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Deciding on an appropriate intervention requires a causal model of a treatment, the outcome, and potential mediators. Causal mediation analysis lets us distinguish between direct and indirect effects of the intervention, but has mostly been studied in a static setting. In healthcare, data come in the form of complex, irregularly sampled time-series, with dynamic interdependencies between a treatment, outcomes, and mediators across time. Existing approaches to dynamic causal mediation analysis are limited to regular measurement intervals, simple parametric models, and disregard long-range mediator--outcome interactions. To address these limitations, we propose a non-parametric mediator--outcome model where the mediator is assumed to be a temporal point process that interacts with the outcome process. With this model, we estimate the direct and indirect effects of an external intervention on the outcome, showing how each of these affects the whole future trajectory. We demonstrate on semi-synthetic data that our method can accurately estimate direct and indirect effects. On real-world healthcare data, our model infers clinically meaningful direct and indirect effect trajectories for blood glucose after a surgery.

Estimating heterogeneous treatment effects is crucial for informing personalized treatment strategies and policies. While multiple studies can improve the accuracy and generalizability of results, leveraging them for estimation is statistically challenging. Existing approaches often assume identical heterogeneous treatment effects across studies, but this may be violated due to various sources of between-study heterogeneity, including differences in study design, confounders, and sample characteristics. To this end, we propose a unifying framework for multi-study heterogeneous treatment effect estimation that is robust to 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 modern machine learning (ML) in the multi-study setting. The multi-study R-learner is easy to implement and flexible in its ability to incorporate ML for estimating heterogeneous treatment effects, nuisance functions, and membership probabilities, which borrow strength across heterogeneous studies. It achieves robustness in confounding adjustment through its loss function and can leverage both randomized controlled trials and observational studies. We provide asymptotic guarantees for the proposed method in the case of series estimation and illustrate using real cancer data that it has the lowest estimation error compared to existing approaches in the presence of between-study heterogeneity.

We develop a methodology for conducting inference on extreme quantiles of unobserved individual heterogeneity (heterogeneous coefficients, heterogeneous treatment effects, etc.) in a panel data or meta-analysis setting. Inference in such settings is challenging: only noisy estimates of unobserved heterogeneity are available, and approximations based on the central limit theorem work poorly for extreme quantiles. For this situation, under weak assumptions we derive an extreme value theorem and an intermediate order theorem for noisy estimates and appropriate rate and moment conditions. Both theorems are then used to construct confidence intervals for extremal quantiles. The intervals are simple to construct and require no optimization. Inference based on the intermediate order theorem involves a novel self-normalized intermediate order theorem. In simulations, our extremal confidence intervals have favorable coverage properties in the tail. Our methodology is illustrated with an application to firm productivity in denser and less dense areas.

The problem of generalization and transportation of treatment effect estimates from a study sample to a target population is central to empirical research and statistical methodology. In both randomized experiments and observational studies, weighting methods are often used with this objective. Traditional methods construct the weights by separately modeling the treatment assignment and study selection probabilities and then multiplying functions (e.g., inverses) of their estimates. In this work, we provide a justification and an implementation for weighting in a single step. We show a formal connection between this one-step method and inverse probability and inverse odds weighting. We demonstrate that the resulting estimator for the target average treatment effect is consistent, asymptotically Normal, multiply robust, and semiparametrically efficient. We evaluate the performance of the one-step estimator in a simulation study. We illustrate its use in a case study on the effects of physician racial diversity on preventive healthcare utilization among Black men in California. We provide R code implementing the methodology.

A treatment policy defines when and what treatments are applied to affect some outcome of interest. Data-driven decision-making requires the ability to predict what happens if a policy is changed. Existing methods that predict how the outcome evolves under different scenarios assume that the tentative sequences of future treatments are fixed in advance, while in practice the treatments are determined stochastically by a policy and may depend, for example, on the efficiency of previous treatments. Therefore, the current methods are not applicable if the treatment policy is unknown or a counterfactual analysis is needed. To handle these limitations, we model the treatments and outcomes jointly in continuous time, by combining Gaussian processes and point processes. Our model enables the estimation of a treatment policy from observational sequences of treatments and outcomes, and it can predict the interventional and counterfactual progression of the outcome after an intervention on the treatment policy (in contrast with the causal effect of a single treatment). We show with real-world and semi-synthetic data on blood glucose progression that our method can answer causal queries more accurately than existing alternatives.

