Treatment Effect Heterogeneity

Quasi-Oracle Estimation of Heterogeneous Treatment Effects

Xinkun Nie, Stefan Wager · 2017 · 840 citations

Flexible estimation of heterogeneous treatment effects lies at the heart of many statistical challenges, such as personalized medicine and optimal resource allocation. In this paper, we develop a general class of two-step algorithms for heterogeneous treatment effect estimation in observational studies. We first estimate marginal effects and treatment propensities in order to form an objective function that isolates the causal component of the signal. Then, we optimize this data-adaptive objective function. Our approach has several advantages over existing methods. From a practical perspective, our method is flexible and easy to use: In both steps, we can use any loss-minimization method, e.g., penalized regression, deep neural networks, or boosting; moreover, these methods can be fine-tuned by cross validation. Meanwhile, in the case of penalized kernel regression, we show that our method has a quasi-oracle property: Even if the pilot estimates for marginal effects and treatment propensities are not particularly accurate, we achieve the same error bounds as an oracle who has a priori knowledge of these two nuisance components. We implement variants of our approach based on penalized regression, kernel ridge regression, and boosting in a variety of simulation setups, and find promising performance relative to existing baselines.

Estimation and Inference of Heterogeneous Treatment Effects using Random Forests

Stefan Wager, Susan Athey · 2015

Many scientific and engineering challenges -- ranging from personalized medicine to customized marketing recommendations -- require an understanding of treatment effect heterogeneity. In this paper, we develop a non-parametric causal forest for estimating heterogeneous treatment effects that extends Breiman's widely used random forest algorithm. In the potential outcomes framework with unconfoundedness, we show that causal forests are pointwise consistent for the true treatment effect, and have an asymptotically Gaussian and centered sampling distribution. We also discuss a practical method for constructing asymptotic confidence intervals for the true treatment effect that are centered at the causal forest estimates. Our theoretical results rely on a generic Gaussian theory for a large family of random forest algorithms. To our knowledge, this is the first set of results that allows any type of random forest, including classification and regression forests, to be used for provably valid statistical inference. In experiments, we find causal forests to be substantially more powerful than classical methods based on nearest-neighbor matching, especially in the presence of irrelevant covariates.

Multi-Study R-Learner for Estimating Heterogeneous Treatment Effects Across Studies Using Statistical Machine Learning

Cathy Shyr, Boyu Ren, Prasad Patil +1 more · 2023 · 3 citations

Estimating heterogeneous treatment effects (HTEs) is crucial for precision medicine. While multiple studies can improve the generalizability of results, leveraging them for estimation is statistically challenging. Existing approaches often assume identical HTEs across studies, but this may be violated due to various sources of between-study heterogeneity, including differences in study design, study populations, and data collection protocols, among others. To this end, we propose a framework for multi-study HTE estimation that accounts for between-study heterogeneity in the nuisance functions and treatment effects. Our approach, the multi-study R-learner, extends the R-learner to obtain principled statistical estimation with machine learning (ML) in the multi-study setting. It involves a data-adaptive objective function that links study-specific treatment effects with nuisance functions through membership probabilities, which enable information to be borrowed across potentially heterogeneous studies. The multi-study R-learner framework can combine data from randomized controlled trials, observational studies, or a combination of both. It's easy to implement and flexible in its ability to incorporate ML for estimating HTEs, nuisance functions, and membership probabilities. In the series estimation framework, we show that the multi-study R-learner is asymptotically normal and more efficient than the R-learner when there is between-study heterogeneity in the propensity score model under homoscedasticity. We illustrate using cancer data that the proposed method performs favorably compared to existing approaches in the presence of between-study heterogeneity.

Comparison of meta-learners for estimating multi-valued treatment heterogeneous effects

Naoufal Acharki, Ramiro Lugo, Antoine Bertoncello +1 more · 2022 · 18 citations

Conditional Average Treatment Effects (CATE) estimation is one of the main challenges in causal inference with observational data. In addition to Machine Learning based-models, nonparametric estimators called meta-learners have been developed to estimate the CATE with the main advantage of not restraining the estimation to a specific supervised learning method. This task becomes, however, more complicated when the treatment is not binary as some limitations of the naive extensions emerge. This paper looks into meta-learners for estimating the heterogeneous effects of multi-valued treatments. We consider different meta-learners, and we carry out a theoretical analysis of their error upper bounds as functions of important parameters such as the number of treatment levels, showing that the naive extensions do not always provide satisfactory results. We introduce and discuss meta-learners that perform well as the number of treatments increases. We empirically confirm the strengths and weaknesses of those methods with synthetic and semi-synthetic datasets.

A Meta-learner for Heterogeneous Effects in Difference-in-Differences

Hui Lan, Haoge Chang, Eleanor Dillon +1 more · 2025 · 3 citations

We address the problem of estimating heterogeneous treatment effects in panel data, adopting the popular Difference-in-Differences (DiD) framework under the conditional parallel trends assumption. We propose a novel doubly robust meta-learner for the Conditional Average Treatment Effect on the Treated (CATT), reducing the estimation to a convex risk minimization problem involving a set of auxiliary models. Our framework allows for the flexible estimation of the CATT, when conditioning on any subset of variables of interest using generic machine learning. Leveraging Neyman orthogonality, our proposed approach is robust to estimation errors in the auxiliary models. As a generalization to our main result, we develop a meta-learning approach for the estimation of general conditional functionals under covariate shift. We also provide an extension to the instrumented DiD setting with non-compliance. Empirical results demonstrate the superiority of our approach over existing baselines.

Model-agnostic meta-learners for estimating heterogeneous treatment effects over time

Dennis Frauen, Konstantin Hess, Stefan Feuerriegel · 2024

Estimating heterogeneous treatment effects (HTEs) over time is crucial in many disciplines such as personalized medicine. For example, electronic health records are commonly collected over several time periods and then used to personalize treatment decisions. Existing works for this task have mostly focused on model-based learners (i.e., learners that adapt specific machine-learning models). In contrast, model-agnostic learners -- so-called meta-learners -- are largely unexplored. In our paper, we propose several meta-learners that are model-agnostic and thus can be used in combination with arbitrary machine learning models (e.g., transformers) to estimate HTEs over time. Here, our focus is on learners that can be obtained via weighted pseudo-outcome regressions, which allows for efficient estimation by targeting the treatment effect directly. We then provide a comprehensive theoretical analysis that characterizes the different learners and that allows us to offer insights into when specific learners are preferable. Finally, we confirm our theoretical insights through numerical experiments. In sum, while meta-learners are already state-of-the-art for the static setting, we are the first to propose a comprehensive set of meta-learners for estimating HTEs in the time-varying setting.

