeneity of the hazard of unexposed individuals (frailty) and heterogeneity in effect (individual modification). For the case of effect heterogeneity, we define the causal hazard ratio.…
Re-examining and calibrating weighted survival analysis for causal inference
College of Economics, China Jiliang University（中国计量大学经济管理学院）；Department of Statistics, Rutgers University（罗格斯大学统计学系）；Institute for Health, Health Care Policy, and Aging Research, Rutgers University（罗格斯大学健康、医疗政策和老龄化研究所）
Investigating the causal relationship between exposure and the time-to-event outcome is an important topic in biomedical research. Previous literature has discussed the potential issues of using the hazard ratio as a marginal causal effect measure due to its noncollapsibility property. In this paper, we advocate using the restricted mean survival time (RMST) difference as the marginal causal effect measure, which is collapsible and has a simple interpretation as the difference of area under survival curves over a certain time horizon. To address both measured and unmeasured confounding, a matc…
Cox's proportional hazards model is one of the most popular statistical models to evaluate associations of exposure with a censored failure time outcome. When confounding factors are not fully observed, the exposure hazard ratio estimated using a Cox model is subject to unmeasured confounding bias. To address this, we propose a novel approach for the identification and estimation of the causal hazard ratio in the presence of unmeasured confounding factors. Our approach is based on a binary instrumental variable, and an additional no-interaction assumption in a first stage regression of the tre…
Often, a community becomes alarmed when high rates of cancer are noticed, and residents suspect that the cancer cases could be caused by a known source of hazard. In response, the CDC recommends that departments of health perform a standardized incidence ratio (SIR) analysis to determine whether the observed cancer incidence is higher than expected. This approach has several limitations that are well documented in the literature. In this paper we propose a novel causal inference approach to cancer cluster investigations, rooted in the potential outcomes framework. Assuming that a source of haz…
Wildland fire smoke contains hazardous levels of fine particulate matter PM2.5, a pollutant shown to adversely effect health. Estimating fire attributable PM2.5 concentrations is key to quantifying the impact on air quality and subsequent health burden. This is a challenging problem since only total PM2.5 is measured at monitoring stations and both fire-attributable PM2.5 and PM2.5 from all other sources are correlated in space and time. We propose a framework for estimating fire-contributed PM2.5 and PM2.5 from all other sources using a novel causal inference framework and bias-adjusted chemi…
In this paper the regression discontinuity design is adapted to the survival analysis setting with right-censored data, studied in an intensity based counting process framework. In particular, a local polynomial regression version of the Aalen additive hazards estimator is introduced as an estimator of the difference between two covariate dependent cumulative hazard rate functions. Large-sample theory for this estimator is developed, including confidence intervals that take into account the uncertainty associated with bias correction. As is standard in the causality literature, the models and …
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…
TCS Research（TCS研究院）；Indraprastha Institute of Information Technology Delhi（因德拉普拉斯信息技术学院德里分校）
Causal inference (CI) in observational studies has received a lot of attention in healthcare, education, ad attribution, policy evaluation, etc. Confounding is a typical hazard, where the context affects both, the treatment assignment and response. In a multiple treatment scenario, we propose the neural network based MultiMBNN, where we overcome confounding by employing generalized propensity score based matching, and learning balanced representations. We benchmark the performance on synthetic and real-world datasets using PEHE, and mean absolute percentage error over ATE as metrics. MultiMBNN…
Debiasing hazard-based, time-varying vaccine effects using vaccine-irrelevant infections: An observational extension of a pivotal Phase 3 COVID-19 vaccine efficacy trial
Causal identification of treatment effects for infectious disease outcomes in interconnected populations is challenging because infection outcomes may be transmissible to others, and treatment given to one individual may affect others' outcomes. Contagion, or transmissibility of outcomes, complicates standard conceptions of treatment interference in which an intervention delivered to one individual can affect outcomes of others. Several statistical frameworks have been proposed to measure causal treatment effects in this setting, including structural transmission models, mediation-based partne…
A fundamental concept in two-arm non-parametric survival analysis is the comparison of observed versus expected numbers of events on one of the treatment arms (the choice of which arm is arbitrary), where the expectation is taken assuming that the true survival curves in the two arms are identical. This concept is at the heart of the counting-process theory that provides a rigorous basis for methods such as the log-rank test. It is natural, therefore, to maintain this perspective when extending the log-rank test to deal with non-proportional hazards, for example by considering a weighted sum o…
