Toward Variation-Independent Regression by Composition
Discussion on "Regression by Composition" by Farewell, Daniel, Stensrud, and Huitfeldt.
stat.OT↗
arXiv subjects
Oliver Dukes
Publications and source records attributed to Oliver Dukes.
A Parameter-Centric View on Regression
Discussion on ``Regression by Composition'' by Farewell, Daniel, Stensrud, and Huitfeldt
stat.OT↗
Order Dependence in Regression by Composition: Discussion on "Regression by Composition'' by Farewell, Daniel, Stensrud, and Huitfeldt
We discuss the regression-by-composition framework of Farewell, Daniel, Stensrud and Huitfeldt, highlighting a key consequence of its sequential construction: order dependence. Reordering the flows may change the implied conditional distribution, the interpretation of model parameters, and the associated estimation problem, with consequences for model specification, interpretation, and inference.
stat.ME↗
Efficient estimation of cumulative incidence curves via data fusion with surrogates: application to integrated analysis of vaccine trial and immunobridging data
Refined vaccine regimens containing variant-matched inserts are often authorized based on historical phase 3 efficacy trials together with immunobridging studies. Phase 3 trials are essential for establishing immune biomarkers that reliably predict disease risk or vaccine efficacy against clinical endpoints. Once such immune correlates are identified, updated vaccine regimens can be approved through immunobridging designs that compare the immunogenicity of the updated regimen to that of an already-approved vaccine. We develop methods of inference for the counterfactual cumulative incidence curve using participant-level data from both a historical vaccine efficacy trial and an immunobridging study. We further extend these methods to pathogens with multiple serotypes -- such as dengue virus and influenza -- by estimating cause-specific cumulative incidence curves. We describe the identification assumptions, propose efficient and multiply robust estimators, and assess their finite-sample performance through simulation studies. We then apply the proposed methods to (1) estimating the hypothetical cumulative incidence curve for a bivalent mRNA booster and (2) testing a key assumption of no controlled direct effects, using data from the COVID-19 Variant Immunologic Landscape (COVAIL) Trial, a multistage randomized clinical study evaluating the safety and immunogenicity of a second COVID-19 booster dose.
stat.ME↗
On estimands in target trial emulation
The target trial framework enables causal inference from longitudinal observational data by emulating randomized trials initiated at multiple time points. Precision is often improved by pooling information across trials, with standard models typically assuming - among other things - a time-constant treatment effect. However, this obscures interpretation when the true treatment effect varies, which we argue to be likely as a result of relying on noncollapsible estimands. To address these challenges, this paper introduces a model-free strategy for target trial analysis, centered around the choice of the estimand, rather than model specification. This ensures that treatment effects remain clearly interpretable for well-defined populations even under model misspecification. We propose estimands suitable for different study designs, and develop accompanying G-computation and inverse probability weighted estimators. Applications on simulations and real data on antimicrobial de-escalation in an intensive care unit setting demonstrate the greater clarity and reliability of the proposed methodology over traditional techniques.
stat.ME↗
Using causal diagrams to assess parallel trends in difference-in-differences studies
Difference-in-differences (DID) is popular because it can allow for unmeasured confounding when the key assumption of parallel trends holds. However, there exists little guidance on how to decide a priori whether this assumption is reasonable. We attempt to develop such guidance by considering the relationship between a causal diagram and the parallel trends assumption. This is challenging because parallel trends is scale-dependent and causal diagrams are generally scale-independent. We develop conditions under which, given a nonparametric causal diagram, one can reject or fail to reject parallel trends. In particular, we adopt a linear faithfulness assumption, which states that all graphically connected variables are correlated, and which is often reasonable in practice. We show that parallel trends can be rejected if either (i) the treatment is affected by pre-treatment outcomes, or (ii) there exist unmeasured confounders for the effect of treatment on pre-treatment outcomes that are not confounders for the post-treatment outcome, or vice versa (more precisely, the two outcomes possess distinct minimally sufficient sets). We also argue that parallel trends should be strongly questioned if (iii) the pre-treatment outcomes affect the post-treatment outcomes (though the two can be correlated) since there exist reasonable semiparametric models in which such an effect violates parallel trends. When (i-iii) are absent, a necessary and sufficient condition for parallel trends is that the association between the common set of confounders and the potential outcomes is constant on an additive scale, pre- and post-treatment. These conditions are similar to, but more general than, those previously derived in linear structural equations models. We discuss our approach in the context of the effect of Medicaid expansion under the U.S. Affordable Care Act on health insurance coverage rates.
