Uncertainty-Aware Multiscale Treatment Response Forecasting in Advanced Non-Small Cell Lung Cancer Using Residual-Variance Conformal Prediction

Voxel-level prediction of treatment response from longitudinal Fluorodexoyglucose (FDG) positron emission tomography / computed tomography (PET/CT) can enable spatially adaptive dose planning in advanced non-small cell lung cancer (NSCLC), but point predictions alone lack the uncertainty quantification needed for safe clinical decision-making. Standard conformal prediction (CP) provides distribution-free coverage but yields spatially uniform intervals and assumes exchangeability—an assumption violated by intra-tumoral spatial correlation. We propose a multiscale CP framework built on a re-optimized VoxelForecast generalized least squares model that explicitly captures voxel-level covariance. Variogram sensitivity analysis identified the Stable model as significantly superior to previouly used Matérn family. The framework combines hierarchical nested leave-one-patient-out calibration, which restores exchangeability for valid voxel-level coverage, with residual-variance CP (VarCP), which learns a heteroscedastic, location-dependent scale to produce adaptive intervals while preserving finite-sample marginal coverage guarantees. On two prospective NSCLC trial cohorts—FLARE-RT (N=25 locally advanced, chemoradio-therapy; 11,100 voxels) and BRIGHT (N=19 metastatic, chemoimmunotherapy; 26,980 voxels)—multiscale feature integration reduced voxel-level prediction error by 35% and 31%, respectively. VarCP maintained nominal coverage while producing 7–18% (FLARE-RT) and 4–8% (BRIGHT) narrower voxel-level intervals than a hierarchically calibrated standard CP baseline (paired Wilcoxon signed-rank, significant at most miscoverage levels), with comparable lesion-level gains (7–18% and 6–10%) via median-based aggregation of voxel residuals. VarCP delivers tighter yet mathematically guaranteed spatial uncertainty maps, supporting both voxel-level dose-adjustment and whole-lesion treatment planning in advanced NSCLC.