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Register a new userGeneralized interpretation and identification of separable effects in competing event settings
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Mats Julius Stensrud
Publication date
2020
fields
Mathematical Statistics
and research's language is
English
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In competing event settings, a counterfactual contrast of cause-specific cumulative incidences quantifies the total causal effect of a treatment on the event of interest. However, effects of treatment on the competing event may indirectly contribute to this total effect, complicating its interpretation. We previously proposed the separable effects (Stensrud et al, 2019) to define direct and indirect effects of the treatment on the event of interest. This definition presupposes a treatment decomposition into two components acting along two separate causal pathways, one exclusively outside of the competing event and the other exclusively through it. Unlike previous definitions of direct and indirect effects, the separable effects can be subject to empirical scrutiny in a study where separate interventions on the treatment components are available. Here we extend and generalize the notion of the separable effects in several ways, allowing for interpretation, identification and estimation under considerably weaker assumptions. We propose and discuss a definition of separable effects that is applicable to general time-varying structures, where the separable effects can still be meaningfully interpreted, even when they cannot be regarded as direct and indirect effects. We further derive weaker conditions for identification of separable effects in observational studies where decomposed treatments are not yet available; in particular, these conditions allow for time-varying common causes of the event of interest, the competing events and loss to follow-up. For these general settings, we propose semi-parametric weighted estimators that are straightforward to implement. As an illustration, we apply the estimators to study the separable effects of intensive blood pressure therapy on acute kidney injury, using data from a randomized clinical trial.
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Researchers are often interested in treatment effects on outcomes that are only defined conditional on a post-treatment event status. For example, in a study of the effect of different cancer treatments on quality of life at end of follow-up, the quality of life of individuals who die during the study is undefined. In these settings, a naive contrast of outcomes conditional on the post-treatment variable is not an average causal effect, even in a randomized experiment. Therefore the effect in the principal stratum of those who would have the same value of the post-treatment variable regardless of treatment, such as the always survivors in a truncation by death setting, is often advocated for causal inference. While this principal stratum effect is a well defined causal contrast, it is often hard to justify that it is relevant to scientists, patients or policy makers, and it cannot be identified without relying on unfalsifiable assumptions. Here we formulate alternative estimands, the conditional separable effects, that have a natural causal interpretation under assumptions that can be falsified in a randomized experiment. We provide identification results and introduce different estimators, including a doubly robust estimator derived from the nonparametric influence function. As an illustration, we estimate a conditional separable effect of chemotherapies on quality of life in patients with prostate cancer, using data from a randomized clinical trial.
Objective Bayesian inference procedures are derived for the parameters of the multivariate random effects model generalized to elliptically contoured distributions. The posterior for the overall mean vector and the between-study covariance matrix is deduced by assigning two noninformative priors to the model parameter, namely the Berger and Bernardo reference prior and the Jeffreys prior, whose analytical expressions are obtained under weak distributional assumptions. It is shown that the only condition needed for the posterior to be proper is that the sample size is larger than the dimension of the data-generating model, independently of the class of elliptically contoured distributions used in the definition of the generalized multivariate random effects model. The theoretical findings of the paper are applied to real data consisting of ten studies about the effectiveness of hypertension treatment for reducing blood pressure where the treatment effects on both the systolic blood pressure and diastolic blood pressure are investigated.
In time-to-event settings, the presence of competing events complicates the definition of causal effects. Here we propose the new separable effects to study the causal effect of a treatment on an event of interest. The separable direct effect is the treatment effect on the event of interest not mediated by its effect on the competing event. The separable indirect effect is the treatment effect on the event of interest only through its effect on the competing event. Similar to Robins and Richardsons extended graphical approach for mediation analysis, the separable effects can only be identified under the assumption that the treatment can be decomposed into two distinct components that exert their effects through distinct causal pathways. Unlike existing definitions of causal effects in the presence of competing events, our estimands do not require cross-world contrasts or hypothetical interventions to prevent death. As an illustration, we apply our approach to a randomized clinical trial on estrogen therapy in individuals with prostate cancer.
Causal effect sizes may vary among individuals and they can even be of opposite directions. When there exists serious effect heterogeneity, the population average causal effect (ACE) is not very informative. It is well-known that individual causal effects (ICEs) cannot be determined in cross-sectional studies, but we will show that ICEs can be retrieved from longitudinal data under certain conditions. We will present a general framework for individual causality where we will view effect heterogeneity as an individual-specific effect modification that can be parameterized with a latent variable, the receptiveness factor. The distribution of the receptiveness factor can be retrieved, and it will enable us to study the contrast of the potential outcomes of an individual under stationarity assumptions. Within the framework, we will study the joint distribution of the individuals potential outcomes conditioned on all individuals factual data and subsequently the distribution of the cross-world causal effect (CWCE). We discuss conditions such that the latter converges to a degenerated distribution, in which case the ICE can be estimated consistently. To demonstrate the use of this general framework, we present examples in which the outcome process can be parameterized as a (generalized) linear mixed model.
Univariate Weibull distribution is a well-known lifetime distribution and has been widely used in reliability and survival analysis. In this paper, we introduce a new family of bivariate generalized Weibull (BGW) distributions, whose univariate marginals are exponentiated Weibull distribution. Different statistical quantiles like marginals, conditional distribution, conditional expectation, product moments, correlation and a measure component reliability are derived. Various measures of dependence and statistical properties along with ageing properties are examined. Further, the copula associated with BGW distribution and its various important properties are also considered. The methods of maximum likelihood and Bayesian estimation are employed to estimate unknown parameters of the model. A Monte Carlo simulation and real data study are carried out to demonstrate the performance of the estimators and results have proven the effectiveness of the distribution in real-life situations
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