Systematic Evaluation of Single-Cell Foundation Model Interpretability Reveals Attention Captures Co-Expression Rather Than Unique Regulatory Signal
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Abstract (arXiv)
We present a systematic evaluation framework - thirty-seven analyses, 153 statistical tests, four cell types, two perturbation modalities - for assessing mechanistic interpretability in single-cell foundation models. Applying this framework to scGPT and Geneformer, we find that attention patterns encode structured biological information with layer-specific organisation - protein-protein interactions in early layers, transcriptional regulation in late layers - but this structure provides no incremental value for perturbation prediction: trivial gene-level baselines outperform both attention and correlation edges (AUROC 0.81-0.88 versus 0.70), pairwise edge scores add zero predictive contribution, and causal ablation of regulatory heads produces no degradation. These findings generalise from K562 to RPE1 cells; the attention-correlation relationship is context-dependent, but gene-level dominance is universal. Cell-State Stratified Interpretability (CSSI) addresses an attention-specific scaling failure, improving GRN recovery up to 1.85x. The framework establishes reusable quality-control standards for the field.
Key facts. Cited by 7 papers in the map (data through 7 Oct 2026). First posted on arXiv 19 Feb 2026.
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Citing papers per year: 2026: 7.
7 papers.
- 2026Sparse autoencoders reveal organized biological knowledge but minimal regulatory logic in single-cell foundation models: a comparative atlas of Geneformer and scGPTcited by 4
- 2026From Observation to Insight: Mechanistic World Models and the Quest for Autonomous Discoverycited by 4
- 2026Multi-Dimensional Spectral Geometry of Biological Knowledge in Single-Cell Transformer Representationscited by 1
- 2026Causal Circuit Tracing Reveals Distinct Computational Architectures in Single-Cell Foundation Models: Inhibitory Dominance, Biological Coherence, and Cross-Model Convergencecited by 1
- 2026What Topological and Geometric Structure Do Biological Foundation Models Learn? Evidence from 141 Hypothesescited by 0
- 2026Discovery of a Hematopoietic Manifold in scGPT Yields a Method for Extracting Performant Algorithms from Biological Foundation Model Internalscited by 0
- 2026Exhaustive Circuit Mapping of a Single-Cell Foundation Model Reveals Massive Redundancy, Heavy-Tailed Hub Architecture, and Layer-Dependent Differentiation Controlcited by 0
- 2026From Observation to Insight: Mechanistic World Models and the Quest for Autonomous Discovery14 Jul 2026
- 2026Exhaustive Circuit Mapping of a Single-Cell Foundation Model Reveals Massive Redundancy, Heavy-Tailed Hub Architecture, and Layer-Dependent Differentiation Control12 Mar 2026
- 2026Discovery of a Hematopoietic Manifold in scGPT Yields a Method for Extracting Performant Algorithms from Biological Foundation Model Internals10 Mar 2026
- 2026Sparse autoencoders reveal organized biological knowledge but minimal regulatory logic in single-cell foundation models: a comparative atlas of Geneformer and scGPT3 Mar 2026
- 2026Causal Circuit Tracing Reveals Distinct Computational Architectures in Single-Cell Foundation Models: Inhibitory Dominance, Biological Coherence, and Cross-Model Convergence2 Mar 2026
- 2026What Topological and Geometric Structure Do Biological Foundation Models Learn? Evidence from 141 Hypotheses25 Feb 2026
- 2026Multi-Dimensional Spectral Geometry of Biological Knowledge in Single-Cell Transformer Representations24 Feb 2026