Understanding the effects of interventions is central to scientific progress, with randomized controlled trials (RCTs) regarded as the gold standard for causal inference in many applied fields. However, RCTs are costly, time-consuming, and often constrained by ethical or practical limitations, motivating the need for causal methods able to draw conclusions from observational data. While such data is collected at ever larger scale, making its use for causal inference is often hindered by the fact that not all variables affecting treatment allocation and the outcome are observed - an issue known as unobserved confounding. In this paper, we introduce a new study design called confounder detection via treatment intent. The idea is to query a human expert who makes treatment decisions, and ask them to compare pairs of units proposed by a principled matching strategy, with the goal of eliciting unobserved variables that explain why treatment decisions differ. We provide a theoretical basis for such a procedure, ascertaining conditions under which such a study design may elicit unobserved confounders. Building on this newly established foundations, we study treatment effects of interventions in the intensive care unit (ICU). First, we show empirical evidence strongly indicating that electronic health records (EHRs) collected in ICUs are subject to unobserved confounding. By using clinical text notes as a proxy for physicians' knowledge and leveraging natural language processing, we provide a proof of concept for our methodology in a semi-synthetic environment with a known ground truth.

Deploying clinical prediction models across healthcare systems often fails when key training covariates are unavailable at deployment and labeled outcomes are limited in the target domain. For example, high-performing models for out-of-hospital cardiac arrest (OHCA) rely on detailed prehospital measurements routinely collected in high-resource settings but unavailable in many international registries. Existing methods either discard missing covariates, sacrificing predictive information, or rely on untestable assumptions about their target distribution. We propose DRUM (\underline{D}istributionally \underline{R}obust \underline{U}nsupervised transfer learning with structurally \underline{M}issing covariates), a framework that transfers prediction models to target populations where certain covariates are structurally absent and outcome labels are unavailable. DRUM partitions covariates into shared components ($X$), observed across all settings, and missing components ($A$), observed only in the source. Rather than imputing missing covariates, DRUM optimizes worst-case predictive performance over the unknown target distribution of $A \mid X$ using a neural network generator, with a robustness parameter controlling allowable deviation from the source conditional. We further develop a bias correction procedure that reduces sensitivity to nuisance estimation error. Simulations show substantial improvements in both mean and worst-case prediction error under distribution shift. Applied to cross-national OHCA prediction, transferring models from a US registry to multiple Asian registries where prehospital variables are unrecorded, DRUM yields better-calibrated predictions and improved clinical classification performance across sites.

In the era of precision medicine, genome-wide epigenetic modifications offer rich data that could inform risk prediction. However, these data are high-dimensional and exhibit complex dependence structures, which makes it difficult to jointly model them with low-dimensional covariates when the goal is to obtain interpretable effect estimates for covariate adjustment. Standard Bayesian additive regression trees (BART) provide strong predictive performance but treat all predictors uniformly within the tree ensemble, obscuring the contributions of significant covariates and complicating variable selection in high-dimensional settings. We propose a semi-parametric BART model (spBART) that addresses this limitation by modeling low-dimensional covariates through a parametric component with interpretable coefficients, while capturing complex nonlinear associations among high-dimensional predictors through the tree ensemble. To perform stable variable selection, we develop a cross-validation-based procedure that aggregates posterior inclusion probabilities across folds and applies Bayesian false discovery rate control. We apply the proposed method to a pooled case--control analysis of high-dimensional genome-wide 5-hydroxymethylcytosine profiles derived from circulating cell-free DNA in two multiple myeloma studies ($N = 869$). The approach identifies a parsimonious set of candidate loci and achieves strong out-of-sample discrimination (AUC $= 0.96$) in a held-out validation set. Overall, spBART provides a unified framework for combining interpretable covariate inference with flexible modeling and variable selection in high-dimensional biomedical studies.

Automated systems built on artificial intelligence (AI) are increasingly deployed across high-stakes domains, raising critical concerns about fairness and the perpetuation of demographic disparities that exist in the world. In this context, causal inference provides a principled framework for reasoning about fairness, as it links observed disparities to underlying mechanisms and aligns naturally with human intuition and legal notions of discrimination. Prior work on causal fairness primarily focuses on the standard machine learning setting, where a decision-maker constructs a single predictive mechanism $f_{\widehat Y}$ for an outcome variable $Y$, while inheriting the causal mechanisms of all other covariates from the real world. The generative AI setting, however, is markedly more complex: generative models can sample from arbitrary conditionals over any set of variables, implicitly constructing their own beliefs about all causal mechanisms rather than learning a single predictive function. This fundamental difference requires new developments in causal fairness methodology. We formalize the problem of causal fairness in generative AI and unify it with the standard ML setting under a common theoretical framework. We then derive new causal decomposition results that enable granular quantification of fairness impacts along both (a) different causal pathways and (b) the replacement of real-world mechanisms by the generative model's mechanisms. We establish identification conditions and introduce efficient estimators for causal quantities of interest, and demonstrate the value of our methodology by analyzing race and gender bias in large language models across different datasets.

