Interpretable machine learning for coeliac disease diagnosis: quantitative morphometry of duodenal biopsies

Background Coeliac disease affects approximately 1% of the global population and remains substantially underdiagnosed. Histopathological assessment of duodenal biopsies is the diagnostic gold standard but is subject to approximately 20% inter-observer disagreement. While machine learning approaches show promise, most prior work relies on black-box models with limited interpretability, restricting clinical adoption. Methods We present an interpretable pipeline that follows established histopathological criteria by extracting clinically meaningful morphological features from H&E-stained whole-slide images. Five sequential stages perform pre-processing, semantic segmentation of villi, crypts, intraepithelial lymphocytes (IELs) and enterocytes, crypt morphometry, villus length estimation via a novel polyline-based keypoint model, and coeliac disease classification using three quantitative features: IEL-to-enterocyte ratio, villus-to-crypt area ratio, and villus-length-to-crypt-depth ratio. Training and validation used data from four institutions; independent testing used 1,357 WSIs from two further institutions including one with a previously unseen scanner manufacturer, spanning five diagnostic categories: coeliac disease, normal mucosa, chronic inflammation, gastric metaplasia, and gastric heterotopia. Results Semantic segmentation achieved villus and crypt precision and recall of 87-90%. Villus length estimation correlated strongly with expert annotations (Pearson's r=0.85, mean relative error 13.5% post-calibration). All three morphological features significantly separated coeliac disease from all non-coeliac diagnostic groups across internal and external datasets (p<0.01 in all comparisons). On the test set the diagnostic classifier achieved accuracy 94.5%, PPV 92.9%, NPV 94.7%, and AUC 0.982. Conclusions This interpretable framework achieves strong multi-centre diagnostic performance while producing quantitative morphological outputs, villus length, crypt depth, and IEL-to-enterocyte ratios, that directly reflect established histopathological criteria, representing a meaningful step towards standardised AI-assisted coeliac disease diagnosis.