Causal Inference with Categorical Unobserved Confounder via Mixture Learning

Aytijhya Saha, Stephen Bates, Devavrat Shah · 2026

Unobserved confounding is a fundamental challenge for estimating causal effects. To address unobserved confounding, recent literature has turned to two different approaches -- proxy variables and the use of multiple treatments. The first approach, commonly referred to as proximal causal inference, requires proxies to be assigned to specific asymmetric roles: treatment-inducing proxies (negative control exposures), variables that act as common causes of the treatment and outcome, and outcome-inducing proxies (negative control outcomes). In practice, however, identifying variables that satisfy these asymmetric roles can be difficult depending on the application domain. The second approach, commonly referred to as the ``Deconfounder," deals with multiple conditionally independent treatments. There has been limited progress towards developing a consistent estimation method for this setting. As the primary contribution of this work, we establish that causal effects are identifiable in both settings when the unobserved confounder is categorical under suitable conditions. Our approach builds on a mixture learning perspective: we show that the underlying confounding structure can be recovered by identifying the corresponding mixture distribution. We propose an estimation procedure based on tensor decomposition, which allows consistent recovery of the latent structure and comes with non-asymptotic guarantees. Simulation studies and real data experiments demonstrate that the proposed method performs well even with limited data.

Meta-Learners for Partially-Identified Treatment Effects Across Multiple Environments

Jonas Schweisthal, Dennis Frauen, Mihaela van der Schaar +1 more · 2024

Estimating the conditional average treatment effect (CATE) from observational data is relevant for many applications such as personalized medicine. Here, we focus on the widespread setting where the observational data come from multiple environments, such as different hospitals, physicians, or countries. Furthermore, we allow for violations of standard causal assumptions, namely, overlap within the environments and unconfoundedness. To this end, we move away from point identification and focus on partial identification. Specifically, we show that current assumptions from the literature on multiple environments allow us to interpret the environment as an instrumental variable (IV). This allows us to adapt bounds from the IV literature for partial identification of CATE by leveraging treatment assignment mechanisms across environments. Then, we propose different model-agnostic learners (so-called meta-learners) to estimate the bounds that can be used in combination with arbitrary machine learning models. We further demonstrate the effectiveness of our meta-learners across various experiments using both simulated and real-world data. Finally, we discuss the applicability of our meta-learners to partial identification in instrumental variable settings, such as randomized controlled trials with non-compliance.

Meta-Learners for Estimation of Causal Effects: Finite Sample Cross-Fit Performance

Gabriel Okasa · 2022 · 14 citations

Estimation of causal effects using machine learning methods has become an active research field in econometrics. In this paper, we study the finite sample performance of meta-learners for estimation of heterogeneous treatment effects under the usage of sample-splitting and cross-fitting to reduce the overfitting bias. In both synthetic and semi-synthetic simulations we find that the performance of the meta-learners in finite samples greatly depends on the estimation procedure. The results imply that sample-splitting and cross-fitting are beneficial in large samples for bias reduction and efficiency of the meta-learners, respectively, whereas full-sample estimation is preferable in small samples. Furthermore, we derive practical recommendations for application of specific meta-learners in empirical studies depending on particular data characteristics such as treatment shares and sample size.

Assessing Surrogate Heterogeneity in Real World Data Using Meta-Learners

Rebecca Knowlton, Layla Parast · 2025 · 0 citations

Surrogate markers are most commonly studied within the context of randomized clinical trials. However, the need for alternative outcomes extends beyond these settings and may be more pronounced in real-world public health and social science research, where randomized trials are often impractical. Research on identifying surrogates in real-world non-randomized data is scarce, as available statistical approaches for evaluating surrogate markers tend to rely on the assumption that treatment is randomized. While the few methods that allow for non-randomized treatment/exposure appropriately handle confounding individual characteristics, they do not offer a way to examine surrogate heterogeneity with respect to patient characteristics. In this paper, we propose a framework to assess surrogate heterogeneity in real-world, i.e., non-randomized, data and implement this framework using various meta-learners. Our approach allows us to quantify heterogeneity in surrogate strength with respect to patient characteristics while accommodating confounders through the use of flexible, off-the-shelf machine learning methods. In addition, we use our framework to identify individuals for whom the surrogate is a valid replacement of the primary outcome. We examine the performance of our methods via a simulation study and application to examine heterogeneity in the surrogacy of hemoglobin A1c as a surrogate for fasting plasma glucose.

Local Covariate Selection for Average Causal Effect Estimation without Pretreatment and Causal Sufficiency Assumptions

Zeyu Liu, Zheng Li, Feng Xie +3 more · 2026

We study the problem of selecting covariates for unbiased estimation of the total causal effect.Existing approaches typically rely on global causal structure learning over all variables, or on strong assumptions such as causal sufficiency - where observed variables share no latent confounders - or the pretreatment assumption, which limits covariates to those unaffected by the treatment or outcome. These requirements are often unrealistic in practice, and global learning becomes computationally prohibitive in high-dimensional settings.To address these challenges, we propose a novel local learning method for covariate selection in nonparametric causal effect estimation that avoids both the pretreatment and causal sufficiency assumptions. We first characterize a local boundary that contains at least one valid adjustment set whenever one exists for identifying the causal effect, and then develop local identification procedures to efficiently search within this boundary.We prove that the proposed method is sound and complete. Experiments on multiple synthetic datasets and two real-world datasets show that our approach achieves accurate causal effect estimation while substantially improving computational efficiency.

Assessing Estimate of CATE from Observational Data via an RCT Study

Bosen Cui, Yuhong Yang · 2026

Conditional average treatment effects (CATEs) are increasingly estimated from observational data and used to guide policy and individualized treatment decisions. Before such estimates can be trusted in practice, their predictive fitness needs to be assessed, yet observational data alone offer limited opportunities for doing so. We propose CATE Assessment via Fitness Evaluation (CAFE), a formal framework for directly assessing the goodness-of-fit of a CATE estimate learned from observational data, rather than the full underlying outcome model, using evidence from a randomized trial. CAFE partitions the trial covariate space according to estimated propensity scores (or the like) and compares observationally derived conditional treatment effects with group-level experimental averages. The framework accommodates a broad class of CATE learners, including parametric models and flexible machine learning methods such as causal forest and boosting. We establish theoretical guarantees under both the null and alternative hypotheses, and introduce a maximum-type extension to improve sensitivity to localized lack of fit. When both randomized trial and observational data are available, we further develop a two-stage procedure to detect the existence of unobserved confounders. Extensive numerical studies show the utility of the CAFE approach when assessing observational-derived CATE estimates.

Understanding Deterioration Random Effects for Causal Discovery in Infrastructure Management

Takato Yasuno · 2026

Infrastructure deterioration poses significant challenges for asset management, yet existing approaches rely on population-averaged models that overlook equipment-specific heterogeneity. We present a novel framework that combines Bayesian hierarchical hazard modeling with causal discovery to identify operational patterns that drive heterogeneous deterioration rates in pump equipment. Our approach first estimates pump-specific random effects $u_i$ using GPU-accelerated No-U-Turn Sampling (NUTS), achieving 3--5$\times$ speedup over CPU implementations. We then employ DirectLiNGAM to discover causal relationships between 22 engineered time-series features and deterioration rates, stratified by positive ($u_i > 0$, faster deterioration) versus negative ($u_i \leq 0$, slower deterioration) random effects. Analyzing 112 pumps with 92,861 observations over 650 days, we uncover striking heterogeneity: the negative group exhibits causal effects 400$\times$ larger than the positive group, with standard deviation (std) showing a strong positive causal effect ($+1.515$) on deterioration rates in low-risk equipment. We validate linearity assumptions through NonlinearLiNGAM comparison and demonstrate practical scalability through GPU acceleration. Our findings enable targeted maintenance strategies by revealing that different operational regimes require fundamentally distinct management approaches, advancing predictive maintenance from population-averaged to heterogeneity-aware decision making.