Identifying causal relationships for a treatment intervention is a fundamental problem in health sciences. Randomized controlled trials (RCTs) are considered the gold standard for identifying causal relationships. However, recent advancements in the theory of causal inference based on the foundations of structural causal models (SCMs) have allowed the identification of causal relationships from observational data, under certain assumptions. Survival analysis provides standard measures, such as the hazard ratio, to quantify the effects of an intervention. While hazard ratios are widely used in …
In animal behavior studies, a common goal is to investigate the causal pathways between an exposure and outcome, and a mediator that lies in between. Causal mediation analysis provides a principled approach for such studies. Although many applications involve longitudinal data, the existing causal mediation models are not directly applicable to settings where the mediators are measured on irregular time grids. In this paper, we propose a causal mediation model that accommodates longitudinal mediators on arbitrary time grids and survival outcomes simultaneously. We take a functional data analys…
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…
Time to event outcomes are often evaluated on the hazard scale, but interpreting hazards may be difficult. Recently, there has been concern in the causal inference literature that hazards actually have a built in selection-effect that prevents simple causal interpretations. This is even a problem in randomized controlled trials, where hazard ratios have become a standard measure of treatment effects. Modeling on the hazard scale is nevertheless convenient, e.g. to adjust for covariates. Using hazards for intermediate calculations may therefore be desirable. Here, we provide a generic method fo…
The timing of antiretroviral therapy (ART) initiation for HIV and tuberculosis (TB) co-infected patients needs to be considered carefully. CD4 cell count can be used to guide decision making about when to initiate ART. Evidence from recent randomized trials and observational studies generally supports early initiation but does not provide information about effects of initiation time on a continuous scale. In this paper, we develop and apply a highly flexible structural proportional hazards model for characterizing the effect of treatment initiation time on a survival distribution. The model ca…
Best for which estimand? A known-truth benchmark of longitudinal-matching and target-trial-emulation methods for time-varying treatments
School of Population and Public Health, University of British Columbia（不列颠哥伦比亚大学公共卫生与人口健康学院）；Centre for Advancing Health Outcomes, St. Paul’s Hospital（圣保罗医院健康结果促进中心）
The problem of how to best select variables for confounding adjustment forms one of the key challenges in the evaluation of exposure effects in observational studies, and has been the subject of vigorous recent activity in causal inference. A major drawback of routine procedures is that there is no finite sample size at which they are guaranteed to deliver exposure effect estimators and associated confidence intervals with adequate performance. In this work, we will consider this problem when inferring conditional causal hazard ratios from observational studies under the assumption of no unmea…
Many research questions involve time-to-event outcomes that can be prevented from occurring due to competing events. In these settings, we must be careful about the causal interpretation of classical statistical estimands. In particular, estimands on the hazard scale, such as ratios of cause specific or subdistribution hazards, are fundamentally hard to be interpret causally. Estimands on the risk scale, such as contrasts of cumulative incidence functions, do have a causal interpretation, but they only capture the total effect of the treatment on the event of interest; that is, effects both th…
In various fields of data science, researchers are often interested in estimating the ratio of conditional expectation functions (CEFR). Specifically in causal inference problems, it is sometimes natural to consider ratio-based treatment effects, such as odds ratios and hazard ratios, and even difference-based treatment effects are identified as CEFR in some empirically relevant settings. This chapter develops the general framework for estimation and inference on CEFR, which allows the use of flexible machine learning for infinite-dimensional nuisance parameters. In the first stage of the fram…
Oslo University Hospital（奥斯陆大学医院）；University of Oslo（奥斯陆大学）；Leiden University Medical Center（莱顿大学医学中心）；Leiden University（莱顿大学）；Erasmus Medical Center, University Medical Center Rotterdam（伊拉斯姆斯医学中心，鹿特丹大学医学中心）
This proposal is motivated by an analysis of the English Longitudinal Study of Ageing (ELSA), which aims to investigate the role of loneliness in explaining the negative impact of hearing loss on dementia. The methodological challenges that complicate this mediation analysis include the use of a time-to-event endpoint subject to competing risks, as well as the presence of feedback relationships between the mediator and confounders that are both repeatedly measured over time. To account for these challenges, we introduce natural effect proportional (cause-specific) hazard models. These extend m…
