arXiv subjects

Eric J. Tchetgen Tchetgen

Publications and source records attributed to Eric J. Tchetgen Tchetgen.

At least 37 records · Page 2Linked to original sources

arXiv2025

Using negative controls to identify causal effects with invalid instrumental variables

Many proposals for the identification of causal effects require an instrumental variable that satisfies strong, untestable unconfoundedness and exclusion restriction assumptions. In this paper, we show how one can potentially identify causal effects under violations of these assumptions by harnessing a negative control population or outcome. This strategy allows one to leverage sub-populations for whom the exposure is degenerate, and requires that the instrument-outcome association satisfies a certain parallel trend condition. We develop the semiparametric efficiency theory for a general instrumental variable model, and obtain a multiply robust, locally efficient estimator of the average treatment effect in the treated. The utility of the estimators is demonstrated in simulation studies and an analysis of the Life Span Study.

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arXiv2024

Regression-Based Proximal Causal Inference

Negative controls are increasingly used to evaluate the presence of potential unmeasured confounding in observational studies. Beyond the use of negative controls to detect the presence of residual confounding, proximal causal inference (PCI) was recently proposed to de-bias confounded causal effect estimates, by leveraging a pair of treatment and outcome negative control or confounding proxy variables. While formal methods for statistical inference have been developed for PCI, these methods can be challenging to implement as they involve solving complex integral equations that are typically ill-posed. We develop a regression-based PCI approach, employing two-stage generalized linear regression models (GLMs) to implement PCI, which obviates the need to solve difficult integral equations. The proposed approach has merit in that (i) it is applicable to continuous, count, and binary outcomes cases, making it relevant to a wide range of real-world applications, and (ii) it is easy to implement using off-the-shelf software for GLMs. We establish the statistical properties of regression-based PCI and illustrate their performance in both synthetic and real-world empirical applications.

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arXiv2024

Using Instruments for Selection to Adjust for Selection Bias in Mendelian Randomization

Selection bias is a common concern in epidemiologic studies. In the literature, selection bias is often viewed as a missing data problem. Popular approaches to adjust for bias due to missing data, such as inverse probability weighting, rely on the assumption that data are missing at random and can yield biased results if this assumption is violated. In observational studies with outcome data missing not at random, Heckman's sample selection model can be used to adjust for bias due to missing data. In this paper, we review Heckman's method and a similar approach proposed by Tchetgen Tchetgen and Wirth (2017). We then discuss how to apply these methods to Mendelian randomization analyses using individual-level data, with missing data for either the exposure or outcome or both. We explore whether genetic variants associated with participation can be used as instruments for selection. We then describe how to obtain missingness-adjusted Wald ratio, two-stage least squares and inverse variance weighted estimates. The two methods are evaluated and compared in simulations, with results suggesting that they can both mitigate selection bias but may yield parameter estimates with large standard errors in some settings. In an illustrative real-data application, we investigate the effects of body mass index on smoking using data from the Avon Longitudinal Study of Parents and Children.

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arXiv2023

Proximal mediation analysis

A common concern when trying to draw causal inferences from observational data is that the measured covariates are insufficiently rich to account for all sources of confounding. In practice, many of the covariates may only be proxies of the latent confounding mechanism. Recent work has shown that in certain settings where the standard 'no unmeasured confounding' assumption fails, proxy variables can be leveraged to identify causal effects. Results currently exist for the total causal effect of an intervention, but little consideration has been given to learning about the direct or indirect pathways of the effect through a mediator variable. In this work, we describe three separate proximal identification results for natural direct and indirect effects in the presence of unmeasured confounding. We then develop a semiparametric framework for inference on natural (in)direct effects, which leads us to locally efficient, multiply robust estimators.