Laplace Approximations for Mixed-Effects and Gaussian Process Quantile Regression

Andrea Nava, Fabio Sigrist · 2026

Laplace approximations are a standard tool for computationally efficient inference in latent Gaussian models, but they fail for quantile regression with the asymmetric Laplace likelihood because the observed Hessian vanishes almost everywhere. We show that this obstacle can be overcome without smoothing the likelihood: the relevant local curvature is given not by the observed Hessian, but by the Fisher information when the model is correctly specified and by the population curvature of the expected loss under misspecification. On this basis, we develop a Laplace approximation framework for quantile regression with mixed-effects and Gaussian process models. We propose practical curvature estimators, including the triangular kernel curvature (TKC) estimator, that yield approximations for posterior distributions and marginal likelihoods, and we establish their asymptotic validity. Empirically, the proposed methods are scalable and numerically stable, and for latent Gaussian models, they achieve accuracy comparable to or better than MCMC and variational competitors at substantially lower computational costs. More broadly, the framework clarifies how Laplace approximations can be justified for non-smooth generalized posteriors through local quadratic behavior of the expected loss.

Conformal Convolution and Monte Carlo Meta-learners for Predictive Inference of Individual Treatment Effects

Jef Jonkers, Jarne Verhaeghe, Glenn Van Wallendael +2 more · 2024 · 6 citations

Generating probabilistic forecasts of potential outcomes and individual treatment effects (ITE) is essential for risk-aware decision-making in domains such as healthcare, policy, marketing, and finance. We propose two novel methods: the conformal convolution T-learner (CCT) and the conformal Monte Carlo (CMC) meta-learner, that generate full predictive distributions of both potential outcomes and ITEs. Our approaches combine weighted conformal predictive systems with either analytic convolution of potential outcome distributions or Monte Carlo sampling, addressing covariate shift through propensity score weighting. In contrast to other approaches that allow the generation of potential outcome predictive distributions, our approaches are model agnostic, universal, and come with finite-sample guarantees of probabilistic calibration under knowledge of the propensity score. Regarding estimating the ITE distribution, we formally characterize how assumptions about potential outcomes' noise dependency impact distribution validity and establish universal consistency under independence noise assumptions. Experiments on synthetic and semi-synthetic datasets demonstrate that the proposed methods achieve probabilistically calibrated predictive distributions while maintaining narrow prediction intervals and having performant continuous ranked probability scores. Besides probabilistic forecasting performance, we observe significant efficiency gains for the CCT- and CMC meta-learners compared to other conformal approaches that produce prediction intervals for ITE with coverage guarantees.

Evaluating causal indirect effects when mediators are left-censored by assay limit of quantification

Cong Jiang, Michael D. Hughes, Nima S. Hejazi · 2026

Causal mediation analysis is essential for disentangling the mechanisms by which investigational therapeutic and preventive agents impact clinical outcomes. However, the measurement of biological mediators is often subject to left-censoring by technical measurement limitations, most commonly an assay's limit of quantification. This form of censoring can pose severe challenges for both identification and estimation of causal mediation estimands, particularly when the censoring mechanism is deterministic and the resulting missingness is missing not at random (MNAR) or nonignorable. Motivated by the question of assessing the role of viral RNA in the action mechanism of monoclonal antibody therapies for COVID-19 in the Accelerating COVID-19 Therapeutics and Vaccine (ACTIV)-2 platform trial, we develop a semi-parametric framework for estimation of the natural direct and indirect effects when the mediator of interest is partially subject to this form of left-censoring. Our proposed strategy combines fractional imputation with a semi-parametric EM algorithm to flexibly estimate key components of the factorized data likelihood. Applying the proposed strategy to circumvent the left-censoring, we discuss both traditional plug-in and asymptotically efficient estimators of the direct and indirect effect estimands, introducing a data-adaptive $m$-out-of-$n$ bootstrap for robust inference under the imputation procedure. We demonstrate in numerical experiments that our approach significantly reduces bias and allows for reliable inference. An application to data from the ACTIV-2 platform trial confirms that monoclonal antibody therapies reduce the risk of hospitalization and death due to COVID-19, while suggesting that changes in viral RNA mediate only a modest proportion of the overall treatment effect.

A new class of functional conditional autoregressive models

Sooran Kim · 2026 · 1 citations

We introduce a new class of conditional autoregressive models for spatially dependent functional data, formulated through conditional means given neighboring functional observations and characterized by a covariance operator and a spatial dependence parameter. Our estimation strategy consists of three components: (i) estimating the covariance operator using conditionally centered data, (ii) estimating the spatial dependence parameter by maximizing the likelihood of projected observations, and (iii) applying a novel profile-based approach to obtain the final estimators. Under an expanding lattice framework, we establish two key theoretical results. First, we establish the consistency of the proposed covariance estimator, which is not attainable using naive methods based on marginally centered data. Second, we prove that the spatial dependence parameter estimator is superconsistent and asymptotically normal, where the latter property enables statistical inference for spatial dependence in functional data -- a contribution that is novel in the existing literature. Numerical studies support the theoretical results and demonstrate the computational efficiency of our method. Finally, we illustrate its practical utility by analyzing weekly PM$_{2.5}$ concentration trajectories in 2019 across counties in the Midwestern United States.

Stable direct estimation for GPLSIAMs using P-splines with dynamically updated boundaries

Danilo V. Silva, Gilberto A. Paula · 2026

Generalized partially linear single-index additive models (GPLSIAMs) have been increasingly applied across diverse areas due to their versatility in integrating functional flexibility with parametric dimension reduction while maintaining interpretability. However, the estimation presents severe computational challenges. This paper introduces a novel stable method that uses the model matrix for each single-index effect, defined by its single-index coefficients, and the penalized complete Fisher information matrix to dynamically update the boundaries of the single-index covariates within a unified iterative framework. The derived model matrices enable the fast computation of the estimated effective degrees of freedom and pointwise confidence bands for the single-index effects. The smoothing parameter updates are integrated into the iterative process via the generalized Fellner-Schall method, which recycles the derived matrix decompositions, thereby providing an efficient approximation to the global penalized optimization problem. Simulation studies with moderate sample sizes under non-Gaussian distributions confirm the empirical consistency of the estimation across multiple scenarios. Notably, the proposed approach remains stable where state-of-the-art competitive methods fail to recover true single-index coefficients and nonlinear functions, and is 80.13 times faster than the usual two-step method in the most computationally intensive scenario. The modeling advantage is illustrated through an application to Capital Bike Sharing data, where we deal with a single-index interaction effect for each year, with distinct single-index coefficients, a complex structure that makes competitive methods inapplicable. The proposed method is implemented in R, with functions available for reproducibility and transparency in the comparisons.

