When analyzing data from randomized clinical trials, covariate adjustment can be used to account for chance imbalance in baseline covariates and to increase precision of the treatment effect estimate. A practical barrier to covariate adjustment is the presence of missing data. In this paper, in the light of recent theoretical advancement, we first review several covariate adjustment methods with incomplete covariate data. We investigate the implications of the missing data mechanism on estimating the average treatment effect in randomized clinical trials with continuous or binary outcomes. In parallel, we consider settings where the outcome data are fully observed or are missing at random; in the latter setting, we propose a full weighting approach that combines inverse probability weighting for adjusting missing outcomes and overlap weighting for covariate adjustment. We highlight the importance of including the interaction terms between the missingness indicators and covariates as predictors in the models. We conduct comprehensive simulation studies to examine the finite-sample performance of the proposed methods and compare with a range of common alternatives. We find that conducting the proposed adjustment methods generally improves the precision of treatment effect estimates regardless of the imputation methods when the adjusted covariate is associated with the outcome. We apply the methods to the Childhood Adenotonsillectomy Trial to assess the effect of adenotonsillectomy on neurocognitive functioning scores.
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Visual Question Answering (VQA) models aim to answer natural language questions about given images. Due to its ability to ask questions that differ from those used when training the model, medical VQA has received substantial attention in recent years. However, existing medical VQA models typically focus on answering questions that refer to an entire image rather than where the relevant content may be located in the image. Consequently, VQA models are limited in their interpretability power and the possibility to probe the model about specific image regions. This paper proposes a novel approach for medical VQA that addresses this limitation by developing a model that can answer questions about image regions while considering the context necessary to answer the questions. Our experimental results demonstrate the effectiveness of our proposed model, outperforming existing methods on three datasets. Our code and data are available at //github.com/sergiotasconmorales/locvqa.
Prior probabilities of clinical hypotheses are not systematically used for clinical trial design yet, due to a concern that poor priors may lead to poor decisions. To address this concern, a conservative approach to Bayesian trial design is illustrated here, requiring that the operational characteristics of the primary trial outcome are stronger than the prior. This approach is complementary to current Bayesian design methods, in that it insures against prior-data conflict by defining a sample size commensurate to a fixed design prior. This approach is ethical, in that it requires designs appropriate to achieving pre-specified levels of clinical equipoise imbalance. Practical examples are discussed, illustrating design of trials with binary or time to event endpoints. Moderate increases in phase II study sample size are shown to deliver strong levels of overall evidence for go/no-go clinical development decisions. Levels of negative evidence provided by group sequential confirmatory designs are found negligible, highlighting the importance of complementing efficacy boundaries with non-binding futility criteria.
Proxy causal learning (PCL) is a method for estimating the causal effect of treatments on outcomes in the presence of unobserved confounding, using proxies (structured side information) for the confounder. This is achieved via two-stage regression: in the first stage, we model relations among the treatment and proxies; in the second stage, we use this model to learn the effect of treatment on the outcome, given the context provided by the proxies. PCL guarantees recovery of the true causal effect, subject to identifiability conditions. We propose a novel method for PCL, the deep feature proxy variable method (DFPV), to address the case where the proxies, treatments, and outcomes are high-dimensional and have nonlinear complex relationships, as represented by deep neural network features. We show that DFPV outperforms recent state-of-the-art PCL methods on challenging synthetic benchmarks, including settings involving high dimensional image data. Furthermore, we show that PCL can be applied to off-policy evaluation for the confounded bandit problem, in which DFPV also exhibits competitive performance.
Multiple systems estimation is a standard approach to quantifying hidden populations where data sources are based on lists of known cases. A typical modelling approach is to fit a Poisson loglinear model to the numbers of cases observed in each possible combination of the lists. It is necessary to decide which interaction parameters to include in the model, and information criterion approaches are often used for model selection. Difficulties in the context of multiple systems estimation may arise due to sparse or nil counts based on the intersection of lists, and care must be taken when information criterion approaches are used for model selection due to issues relating to the existence of estimates and identifiability of the model. Confidence intervals are often reported conditional on the model selected, providing an over-optimistic impression of the accuracy of the estimation. A bootstrap approach is a natural way to account for the model selection procedure. However, because the model selection step has to be carried out for every bootstrap replication, there may be a high or even prohibitive computational burden. We explore the merit of modifying the model selection procedure in the bootstrap to look only among a subset of models, chosen on the basis of their information criterion score on the original data. This provides large computational gains with little apparent effect on inference. Another model selection approach considered and investigated is a downhill search approach among models, possibly with multiple starting points.
In covariance matrix estimation, one of the challenges lies in finding a suitable model and an efficient estimation method. Two commonly used modelling approaches in the literature involve imposing linear restrictions on the covariance matrix or its inverse. Another approach considers linear restrictions on the matrix logarithm of the covariance matrix. In this paper, we present a general framework for linear restrictions on different transformations of the covariance matrix, including the mentioned examples. Our proposed estimation method solves a convex problem and yields an M-estimator, allowing for relatively straightforward asymptotic and finite sample analysis. After developing the general theory, we focus on modelling correlation matrices and on sparsity. Our geometric insights allow to extend various recent results in covariance matrix modelling. This includes providing unrestricted parametrizations of the space of correlation matrices, which is alternative to a recent result utilizing the matrix logarithm.
