CASCADE Conformal Prediction: Uncertainty-Adaptive Prediction Intervals for Two-Stage Clinical Decision Support

Effective medication management in Parkinson's Disease (PD) is challenging due to heterogeneous disease progression, variable patient response, and medication side effects. While AI models can forecast levodopa equivalent daily dose (LEDD) as a measure of medication needs, standard uncertainty quantification often fails to communicate the reliability of these predictions, treating high and low confidence clinical decisions identically. We introduce CASCADE (Calibrated Adaptive Scaling via Conformal And Distributional Estimation), a novel conformal prediction framework that propagates epistemic uncertainty from a screening classifier to adapt downstream predictions. Unlike standard conformal methods that rely on auxiliary residual regression, we leverage epistemic uncertainty from a primary classification task (identifying whether a medication change is needed) to dynamically scale the prediction intervals of a secondary regression task (predicting how much change). By mapping Venn-Abers multi-probabilistic uncertainty directly to non-conformity scores, our framework achieves continuous risk adaptation. We demonstrate that this ``cascade effect'' produces highly efficient intervals for confident patients (38.9% narrower than standard conformal baselines) while automatically expanding intervals to ensure robust coverage for uncertain cases, bridging the gap between discrete clinical decision-making and continuous dose forecasting in PD.

Uncertainty-Aware Prediction of Parkinson's Disease Medication Needs: A Two-Stage Conformal Prediction Approach

Parkinson's Disease (PD) medication management presents unique challenges due to heterogeneous disease progression and treatment response. Neurologists must balance symptom control with optimal dopaminergic dosing based on functional disability while minimizing side effects. This balance is crucial as inadequate or abrupt changes can cause levodopa-induced dyskinesia, wearing off, and neuropsychiatric effects, significantly reducing quality of life. Current approaches rely on trial-and-error decisions without systematic predictive methods. Despite machine learning advances, clinical adoption remains limited due to reliance on point predictions that do not account for prediction uncertainty, undermining clinical trust and utility. Clinicians require not only predictions of future medication needs but also reliable confidence measures. Without quantified uncertainty, adjustments risk premature escalation to maximum doses or prolonged inadequate symptom control. We developed a conformal prediction framework anticipating medication needs up to two years in advance with reliable prediction intervals and statistical guarantees. Our approach addresses zero-inflation in PD inpatient data, where patients maintain stable medication regimens between visits. Using electronic health records from 631 inpatient admissions at University of Florida Health (2011-2021), our two-stage approach identifies patients likely to need medication changes, then predicts required levodopa equivalent daily dose adjustments. Our framework achieved marginal coverage while reducing prediction interval lengths compared to traditional approaches, providing precise predictions for short-term planning and wider ranges for long-term forecasting. By quantifying uncertainty, our approach enables evidence-based decisions about levodopa dosing, optimizing symptom control while minimizing side effects and improving life quality.

LAVA: Granular Neuron-Level Explainable AI for Alzheimer's Disease Assessment from Fundus Images

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the leading cause of dementia. Early diagnosis is critical for patients to benefit from potential intervention and treatment. The retina has been hypothesized as a diagnostic site for AD detection owing to its anatomical connection with the brain. Developed AI models for this purpose have yet to provide a rational explanation about the decision and neither infer the stage of disease's progression. Along this direction, we propose a novel model-agnostic explainable-AI framework, called Granular Neuron-level Explainer (LAVA), an interpretation prototype that probes into intermediate layers of the Convolutional Neural Network (CNN) models to assess the AD continuum directly from the retinal imaging without longitudinal or clinical evaluation. This method is applied to validate the retinal vasculature as a biomarker and diagnostic modality for Alzheimer's Disease (AD) evaluation. UK Biobank cognitive tests and vascular morphological features suggest LAVA shows strong promise and effectiveness in identifying AD stages across the progression continuum.