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We consider a causal effect that is confounded by an unobserved variable, but for which observed proxy variables of the confounder are available. We show that with at least two independent proxy variables satisfying a certain rank condition, the causal effect can be nonparametrically identified, even if the measurement error mechanism, i.e., the conditional distribution of the proxies given the confounder, may not be identified. Our result generalizes the identification strategy of Kuroki & Pearl (2014), which rests on identification of the measurement error mechanism. When only one proxy for the confounder is available, or when the required rank condition is not met, we develop a strategy for testing the null hypothesis of no causal effect.

While estimation of the marginal (total) causal effect of a point exposure on an outcome is arguably the most common objective of experimental and observational studies in the health and social sciences, in recent years, investigators have also become increasingly interested in mediation analysis. Specifically, upon evaluating the total effect of the exposure, investigators routinely wish to make inferences about the direct or indirect pathways of the effect of the exposure, through a mediator variable or not, that occurs subsequently to the exposure and prior to the outcome. Although powerful semiparametric methodologies have been developed to analyze observational studies that produce double robust and highly efficient estimates of the marginal total causal effect, similar methods for mediation analysis are currently lacking. Thus, this paper develops a general semiparametric framework for obtaining inferences about so-called marginal natural direct and indirect causal effects, while appropriately accounting for a large number of pre-exposure confounding factors for the exposure and the mediator variables. Our analytic framework is particularly appealing, because it gives new insights on issues of efficiency and robustness in the context of mediation analysis. In particular, we propose new multiply robust locally efficient estimators of the marginal natural indirect and direct causal effects, and develop a novel double robust sensitivity analysis framework for the assumption of ignorability of the mediator variable.

Unmeasured confounding is a threat to causal inference in observational studies. In recent years, the use of negative controls to mitigate unmeasured confounding has gained increasing recognition and popularity. Negative controls have a long-standing tradition in laboratory sciences and epidemiology to rule out non-causal explanations, although they have been used primarily for bias detection. Recently, Miao and colleagues have described sufficient conditions under which a pair of negative control exposure and outcome variables can be used to identify non-parametrically the average treatment effect (ATE) from observational data subject to uncontrolled confounding. We establish non-parametric identification of the ATE under weaker conditions in the case of categorical unmeasured confounding and negative control variables.We also provide a general semiparametric framework for obtaining inferences about the ATE while leveraging information about a possibly large number of measured covariates. In particular, we derive the semiparametric efficiency bound in the non-parametric model, and we proposemultiply robust and locally efficient estimators when non-parametric estimation may not be feasible.We assess the finite sample performance of our methods in extensive simulation studies. Finally, we illustrate our methods with an application to the post-licensure surveillance of vaccine safety among children.

Interference is said to be present when the exposure or treatment received by one individual may affect the outcomes of other individuals. Such interference can arise in settings in which the outcomes of the various individuals come about through social interactions. When interference is present, causal inference is rendered considerably more complex, and the literature on causal inference in the presence of interference has just recently begun to develop. In this article we summarise some of the concepts and results from the existing literature and extend that literature in considering new results for finite sample inference, new inverse probability weighting estimators in the presence of interference and new causal estimands of interest.

Suppose we are interested in the mean of an outcome variable missing not at random. Suppose however that one has available a fully observed shadow variable, which is associated with the outcome but independent of the missingness process conditional on covariates and the possibly unobserved outcome. Such a variable may be a proxy or a mismeasured version of the outcome and is available for all individuals. We have previously established necessary and sufficient conditions for identification of the full data law in such a setting, and have described semiparametric estimators including a doubly robust estimator of the outcome mean. Here, we propose two alternative estimators, which may be viewed as extensions of analogous methods under missingness at random, but enjoy different properties. We assess the correctness of the required working models via straightforward goodness-of-fit tests.

We consider causal mediation analysis when exposures and mediators vary over time. We give non-parametric identification results, discuss parametric implementation and also provide a weighting approach to direct and indirect effects based on combining the results of two marginal structural models. We also discuss how our results give rise to a causal interpretation of the effect estimates produced from longitudinal structural equation models. When there are time varying confounders affected by prior exposure and a mediator, natural direct and indirect effects are not identified. However, we define a randomized interventional analogue of natural direct and indirect effects that are identified in this setting. The formula that identifies these effects we refer to as the 'mediational g-formula'. When there is no mediation, the mediational g-formula reduces to Robins's regular g-formula for longitudinal data. When there are no time varying confounders affected by prior exposure and mediator values, then the mediational g-formula reduces to a longitudinal version of Pearl's mediation formula. However, the mediational g-formula itself can accommodate both mediation and time varying confounders and constitutes a general approach to mediation analysis with time varying exposures and mediators.

