Hierarchical Classification via Cascading Feature Elimination: Application to Human Phenotype Ontology-Aligned Facial Phenotyping (FaceMesh2HPO)

More than 300 million people worldwide are affected by one of over 7,000 known rare diseases, yet diagnosis remains difficult because patients initially present with incomplete and heterogeneous phenotypes. We present HPOQuest, a training-free framework for sequential phenotype acquisition in rare-disease diagnosis. Starting from a small set of observed patient phenotypes, HPOQuest maintains a probabilistic disease ranking and iteratively selects informative follow-up questions to support clinicians during patient assessment. Confirmed phenotypes update the disease ranking, while all responses update the candidate question set. Across four benchmark cohorts, HPOQuest substantially improves diagnosis from sparse initial phenotypes, with gains of up to 30% points at Recall@1 and 45% points at Recall@5. These results demonstrate that sequential phenotype acquisition can substantially improve rare-disease diagnosis from limited initial clinical evidence.

AI-assisted facial phenotyping supports rare genetic disorder prioritization by retrieving visually similar diagnosed cases from facial image reference databases such as the GestaltMatcher Database (GMDB). Existing GestaltMatcher-based retrieval frameworks compare each test image with individual gallery images in a facial phenotype embedding space. However, this pointwise formulation does not fully exploit available evidence, because patients may have multiple images and disorders may be represented by multiple diagnosed gallery patients. We propose an inference-time multi-level evidence aggregation framework that improves facial phenotype retrieval without modifying the underlying GestaltMatcher-Arc encoder. The framework combines embedding-level patient aggregation of multiple images from the same individual, patient-weighted disorder centroids, and hybrid individual-centroid scoring to integrate test-patient observations, disorder-level gallery evidence, and local nearest-neighbor evidence. We evaluated the approach on GMDB v1.1.4 across disorders represented during training (GMDB-Freq), unseen disorders (GMDB-Rare), and multi-image patient subsets, using a unified gallery containing both GMDB-Freq and GMDB-Rare disorders. Multi-level evidence aggregation improved mean per-disorder top-$N$ retrieval accuracy across all evaluation subsets. Top-1 accuracy increased from 38.52% to 48.82% on GMDB-Freq and from 19.38% to 23.79% on GMDB-Rare. On multi-image subsets, top-1 accuracy increased from 46.12% to 60.94% on GMDB-Multi-Freq and from 18.54% to 26.71% on GMDB-Multi-Rare. These findings show that inference-time aggregation can improve next-generation facial phenotype retrieval without retraining the encoder, supporting a shift from isolated single-image matching toward multi-level aggregation of patient and disorder evidence for rare-disorder prioritization.

Bone-marrow cytology is inherently structured: each cell belongs to a hematopoietic lineage, and many cell types lie on ordered maturation trajectories. Standard flat classifiers ignore this structure, treating a mild same-lineage confusion the same as a severe cross-lineage mistake and predicting only discrete labels. We propose HemaHier, an ordinal-hierarchical prediction head for a frozen or lightly adapted cytology foundation model. Its central component is a chain-conditioned maturity score that reads a single maturity value under a per-chain query, supervised only on biologically valid healthy chains, while dysplastic and off-chain cell types remain classes but are excluded from maturity supervision. Fine and lineage predictions are coupled through a shared posterior that guarantees hierarchical consistency, and a staged objective first stabilizes recognition, then adds lineage and maturity supervision. On three bone-marrow datasets under a shared ontology, HemaHier achieves competitive recognition while reducing biologically severe errors and adding a within-lineage maturity ordering that flat classifiers lack. Code is available at https://github.com/xmindflow/HemaHier.