Missing data and cluster graphs: cluster-level missingness vs variable-level missingness

Willow Scott, Eugenio Valdano, Charles Assaad · 2026

Missing data is pervasive in many scientific domains such as public health, environmental science, and the social sciences. Recoverability from missing data is typically studied using fully specified variable-level missingness models despite that, in many applications, only coarse structural information is available, for instance when variables are grouped into clusters due to limited knowledge or interpretability reasons. In this paper, we investigate recoverability from such abstract representations. We introduce two classes of cluster-based missingness graphs: the m-C-DMG, which retains variable-specific missingness indicators, and the cm-C-DMG, which aggregates missingness mechanisms at the cluster level. We formalize the notion of compatibility between these abstract graphs and underlying variable-level missingness models, and study how this abstraction affects the recoverability of probabilistic and causal queries. In particular, we give graphical conditions of recovering the joint distribution as well as graphical conditions of recovering a macro causal effect. Overall, our results clarify when cluster-level missingness information is sufficient for valid inference, and when finer-grained modeling is necessary.

Variance Reduction for Expectations with Diffusion Teachers

Jesse Bettencourt, Xindi Wu, Matan Atzmon +2 more · 2026

Pretrained diffusion models serve as frozen teachers feeding downstream pipelines such as text-to-3D, single-step distillation, and data attribution. The teacher gradients these pipelines consume are Monte Carlo (MC) expectations over noise levels and Gaussian noise samples; their estimator variance dominates compute cost because each draw requires expensive upstream work (rendering, simulation, encoding). We introduce CARV, a compute-aware variance-accounting framework that motivates a hierarchical MC estimator: amortize the expensive upstream computation over cheap diffusion-noise resamples, sharpened by timestep importance sampling and a stratified-inverse-CDF construction. In our text-to-3D distillation and attribution experiments, CARV delivers 2-3x effective compute multipliers (most from amortized reuse; ~25% additional from IS+stratification) without changing the objective; in single-step distillation, the same techniques cut gradient variance by an order of magnitude but do not improve downstream FID, marking the regime where MC variance is no longer the bottleneck.

CausalGuard: Conformal Inference under Graph Uncertainty

Vikash Singh, Weicong Chen, Debargha Ganguly +12 more · 2026

Estimating treatment effects from observational data requires choosing an adjustment set, but valid adjustment depends on an unknown causal graph. Graph misspecification can cause under-coverage, while graph-agnostic conformal wrappers may regain nominal coverage only through large padding. We introduce CausalGuard, a structure-weighted conformal framework that calibrates after aggregating graph-conditional doubly robust pseudo-outcomes. Candidate DAGs are proposed from an LLM-derived edge prior, pruned by conditional-independence tests, and reweighted by Bayesian Information Criterion. A composite nonconformity score then calibrates the posterior-weighted pseudo-outcome. CausalGuard provides distribution-free finite-sample marginal coverage for this aggregated pseudo-outcome; under causal identification, overlap, conditional-mean nuisance stability, and concentration on target-aligned valid adjustment strategies, its conditional mean converges to the true Conditional Average Treatment Effect. Across five benchmarks, CausalGuard attains mean coverage above the nominal 90% level for the directly evaluable target and reduces width when graph-agnostic conformal baselines require large padding. Stress tests show that CausalGuard suppresses invalid collider adjustment and remains stable under misspecified priors when the retained candidate set is data-supported.

Positive-definiteness in separable priors: effects on prior interpretability and inference

Jack Storror Carter, David Rossell · 2026

A popular class of priors for symmetric positive-definite matrices assumes independent entries and adds a truncation to ensure positive-definiteness. While conceptually simple and often computationally convenient, unless done carefully this truncation can have unintended effects. If the truncated prior or its margins are significantly different from their untruncated counterpart, then its interpretability may suffer, its shrinkage properties become harder to characterise, and posterior inference may be affected in unanticipated ways. We investigate the effect of the truncation both for dense and sparse matrices, and show how to set prior parameters such as the variance of off-diagonal entries such that said effect is mitigated as the matrix dimension grows. We pay particular attention to sparse inference where, unless prior parameters are set carefully, the truncated prior and hence its corresponding posterior assign systematically higher mass to sparser structures than the untruncated prior.

Conditional regularized halfspace depth for sparse functional data and its applications

Hyemin Yeon, Xiongtao Dai, Sara Lopez-Pintado · 2026

Many functional datasets are observed sparsely and irregularly. Ordering such data is challenging because only limited information is available from each observation, while the underlying trajectories remain infinite-dimensional. This paper develops a novel depth notion for sparse functional data, called the conditional regularized halfspace depth (CRHD). CRHD is defined as the infimum of conditional halfspace probabilities of the underlying trajectory given the observed sparse measurements, thereby enabling depth evaluation directly at sparse observations without requiring trajectory reconstruction. We study several basic theoretical properties of CRHD that clarify its behavior as a depth measure. The proposed depth is applicable even to extremely sparsely observed functional data, overcoming key limitations of existing sparse functional depths that often rely on reconstructed curves. In addition, CRHD induces meaningful rankings for complex functional data. Its numerical performance is demonstrated through rank-based tests, and its practical utility is illustrated using an infant growth dataset.

Departure from Regularity: Degree Heterogeneity and Eigengap as the Structural Drivers of ASE-LSE Latent Subspace Disagreement

Minh Triet Pham, Ian Gallagher · 2026

Two of the most widely used methods for analysing graph data, Adjacency Spectral Embedding and Laplacian Spectral Embedding, often produce different results when applied to the same network. Yet the structural reasons behind this disagreement remain incompletely understood. This paper provides a structural account. We show that regularity is a sufficient condition for perfect agreement: when every node has the same number of connections, the two methods produce identical latent subspaces. Any departure from this regularity introduces disagreement, and we prove an explicit bound whose two terms suggest the structural ingredients controlling it: degree heterogeneity, which pushes the methods apart, and community structure strength, which pulls them back together. We validate both drivers empirically across thousands of simulated networks, confirming that heterogeneity drives disagreement up, community strength suppresses it, and their ratio provides a strong predictor of when the two embeddings can be treated as interchangeable and when they cannot.