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arXiv2023

Proximal Causal Inference for Synthetic Control with Surrogates

The synthetic control method (SCM) has become a popular tool for estimating causal effects in policy evaluation, where a single treated unit is observed, and a heterogeneous set of untreated units with pre- and post-policy change data are also observed. However, the synthetic control method faces challenges in accurately predicting post-intervention potential outcome had, contrary to fact, the treatment been withheld, when the pre-intervention period is short or the post-intervention period is long. To address these issues, we propose a novel method that leverages post-intervention information, specifically time-varying correlates of the causal effect called "surrogates", within the synthetic control framework. We establish conditions for identifying model parameters using the proximal inference framework and apply the generalized method of moments (GMM) approach for estimation and inference about the average treatment effect on the treated (ATT). Interestingly, we uncover specific conditions under which exclusively using post-intervention data suffices for estimation within our framework. Moreover, we explore several extensions, including covariates adjustment, relaxing linearity assumptions through non-parametric identification, and incorporating so-called "contaminated" surrogates, which do not exactly satisfy conditions to be valid surrogates but nevertheless can be incorporated via a simple modification of the proposed approach. Through a simulation study, we demonstrate that our method can outperform other synthetic control methods in estimating both short-term and long-term effects, yielding more accurate inferences. In an empirical application examining the Panic of 1907, one of the worst financial crises in U.S. history, we confirm the practical relevance of our theoretical results.

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arXiv2023

The Proximal ID Algorithm

Unobserved confounding is a fundamental obstacle to establishing valid causal conclusions from observational data. Two complementary types of approaches have been developed to address this obstacle: obtaining identification using fortuitous external aids, such as instrumental variables or proxies, or by means of the ID algorithm, using Markov restrictions on the full data distribution encoded in graphical causal models. In this paper we aim to develop a synthesis of the former and latter approaches to identification in causal inference to yield the most general identification algorithm in multivariate systems currently known -- the proximal ID algorithm. In addition to being able to obtain nonparametric identification in all cases where the ID algorithm succeeds, our approach allows us to systematically exploit proxies to adjust for the presence of unobserved confounders that would have otherwise prevented identification. In addition, we outline a class of estimation strategies for causal parameters identified by our method in an important special case. We illustrate our approach by simulation studies and a data application.

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arXiv2022

A self-censoring model for multivariate nonignorable nonmonotone missing data

We introduce a self-censoring model for multivariate nonignorable nonmonotone missing data, where the missingness process of each outcome is affected by its own value and is associated with missingness indicators of other outcomes, while conditionally independent of the other outcomes. The self-censoring model complements previous graphical approaches for the analysis of multivariate nonignorable missing data. It is identified under a completeness condition stating that any variability in one outcome can be captured by variability in the other outcomes among complete cases. For estimation, we propose a suite of semiparametric estimators including doubly robust estimators that deliver valid inferences under partial misspecification of the full-data distribution. We evaluate the performance of the proposed estimators with simulations and apply them to analyze a study about the effect of highly active antiretroviral therapy on preterm delivery of HIV-positive mothers.

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arXiv2022

Proximal Causal Inference for Complex Longitudinal Studies

A standard assumption for causal inference about the joint effects of time-varying treatment is that one has measured sufficient covariates to ensure that within covariate strata, subjects are exchangeable across observed treatment values, also known as "sequential randomization assumption (SRA)". SRA is often criticized as it requires one to accurately measure all confounders. Realistically, measured covariates can rarely capture all confounders with certainty. Often covariate measurements are at best proxies of confounders, thus invalidating inferences under SRA. In this paper, we extend the proximal causal inference (PCI) framework of Miao et al. (2018) to the longitudinal setting under a semiparametric marginal structural mean model (MSMM). PCI offers an opportunity to learn about joint causal effects in settings where SRA based on measured time-varying covariates fails, by formally accounting for the covariate measurements as imperfect proxies of underlying confounding mechanisms. We establish nonparametric identification with a pair of time-varying proxies and provide a corresponding characterization of regular and asymptotically linear estimators of the parameter indexing the MSMM, including a rich class of doubly robust estimators, and establish the corresponding semiparametric efficiency bound for the MSMM. Extensive simulation studies and a data application illustrate the finite sample behavior of proposed methods.

