Integrated analysis of multimodal single-cell data (version 2)
Yuhan Hao, Stephanie Hao, Erica Andersen-Nissen, William M. Mauck III, Shiwei Zheng, Andrew Butler, Maddie J. Lee, Aaron J. Wilk, Charlotte Darby, Michael Zager, Paul Hoffman, Marlon Stoeckius, Efthymia Papalexi, Eleni P. Mimitou, Jaison Jain, Avi Srivastava, Tim Stuart, Lamar M. Fleming, Bertrand Yeung, Angela J. Rogers, Juliana M. McElrath, Catherine A. Blish, Raphael Gottardo, Peter Smibert, Rahul Satija
Abstract
The simultaneous measurement of multiple modalities represents an exciting frontier for single-cell genomics and necessitates computational methods that can define cellular states based on multimodal data. 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 211,000 human peripheral blood mononuclear cells (PBMCs) with panels extending to 228 antibodies to construct a multimodal reference atlas of the circulating immune system. Multimodal analysis substantially improves our ability to resolve cell states, allowing us to identify and validate 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 coronavirus disease 2019 (COVID-19). Our approach represents a broadly applicable strategy to analyze single-cell multimodal datasets and to look beyond the transcriptome toward a unified and multimodal definition of cellular identity.
Datasets
1. Human - Lung v2 (HLCA)
Metadata
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surgical_resection60977 cells Illumina NovaSeq 6000199166 cells Illumina HiSeq 4000159356 cells Illumina NextSeq 50098666 cells Illumina NovaSeq 6000 S457221 cells Illumina NovaSeq 6000 S140994 cells Illumina NovaSeq 6000 S221369 cells Illumina NovaSeq 6000; Illumina HiSeq 40005815 cells Illumina NovaSeq 6000 SP1920 cells Banovich_Kropski_2020121881 cells Barbry_Leroy_202074486 cells Misharin_Budinger_201841216 cells Jain_Misharin_2021_10Xv233135 cells Seibold_2020_10Xv321466 cells Lafyatis_Rojas_2019_10Xv221260 cells Jain_Misharin_2021_10Xv112422 cells Teichmann_Meyer_201912229 cells Seibold_2020_10Xv212127 cells Lafyatis_Rojas_2019_10Xv12920 cells parenchyma lower lobe118594 cells inferior turbinate78279 cells lobular bronchi74463 cells parenchyma upper lobe61727 cells distal lobular airways27541 cells parenchyma right middle lobe18540 cells left or right main bronchus9417 cells segmental bronchi7769 cells parenchyma left lower lobe65018 cells 2_lobular bronchi55805 cells inferior turbinate right nostril53378 cells 2_parenchyma lower lobe45465 cells parenchyma right upper lobe29671 cells parenchyma left upper lobe26133 cells 2_parenchyma right middle lobe18540 cells 2_inferior turbinate17779 cells distal airways middle right lobe16226 cells 2_left or right main bronchus9417 cells parenchyma right lower lobe8111 cells 2_segmental bronchi7769 cells inferior turbinate left nostril7122 cells lobular bronchi upper left lobe7049 cells 2_parenchyma upper lobe5923 cells lobular bronchi lower right lobe5056 cells distal airways lower right lobe4080 cells lobular bronchi lower left lobe3411 cells lobular bronchi upper right lobe3142 cells distal airways upper left lobe2773 cells distal airways upper right lobe2477 cells distal airways lower left lobe1985 cells Alveolar macrophages68487 cells Goblet (nasal)35833 cells Multiciliated (non-nasal)35225 cells Monocyte-derived Mφ28223 cells Classical monocytes17695 cells EC general capillary16048 cells Club (non-nasal)12043 cells Adventitial fibroblasts10321 cells Non-classical monocytes8834 cells Alveolar Mφ CCL3+8065 cells EC aerocyte capillary7157 cells EC venous systemic6557 cells EC venous pulmonary6418 cells Alveolar fibroblasts5182 cells Multiciliated (nasal)4869 cells Interstitial Mφ perivascular4805 cells Lymphatic EC mature4001 cells Transitional Club-AT23975 cells Goblet (bronchial)1670 cells Peribronchial fibroblasts1573 cells SMG serous (nasal)1472 cells SMG serous (bronchial)1417 cells Alveolar Mφ MT-positive1203 cells Alveolar Mφ proliferating1061 cells AT2 proliferating976 cells Goblet (subsegmental)968 cells Lymphatic EC differentiating566 cells SM activated stress response556 cells Plasmacytoid DCs552 cells T cells proliferating500 cells Subpleural fibroblasts276 cells Lymphatic EC proliferating28 cells Airway epithelium207253 cells