Directional coherence and effect magnitude in single-cell CRISPR perturbation responses

[2604.16642] Directional coherence and effect magnitude in single-cell CRISPR perturbation responses Skip to main content Search Submit Donate Log in Quantitative Biology > Quantitative Methods arXiv:2604.16642 (q-bio) [Submitted on 17 Apr 2026 ( v1 ), last revised 27 Aug 2026 (this version, v4)] Title: Directional coherence and effect magnitude in single-cell CRISPR perturbation responses Authors: Prashant C. Raju View PDF HTML (experimental) Abstract: Single-cell CRISPR screens summarize each perturbation by how far cells move from their unperturbed state, averaging over cell-to-cell variation. Whether the cells moved together is not captured: two perturbations with identical effect magnitude can differ qualitatively, one driving cells along a shared trajectory, the other scattering them around the same mean. We define Shesha\textsubscript{P} coherence ($S_p$), the mean cosine similarity between individual cell displacement vectors and their mean, and ask what it adds across six Perturb-seq datasets (2,285 perturbations; CRISPRa, CRISPRi, Cas9 knockout). Coherence and effect magnitude are closely coupled (Spearman $\rho =0.84$--$0.98$), and the coupling persists in a foundation-model embedding, under alternative effect-size definitions, and when analysis is restricted to responding cells. Associations reported without conditioning on effect size largely recover it, shown here for two comparisons that vanish under conditioning. Effect size accounts for 89--96\% of coherence variance; within the remainder, coherence is negatively associated with apoptosis and p53 signalling in the two largest screens. Two standard responder classifiers agree on only 68\% of cells. Directional coherence is largely a restatement of effect magnitude, and heterogeneity measures should report their redundancy with effect size as a matter of course. $S_p$ is implemented in the open-source shesha-geometry Python package. Subjects: Quantitative Methods (q-bio.QM) ; Cell Behavior (q-bio.CB); Genomics (q-bio.GN); Applications (stat.AP) Cite as: arXiv:2604.16642 [q-bio.QM] (or arXiv:2604.16642v4 [q-bio.QM] for this version) https://doi.org/10.48550/arXiv.2604.16642 Focus to learn more arXiv-issued DOI via DataCite Submission history From: Prashant Raju [ view email ] [v1] Fri, 17 Apr 2026 19:01:05 UTC (4,917 KB) [v2] Tue, 12 May 2026 17:01:20 UTC (4,836 KB) [v3] Mon, 22 Jun 2026 17:29:12 UTC (5,551 KB) [v4] Thu, 27 Aug 2026 01:33:32 UTC (3,368 KB) Full-text links: Access Paper: View PDF HTML (experimental) TeX Source view license Current browse context: q-bio.QM < prev | next > new | recent | 2026-04 Change to browse by: q-bio q-bio.CB q-bio.GN stat stat.AP References & Citations NASA ADS Google Scholar Semantic Scholar export BibTeX citation Bookmark Bibliographic Tools Bibliographic and Citation Tools Bibliographic Explorer Toggle Bibliographic Explorer ( What is the Explorer? ) Connected Papers Toggle Connected Papers ( What is Connected Papers? ) Litmaps Toggle Litmaps ( What is Litmaps? ) scite.ai Toggle scite Smart Citations ( What are Smart Citations? ) Code, Data, Media Code, Data and Media Associated with this Article alphaXiv Toggle alphaXiv ( What is alphaXiv? ) Links to Code Toggle CatalyzeX Code Finder for Papers ( What is CatalyzeX? ) DagsHub Toggle DagsHub ( What is DagsHub? ) GotitPub Toggle Gotit.pub ( What is GotitPub? ) Huggingface Toggle Hugging Face ( What is Huggingface? ) ScienceCast Toggle ScienceCast ( What is ScienceCast? ) Demos Demos Replicate Toggle Replicate ( What is Replicate? ) Spaces Toggle Hugging Face Spaces ( What is Spaces? ) Spaces Toggle TXYZ.AI ( What is TXYZ.AI? ) Related Papers Recommenders and Search Tools Link to Influence Flower Influence Flower ( What are Influence Flowers? ) Core recommender toggle CORE Recommender ( What is CORE? ) Author Venue Institution Topic About arXivLabs arXivLabs: experimental projects with community collaborators arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website. Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them. Have an idea for a project that will add value for arXiv's community? Learn more about arXivLabs . Which authors of this paper are endorsers? | Disable MathJax ( What is MathJax? ) We gratefully acknowledge support from our major funders , member institutions , and all contributors. About · Help · Contact · Subscribe · Copyright · Privacy · Accessibility · Operational Status (opens in new tab) Major funding support from

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