Training-inference input alignment outweighs framework choice in longitudinal retinal image prediction

TL;DR

This study shows that aligning training and inference inputs is more crucial than model complexity for predicting retinal disease progression from longitudinal images, especially when variability dominates disease signals.

Contribution

The paper introduces a framework to assess the necessary generative complexity based on task entropy and demonstrates its effectiveness in retinal image prediction tasks.

Findings

Training-inference alignment significantly improves prediction quality.

Framework-based assessment guides appropriate model complexity.

Deterministic models perform comparably or better when disease progression is slow.

Abstract

Predicting disease progression from longitudinal imaging is useful for clinical decision making and trial design. Recent methods have moved toward increasing generative complexity, but the conditions under which this complexity is necessary remain unclear. We propose that generative complexity should match the entropy of the predictable component of a task's conditional posterior, with training-inference input alignment required in all regimes. Two model-light measurements, a task-entropy analysis on raw image pairs and a posterior-concentration analysis on a stochastic model, let practitioners assess the complexity a task warrants before committing to a modeling framework. We validated this framework on a fundus autofluorescence (FAF) dataset by contrasting five conditioning configurations, sharing one architecture and training set, spanning standard conditional diffusion, inference-aligned stochastic training, and deterministic regression. Training-inference alignment produced large gains (delta-SSIM +0.082, SSIM +0.086, both p < 0.001), while the choice among aligned frameworks produced no clinically meaningful difference across evaluated metrics. Across two FAF platforms, inter-visit change was dominated by time-invariant acquisition variability rather than disease progression, and the stochastic models' posteriors collapsed to an effective point, explaining the framework equivalence. We trained a deterministic Temporal Retinal U-Net (TRU) and evaluated it on 28,899 eyes across three manufacturers and two modalities (two FAF platforms and en-face SLO), with three independent cohorts evaluated zero-shot. TRU matched or exceeded three published baselines on delta-SSIM, SSIM, and PSNR. These findings show that when disease progression is slow compared with acquisition variability, a deterministic regression model matches or outperforms more complex stochastic alternatives.