A Unified Framework for Structure-Aware Clustering and Heterogeneous Causal Graph Learning

Honglin Du, Muxuan Liang, Xiang Zhong · 2026 · 1 citations

In complex multivariate systems, interactions among variables are defined by dependency structures, often encoded as directed acyclic graphs ($\text{DAGs}$). However, dependency structures can vary across subjects, and ignoring this structural heterogeneity introduces bias and obscures subpopulation-specific dependencies. To address this, we propose Directed Acyclic Graph-based Dependency Clustering via Alternating Direction Method of Multipliers (DAG-DC-ADMM), a unified framework built upon Structural Equation Modeling (SEM) that jointly learns cluster assignments and cluster-specific dependency structures. We encode acyclicity via a smooth constraint and integrate a groupwise truncated Lasso fusion penalty (gTLP) to cluster subjects based on their structural similarity. This yields a nonconvex optimization problem that incorporates sparsity, acyclicity, and structural consensus constraints. We address the nonconvexity by using the augmented Lagrangian method and solve it with an adapted version of the Alternating Direction Method of Multipliers (ADMM) for difference-of-convex programs. For certain graph structures, such as upper triangular adjacency matrices, our algorithm is guaranteed to converge to a Karush-Kuhn-Tucker (KKT) point. Experiments demonstrate that our method recovers cluster-specific causal dependency structures with a high true positive rate and a low false discovery rate. This capability enables the robust discovery of heterogeneous dependencies across subjects where the subpopulation label is unknown.

From Sequential Nodes to GPU Batches: Parallel Branch and Bound for Optimal $k$-Sparse GLMs

Jiachang Liu, Andrea Lodi · 2026

GPUs have significantly accelerated first-order methods for large-scale optimization, especially in continuous optimization. However, this success has not transferred cleanly to problems with discrete variables, combinatorial structure, and nonlinear objectives, such as certifying optimal solutions for cardinality-constrained generalized linear models. Major challenges include the sequential processing of heterogeneous nodes in branch and bound (BnB) and frequent data movement between the CPU and GPU. We propose a simple, generic, and modular CPU--GPU framework that processes multiple BnB nodes in batches on GPUs. The framework is built around a small set of GPU-efficient routines and uses padding together with lightweight custom kernels to handle irregular node data structures. Experiments show one to two orders of magnitude speedups and zero optimality gap on challenging instances. The framework can also be extended to collect the entire Rashomon set, enabling downstream statistical analysis such as variable-importance analysis and model selection under secondary user-specific measures (e.g., AUC in classification).

Causal Bias Detection in Generative Artificial Intelligence

Drago Plecko · 2026

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.

Causal Discovery in Structural VAR Models Under Equal Noise Variance

SeyedSina Seyedi HasanAbadi, Fahimeh Arab, Erfan Nozari +1 more · 2026 · 5 citations

Causal discovery from multivariate time series is challenging when causal effects may occur both across time and within the same sampling interval. This issue is especially important in applications such as neuroscience, where the sampling rate may be coarse relative to the underlying dynamics and contemporaneous effects need not form an acyclic graph. We study causal discovery in linear Gaussian structural VAR models under an equal noise variance assumption, meaning that the structural noise terms have a common variance. Unlike the DAG-based cross-sectional equal noise variance setting, the time-series setting considered here does not generally yield point identification of a unique causal graph. Instead, multiple structural VAR parameterizations can induce the same stationary observed process law. We introduce a notion of observational equivalence tailored to this setting and show that the corresponding equivalence class is characterized by orthogonal transformations of the structural equations together with a global positive scale. This characterization leads to an equivalence-aware model discrepancy, the observational alignment discrepancy, which compares structural models modulo transformations that preserve the observed law. Building on this theory, we propose ENVAR, a sparsity-based procedure that searches over the induced observational equivalence class for a sparse normalized structural representative. We evaluate the proposed methodology on synthetic structural VAR data and on an fMRI dataset.

On the Regularity and Generalization of One-Step Wasserstein-guided Generative Models for PDE-Induced Measures

Likun Lin, Zhongjian Wang, Jack Xin +1 more · 2026

Despite the remarkable empirical success of generative models, the available theory on their statistical accuracy in scientific computing remains largely pessimistic. This paper develops a theoretical framework for understanding the regularity of transport maps and the generalization properties of one-step Wasserstein-guided generative models for PDE-induced probability measures. We consider normalized target densities associated with linear elliptic and parabolic equations on bounded domains, as well as diffusion and Fokker--Planck equations on the torus. Under standard structural assumptions, we prove that these target measures satisfy doubling conditions. By combining this fact with regularity theory for optimal transport between doubling measures, we show that the optimal transport map from a uniform source measure to the target measure is Hölder continuous. This regularity yields an approximation-theoretic justification for one-step generative models that learn PDE-induced distributions via a single pushforward map. As a representative instance, we study DeepParticle and derive excess-risk bounds characterizing the discrepancy between the learned map and the population-optimal map. We also establish a robustness estimate under target shift and illustrate the theory with experiments which support the derived rates.

A Mixed Self-Exciting Process to Model Epileptic Seizures

Karen Kanaster, Giovani L. Silva, Peter Mueller +2 more · 2026

Epilepsy is a neurological disorder characterized by recurrent seizures affecting more than 70 million people worldwide. Often, an individual with epilepsy is more likely to experience subsequent seizures following an initial seizure, a process we call seizure clustering. Motivated by seizure diary data collected over three years from 407 individuals newly diagnosed with focal epilepsy in the Human Epilepsy Project (HEP), we propose a Bayesian mixed Hawkes process model that addresses seizure clustering and heterogeneity between individuals. In the Hawkes process, the intensity is accelerated each time an event occurs, through the composition of background and excitation intensity functions. The proposed model incorporates a Weibull baseline intensity to model a trend in background seizure rates over time, while the excitation process accounts for seizure clustering within individuals. We model heterogeneity among individuals by including covariates and random effects in both the background and excitation intensities. In the HEP study, the average time between primary and secondary seizures within an individual is 1.57 (95\% CrI: 1.43, 1.70) days, with an average of 2.20 (1.96, 2.47) seizures per cluster. We demonstrate that omitting random effects in the presence of heterogeneity leads to underestimation of the background intensity and overestimation of excitation rates.

The Illusion of Intervention: Your LLM-Simulated Experiment is an Observational Study

Victoria Lin, Taedong Yun, Maja Matarić +3 more · 2026

Large language models (LLMs) show potential as simulators of human behavior, offering a scalable way to study responses to interventions. However, because LLMs are trained largely on observational data, interventions in experiments with LLM-simulated synthetic users can induce unintended shifts in latent user attributes, causing user drift where the implicit simulated population differs across treatment conditions, potentially distorting effect estimates. We formalize the confounding or selection bias that can arise due to user drift and show how intervention-dependent shifts can inflate or attenuate observed differences in user responses under intervention. To diagnose confounding, we propose using negative control outcomes--attributes that should remain invariant under intervention--to identify distribution shifts across intervention conditions, providing evidence of user drift. To mitigate drift, we study adjusting the persona specification by eliciting additional confounders, finding that targeted, setting-relevant confounders can substantially reduce bias across survey-style and multi-turn agent evaluations.

Policy Learning with Observational Data: The Case of Hepatitis C Treatment for HIV/HCV Co-Infected Patients

Raphaël Langevin · 2026

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.