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arXiv2022

A Semiparametric Approach to Model-based Sensitivity Analysis in Observational Studies

When drawing causal inference from observational data, there is always concern about unmeasured confounding. One way to tackle this is to conduct a sensitivity analysis. One widely-used sensitivity analysis framework hypothesizes the existence of a scalar unmeasured confounder U and asks how the causal conclusion would change were U measured and included in the primary analysis. Works along this line often make various parametric assumptions on U, for the sake of mathematical and computational simplicity. In this article, we further this line of research by developing a valid sensitivity analysis that leaves the distribution of U unrestricted. Our semiparametric estimator has three desirable features compared to many existing methods in the literature. First, our method allows for a larger and more flexible family of models, and mitigates observable implications (Franks et al., 2019). Second, our methods work seamlessly with any primary analysis that models the outcome regression parametrically. Third, our method is easy to use and interpret. We construct both pointwise confidence intervals and confidence bands that are uniformly valid over a given sensitivity parameter space, thus formally accounting for unknown sensitivity parameters. We apply our proposed method on an influential yet controversial study of the causal relationship between war experiences and political activeness using observational data from Uganda.

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arXiv2022

Proximal Causal Inference for Marginal Counterfactual Survival Curves

Contrasting marginal counterfactual survival curves across treatment arms is an effective and popular approach for inferring the causal effect of an intervention on a right-censored time-to-event outcome. A key challenge to drawing such inferences in observational settings is the possible existence of unmeasured confounding, which may invalidate most commonly used methods that assume no hidden confounding bias. In this paper, rather than making the standard no unmeasured confounding assumption, we extend the recently proposed proximal causal inference framework of Miao et al. (2018), Tchetgen et al. (2020), Cui et al. (2020) to obtain nonparametric identification of a causal survival contrast by leveraging observed covariates as imperfect proxies of unmeasured confounders. Specifically, we develop a proximal inverse probability-weighted (PIPW) estimator, the proximal analog of standard IPW, which allows the observed data distribution for the time-to-event outcome to remain completely unrestricted. PIPW estimation relies on a parametric model for a so-called treatment confounding bridge function relating the treatment process to confounding proxies. As a result, PIPW might be sensitive to model misspecification. To improve robustness and efficiency, we also propose a proximal doubly robust estimator and establish uniform consistency and asymptotic normality of both estimators. We conduct extensive simulations to examine the finite sample performance of our estimators, and proposed methods are applied to a study evaluating the effectiveness of right heart catheterization in the intensive care unit of critically ill patients.

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arXiv2021

Identification and Estimation of Causal Peer Effects Using Double Negative Controls for Unmeasured Network Confounding

Scientists have been interested in estimating causal peer effects to understand how people's behaviors are affected by their network peers. However, it is well known that identification and estimation of causal peer effects are challenging in observational studies for two reasons. The first is the identification challenge due to unmeasured network confounding, for example, homophily bias and contextual confounding. The second issue is network dependence of observations, which one must take into account for valid statistical inference. Negative control variables, also known as placebo variables, have been widely used in observational studies including peer effect analysis over networks, although they have been used primarily for bias detection. In this article, we establish a formal framework which leverages a pair of negative control outcome and exposure variables (double negative controls) to nonparametrically identify causal peer effects in the presence of unmeasured network confounding. We then propose a generalized method of moments estimator for causal peer effects, and establish its consistency and asymptotic normality under an assumption about $ψ$-network dependence. Finally, we provide a network heteroskedasticity and autocorrelation consistent variance estimator. Our methods are illustrated with an application to peer effects in education.

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arXiv2021

Conditional separable effects

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.