stat.ME↗
Nonparametric tests of treatment effect homogeneity for policy-makers
Recent work has focused on nonparametric estimation of conditional treatment effects, but inference has remained relatively unexplored. We propose a class of nonparametric tests for both quantitative and qualitative treatment effect heterogeneity. The tests can incorporate a variety of structured assumptions on the conditional average treatment effect, allow for both continuous and discrete covariates, and do not require sample splitting to obtain a tractable asymptotic null distribution. Furthermore, we show how the tests are tailored to detect alternatives where the population impact of adopting a personalized decision rule differs from using a rule that discards covariates. The proposal is thus relevant for guiding treatment policies. The utility of the proposal is borne out in simulation studies and a re-analysis of an AIDS clinical trial.
stat.ME↗
Doubly-robust inference and optimality in structure-agnostic models with smoothness
We study the problem of constructing an estimator of the average treatment effect (ATE) with observational data. The celebrated doubly-robust, augmented-IPW (AIPW) estimator generally requires consistent estimation of both nuisance functions for standard root-n inference, and moreover that the product of the errors of the nuisances should shrink at a rate faster than $n^{-1/2}$. A recent strand of research has aimed to understand the extent to which the AIPW estimator can be improved upon (in a minimax sense). Under structural assumptions on the nuisance functions, the AIPW estimator is typically not minimax-optimal, and improvements can be made using higher-order influence functions (Robins et al, 2017). Conversely, without any assumptions on the nuisances beyond the mean-square-error rates at which they can be estimated, the rate achieved by the AIPW estimator is already optimal (Balakrishnan et al, 2023; Jin and Syrgkanis, 2024). We make three main contributions. First, we propose a new hybrid class of distributions that combine structural agnosticism regarding the nuisance function space with additional smoothness constraints. Second, we calculate minimax lower bounds for estimating the ATE in the new class, as well as in the pure structure-agnostic one. Third, we propose a new estimator of the ATE that enjoys doubly-robust asymptotic linearity; it can yield asymptotically valid Wald-type confidence intervals even when the propensity score or the outcome model is inconsistently estimated, or estimated at a slow rate. Under certain conditions, we show that its rate of convergence in the new class can be much faster than that achieved by the AIPW estimator and, in particular, matches the minimax lower bound rate, thereby establishing its optimality. Finally, we complement our theoretical findings with simulations.
stat.ME↗
Nested Instrumental Variables Analysis: Switcher Average Treatment Effect, Identification, Efficient Estimation and Generalizability
Instrumental variables (IVs) are widely used to estimate causal effects from non-randomized data. A canonical example is a randomized trial with noncompliance, in which the randomized treatment assignment serves as an IV for the non-ignorable treatment received. Under a monotonicity assumption, a valid IV nonparametrically identifies the average treatment effect among a latent complier subgroup, whose generalizability is often under debate. In many studies, there exist multiple versions of an IV, for instance, different nudges to take the same treatment in different study sites in a multicenter clinical trial. These different versions of an IV may result in different compliance rates and offer a unique opportunity to study IV estimates' generalizability. In this article, we introduce a novel nested IV assumption and study identification of the average treatment effect among two latent subgroups: always-compliers and switchers, who are defined based on the joint potential treatment received under two versions of a binary IV. We derive the efficient influence function for the SWitcher Average Treatment Effect (SWATE) under a nonparametric model and propose efficient estimators. We then propose formal statistical tests of the generalizability of IV estimates under the nested IV framework. The proposed tests are flexible nonparametric generalizations of classical overidentification tests that allow estimating nuisance parameters using machine learning tools. We apply the proposed method to the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and study the causal effect of colorectal cancer screening and its generalizability.
stat.ME↗
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.