Alveolar epithelium70112 cells Fibroblast lineage21100 cells Submucosal Gland4700 cells T cell lineage50859 cells Multiciliated lineage41098 cells Innate lymphoid cell NK16978 cells Dendritic cells10319 cells Submucosal Secretory4700 cells Lymphatic EC mature4001 cells Lymphatic EC differentiating566 cells SM activated stress response556 cells Lymphatic EC proliferating28 cells Alveolar macrophages78816 cells Interstitial macrophages33028 cells Classical monocytes17695 cells EC general capillary16048 cells Adventitial fibroblasts10321 cells Non-classical monocytes8834 cells EC aerocyte capillary7157 cells EC venous systemic6557 cells EC venous pulmonary6418 cells Alveolar fibroblasts5182 cells Transitional Club-AT23975 cells Peribronchial fibroblasts1573 cells AT2 proliferating976 cells Plasmacytoid DCs552 cells T cells proliferating500 cells Subpleural fibroblasts276 cells Goblet (nasal)35833 cells Multiciliated (non-nasal)35225 cells Monocyte-derived Mφ28223 cells Club (non-nasal)12043 cells Alveolar Mφ CCL3+8065 cells Multiciliated (nasal)4869 cells Interstitial Mφ perivascular4805 cells Goblet (bronchial)1670 cells SMG serous (nasal)1472 cells SMG serous (bronchial)1417 cells Alveolar Mφ MT-positive1203 cells Alveolar Mφ proliferating1061 cells Goblet (subsegmental)968 cells Alveolar macrophages78816 cells T cell lineage50859 cells Monocyte-derived Mφ28223 cells Innate lymphoid cell NK16978 cells Adventitial fibroblasts10321 cells Alveolar fibroblasts5182 cells Interstitial Mφ perivascular4805 cells Transitional Club-AT23975 cells Peribronchial fibroblasts1573 cells Plasmacytoid DCs552 cells Subpleural fibroblasts276 cells secretory cell80557 cells type II pneumocyte62175 cells multi-ciliated epithelial cell41098 cells capillary endothelial cell23205 cells NKp46-positive innate lymphoid cell, human16978 cells vein endothelial cell12975 cells dendritic cell10319 cells type I pneumocyte7937 cells endothelial cell of artery7391 cells lung secretory cell4700 cells endothelial cell of lymphatic vessel4595 cells myofibroblast cell716 cells tracheobronchial smooth muscle cell556 cells lung parenchyma333411 cells respiratory airway173194 cells Hispanic or Latin American14131 cells Pacific Islander2232 cells 25-year-old human stage49572 cells 50-year-old human stage46302 cells 52-year-old human stage41505 cells 57-year-old human stage41173 cells 30-year-old human stage35646 cells 46-year-old human stage28790 cells 55-year-old human stage25787 cells 59-year-old human stage23026 cells 27-year-old human stage23001 cells 42-year-old human stage18281 cells 35-year-old human stage17710 cells 29-year-old human stage17533 cells 41-year-old human stage16275 cells 64-year-old human stage16258 cells 67-year-old human stage14725 cells 49-year-old human stage14613 cells 23-year-old human stage11591 cells 38-year-old human stage9406 cells 62-year-old human stage9275 cells 34-year-old human stage9133 cells 47-year-old human stage8015 cells 24-year-old human stage7543 cells 75-year-old human stage7521 cells 33-year-old human stage6816 cells 31-year-old human stage6389 cells 37-year-old human stage6255 cells 66-year-old human stage6114 cells 26-year-old human stage6001 cells 56-year-old human stage5777 cells 63-year-old human stage5390 cells 21-year-old human stage4879 cells 53-year-old human stage4591 cells 69-year-old human stage4305 cells 22-year-old human stage4240 cells 54-year-old human stage4061 cells 32-year-old human stage3769 cells 18-year-old human stage3272 cells 68-year-old human stage2626 cells 61-year-old human stage2591 cells 36-year-old human stage2542 cells 10-year-old human stage2232 cells 44-year-old human stage2230 cells 40-year-old human stage1739 cells 58-year-old human stage1605 cells 76-year-old human stage704 cells 71-year-old human stage601 cells 15-year-old human stage47 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/2f75d249-1bec-459b-bf2b-b86221097ced
Alias names
PMID34062119, PMC8238499
Cite this study
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W.M., Zheng, S., Butler, A., Lee, M.J., Wilk, A.J., Darby, C., Zager, M. and Hoffman, P., 2021. Integrated analysis of multimodal single-cell data. Cell, 184(13), pp.3573-3587. https://doi.org/10.1016/j.cell.2021.04.048