This paper presents a robust version of the stratified sampling method when multiple uncertain input models are considered for stochastic simulation. Various variance reduction techniques have demonstrated their superior performance in accelerating simulation processes. Nevertheless, they often use a single input model and further assume that the input model is exactly known and fixed. We consider more general cases in which it is necessary to assess a simulation's response to a variety of input models, such as when evaluating the reliability of wind turbines under nonstationary wind conditions or the operation of a service system when the distribution of customer inter-arrival time is heterogeneous at different times. Moreover, the estimation variance may be considerably impacted by uncertainty in input models. To address such nonstationary and uncertain input models, we offer a distributionally robust (DR) stratified sampling approach with the goal of minimizing the maximum of worst-case estimator variances among plausible but uncertain input models. Specifically, we devise a bi-level optimization framework for formulating DR stochastic problems with different ambiguity set designs, based on the $L_2$-norm, 1-Wasserstein distance, parametric family of distributions, and distribution moments. In order to cope with the non-convexity of objective function, we present a solution approach that uses Bayesian optimization. Numerical experiments and the wind turbine case study demonstrate the robustness of the proposed approach.

We consider the task of estimating a conditional density using i.i.d. samples from a joint distribution, which is a fundamental problem with applications in both classification and uncertainty quantification for regression. For joint density estimation, minimax rates have been characterized for general density classes in terms of uniform (metric) entropy, a well-studied notion of statistical capacity. When applying these results to conditional density estimation, the use of uniform entropy -- which is infinite when the covariate space is unbounded and suffers from the curse of dimensionality -- can lead to suboptimal rates. Consequently, minimax rates for conditional density estimation cannot be characterized using these classical results. We resolve this problem for well-specified models, obtaining matching (within logarithmic factors) upper and lower bounds on the minimax Kullback--Leibler risk in terms of the empirical Hellinger entropy for the conditional density class. The use of empirical entropy allows us to appeal to concentration arguments based on local Rademacher complexity, which -- in contrast to uniform entropy -- leads to matching rates for large, potentially nonparametric classes and captures the correct dependence on the complexity of the covariate space. Our results require only that the conditional densities are bounded above, and do not require that they are bounded below or otherwise satisfy any tail conditions.

Learning individualized treatment rules (ITRs) is an important topic in precision medicine. Current literature mainly focuses on deriving ITRs from a single source population. We consider the observational data setting when the source population differs from a target population of interest. Compared with causal generalization for the average treatment effect which is a scalar quantity, ITR generalization poses new challenges due to the need to model and generalize the rules based on a prespecified class of functions which may not contain the unrestricted true optimal ITR. The aim of this paper is to develop a weighting framework to mitigate the impact of such misspecification and thus facilitate the generalizability of optimal ITRs from a source population to a target population. Our method seeks covariate balance over a non-parametric function class characterized by a reproducing kernel Hilbert space and can improve many ITR learning methods that rely on weights. We show that the proposed method encompasses importance weights and overlap weights as two extreme cases, allowing for a better bias-variance trade-off in between. Numerical examples demonstrate that the use of our weighting method can greatly improve ITR estimation for the target population compared with other weighting methods.

Mean-based estimators of the causal effect in a completely randomized experiment (e.g., the difference-in-means estimator) may behave poorly if the potential outcomes have a heavy-tail, or contain outliers. We study an alternative estimator by Rosenbaum that estimates the constant additive treatment effect by inverting a randomization test using ranks. By investigating the breakdown point and asymptotic relative efficiency of this rank-based estimator, we show that it is provably robust against heavy-tailed potential outcomes, and has variance that is asymptotically, in the worst case, at most about 1.16 times that of the difference-in-means estimator; and its variance can be much smaller when the potential outcomes are not light-tailed. We further derive a consistent estimator of the asymptotic standard error for Rosenbaum's estimator which yields a readily computable confidence interval for the treatment effect. Further, we study a regression adjusted version of Rosenbaum's estimator to incorporate additional covariate information in randomization inference. We prove gain in efficiency by this regression adjustment method under a linear regression model. We illustrate through synthetic and real data that, unlike the mean-based estimators, these rank-based estimators (both unadjusted or regression adjusted) are efficient and robust against heavy-tailed distributions, contamination, and model misspecification.

In this paper, we focus on three problems in deep learning based medical image segmentation. Firstly, U-net, as a popular model for medical image segmentation, is difficult to train when convolutional layers increase even though a deeper network usually has a better generalization ability because of more learnable parameters. Secondly, the exponential ReLU (ELU), as an alternative of ReLU, is not much different from ReLU when the network of interest gets deep. Thirdly, the Dice loss, as one of the pervasive loss functions for medical image segmentation, is not effective when the prediction is close to ground truth and will cause oscillation during training. To address the aforementioned three problems, we propose and validate a deeper network that can fit medical image datasets that are usually small in the sample size. Meanwhile, we propose a new loss function to accelerate the learning process and a combination of different activation functions to improve the network performance. Our experimental results suggest that our network is comparable or superior to state-of-the-art methods.