ELISA: An Interpretable Hybrid Generative AI Agent for Expression-Grounded Discovery in Single-Cell Genomics
This addresses the problem of opaque and inaccessible transcriptomic data analysis for researchers in genomics and biology, though it appears incremental as it builds on existing models like scGPT and BioBERT.
The paper tackles the bottleneck of translating single-cell RNA sequencing data into biological hypotheses by introducing ELISA, a hybrid AI agent that unifies expression embeddings with semantic retrieval and LLM interpretation, significantly outperforming CellWhisperer in cell type retrieval (p < 0.001) with large gains on gene-signature queries (Cohen's d = 5.98).
Translating single-cell RNA sequencing (scRNA-seq) data into mechanistic biological hypotheses remains a critical bottleneck, as agentic AI systems lack direct access to transcriptomic representations while expression foundation models remain opaque to natural language. Here we introduce ELISA (Embedding-Linked Interactive Single-cell Agent), an interpretable framework that unifies scGPT expression embeddings with BioBERT-based semantic retrieval and LLM-mediated interpretation for interactive single-cell discovery. An automatic query classifier routes inputs to gene marker scoring, semantic matching, or reciprocal rank fusion pipelines depending on whether the query is a gene signature, natural language concept, or mixture of both. Integrated analytical modules perform pathway activity scoringacross 60+ gene sets, ligand--receptor interaction prediction using 280+ curated pairs, condition-aware comparative analysis, and cell-type proportion estimation all operating directly on embedded data without access to the original count matrix. Benchmarked across six diverse scRNA-seq datasets spanning inflammatory lung disease, pediatric and adult cancers, organoid models, healthy tissue, and neurodevelopment, ELISA significantly outperforms CellWhisperer in cell type retrieval (combined permutation test, $p < 0.001$), with particularly large gains on gene-signature queries (Cohen's $d = 5.98$ for MRR). ELISA replicates published biological findings (mean composite score 0.90) with near-perfect pathway alignment and theme coverage (0.98 each), and generates candidate hypotheses through grounded LLM reasoning, bridging the gap between transcriptomic data exploration and biological discovery. Code available at: https://github.com/omaruno/ELISA-An-AI-Agent-for-Expression-Grounded-Discovery-in-Single-Cell-Genomics.git (If you use ELISA in your research, please cite this work).