When perfect is a warning: explanations expose shortcuts that accuracy hides in cancer gene-expression classifiers

When the classes in a training set come from different data sources, a classifier can score near-perfectly while learning where a sample came from. We show this for cancer classifiers trained on tumours from The Cancer Genome Atlas and normal tissue from the Genotype Tissue Expression project. Six model families, including a tabular foundation model, reached an area under the curve of 1.000 yet called 80 to 97% of tumour adjacent normal tissue cancer, and 100% in an independent cohort; a few matched normal samples per tissue removed most of this shortcut. Near-perfect accuracy could not tell a shortcut from an honestly easy task, flagging 87 to 92% of models trained on such tasks. We introduce a label free score, computed from model explanations, that uses the fact that a source difference looks the same in every tissue whereas cancer changes do not. It raised no false alarms, ranked models by their real reliance on the source, transferred to unseen model types and data, and failed where its theory predicts.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-11-03
DOI
https://doi.org/10.64898/2026.11.02.763649
Primary Topic
Gene expression and cancer classification
Type
preprint
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preprint

When perfect is a warning: explanations expose shortcuts that accuracy hides in cancer gene-expression classifiers

Hamail Ayaz, Muhammad Mahmood Ali, Ayodeji Ibitoye, OLADOSU OLADIMEJI et al.
bioRxiv (Cold Spring Harbor Laboratory)
Gene expression and cancer classification
preprint

When perfect is a warning: explanations expose shortcuts that accuracy hides in cancer gene-expression classifiers

Hamail Ayaz, Muhammad Mahmood Ali, Ayodeji Ibitoye, OLADOSU OLADIMEJI, Pooja Verma
preprint en

Abstract

When the classes in a training set come from different data sources, a classifier can score near-perfectly while learning where a sample came from. We show this for cancer classifiers trained on tumours from The Cancer Genome Atlas and normal tissue from the Genotype Tissue Expression project. Six model families, including a tabular foundation model, reached an area under the curve of 1.000 yet called 80 to 97% of tumour adjacent normal tissue cancer, and 100% in an independent cohort; a few matched normal samples per tissue removed most of this shortcut. Near-perfect accuracy could not tell a shortcut from an honestly easy task, flagging 87 to 92% of models trained on such tasks. We introduce a label free score, computed from model explanations, that uses the fact that a source difference looks the same in every tissue whereas cancer changes do not. It raised no false alarms, ranked models by their real reliance on the source, transferred to unseen model types and data, and failed where its theory predicts.

bioRxiv (Cold Spring Harbor Laboratory)
University of Greenwich (GB)
Gene expression and cancer classification
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When perfect is a warning: explanations expose shortcuts that accuracy hides in cancer gene-expression classifiers — Hamail Ayaz, Muhammad Mahmood Ali, et al. · bioRxiv (Cold Spring Harbor Laboratory) (2026) | TGRS Research Map | TGRS