Cited by 1,698Single-cell and spatial transcriptomicsTopological and Geometric Data AnalysisGene Regulatory Network Analysis

PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells

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Wolf, F. Alexander, Hamey, Fiona K., Plass, Mireya, Solana, Jordi, Dahlin, Joakim S., Göttgens, Berthold, Rajewsky, Nikolaus, Simon, Lukas +1 more·2019·Genome Biology

Published version of a preprint

Abstract

Abstract Single-cell RNA-seq quantifies biological heterogeneity across both discrete cell types and continuous cell transitions. Partition-based graph abstraction (PAGA) provides an interpretable graph-like map of the arising data manifold, based on estimating connectivity of manifold partitions ( https://github.com/theislab/paga ). PAGA maps provide interpretable discrete and continuous latent coordinates for both disconnected and continuous structure in data, preserve the global topology of data, allow analyzing data at different resolutions and result in much higher computational efficiency of the typical exploratory data analysis workflow — one million cells take on the order of a minute, a speedup of 130 times compared to UMAP. We demonstrate the method by inferring structure-rich cell maps with consistent topology across four hematopoietic datasets, confirm the reconstruction of lineage relations of adult planaria and the zebrafish embryo, benchmark computational performance on a neuronal dataset and detect a biological trajectory in one deep-learning processed image dataset.

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Crossref · 10.1186/s13059-019-1663-x

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72 of 72 references verified0 citation errors · 0 not checkable

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  • Within the MkPs, the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline.

    “However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [57]

    The Results section on hematopoiesis discusses progenitor-cell trajectories and gene-expression changes, not IFNa treatment or proliferation in CALR-mutated MkPs. Searches for IFNa, CALR, and thrombopoietin-receptor effects found no passage addressing the claimed baseline comparison. In the quoted sentence, the numbered citations appear beside the separate CALR-receptor explanation; the IFNa comparison points to Fig. 3e. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • The rate of cell cycle entry of the mutated cells was already near or at the point of saturation due to the CALR mutation.

    “However, in contrast to the other myeloid progenitors, within the MkPs (wherein the CALR mutation exerts the greatest phenotypic effects due to the activation of the thrombopoietin receptor 21,54-57 ), the proliferative effects of IFNa were modest in the mutated cells compared to those at baseline ( Fig. 3e ), suggesting that the rate of cell cycle entry of the mutated cells was already near or at”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [57]

    The Results section discusses PAGA analyses of hematopoietic differentiation and megakaryocyte progenitors, but not CALR-mutated cells or their proliferation. Searches for CALR, IFNa, and saturation of cell-cycle entry found no passage addressing the claim; the copy is not truncated. (LLM, conf=0.76)

    Experimental — accuracy not yet measured
  • The resulting KNN graph captures the underlying topology of the expression data.

    “The resulting graph captures the underlying topology of the expression data (Wolf et al, 2019).”

    From Current best practices in single-cell RNA-seq analysis: a tutorial (2019) · cites this paper as Wolf et al, 2019

  • PAGA has been shown to adequately approximate the topology of the data while coarse-graining the visualization using clusters.

    “This tool has been shown to adequately approximate the topology of the data while coarse‐graining the visualization using clusters.”

    From Current best practices in single-cell RNA-seq analysis: a tutorial (2019) · cites this paper as Wolf et al, 2019

  • UMAP and SPRING's ForceAtlas2 arguably represent the best approximation of the underlying topology.

    “UMAP and SPRING's force‐directed layout algorithm ForceAtlas2 arguably represent the best approximation of the underlying topology (Wolf et al, 2019, Supplemental Note 4).”

    From Current best practices in single-cell RNA-seq analysis: a tutorial (2019) · cites this paper as Wolf et al, 2019

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Research works printed but not linked: 1

  1. [38]Wolf FA, Hamey F, Plass M, Solana J, Dahlin JS, Göttgens B, Rajewsky N, Simon L, Theis FJ. PAGA: Graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells. GitHub repository. 2019. https://github.com/theislab/paga. PMC6425583 30890159

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Authors
Wolf, F. A., Hamey, F. K., Plass, M., Solana, J., Dahlin, J. S., Göttgens, B., Rajewsky, N., Simon, L., & Theis, F. J.
Affiliations
  • Helmholtz Munich (DE)
  • Wellcome/MRC Cambridge Stem Cell Institute (GB)
  • Max Delbrück Center (DE)
  • Karolinska University Hospital (SE)
Corresponding author
Theis, Fabian J.
Venue
Genome Biology
Published
2019-03-19
Volume
20
Issue
1
Pages
59-59
ISSN
  • 1465-6906 (ISSN-L)
  • 1474-760X
OpenAlex
W2950372712
Cited by
1,698
References
72
Citations by year
2026: 226 · 2025: 301 · 2024: 324 · 2023: 225 · 2022: 246 · 2021: 174 · 2020: 138 · 2019: 53 · 2018: 10 · 2017: 1
FWCI
52.76
Type
journal article
Language
en
Open access
Locations
  • Genome biology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • mediaTUM (Technical University of Munich) (submittedVersion, other-oa)
  • PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (206328/Z/17/Z, 079895/Z/06/Z, 203151/Z/16/Z)
  • Deutsches Zentrum für Herz-Kreislaufforschung (DZHK BER1.2VD)
  • Cancer Research UK
  • Deutsche Forschungsgemeinschaft (RA 838/5-1, Subproject A17)
  • Vetenskapsrådet
  • Blood Cancer UK
  • National Institutes of Health
  • Medical Research Council (MC_PC_12009)
  • Cambridge Institute for Medical Research, University of Cambridge
  • National Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Topological and Geometric Data Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
Paga, graph abstraction, single-cell RNA sequencing, cell trajectory inference, cell clustering, topology of manifolds, cell-type resolution, hematopoietic development, Tricladida, zebrafish embryos, neuronal connectivity, computational efficiency
MeSH terms
Algorithms, Animals, Computer Graphics, Embryo, Nonmammalian, Hematopoietic Stem Cells, Humans, Planarians, Reference Standards, Software, Zebrafish, Sequence Analysis, RNA, Gene Expression Regulation, Developmental, Computational Biology, Single-Cell Analysis, High-Throughput Nucleotide Sequencing

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