Conditioning Gaussian Processes on Almost Anything

Henry Moss, Lachlan Astfalck, Thomas Cowperthwaite +5 more · 2026

Gaussian processes (GPs) offer a principled probabilistic model over functions, but exact inference is restricted to the linear-Gaussian regime. We establish an explicit equivalence between GPs and a class of linear diffusion models, recasting predictive sampling as an ODE with closed-form Gaussian dynamics and a likelihood-dependent guidance term that admits a simple Monte Carlo approximation. In the linear-Gaussian setting, we recover standard GP conditioning exactly; beyond conjugacy, the same machinery handles any conditioning statement admitting point-wise likelihood evaluation -- including non-linear physics, and, for the first time, natural language via large language models. Whitening isolates the irreducible non-Gaussian dynamics, minimising Wasserstein-2 transport cost and eliminating numerical stiffness. The result is a general-purpose GP inference scheme requiring no bespoke derivations. Together, these results provide a general mechanism for incorporating the full richness of real-world knowledge as conditioning information, opening a new frontier for the probabilistic modelling of real-world problems.

CAST: Causal Anchored Simplex Transport for Distribution-Valued Time Series

Jiecheng Lu, Jieqi Di, Runhua Wu +1 more · 2026

Many decision-facing stochastic systems are observed through aggregate distributions rather than scalar trajectories: queue occupancies, mobility shares, public-health mixtures, generation-source shares, ecological compositions, and air-quality severity profiles all live on the probability simplex and evolve over time. We study causal (online) forecasting for these distribution-valued time series and argue that the transition operator itself should be structured around the simplex. We introduce CAST (Causal Anchored Simplex Transport), a successor-local operator that (i) retrieves empirical successors from causal context, (ii) stabilizes them with a persistence anchor, and (iii) applies a bounded local stochastic transport on ordered supports; every stage preserves the simplex by construction. We identify a structural failure mode, latent transition-kernel aliasing, where similar observed distributions evolve differently under different contextual regimes, and prove that any forecaster depending only on an aliased summary incurs an irreducible weighted Jensen-Shannon excess-risk lower bound, while the CAST hypothesis class contains the regime-aware Bayes successor; for ordered supports an additional Pinsker separation holds whenever the transported successor lies outside the no-transport anchor hull. On eleven public and simulated benchmarks spanning ecology, energy, diet, mortality, employment, air quality, severe weather, mobility, and G/G/1, G_t/G/1 queue occupancy, CAST attains the best average rank on both one-step KL (1.27) and autoregressive rollout JSD (1.91), winning 8/11 sections on each metric against a broad statistical, compositional, recurrent, convolutional, and Transformer baseline set, and top-2 on all 11 sections for offline KL. Component ablations and a controlled synthetic aliasing experiment corroborate the theory.

Scale-Calibrated Median-of-Means for Robust Distributed Principal Component Analysis

Kisung You · 2026

Distributed principal component analysis (PCA) produces node-level estimates of both a mean vector and a principal subspace. Robustly aggregating these heterogeneous objects requires a relative scale between mean error and subspace error. We study a scale-calibrated median-of-means estimator for this problem using the product geometry of Euclidean space and the Grassmann manifold. A node-level PCA expansion shows that the mean component has the usual linear influence, whereas the subspace component is an eigengap-weighted covariance perturbation. We prove a local reduction showing that the proposed product-manifold median-of-means estimator is asymptotically equivalent to a scaled spatial median of node influence errors. This yields fixed-node non-Gaussian limits, growing-node Gaussian limits with finite-block bias, and an explicit scale-dependent covariance formula. We propose robust block-scale and inference-optimal calibration rules, establish high-probability median-of-means bounds, characterize factorwise bad-node influence, and prove node-bootstrap validity. Simulations and large-scale single-cell RNA-seq data show that scale calibration adapts to eigengap-driven subspace uncertainty and provides a robust distributed PCA summary.

Causal Algorithmic Recourse: Foundations and Methods

Drago Plecko, Collin Wang, Elias Bareinboim · 2026

The trustworthiness of AI decision-making systems is increasingly important. A key feature of such systems is the ability to provide recommendations for how an individual may reverse a negative decision, a problem known as algorithmic recourse. Existing approaches treat recourse outcomes as counterfactuals of a fixed unit, ignoring that real-world recourse involves repeated decisions on the same individual under possibly different latent conditions. We develop a causal framework that models recourse as a process over pre- and post-intervention outcomes, allowing for partial stability and resampling of latent variables. We introduce post-recourse stability conditions that enable reasoning about recourse from observational data alone, and develop a copula-based algorithm for inferring the effects of recourse under these conditions. For settings where paired observations of the same individual before and after intervention are available (called recourse data), we develop methods for inferring copula parameters and performing goodness-of-fit testing. When the copula model is rejected, we provide a distribution-free algorithm for learning recourse effects directly from recourse data. We demonstrate the value of the proposed methods on real and semi-synthetic datasets.

Distribution-free root cause analysis

Rohan Hore, Aaditya Ramdas · 2026

We study distribution-free root cause analysis in multi-stream data, where an evolving underlying system is observed through multiple data streams that may each undergo distributional changes at unknown timepoints. In such settings, the stream exhibiting the earliest change provides a natural starting point for investigating the underlying cause, which we refer to as the root-cause index. Leveraging conformal $p$-values, we propose a novel framework, Conformal Root Cause Analysis (CROC), which constructs finite-sample valid confidence sets for the root-cause index under minimal assumptions: the data streams are independent, and within each stream the pre- and post-change observations are sampled exchangeably from arbitrary and unknown distributions. We further establish a universality property, showing that any distribution-free method for root cause localization can be represented within the CROC framework. In addition, under mild regularity conditions and principled score design, our method yields asymptotically sharp confidence sets that efficiently isolate the root cause. We further extend CROC to efficiently handle cross-stream dependence when present. Extensive simulations demonstrate accurate localization of the root stream, supporting our theoretical guarantees.

Divide et Calibra: Multiclass Local Calibration via Vector Quantization

Cesare Barbera, Lorenzo Perini, Giovanni De Toni +2 more · 2026

Accurate and well-calibrated Machine Learning (ML) models are mandatory in high-stakes settings, yet effective multiclass calibration remains challenging: global approaches assume calibration errors are homogeneous across the latent space, while local methods often rely on latent-space dimensionality reduction, which leads to information loss. To address these issues, we propose a compositional approach to multiclass calibration, where region-specific calibration maps are constructed from shared codeword-dependent factors. We instantiate this idea via Vector Quantization (VQ), which induces a structured partition of the representation space, and an indexed parameterization of Dirichlet concentrations that enables parameter sharing across regions. Our approach learns heterogeneous calibration maps that generalize well even to sparse regions of the latent space. Experiments on benchmark datasets show significant improvements in local calibration while maintaining competitive global calibration and predictive performance.