Decision-makers frequently must choose a single action from a finite set of alternatives -- for example, physicians selecting a treatment, investors choosing a portfolio risk level, or judges determining sentences. To improve outcomes, policymakers often issue policy rules or guidelines to inform such choices. In this paper, I show how to generally derive policy rules from observational data in a multi-action framework under relatively weak assumptions about the underlying structure of the heterogeneous sampled population. Conditional average treatment effects (CATEs) are consistently estimated via a weighted K-means algorithm, assuming the outcome model is correctly specified within each homogeneous subgroup. Feasible policy rules are then implemented via a standard decision tree, allowing for both perfect and imperfect adherence to treatment. The methodology is applied to treatment options for Hepatitis C (HCV) among patients co-infected with human immunodeficiency virus (HIV), a setting in which no uniform guideline exists for modern pharmaceutical therapies. The results identify a subgroup of patients with approximately an 80% probability of spontaneous HCV clearance without treatment. Estimation results also show that reallocating treatments among treated individuals could have reduced total treatment costs by CAN$3.6-4.9 million while still increasing aggregate health benefits relative to the status quo. These findings demonstrate that the proposed approach can generate improved, data-driven treatment guidelines for the management of HIV/HCV co-infected patients.

We consider the following two-player game: using observational data, the leader chooses a prediction function for a response variable $Y$ from given covariates. The follower then reacts with an intervention on some covariates in the underlying structural causal model to maximize their own objective. The leader knows the intervention targets, but may have limited knowledge of the follower's objective. We call this setup a prediction-intervention game, a special case of a Stackelberg game. Finding an optimal strategy for the leader is generally difficult. To avoid severe performance loss, the leader may base their prediction on the causal parents of $Y$, or more generally on an invariant subset of covariates. We prove, for two common classes of follower objectives, that predictors based on the stable blanket, a specific invariant subset, are always better or as good as those based on the causal parents. We further upper bound the leader's post-intervention risk by a worst-case risk over allowed interventions and strengthen existing distribution generalization results to analyze this bound: we give sufficient conditions under which stable-blanket predictors are worst-case optimal, and show by examples that these conditions cannot in general be dropped. Finally, we discuss practical strategies for settings with known and unknown graph, and test them on simulated and real-world data.

Flexible continuous-time survival modeling is critical for capturing complex time-varying hazard dynamics in high-dimensional data; however, training such models remains challenging due to the intractable integral required for likelihood estimation. We introduce QSurv, a scalable deep learning framework that enables nonparametric continuous-time modeling without relying on time discretization or restrictive distributional assumptions. We propose a training objective based on Gauss-Legendre numerical quadrature, which approximates the cumulative hazard with high-order accuracy while facilitating efficient end-to-end training via standard backpropagation. Furthermore, to effectively capture non-stationary hazard dynamics in complex architectures, we introduce time-conditioned low-rank adaptation, a mechanism that conditions general neural backbones on time by dynamically modulating weights via low-rank updates. We provide theoretical analysis establishing approximation error bounds for cumulative-hazard evaluation. Comprehensive experiments across synthetic benchmarks, large-scale real-world tabular datasets, and high-dimensional medical imaging tasks demonstrate that QSurv achieves competitive predictive performance with advantages in instantaneous hazard function estimation, enabling more interpretable characterization of time-varying risk patterns.

Single-arm trials are an important study design for evaluating drug efficacy and safety without enrolling patients into a control arm. Although they do not provide the gold-standard evidence of randomized controlled trials, they are increasingly used in clinical development as they offer an efficient, ethical, and practical alternative. A wide variety of approaches can be used to construct control comparators and estimate treatment effects, from fixed comparators informed by clinical knowledge to data-based and model-based patient-level comparators, also known as synthetic controls. Powerful and flexible machine learning models can allow outcome-model-based synthetic controls to overcome key limitations of direct data-based approaches, yield more robust estimates of treatment effects, and provide a principled way to incorporate corrections or encode additional assumptions when external data are not directly comparable. In this work, we argue that outcome-model-based synthetic control arms are an important tool for single-arm trials. We focus on digital twins, personalized predictions of disease progression generated from machine learning models trained on historical datasets, which naturally leverage these flexible approaches. We review doubly robust estimators, present power and sample size formulas, and discuss trade-offs in selecting historical data for training and analysis. We also outline practical considerations for deploying digital twins within the framework of recent FDA draft guidance on the use of artificial intelligence in drug development. Finally, we reanalyze data from trials in amyotrophic lateral sclerosis and Huntington's disease to demonstrate the proposed methods.

Experimental design has emerged as a powerful approach for improving the sample efficiency of A/B testing, yet existing designs rely critically on correctly specified models. We study robust sequential experimental design under model misspecification and develop a unified framework that covers both contextual bandit and dynamic settings. Theoretically, we prove that our design bounds the worst-case mean squared error of the estimated treatment effect. Empirically, we demonstrate the effectiveness of the proposed approach using synthetic and real-world datasets from a leading technology company.

Randomization tests and flexible treatment-effect models offer complementary strengths for analyzing data from randomized panel experiments: the former provide valid inference under the known assignment mechanism, while the latter can capture complex patterns of effect heterogeneity. We develop model-assisted randomization tests that combine these strengths without sample splitting. The key idea is to estimate an unsigned version of the conditional average treatment effect (CATE) from the covariance structure of residualized outcomes, while leaving the realized assignments for randomization inference. The remaining sign can be chosen to best fit the observed outcomes. We establish identification and consistency for the proposed unsigned CATE estimators, as well as validity for the CATE-assisted randomization tests. Across synthetic and semi-synthetic experiments, the CATE-assisted randomization tests control Type I error and achieve higher power than covariate-adjusted and sample-split alternatives. Finally, we show that the assignment-free CATE estimates can be used to discover heterogeneous subgroups and test subgroup-specific treatment effects.