# HiRef: Leveraging Hierarchical Ontology and Network Refinement for Robust Medication Recommendation

arXiv: https://arxiv.org/abs/2508.10425 · HTML: https://mlsanity.com/paper/2508.10425/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 9 of its 29 references that are in the map.
- First posted on arXiv 14 Aug 2025.

## Builds on (most cited first, 9 of 9)

- [Large Language Models Encode Clinical Knowledge](https://mlsanity.com/paper/2212.13138/) (2022)
- [Poincar'e Embeddings for Learning Hierarchical Representations](https://mlsanity.com/paper/1705.08039/) (2017)
- [RETAIN: An Interpretable Predictive Model for Healthcare using Reverse Time Attention Mechanism](https://mlsanity.com/paper/1608.05745/) (2016)
- [GRAM: Graph-based Attention Model for Healthcare Representation Learning](https://mlsanity.com/paper/1611.07012/) (2016)
- [Pre-training of Graph Augmented Transformers for Medication Recommendation](https://mlsanity.com/paper/1906.00346/) (2019)
- [GAMENet: Graph Augmented MEmory Networks for Recommending Medication Combination](https://mlsanity.com/paper/1809.01852/) (2018)
- [SafeDrug: Dual Molecular Graph Encoders for Recommending Effective and Safe Drug Combinations](https://mlsanity.com/paper/2105.02711/) (2021)
- [Sparse Graph Attention Networks](https://mlsanity.com/paper/1912.00552/) (2019)
- [Change Matters: Medication Change Prediction with Recurrent Residual Networks](https://mlsanity.com/paper/2105.01876/) (2021)

## Abstract (arXiv)

Medication recommendation is a crucial task for assisting physicians in making timely decisions from longitudinal patient medical records. However, real-world EHR data present significant challenges due to the presence of rarely observed medical entities and incomplete records that may not fully capture the clinical ground truth. While data-driven models trained on longitudinal Electronic Health Records often achieve strong empirical performance, they struggle to generalize under missing or novel conditions, largely due to their reliance on observed co-occurrence patterns. To address these issues, we propose Hierarchical Ontology and Network Refinement for Robust Medication Recommendation (HiRef), a unified framework that combines two complementary structures: (i) the hierarchical semantics encoded in curated medical ontologies, and (ii) refined co-occurrence patterns derived from real-world EHRs. We embed ontology entities in hyperbolic space, which naturally captures tree-like relationships and enables knowledge transfer through shared ancestors, thereby improving generalizability to unseen codes. To further improve robustness, we introduce a prior-guided sparse regularization scheme that refines the EHR co-occurrence graph by suppressing spurious edges while preserving clinically meaningful associations. Our model achieves strong performance on EHR benchmarks (MIMIC-III and MIMIC-IV) and maintains high accuracy under simulated unseen-code settings. Extensive experiments with comprehensive ablation studies demonstrate HiRef's resilience to unseen medical codes, supported by in-depth analyses of the learned sparsified graph structure and medical code embeddings.