Application of Propensity Score Models and Causal Estimators in Observational Studies under Model Misspecification

Apu Chandra Das, Sakib Salam, Md Robiul Islam Talukder +3 more · 2026

Propensity score (PS) methods are widely used in observational studies to reduce confounding and estimate causal treatment effects. However, the validity of PS-based causal estimators depends heavily on correct model specification, and model misspecification may lead to substantial bias and instability. In this study, we systematically evaluate the performance of commonly used causal estimators, including response surface modeling (RSM), inverse probability weighting (IPW), and augmented inverse probability weighting (AIPW), under varying levels of PS and outcome model misspecification. We compare classical logistic regression with several machine learning approaches for PS estimation, including random forests (RF), support vector machines (SVM), and linear discriminant analysis (LDA). Extensive simulation studies were conducted under multiple scenarios defined by combinations of correctly specified and misspecified PS and outcome models, varying sample sizes, and different covariate correlation structures. Estimator performance was assessed using bias, absolute bias, root mean squared error, empirical standard error, and confidence interval width. Results demonstrate that AIPW consistently provides robust and stable estimates across most scenarios due to its doubly robust property, whereas IPW is highly sensitive to PS misspecification and unstable PS estimates produced by flexible machine learning methods. RSM performs well only when the outcome model is correctly specified. Real-world applications using the ACTG175 clinical trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset further illustrate the practical implications of estimator choice and PS modeling strategy. Overall, our findings highlight the importance of integrating flexible machine learning approaches within doubly robust frameworks to improve causal effect estimation in observational studies.

Minimax Rates and Spectral Distillation for Tree Ensembles

Binh Duc Vu, David S. Watson · 2026 · 0 citations

Tree ensembles such as random forests (RFs) and gradient boosting machines (GBMs) are among the most widely used supervised learners, yet their theoretical properties remain incompletely understood. We adopt a spectral perspective on these algorithms, with two main contributions. First, we derive minimax-optimal convergence for RF regression, showing that, under mild regularity conditions on tree growth, the eigenvalue decay of the induced kernel operator governs the statistical rate. Second, we exploit this spectral viewpoint to develop compression schemes for tree ensembles. For RFs, leading eigenfunctions of the kernel operator capture the dominant predictive directions; for GBMs, leading singular vectors of the smoother matrix play an analogous role. Learning nonlinear maps for these spectral representations yields distilled models that are orders of magnitude smaller than the originals while maintaining competitive predictive performance. Our methods compare favorably to state of the art algorithms for forest pruning and rule extraction, with applications to resource constrained computing.

Stable Causal Discovery via Directed Acyclic Graph Aggregation

Yunan Wu, Yue Wang, Chunlin Li +1 more · 2026

Directed Acyclic Graphs (DAGs) are central to uncovering causal structure in complex systems, yet learning a single DAG from data is often challenging: model uncertainty, finite samples, and a combinatorially large search space frequently yield unstable estimates. We propose DAGgr, a model averaging framework that aggregates multiple candidate DAGs into a single stable representation. Candidate graphs are weighted by their out-of-sample predictive likelihood across repeated data splits, and a thresholding rule on the resulting edge-importance scores guarantees that the aggregated graph is itself acyclic. We establish a finite-sample risk bound, prove that the procedure preserves acyclicity, and show that edge selection is consistent under mild conditions on the weights. Simulations across random, hub, and chain structures, together with an analysis of the Sachs et al. (2005) protein-signaling network, show that DAGgr matches or exceeds the best individual candidate while consistently outperforming bootstrap-aggregation baselines across structural recovery metrics.

Representation Gap: Explaining the Unreasonable Effectiveness of Neural Networks from a Geometric Perspective

David Perera, Victor Moura, Lais Isabelle Alves dos Santos +2 more · 2026

Characterizing precisely the asymptotic generalization error of neural networks using parameters that can be estimated efficiently is a crucial problem in machine learning, which relies heavily on heuristics and practitioners' intuition to make key design choices. In order to mitigate this issue, we introduce the Representation Gap, a metric closely related to the generalization error, but admitting better-behaved asymptotic dynamics. Focusing on equivariant diffusion models and leveraging results from optimal quantization and point-process theory, we derive a precise asymptotic equivalent of the Representation Gap and show that it is governed by a single parameter, the \textit{intrinsic dimension} of the task, which is easy to interpret, efficient to estimate, and can be linked to the equivariances of common neural network architectures. We show that this asymptotic dynamic also extends to a broader range of tasks and training algorithms. Finally, we demonstrate empirically that our asymptotic law and intrinsic dimension estimation are accurate on a wide range of synthetic datasets, where these quantities are known, as well as on more realistic datasets, where we obtain results consistent with the related literature.

Meta-analysis and network meta-analysis of time-to-event outcomes with non-proportional hazards: a Bayesian time-varying hazard ratio approach

Rhiannon K Owen, Keith R Abrams · 2026

Background: Often when undertaking meta-analyses of time-to-event (TTE) outcomes, especially in a Health Technology Assessment context, a hazard ratio (HR) scale is used. However, issues arise when there is evidence of non-proportional hazards in some of the studies included. A number of methods have been advocated, but their use has been limited by either their complexity and/or the ease with which their results can be used in HTA. An alternative approach is to assume a treatment-log(time) interaction within a Cox proportional hazards model for each study, and to then undertake a bivariate meta-analysis of the resulting treatment and interaction coefficients, so that an overall time-varying HR (TVHR) can be obtained. Methods: A TVHR approach was applied to a meta-analysis of chemotherapy compared to Standard of Care for advanced recurrent gastric cancer, and in which Progression-Free Survival (PFS) was an outcome. The approach was also applied to a network meta-analysis (NMA) evaluating overall survival (OS) in advanced BRAF-mutated melanoma. Results: Five trials in the advanced gastric cancer meta-analysis displayed evidence of non-proportional hazards for PFS. Using a TVHR model produced HRs ranging from 0.83 (CrI:0.75-0.91) at 0.5 years to 0.99 (CrI:0.79-1.23) at 3.5 years. Three studies showed evidence of non-proportional hazards in the advanced BRAF-mutated melanoma NMA for OS. Using a TVHR model, nivolumab plus ipilimumab demonstrated consistent superiority from month 7 onwards, with a HR improving from 0.37 (CrI:0.26-0.51) at one year to 0.24 (CrI:0.12-0.45) at five years. Conclusions: A TVHR approach to the meta-analysis or NMA of TTE outcomes when the proportional hazards assumption appears not to hold, produces an intuitive solution which can be readily used in HTA.

How does limma-trend work? An empirical partially Bayes perspective

Sagnik Nandy, Wanyi Ling, Nikolaos Ignatiadis · 2026

In high-throughput biology, it is common to fit thousands of linear regressions -- one per gene, protein, or other unit -- with very few samples per unit. Limma-trend, one of the most widely used methods in this setting, improves power by shrinking variance estimates parametrically toward a fitted curve (the trend) relating variance to a unit-level summary (e.g., average intensity, peptide count), before computing p-values and applying the Benjamini-Hochberg procedure to control the false discovery rate (FDR). We study limma-trend through the lens of empirical partially Bayes inference, a paradigm in which a prior is posited and estimated for the nuisance parameters while parameters of interest remain fixed. From this perspective, limma-trend computes approximate partially Bayes p-values that condition on the residual sample variance and the unit-level summary. The same framework explains why MAnorm2, a popular variant for ChIP-seq, can sometimes fail to control FDR. We then derive a nonparametric generalization of limma-trend that estimates the residual variance prior using nonparametric maximum likelihood. Under dense signals, this procedure asymptotically controls the FDR -- even when the trend is misspecified or inconsistently estimated. To allow the full shape of the conditional variance distribution to depend on the unit-level summary, we develop a second procedure that learns it directly.

