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Integrated analysis of multimodal single-cell data

Yuhan Hao, View ORCID ProfileStephanie Hao, View ORCID ProfileErica Andersen-Nissen, View ORCID ProfileWilliam M. Mauck III, View ORCID ProfileShiwei Zheng, View ORCID ProfileAndrew Butler, Maddie J. Lee, View ORCID ProfileAaron J. Wilk, View ORCID ProfileCharlotte Darby, Michael Zagar, View ORCID ProfilePaul Hoffman, View ORCID ProfileMarlon Stoeckius, View ORCID ProfileEfthymia Papalexi, View ORCID ProfileEleni P. Mimitou, View ORCID ProfileJaison Jain, View ORCID ProfileAvi Srivastava, View ORCID ProfileTim Stuart, View ORCID ProfileLamar B. Fleming, View ORCID ProfileBertrand Yeung, View ORCID ProfileAngela J. Rogers, View ORCID ProfileJuliana M. McElrath, View ORCID ProfileCatherine A. Blish, View ORCID ProfileRaphael Gottardo, View ORCID ProfilePeter Smibert, View ORCID ProfileRahul Satija
doi: https://doi.org/10.1101/2020.10.12.335331
Yuhan Hao
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
2New York Genome Center, New York, NY, USA
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Stephanie Hao
3Technology Innovation Lab, New York Genome Center, New York, NY, USA
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  • ORCID record for Stephanie Hao
Erica Andersen-Nissen
4Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
5Cape Town HVTN Immunology Lab, Hutchinson Cancer Research Institute of South Africa, Cape Town, South Africa
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William M. Mauck III
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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  • ORCID record for William M. Mauck III
Shiwei Zheng
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
2New York Genome Center, New York, NY, USA
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Andrew Butler
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
2New York Genome Center, New York, NY, USA
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Maddie J. Lee
6Department of Medicine, Stanford University School of Medicine, Stanford CA
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Aaron J. Wilk
6Department of Medicine, Stanford University School of Medicine, Stanford CA
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Charlotte Darby
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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  • ORCID record for Charlotte Darby
Michael Zagar
7Center for Data Visualization, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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Paul Hoffman
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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Marlon Stoeckius
3Technology Innovation Lab, New York Genome Center, New York, NY, USA
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  • ORCID record for Marlon Stoeckius
Efthymia Papalexi
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
2New York Genome Center, New York, NY, USA
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Eleni P. Mimitou
3Technology Innovation Lab, New York Genome Center, New York, NY, USA
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  • ORCID record for Eleni P. Mimitou
Jaison Jain
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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Avi Srivastava
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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Tim Stuart
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
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Lamar B. Fleming
4Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • ORCID record for Lamar B. Fleming
Bertrand Yeung
8BioLegend Inc., San Diego, CA, USA
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Angela J. Rogers
6Department of Medicine, Stanford University School of Medicine, Stanford CA
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Juliana M. McElrath
4Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • ORCID record for Juliana M. McElrath
Catherine A. Blish
6Department of Medicine, Stanford University School of Medicine, Stanford CA
9Chan Zuckerberg Biohub, San Francisco USA
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  • ORCID record for Catherine A. Blish
Raphael Gottardo
4Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA USA
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  • ORCID record for Raphael Gottardo
Peter Smibert
3Technology Innovation Lab, New York Genome Center, New York, NY, USA
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  • For correspondence: rsatija@nygenome.org psmibert@nygenome.org
Rahul Satija
1Center for Genomics and Systems Biology, New York University, New York, NY, USA
2New York Genome Center, New York, NY, USA
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  • ORCID record for Rahul Satija
  • For correspondence: rsatija@nygenome.org psmibert@nygenome.org
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Abstract

The simultaneous measurement of multiple modalities, known as multimodal analysis, represents an exciting frontier for single-cell genomics and necessitates new computational methods that can define cellular states based on multiple data types. Here, we introduce ‘weighted-nearest neighbor’ analysis, an unsupervised framework to learn the relative utility of each data type in each cell, enabling an integrative analysis of multiple modalities. We apply our procedure to a CITE-seq dataset of hundreds of thousands of human white blood cells alongside a panel of 228 antibodies to construct a multimodal reference atlas of the circulating immune system. We demonstrate that integrative analysis substantially improves our ability to resolve cell states and validate the presence of previously unreported lymphoid subpopulations. Moreover, we demonstrate how to leverage this reference to rapidly map new datasets, and to interpret immune responses to vaccination and COVID-19. Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets, including paired measurements of RNA and chromatin state, and to look beyond the transcriptome towards a unified and multimodal definition of cellular identity.

Availability Installation instructions, documentation, tutorials, and CITE-seq datasets are available at http://www.satijalab.org/seurat

Competing Interest Statement

In the past three years, RS has worked as a consultant for Bristol-Myers Squibb, Regeneron, and Kallyope, and served as an SAB member for ImmunAI, Apollo Life Sciences GmbH, Nanostring and the NYC Pandemic Response Lab. R.G. has received consulting income from Juno Therapeutics, Takeda, Infotech Soft, Celgene, Merck and has received research support from Janssen Pharmaceuticals and Juno Therapeutics, and declares ownership in CellSpace Biosciences. PS is a co-inventor of a patent related to this work. BZY is an employee at BioLegend Inc., which is the exclusive licensee of the New York Genome Center patent application related to this work.

Footnotes

  • http://www.satijalab.org/seurat

  • https://github.com/satijalab/seurat

  • https://atlas.fredhutch.org/nygc/multimodal-pbmc/

  • http://www.satijalab.org/azimuth

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 12, 2020.
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Integrated analysis of multimodal single-cell data
Yuhan Hao, Stephanie Hao, Erica Andersen-Nissen, William M. Mauck III, Shiwei Zheng, Andrew Butler, Maddie J. Lee, Aaron J. Wilk, Charlotte Darby, Michael Zagar, Paul Hoffman, Marlon Stoeckius, Efthymia Papalexi, Eleni P. Mimitou, Jaison Jain, Avi Srivastava, Tim Stuart, Lamar B. Fleming, Bertrand Yeung, Angela J. Rogers, Juliana M. McElrath, Catherine A. Blish, Raphael Gottardo, Peter Smibert, Rahul Satija
bioRxiv 2020.10.12.335331; doi: https://doi.org/10.1101/2020.10.12.335331
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Integrated analysis of multimodal single-cell data
Yuhan Hao, Stephanie Hao, Erica Andersen-Nissen, William M. Mauck III, Shiwei Zheng, Andrew Butler, Maddie J. Lee, Aaron J. Wilk, Charlotte Darby, Michael Zagar, Paul Hoffman, Marlon Stoeckius, Efthymia Papalexi, Eleni P. Mimitou, Jaison Jain, Avi Srivastava, Tim Stuart, Lamar B. Fleming, Bertrand Yeung, Angela J. Rogers, Juliana M. McElrath, Catherine A. Blish, Raphael Gottardo, Peter Smibert, Rahul Satija
bioRxiv 2020.10.12.335331; doi: https://doi.org/10.1101/2020.10.12.335331

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