Knowledgeable Language Models as Black-Box Optimizers for Personalized Medicine

ICLR 2026 Conference Submission22172 Authors

Keywords: Large language models, Personalized medicine, Black-box optimization, Distribution shift

TL;DR: We show how to use large language models to draw on medical knowledge to suggest personalized treatments for patients under distribution shift.

Abstract: The goal of personalized medicine is to discover a treatment regimen that optimizes a patient's clinical outcome based on their personal genetic and environmental factors. However, candidate treatments cannot be arbitrarily administered to the patient to assess their efficacy; we often instead have access to an *in silico* surrogate model that approximates the true fitness of a proposed treatment. Unfortunately, such surrogate models have been shown to fail to generalize to previously unseen patient-treatment combinations. We hypothesize that domain-specific prior knowledge—such as medical textbooks and biomedical knowledge graphs—can provide a meaningful alternative signal of the fitness of proposed treatments. To this end, we introduce **L**LM-based **E**ntropy-guided **O**ptimization with k**N**owledgeable priors (**LEON**), a mathematically principled approach to leverage large language models (LLMs) as black-box optimizers without any task-specific fine-tuning, taking advantage of their ability to contextualize unstructured domain knowledge to propose personalized treatment plans in natural language. In practice, we implement LEON via 'optimization by prompting,' which uses LLMs as stochastic engines for proposing treatment designs. Experiments on real-world optimization tasks show LEON outperforms both traditional and LLM-based methods in proposing individualized treatments for patients.

Primary Area: applications to physical sciences (physics, chemistry, biology, etc.)

Submission Number: 22172