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# Cell-o1: Training LLMs to Solve Single-Cell Reasoning Puzzles with Reinforcement Learning
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> [!Note]
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> Please refer to our [repository](https://github.com/ncbi-nlp/cell-o1) and [paper](https://www.arxiv.org/abs/2506.02911) for more details.
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Cell type annotation is a key task in analyzing the heterogeneity of single-cell RNA sequencing data. Although recent foundation models automate this process, they typically annotate cells independently, without considering batch-level cellular context or providing explanatory reasoning. In contrast, human experts often annotate distinct cell types for different cell clusters based on their domain knowledge.
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To mimic this expert behavior, we introduce ***CellPuzzles***—a benchmark requiring unique cell-type assignments across cell batches. Existing LLMs struggle with this task, with the best baseline (OpenAI's o1) achieving only 19.0% batch accuracy. To address this, we present ***Cell-o1***, a reasoning-enhanced language model trained via SFT on distilled expert traces, followed by RL with batch-level rewards. ***Cell-o1*** outperforms all baselines on both cell-level and batch-level metrics, and exhibits emergent behaviors such as self-reflection and curriculum reasoning, offering insights into its interpretability and generalization.
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## 🚀 How to Run Inference
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# Cell-o1: Training LLMs to Solve Single-Cell Reasoning Puzzles with Reinforcement Learning
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> [!Note]
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> Please refer to our [repository](https://github.com/ncbi-nlp/cell-o1) and [paper](https://www.arxiv.org/abs/2506.02911) for more details.
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Cell type annotation is a key task in analyzing the heterogeneity of single-cell RNA sequencing data. Although recent foundation models automate this process, they typically annotate cells independently, without considering batch-level cellular context or providing explanatory reasoning. In contrast, human experts often annotate distinct cell types for different cell clusters based on their domain knowledge.
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To mimic this expert behavior, we introduce ***CellPuzzles***—a benchmark requiring unique cell-type assignments across cell batches. Existing LLMs struggle with this task, with the best baseline (OpenAI's o1) achieving only 19.0% batch accuracy. To address this, we present ***Cell-o1***, a reasoning-enhanced language model trained via SFT on distilled expert traces, followed by RL with batch-level rewards. ***Cell-o1*** outperforms all baselines on both cell-level and batch-level metrics, and exhibits emergent behaviors such as self-reflection and curriculum reasoning, offering insights into its interpretability and generalization.
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<p align="center">
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<img src="assets/overview.png" alt="CellPuzzles Overview" width="95%">
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</p>
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## 🚀 How to Run Inference
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