Diagnosing Low-Confidence Patient Profiles via Localized Harmful Covariate Shift Detection

Understanding how a prediction model will perform in a new environment before deployment is essential to preventing harm when algorithms inform decision-making. Two common sources of model performance degradation are (i) covariate shift, where the target covariate distribution differs from the source, and (ii) selective labels, where the observability of outcomes depends on historical decisions. We study pre-deployment model evaluation under the joint presence of covariate shift and labeling of outcomes selectively based on observed features. In particular, we present a double machine learning procedure for estimating the target risk of an arbitrary black-box prediction model under a general loss function. We show identification of this estimand under standard assumptions and derive a bias-corrected estimator based on the influence function of the target risk. Finally, we evaluate our estimator through experiments using the eICU electronic health records database, showing that it tracks the true target risk more accurately than methods that address either selective labels or covariate shift alone, as well as baselines that combine standard plug-in approaches.

In routine care, individuals identified a priori as high-risk are usually tested for conditions more frequently. Protected attributes, such as sex or ethnicity may also determine testing frequency. Such heterogeneous detection rates across a population induce label error. This causes systematic model error for specific groups and biases performance metrics during validation. This paper proposes a method to correct for such bias in prediction models due to differential diagnostic delay. We use a causal inference framework to define our target estimand: an individual's diagnosis probability in a counterfactual scenario where their diagnosis rate matches that of a reference group. We model the longitudinal process as a hidden Markov model, in which confirmatory test results are emissions from a latent progressive disease stage. We validate our approach in simulated data and apply it to a case study of chronic kidney disease prediction using electronic health records. In simulations, our method reduces prediction bias and improves calibration-in-the-large, correcting the Observed:Expected ratio in the underdiagnosed group from 1.34 (standard deviation: 0.09) in a model developed without any correction for underdiagnosis bias to 1.02 (0.09). Violations of assumptions in the simulation affected the estimation of model parameters, but the proposed approach nonetheless remained better calibrated than the standard model. In the clinical case study, we identify diabetes as the main driver of observability, with an odds ratio of 10.36 (95% confidence interval, 9.80 - 11.02) in 6-month urine albumin-creatinine ratio testing rate. Using our approach to predict the counterfactual diagnostic rate in patients without diabetes, we improved the Observed:Expected ratio of a developed clinical prediction model from 1.55 (1.51 - 1.59) to 1.01 (0.98 - 1.04).

Developing predictive models that perform reliably across diverse patient populations and heterogeneous environments is a core aim of medical research. However, generalization is only possible if the learned model is robust to statistical differences between data used for training and data seen at the time and place of deployment. Domain generalization methods provide strategies to address data shifts, but each method comes with its own set of assumptions and trade-offs. To apply these methods in healthcare, we must understand how domain shifts arise, what assumptions we prefer to make, and what our design constraints are. This article proposes a causal framework for the design of predictive models to improve generalization. Causality provides a powerful language to characterize and understand diverse domain shifts, regardless of data modality. This allows us to pinpoint why models fail to generalize, leading to more principled strategies to prepare for and adapt to shifts. We recommend general mitigation strategies, discussing trade-offs and highlighting existing work. Our causality-based perspective offers a critical foundation for developing robust, interpretable, and clinically relevant AI solutions in healthcare, paving the way for reliable real-world deployment.