Targeted maximum likelihood estimation of vaccine effectiveness and immune correlates in test-negative design studies with missing data

Leah I. B. Andrews, Lars van der Laan, Peter B. Gilbert · 2026

The test-negative design (TND) is a resource-efficient observational study design that can assess vaccine effectiveness and exposure-proximal immune correlates of disease. The TND enrolls symptomatic individuals seeking diagnostic testing and compares case status by an exposure variable, such as vaccination status or immune marker level, that is measured at testing. While the TND reduces confounding by healthcare-seeking behavior, other sources of confounding may remain. TND studies may also have missing data in the exposure variable due to incomplete records or two-phase sampling designs. We present a targeted maximum likelihood estimation approach involving a semiparametric logistic regression model that targets a causal conditional risk ratio of symptomatic disease in the healthcare-seeking population. Under causal and missing at random assumptions, our method produces an efficient, asymptotically linear estimator that provides flexible, data-driven confounding control and valid causal inference when analyzing TND studies with missing exposure variable data. We evaluate our method's finite sample properties using plasmode simulations of a two-phase TND immune correlates study. We also apply our method to assess COVID-19 vaccine effectiveness and antibody marker correlates of COVID-19 from TND study cohorts derived from the Moderna Coronavirus Efficacy phase 3 trial.

Expectation Consistency Loss: Rethink Confidence Calibration under Covariate Shift

Jinzong Dong, Zhaohui Jiang, Bo Yang · 2026

Confidence calibration for classification models is vital in safety-critical decision-making scenarios and has received extensive attention. General confidence calibration methods assume training and test data are independent and identically distributed, limiting their effectiveness under covariate shifts. Previous calibration methods under covariate shift struggle with class-wise or canonical calibrations and often rely on unstable importance weighting when density ratios are large or unbounded. Given the above limitations, this paper rethinks confidence calibration under covariate shifts. First, we derive a necessary and sufficient condition for confidence calibration under covariate shifts, named Expectation consistency condition, which reveals covariate shifts do not necessarily lead to uncalibrated confidence and provides a weaker condition for confidence calibration than global covariate distribution alignment. Then, utilizing Expectation consistency condition, this paper proposes an unsupervised domain adaptation loss to calibrate confidence of the target domain, named Expectation consistency loss (ECL), which is compatible with canonical calibration, class-wise calibration, and top-label calibration. Third, we prove that computing ECL loss has the same sample complexity as Expected Calibration Error (ECE) and provide a theoretically grounded mini-batch trainable scheme for ECL loss. Finally, we validate the effectiveness of our method on both simulated and real-world covariate shift datasets.

Data driven extreme value distribution estimation: Derivation of the Mean Integrated Squared Error, optimal bandwidth selection and stability conditions

Michael Sandbichler, Tobias Hell · 2026

We introduce the data driven extreme value distribution (DDEVD) estimator, a kernel-based method for estimating extreme value distributions from data. We derive its mean integrated squared error (MISE) in detail, use it to compute the optimal bandwidth and establish stability conditions for the bandwidth optimization procedure.

SDPM: Survival Diffusion Probabilistic Model for Continuous-Time Survival Analysis

Stanislav R. Kirpichenko, Andrei V. Konstantinov, Lev V. Utkin · 2026 · 3 citations

Survival analysis aims to estimate a time-to-event distribution from data with censored observations. Many existing methods either impose structural assumptions on the hazard function or discretize the time axis, which may limit flexibility and introduce approximation errors. We propose the Survival Diffusion Probabilistic Model (SDPM), a generative approach to continuous-time survival analysis. SDPM models the conditional distribution of the survival outcome, represented by the pair of observed time and censoring indicator, $\mathbb{P}(T,δ\mid \mathbf{x})$, using a denoising diffusion model. Under the assumption of conditionally independent censoring, conditional samples generated by the model can be transformed into survival function estimates using the Kaplan-Meier estimator. This formulation avoids parametric assumptions on the event-time distribution and does not require a discretization of the output time space. The model operates in a transformed target space, using standardized log-times and a continuous Gaussian-mixture representation of the censoring indicator. We evaluate SDPM on ten real survival datasets and compare it with five strong baselines, including tree-based, boosting-based, and neural survival models. Results show that SDPM achieves competitive predictive performance across C-index, integrated time-dependent AUC, and integrated Brier score. A study on synthetic Cox-Weibull data demonstrates that SDPM can recover the shape of an underlying continuous survival distribution more accurately than a strong nonparametric baseline when sufficiently many samples are generated. An ablation study confirms the importance of the proposed target-space transformations, which improve event-rate calibration, reduce invalid generated times, and provide consistent gains in predictive discrimination. Codes implementing the proposed model are publicly available.

Score-Based Causal Discovery of Latent Variable Causal Models

Ignavier Ng, Xinshuai Dong, Haoyue Dai +3 more · 2026 · 18 citations

Identifying latent variables and the causal structure involving them is essential across various scientific fields. While many existing works fall under the category of constraint-based methods (with e.g. conditional independence or rank deficiency tests), they may face empirical challenges such as testing-order dependency, error propagation, and choosing an appropriate significance level. These issues can potentially be mitigated by properly designed score-based methods, such as Greedy Equivalence Search (GES) (Chickering, 2002) in the specific setting without latent variables. Yet, formulating score-based methods with latent variables is highly challenging. In this work, we develop score-based methods that are capable of identifying causal structures containing causally-related latent variables with identifiability guarantees. Specifically, we show that a properly formulated scoring function can achieve score equivalence and consistency for structure learning of latent variable causal models. We further provide a characterization of the degrees of freedom for the marginal over the observed variables under multiple structural assumptions considered in the literature, and accordingly develop both exact and continuous score-based methods. This offers a unified view of several existing constraint-based methods with different structural assumptions. Experimental results validate the effectiveness of the proposed methods.

Causal Learning with the Invariance Principle

Francesco Montagna, Francesco Locatello · 2026

Causal discovery, the problem of inferring the direction of causality, is generally ill-posed. We use the language of structural causal models (SCM) to show that assuming that the causal relations are acyclic and invariant across multiple environments (e.g., the way minimum wage affects employment rate is stable across different geographical regions), \textit{only} two auxiliary environments are sufficient to infer the causal graph for arbitrary nonlinear mechanisms. Moreover, we demonstrate that this implies identifiability of the SCM functional mechanisms: as a corollary, we show that \textit{two} auxiliary environments are sufficient to guarantee correct counterfactual inference. We empirically support our theoretical results on synthetic data.