# Survey and Improvement Strategies for Gene Prioritization with Large Language Models

arXiv: https://arxiv.org/abs/2501.18794 · HTML: https://mlsanity.com/paper/2501.18794/

## Key facts

- Cited by 2 papers in the map (data through 14 Oct 2026).
- Builds on 15 of its 42 references that are in the map.
- First posted on arXiv 30 Jan 2025.

## Builds on (most cited first, 15 of 15)

- [Attention Is All You Need](https://mlsanity.com/paper/1706.03762/) (2017)
- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [GPT-4 Technical Report](https://mlsanity.com/paper/2303.08774/) (2023)
- [Llama 2: Open Foundation and Fine-Tuned Chat Models](https://mlsanity.com/paper/2307.09288/) (2023)
- [Judging LLM-as-a-Judge with MT-Bench and Chatbot Arena](https://mlsanity.com/paper/2306.05685/) (2023)
- [Sparks of Artificial General Intelligence: Early experiments with GPT-4](https://mlsanity.com/paper/2303.12712/) (2023)
- [Large Language Models Encode Clinical Knowledge](https://mlsanity.com/paper/2212.13138/) (2022)
- [Mixtral of Experts](https://mlsanity.com/paper/2401.04088/) (2024)
- [SuperGLUE: A Stickier Benchmark for General-Purpose Language Understanding Systems](https://mlsanity.com/paper/1905.00537/) (2019)
- [Can Generalist Foundation Models Outcompete Special-Purpose Tuning? Case Study in Medicine](https://mlsanity.com/paper/2311.16452/) (2023)
- [BioMistral: A Collection of Open-Source Pretrained Large Language Models for Medical Domains](https://mlsanity.com/paper/2402.10373/) (2024)
- [Adapted Large Language Models Can Outperform Medical Experts in Clinical Text Summarization](https://mlsanity.com/paper/2309.07430/) (2023)
- [LLM-Eval: Unified Multi-Dimensional Automatic Evaluation for Open-Domain Conversations with Large Language Models](https://mlsanity.com/paper/2305.13711/) (2023)
- [Look at the First Sentence: Position Bias in Question Answering](https://mlsanity.com/paper/2004.14602/) (2020)
- [Large Language Models for Healthcare Data Augmentation: An Example on Patient-Trial Matching](https://mlsanity.com/paper/2303.16756/) (2023)

## Built on by (most cited first, 2 of 2)

- [Self-ensemble: Mitigating Confidence Mis-calibration for Large Language Models](https://mlsanity.com/paper/2506.01951/) (2025)
- [LA-MARRVEL: A Knowledge-Grounded, Language-Aware LLM Framework for Clinically Robust Rare Disease Gene Prioritization](https://mlsanity.com/paper/2511.02263/) (2025)

## Abstract (arXiv)

Rare diseases are challenging to diagnose due to limited patient data and genetic diversity. Despite advances in variant prioritization, many cases remain undiagnosed. While large language models (LLMs) have performed well in medical exams, their effectiveness in diagnosing rare genetic diseases has not been assessed. To identify causal genes, we benchmarked various LLMs for gene prioritization. Using multi-agent and Human Phenotype Ontology (HPO) classification, we categorized patients based on phenotypes and solvability levels. As gene set size increased, LLM performance deteriorated, so we used a divide-and-conquer strategy to break the task into smaller subsets. At baseline, GPT-4 outperformed other LLMs, achieving near 30% accuracy in ranking causal genes correctly. The multi-agent and HPO approaches helped distinguish confidently solved cases from challenging ones, highlighting the importance of known gene-phenotype associations and phenotype specificity. We found that cases with specific phenotypes or clear associations were more accurately solved. However, we observed biases toward well-studied genes and input order sensitivity, which hindered gene prioritization. Our divide-and-conquer strategy improved accuracy by overcoming these biases. By utilizing HPO classification, novel multi-agent techniques, and our LLM strategy, we improved causal gene identification accuracy compared to our baseline evaluation. This approach streamlines rare disease diagnosis, facilitates reanalysis of unsolved cases, and accelerates gene discovery, supporting the development of targeted diagnostics and therapies.