stat.ME↗
The Use of Covariate Adjustment in Randomized Controlled Trials: An Overview
There has been a growing interest in covariate adjustment in the analysis of randomized controlled trials in past years. For instance, the U.S. Food and Drug Administration recently issued guidance that emphasizes the importance of distinguishing between conditional and marginal treatment effects. Although these effects coincide in linear models, this is not typically the case in other settings, and this distinction is often overlooked in clinical trial practice. Considering these developments, this paper provides a review of when and how to utilize covariate adjustment to enhance precision in randomized controlled trials. We describe the differences between conditional and marginal estimands and stress the necessity of aligning statistical analysis methods with the chosen estimand. Additionally, we highlight the potential misalignment of current practices in estimating marginal treatment effects. Instead, we advocate for the utilization of standardization, which can improve efficiency by leveraging the information contained in baseline covariates while remaining robust to model misspecification. Finally, we present practical considerations that have arisen in our respective consultations to further clarify the advantages and limitations of covariate adjustment.
stat.ME↗
Augmented balancing weights as linear regression
We provide a novel characterization of augmented balancing weights, also known as automatic debiased machine learning (AutoDML). These popular doubly robust or de-biased machine learning estimators combine outcome modeling with balancing weights - weights that achieve covariate balance directly in lieu of estimating and inverting the propensity score. When the outcome and weighting models are both linear in some (possibly infinite) basis, we show that the augmented estimator is equivalent to a single linear model with coefficients that combine the coefficients from the original outcome model and coefficients from an unpenalized ordinary least squares (OLS) fit on the same data. We see that, under certain choices of regularization parameters, the augmented estimator often collapses to the OLS estimator alone; this occurs for example in a re-analysis of the Lalonde 1986 dataset. We then extend these results to specific choices of outcome and weighting models. We first show that the augmented estimator that uses (kernel) ridge regression for both outcome and weighting models is equivalent to a single, undersmoothed (kernel) ridge regression. This holds numerically in finite samples and lays the groundwork for a novel analysis of undersmoothing and asymptotic rates of convergence. When the weighting model is instead lasso-penalized regression, we give closed-form expressions for special cases and demonstrate a ``double selection'' property. Our framework opens the black box on this increasingly popular class of estimators, bridges the gap between existing results on the semiparametric efficiency of undersmoothed and doubly robust estimators, and provides new insights into the performance of augmented balancing weights.
stat.ME↗
Generalizing the intention-to-treat effect of an active control against placebo from historical placebo-controlled trials to an active-controlled trial: A case study of the efficacy of daily oral TDF/FTC in the HPTN 084 study
In many clinical settings, an active-controlled trial design (e.g., a non-inferiority or superiority design) is often used to compare an experimental medicine to an active control (e.g., an FDA-approved, standard therapy). One prominent example is a recent phase 3 efficacy trial, HIV Prevention Trials Network Study 084 (HPTN 084), comparing long-acting cabotegravir, a new HIV pre-exposure prophylaxis (PrEP) agent, to the FDA-approved daily oral tenofovir disoproxil fumarate plus emtricitabine (TDF/FTC) in a population of heterosexual women in 7 African countries. One key complication of interpreting study results in an active-controlled trial like HPTN 084 is that the placebo arm is not present and the efficacy of the active control (and hence the experimental drug) compared to the placebo can only be inferred by leveraging other data sources. \bz{In this article, we study statistical inference for the intention-to-treat (ITT) effect of the active control using relevant historical placebo-controlled trials data under the potential outcomes (PO) framework}. We highlight the role of adherence and unmeasured confounding, discuss in detail identification assumptions and two modes of inference (point versus partial identification), propose estimators under identification assumptions permitting point identification, and lay out sensitivity analyses needed to relax identification assumptions. We applied our framework to estimating the intention-to-treat effect of daily oral TDF/FTC versus placebo in HPTN 084 using data from an earlier Phase 3, placebo-controlled trial of daily oral TDF/FTC (Partners PrEP).
