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Autonomous learning of pathologists' cancer grading rules

Nguyen, T. H.; Panwar, V.; Jarmale, V.; Perny, A.; Dusek, C.; Cai, Q.; Kapur, P. H.; Danuser, G.; Rajaram, S.

2025-03-19 bioinformatics
10.1101/2025.03.18.643999 bioRxiv
Show abstract

Deep learning has revealed that tissue morphology contains rich biological information beyond human understanding. However, approaches to convert these spatially distributed signals into precise subcellular insights informing disease mechanism are lacking. We introduce Delta-Marches, an interpretability-first approach that nominates distinguishing morphological features rather than explaining existing models decisions. Delta-Marches leverages a generative AI framework with latent-space traversals that simulate idealized morphological changes between classes. Comparing each image to its class-shifted counterpart allows downstream feature extractors to infer aspects most affected by the shift, reducing sample-to-sample variability and yielding interpretable morphological transformations at subcellular resolution. Prototyped in renal carcinoma histopathological grading, Delta-Marches generates realistic grade transitions and pinpoints tumor-cell nuclear phenotypes as key properties of tumor grades. It also reveals reduced vasculature associated with increasing grade, a pattern reported in studies but absent from standard grading rubrics. These results indicate Delta-Marchs ability to parse complex image phenotypes and catalyze hypothesis generation.

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