Alaleh Azhir

Jingya Cheng, Alaleh Azhir, Jiazi Tian et al.

Counterfactual inference enables clinicians to ask "what if" questions about patient outcomes, but standard methods assume feature independence and simultaneous modifiability -- assumptions violated by longitudinal clinical data. We introduce the Sequential Counterfactual Framework, which respects temporal dependencies in electronic health records by distinguishing immutable features (chronic diagnoses) from controllable features (lab values) and modeling how interventions propagate through time. Applied to 2,723 COVID-19 patients (383 Long COVID heart failure cases, 2,340 matched controls), we demonstrate that 38-67% of patients with chronic conditions would require biologically impossible counterfactuals under naive methods. We identify a cardiorenal cascade (CKD -> AKI -> HF) with relative risks of 2.27 and 1.19 at each step, illustrating temporal propagation that sequential -- but not naive -- counterfactuals can capture. Our framework transforms counterfactual explanation from "what if this feature were different?" to "what if we had intervened earlier, and how would that propagate forward?" -- yielding clinically actionable insights grounded in biological plausibility.

Jingya Cheng, Alaleh Azhir, Jiazi Tian et al.

Counterfactual inference provides a mathematical framework for reasoning about hypothetical outcomes under alternative interventions, bridging causal reasoning and predictive modeling. We present a counterfactual inference framework for individualized risk estimation and intervention analysis, illustrated through a clinical application to post-acute sequelae of COVID-19 (PASC) among patients with pre-existing heart failure (HF). Using longitudinal diagnosis, laboratory, and medication data from a large health-system cohort, we integrate regularized predictive modeling with counterfactual search to identify actionable pathways to PASC-related HF hospital admissions. The framework combines exact enumeration with optimization-based methods, including the Nearest Instance Counterfactual Explanations (NICE) and Multi-Objective Counterfactuals (MOC) algorithms, to efficiently explore high-dimensional intervention spaces. Applied to more than 2700 individuals with confirmed SARS-CoV-2 infection and prior HF, the model achieved strong discriminative performance (AUROC: 0.88, 95% CI: 0.84-0.91) and generated interpretable, patient-specific counterfactuals that quantify how modifying comorbidity patterns or treatment factors could alter predicted outcomes. This work demonstrates how counterfactual reasoning can be formalized as an optimization problem over predictive functions, offering a rigorous, interpretable, and computationally efficient approach to personalized inference in complex biomedical systems.

Jingya Cheng, Jiazi Tian, Federica Spoto et al.

\textbf{Background:} Machine learning models trained on electronic health records (EHRs) often degrade across healthcare systems due to distributional shift. A fundamental but underexplored factor is diagnostic signal decay: variability in diagnostic quality and consistency across institutions, which affects the reliability of codes used for training and prediction. \textbf{Objective:} To develop a Signal Fidelity Index (SFI) quantifying diagnostic data quality at the patient level in dementia, and to test SFI-aware calibration for improving model performance across heterogeneous datasets without outcome labels. \textbf{Methods:} We built a simulation framework generating 2,500 synthetic datasets, each with 1,000 patients and realistic demographics, encounters, and coding patterns based on dementia risk factors. The SFI was derived from six interpretable components: diagnostic specificity, temporal consistency, entropy, contextual concordance, medication alignment, and trajectory stability. SFI-aware calibration applied a multiplicative adjustment, optimized across 50 simulation batches. \textbf{Results:} At the optimal parameter ($α$ = 2.0), SFI-aware calibration significantly improved all metrics (p $<$ 0.001). Gains ranged from 10.3\% for Balanced Accuracy to 32.5\% for Recall, with notable increases in Precision (31.9\%) and F1-score (26.1\%). Performance approached reference standards, with F1-score and Recall within 1\% and Balanced Accuracy and Detection Rate improved by 52.3\% and 41.1\%, respectively. \textbf{Conclusions:} Diagnostic signal decay is a tractable barrier to model generalization. SFI-aware calibration provides a practical, label-free strategy to enhance prediction across healthcare contexts, particularly for large-scale administrative datasets lacking outcome labels.