In health and social sciences, it is critically important to identify subgroups of the study population where there is notable heterogeneity of treatment effects (HTE) with respect to the population average. Decision trees have been proposed and commonly adopted for data-driven discovery of HTE due to their high level of interpretability. However, single-tree discovery of HTE can be unstable and oversimplified. This paper introduces Causal Rule Ensemble (CRE), a new method for HTE discovery and estimation through an ensemble-of-trees approach. CRE offers several key features, including 1) an interpretable representation of the HTE; 2) the ability to explore complex heterogeneity patterns; and 3) high stability in subgroups discovery. The discovered subgroups are defined in terms of interpretable decision rules. Estimation of subgroup-specific causal effects is performed via a two-stage approach for which we provide theoretical guarantees. Via simulations, we show that the CRE method is highly competitive when compared to state-of-the-art techniques. Finally, we apply CRE to discover the heterogeneous health effects of exposure to air pollution on mortality for 35.3 million Medicare beneficiaries across the contiguous U.S.
Linear models are commonly used in causal inference for the analysis of experimental data. This is motivated by the ability to adjust for confounding variables and to obtain treatment effect estimators of increased precision through variance reduction. There is, however, a replicability crisis in applied research through unknown reporting of the data collection process. In modern A/B tests, there is a demand to perform regression-adjusted inference on experimental data in real-time. Linear models are a viable solution because they can be computed online over streams of data. Together, these motivate modernizing linear model theory by providing ``Anytime-Valid'' inference. These replace classical fixed-n Type I error and coverage guarantees with time-uniform guarantees, safeguarding applied researchers from p-hacking, allowing experiments to be continuously monitored and stopped using data-dependent rules. Our contributions leverage group invariance principles and modern martingale techniques. We provide sequential $t$-tests and confidence sequences for regression coefficients of a linear model, in addition to sequential $F$-tests and confidence sequences for collections of regression coefficients. With an emphasis on experimental data, we are able to relax the linear model assumption in randomized designs. In particular, we provide completely nonparametric confidence sequences for the average treatment effect in randomized experiments, without assuming linearity or Gaussianity. A particular feature of our contributions is their simplicity. Our test statistics and confidence sequences have closed-form expressions of the original classical statistics, meaning they are no harder to use in practice. This means that published results can be revisited and reevaluated, and software libraries which implement linear regression can be easily wrapped.
Randomized controlled trials (RCTs) are the gold standard for causal inference, but they are often powered only for average effects, making estimation of heterogeneous treatment effects (HTEs) challenging. Conversely, large-scale observational studies (OS) offer a wealth of data but suffer from confounding bias. Our paper presents a novel framework to leverage OS data for enhancing the efficiency in estimating conditional average treatment effects (CATEs) from RCTs while mitigating common biases. We propose an innovative approach to combine RCTs and OS data, expanding the traditionally used control arms from external sources. The framework relaxes the typical assumption of CATE invariance across populations, acknowledging the often unaccounted systematic differences between RCT and OS participants. We demonstrate this through the special case of a linear outcome model, where the CATE is sparsely different between the two populations. The core of our framework relies on learning potential outcome means from OS data and using them as a nuisance parameter in CATE estimation from RCT data. We further illustrate through experiments that using OS findings reduces the variance of the estimated CATE from RCTs and can decrease the required sample size for detecting HTEs.
While meta-analyzing retrospective cancer patient cohorts, an investigation of differences in the expressions of target oncogenes across cancer subtypes is of substantial interest because the results may uncover novel tumorigenesis mechanisms and improve screening and treatment strategies. Weighting methods facilitate unconfounded comparisons of multigroup potential outcomes in multiple observational studies. For example, Guha et al. (2022) introduced concordant weights, allowing integrative analyses of survival outcomes by maximizing the effective sample size. However, it remains unclear how to use this or other weighting approaches to analyze a variety of continuous, categorical, ordinal, or multivariate outcomes, especially when research interests prioritize uncommon or unplanned estimands suggested by post hoc analyses; examples include percentiles and moments of group potential outcomes and pairwise correlations of multivariate outcomes. This paper proposes a unified meta-analytical approach accommodating various types of endpoints and fosters new estimators compatible with most weighting frameworks. Asymptotic properties of the estimators are investigated under mild assumptions. For undersampled groups, we devise small-sample procedures for quantifying estimation uncertainty. We meta-analyze multi-site TCGA breast cancer data, shedding light on the differential mRNA expression patterns of eight targeted genes for the subtypes infiltrating ductal carcinoma and infiltrating lobular carcinoma.
This paper focuses on the expected difference in borrower's repayment when there is a change in the lender's credit decisions. Classical estimators overlook the confounding effects and hence the estimation error can be magnificent. As such, we propose another approach to construct the estimators such that the error can be greatly reduced. The proposed estimators are shown to be unbiased, consistent, and robust through a combination of theoretical analysis and numerical testing. Moreover, we compare the power of estimating the causal quantities between the classical estimators and the proposed estimators. The comparison is tested across a wide range of models, including linear regression models, tree-based models, and neural network-based models, under different simulated datasets that exhibit different levels of causality, different degrees of nonlinearity, and different distributional properties. Most importantly, we apply our approaches to a large observational dataset provided by a global technology firm that operates in both the e-commerce and the lending business. We find that the relative reduction of estimation error is strikingly substantial if the causal effects are accounted for correctly.
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