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arXiv2021

A New Causal Approach to Account for Treatment Switching in Randomized Experiments under a Structural Cumulative Survival Model

Treatment switching in a randomized controlled trial is said to occur when a patient randomized to one treatment arm switches to another treatment arm during follow-up. This can occur at the point of disease progression, whereby patients in the control arm may be offered the experimental treatment. It is widely known that failure to account for treatment switching can seriously dilute the estimated effect of treatment on overall survival. In this paper, we aim to account for the potential impact of treatment switching in a re-analysis evaluating the treatment effect of NucleosideReverse Transcriptase Inhibitors (NRTIs) on a safety outcome (time to first severe or worse sign or symptom) in participants receiving a new antiretroviral regimen that either included or omitted NRTIs in the Optimized Treatment That Includes or OmitsNRTIs (OPTIONS) trial. We propose an estimator of a treatment causal effect under a structural cumulative survival model (SCSM) that leverages randomization as an instrumental variable to account for selective treatment switching. Unlike Robins' accelerated failure time model often used to address treatment switching, the proposed approach avoids the need for artificial censoring for estimation. We establish that the proposed estimator is uniformly consistent and asymptotically Gaussian under standard regularity conditions. A consistent variance estimator is also given and a simple resampling approach provides uniform confidence bands for the causal difference comparing treatment groups overtime on the cumulative intensity scale. We develop an R package named "ivsacim" implementing all proposed methods, freely available to download from R CRAN. We examine the finite performance of the estimator via extensive simulations.

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arXiv2020

A coherent likelihood parametrization for doubly robust estimation of a causal effect with missing confounders

Missing data and confounding are two problems researchers face in observational studies for comparative effectiveness. Williamson et al. (2012) recently proposed a unified approach to handle both issues concurrently using a multiply-robust (MR) methodology under the assumption that confounders are missing at random. Their approach considers a union of models in which any submodel has a parametric component while the remaining models are unrestricted. We show that while their estimating function is MR in theory, the possibility for multiply robust inference is complicated by the fact that parametric models for different components of the union model are not variation independent and therefore the MR property is unlikely to hold in practice. To address this, we propose an alternative transparent parametrization of the likelihood function, which makes explicit the model dependencies between various nuisance functions needed to evaluate the MR efficient score. The proposed method is genuinely doubly-robust (DR) in that it is consistent and asymptotic normal if one of two sets of modeling assumptions holds. We evaluate the performance and doubly robust property of the DR method via a simulation study.

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arXiv2020

Generalized interpretation and identification of separable effects in competing event settings

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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arXiv2020

Counterexamples to "The Blessings of Multiple Causes" by Wang and Blei

This note has been updated (April, 2020) to respond to "Towards Clarifying the Theory of the Deconfounder" by Yixin Wang, David M. Blei (arXiv:2003.04948). This original note, posted in January, 2020, is meant to complement our previous comment on "The Blessings of Multiple Causes" by Wang and Blei (2019). We provide a more succinct and transparent explanation of the fact that the deconfounder does not control for multi-cause confounding. The argument given in Wang and Blei (2019) makes two mistakes: (1) attempting to infer independence conditional on one variable from independence conditional on a different, unrelated variable, and (2) attempting to infer joint independence from pairwise independence. We give two simple counterexamples to the deconfounder claim.

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arXiv2020

Quantifying and Detecting Individual Level `Always Survivor' Causal Effects Under `Truncation by Death' and Censoring Through Time

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 patients with prostate cancer. Our methodology is the first and, as of yet, only proposed procedure that enables detecting causal effects in the presence of truncation by death using only the assumptions that are guaranteed by design of the clinical trial. This methodology is applicable to all types of outcomes.

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arXiv2019

A causal framework for classical statistical estimands in failure time settings with competing events

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 a formal framework for characterizing causal effects and their identifying conditions, which makes it difficult to interpret effect estimates and assess recommendations regarding analytic choices. Here we use a counterfactual framework to explicitly define each of these classical estimands. We clarify that, depending on whether competing events are defined as censoring events, contrasts of risks can define a total effect of the treatment on the event of interest, or a direct effect of the treatment on the event of interest not mediated through the competing event. In contrast, regardless of whether competing events are defined as censoring events, counterfactual hazard contrasts cannot generally be interpreted as causal effects. We illustrate how identifying assumptions for all of these counterfactual estimands can be represented in causal diagrams in which competing events are depicted as time-varying covariates. We present an application of these ideas to data from a randomized trial designed to estimate the effect of estrogen therapy on prostate cancer mortality.

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