GraphRareBench: An Auditable Graph-Evidence Benchmark for Phenotype-Driven Rare-Disease Diagnosis

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.

Deeply phenotyped cohorts combine clinical, imaging, molecular, and wearable observations across timescales from seconds to years, but heterogeneous analyses are not directly comparable. We present PhenoBench, an executable benchmark that turns deep-phenotyping measurements into explicit questions and controlled comparisons of information sources and predictive models. It is built around the Human Phenotype Project, with more than 13,000 participants at the initial visit. Each question fixes the target, population, timing, and allowed information; its evaluation contract specifies the split, metric, baseline, and claim boundary. PhenoBench defines 90 clinically grounded tasks across 15 domains and 26 input modalities. Across 160 matched regression comparisons spanning 52 tasks, six pretrained tabular models ranked above the evaluated task-specific baselines, including XGBoost and CatBoost, under a fixed single-estimator protocol with bounded tuning. Giving each task equal weight, their mean advantage over ridge was 0.0103 $R^2$ (95% task-bootstrap interval, 0.0071-0.0136). We also evaluated 14 language models, collectively covering 40 tasks spanning phenotype recovery, classification, follow-up forecasting, and participant ordering. Without cohort-specific fitting, language models made informative predictions on some tasks but showed task-specific capability gaps, shared failures of scale, and rarely surpassed task-specific ridge or logistic regression models fitted on the same input fields. PhenoBench provides a versioned, auditable evaluation system where new questions, measurements, and models can be added without redefining existing comparisons.