Bias due to unobserved confounding can seldom be ruled out with certainty when estimating the causal effect of a nonrandomized treatment. The instrumental variable (IV) design offers, under certain assumptions, the opportunity to tame confounding bias, without directly observing all confounders. The IV approach is very well developed in the context of linear regression and also for certain generalized linear models with a nonlinear link function. However, IV methods are not as well developed for regression analysis with a censored survival outcome. In this article, we develop the IV approach for regression analysis in a survival context, primarily under an additive hazards model, for which we describe 2 simple methods for estimating causal effects. The first method is a straightforward 2-stage regression approach analogous to 2-stage least squares commonly used for IV analysis in linear regression. In this approach, the fitted value from a first-stage regression of the exposure on the IV is entered in place of the exposure in the second-stage hazard model to recover a valid estimate of the treatment effect of interest. The second method is a so-called control function approach, which entails adding to the additive hazards outcome model, the residual from a first-stage regression of the exposure on the IV. Formal conditions are given justifying each strategy, and the methods are illustrated in a novel application to a Mendelian randomization study to evaluate the effect of diabetes on mortality using data from the Health and Retirement Study. We also establish that analogous strategies can also be used under a proportional hazards model specification, provided the outcome is rare over the entire follow-up.

Instrumental variables are widely used for estimating causal effects in the presence of unmeasured confounding. Under the standard instrumental variable model, however, the average treatment effect is only partially identifiable. To address this, we propose novel assumptions that enable identification of the average treatment effect. Our identification assumptions are clearly separated from model assumptions that are needed for estimation, so researchers are not required to commit to a specific observed data model in establishing identification. We then construct multiple estimators that are consistent under three different observed data models, and multiply robust estimators that are consistent in the union of these observed data models. We pay special attention to the case of binary outcomes, for which we obtain bounded estimators of the average treatment effect that are guaranteed to lie between − 1 and 1. Our approaches are illustrated with simulations and a data analysis evaluating the causal effect of education on earnings.

Standard methods for inference about direct and indirect effects require stringent no-unmeasured-confounding assumptions which often fail to hold in practice, particularly in observational studies. The goal of the paper is to introduce a new form of indirect effect, the population intervention indirect effect, that can be non-parametrically identified in the presence of an unmeasured common cause of exposure and outcome. This new type of indirect effect captures the extent to which the effect of exposure is mediated by an intermediate variable under an intervention that holds the component of exposure directly influencing the outcome at its observed value. The population intervention indirect effect is in fact the indirect component of the population intervention effect, introduced by Hubbard and Van der Laan. Interestingly, our identification criterion generalizes Judea Pearl’s front door criterion as it does not require no direct effect of exposure not mediated by the intermediate variable. For inference, we develop both parametric and semiparametric methods, including a novel doubly robust semiparametric locally efficient estimator, that perform very well in simulation studies. Finally, the methods proposed are used to measure the effectiveness of monetary saving recommendations among women enrolled in a maternal health programme in Tanzania.

AbstractObjectiveTo evaluate trials of drugs that target amyloid to determine whether reductions in amyloid levels are likely to improve cognition.DesignInstrumental variable meta-analysis.Setting14 randomized controlled trials of drugs for the prevention or treatment of Alzheimer’s disease that targeted an amyloid mechanism, identified from ClinicalTrials.gov.PopulationAdults enrolled in randomized controlled trials of amyloid targeting drugs. Inclusion criteria for trials vary, but typically include adults aged 50 years or older with a diagnosis of mild cognitive impairment or Alzheimer’s disease, and amyloid positivity at baseline.Main outcome measuresAnalyses included trials for which information could be obtained on both change in brain amyloid levels measured with amyloid positron emission tomography and change in at least one cognitive test score reported for each randomization arm.ResultsPooled results from the 14 randomized controlled trials were more precise than estimates from any single trial. The pooled estimate for the effect of reducing amyloid levels by 0.1 standardized uptake value ratio units was an improvement in the mini-mental state examination score of 0.03 (95% confidence interval −0.06 to 0.1) points. This study provides a web application that allows for the re-estimation of the results when new data become available and illustrates the magnitude of the new evidence that would be necessary to achieve a pooled estimate supporting the benefit of reducing amyloid levels.ConclusionsPooled evidence from available trials reporting both reduction in amyloid levels and change in cognition suggests that amyloid reduction strategies do not substantially improve cognition.