stat.ME↗
Reconciling model-X and doubly robust approaches to conditional independence testing
Model-X approaches to testing conditional independence between a predictor and an outcome variable given a vector of covariates usually assume exact knowledge of the conditional distribution of the predictor given the covariates. Nevertheless, model-X methodologies are often deployed with this conditional distribution learned in sample. We investigate the consequences of this choice through the lens of the distilled conditional randomization test (dCRT). We find that Type-I error control is still possible, but only if the mean of the outcome variable given the covariates is estimated well enough. This demonstrates that the dCRT is doubly robust, and motivates a comparison to the generalized covariance measure (GCM) test, another doubly robust conditional independence test. We prove that these two tests are asymptotically equivalent, and show that the GCM test is optimal against (generalized) partially linear alternatives by leveraging semiparametric efficiency theory. In an extensive simulation study, we compare the dCRT to the GCM test. These two tests have broadly similar Type-I error and power, though dCRT can have somewhat better Type-I error control but somewhat worse power in small samples or when the response is discrete. We also find that post-lasso based test statistics (as compared to lasso based statistics) can dramatically improve Type-I error control for both methods.
stat.ME↗
Alternative approaches for analysing repeated measures data that are missing not at random
We consider studies where multiple measures on an outcome variable are collected over time, but some subjects drop out before the end of follow up. Analyses of such data often proceed under either a 'last observation carried forward' or 'missing at random' assumption. We consider two alternative strategies for identification; the first is closely related to the difference-in-differences methodology in the causal inference literature. The second enables correction for violations of the parallel trend assumption, so long as one has access to a valid 'bespoke instrumental variable'. These are compared with existing approaches, first conceptually and then in an analysis of data from the Framingham Heart Study.
stat.ME↗
Structural Nested Mean Models Under Parallel Trends Assumptions
We link and extend two approaches to estimating time-varying treatment effects on repeated continuous outcomes--time-varying Difference in Differences (DiD; see Roth et al. (2023) and Chaisemartin et al. (2023) for reviews) and Structural Nested Mean Models (SNMMs; see Vansteelandt and Joffe (2014) for a review). In particular, we show that SNMMs, previously known to be nonparametrically identified under a no unobserved confounding assumption, are also identified under a conditional parallel trends assumption similar to those typically used to justify time-varying DiD methods (but more amenable to time-varying confounding). Because SNMMs model a broader set of causal estimands, our results allow practitioners of time-varying DiD approaches to address additional types of substantive questions under similar assumptions. SNMMs enable estimation of time-varying effect heterogeneity, lasting effects of a `blip' of treatment at a single time point, effects of sustained interventions (possibly on continuous or multi-dimensional treatments) when treatment repeatedly changes value in the data, controlled direct effects, effects of dynamic treatment strategies that depend on covariate history, and more. We provide a method for sensitivity analysis to violations of our parallel trends assumption. We further explain how to estimate optimal treatment regimes via optimal regime SNMMs under parallel trends assumptions plus an assumption that there is no effect modification by unobserved confounders. Finally, we illustrate our methods with real data applications estimating effects of Medicaid expansion on uninsurance rates, effects of floods on flood insurance take-up, and effects of sustained changes in temperature on crop yields.
stat.ME↗
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.
stat.ME↗
Demystifying statistical learning based on efficient influence functions
Evaluation of treatment effects and more general estimands is typically achieved via parametric modelling, which is unsatisfactory since model misspecification is likely. Data-adaptive model building (e.g. statistical/machine learning) is commonly employed to reduce the risk of misspecification. Naive use of such methods, however, delivers estimators whose bias may shrink too slowly with sample size for inferential methods to perform well, including those based on the bootstrap. Bias arises because standard data-adaptive methods are tuned towards minimal prediction error as opposed to e.g. minimal MSE in the estimator. This may cause excess variability that is difficult to acknowledge, due to the complexity of such strategies. Building on results from non-parametric statistics, targeted learning and debiased machine learning overcome these problems by constructing estimators using the estimand's efficient influence function under the non-parametric model. These increasingly popular methodologies typically assume that the efficient influence function is given, or that the reader is familiar with its derivation. In this paper, we focus on derivation of the efficient influence function and explain how it may be used to construct statistical/machine-learning-based estimators. We discuss the requisite conditions for these estimators to perform well and use diverse examples to convey the broad applicability of the theory.
math.ST↗