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.

Alaleh Azhir, Shawn N. Murphy, Hossein Estiri

Machine learning in medicine is typically optimized for population averages. This frequency weighted training privileges common presentations and marginalizes rare yet clinically critical cases, a bias we call the average patient fallacy. In mixture models, gradients from rare cases are suppressed by prevalence, creating a direct conflict with precision medicine. Clinical vignettes in oncology, cardiology, and ophthalmology show how this yields missed rare responders, delayed recognition of atypical emergencies, and underperformance on vision-threatening variants. We propose operational fixes: Rare Case Performance Gap, Rare Case Calibration Error, a prevalence utility definition of rarity, and clinically weighted objectives that surface ethical priorities. Weight selection should follow structured deliberation. AI in medicine must detect exceptional cases because of their significance.

Pedram Fard, Alaleh Azhir, Neguine Rezaii et al.

Artificial intelligence in medicine is built to serve the average patient. By minimizing error across large datasets, most systems deliver strong aggregate accuracy yet falter at the margins: patients with rare variants, multimorbidity, or underrepresented demographics. This average patient fallacy erodes both equity and trust. We propose a different design: a multi-agent ecosystem for N-of-1 decision support. In this environment, agents clustered by organ systems, patient populations, and analytic modalities draw on a shared library of models and evidence synthesis tools. Their results converge in a coordination layer that weighs reliability, uncertainty, and data density before presenting the clinician with a decision-support packet: risk estimates bounded by confidence ranges, outlier flags, and linked evidence. Validation shifts from population averages to individual reliability, measured by error in low-density regions, calibration in the small, and risk--coverage trade-offs. Anticipated challenges include computational demands, automation bias, and regulatory fit, addressed through caching strategies, consensus checks, and adaptive trial frameworks. By moving from monolithic models to orchestrated intelligence, this approach seeks to align medical AI with the first principle of medicine: care that is transparent, equitable, and centered on the individual.

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.

Louis-Henri Merino, Simone Colombo, Rene Reyes et al.

Online voting is convenient and flexible, but amplifies the risks of voter coercion and vote buying. One promising mitigation strategy enables voters to give a coercer fake voting credentials, which silently cast votes that do not count. Current systems along these lines make problematic assumptions about credential issuance, however, such as strong trust in a registrar and/or in voter-controlled hardware, or expecting voters to interact with multiple registrars. Votegral is the first coercion-resistant voting architecture that leverages the physical security of in-person registration to address these credential-issuance challenges, amortizing the convenience costs of in-person registration by reusing credentials across successive elections. Votegral's registration component, TRIP, gives voters a kiosk in a privacy booth with which to print real and fake credentials on paper, eliminating dependence on trusted hardware in credential issuance. The voter learns and can verify in the privacy booth which credential is real, but real and fake credentials thereafter appear indistinguishable to others. Only voters actually under coercion, a hopefully-rare case, need to trust the kiosk. To achieve verifiability, each paper credential encodes an interactive zero-knowledge proof, which is sound in real credentials but unsound in fake credentials. Voters observe the difference in the order of printing steps, but need not understand the technical details. Experimental results with our prototype suggest that Votegral is practical and sufficiently scalable for real-world elections. User-visible latency of credential issuance in TRIP is at most 19.7 seconds even on resource-constrained kiosk hardware. A companion usability study indicates that TRIP's usability is competitive with other e-voting systems, and formal proofs support TRIP's combination of coercion-resistance and verifiability.