PreprintCited by 1,694Single-cell and spatial transcriptomicsBioinformatics and Genomic NetworksGene Regulatory Network Analysis

The DOI matches its Crossref record; 110 of the 110 references it cites were found in a registry or an index; none of the 12 sources its claims cite is checked for support yet.

scGPT: Towards Building a Foundation Model for Single-Cell Multi-omics Using Generative AI

Open access
Cui, Haotian, Wang, Chloe, Maan, Hassaan, Pang, Kuan, Luo, Fengning, Wang, Bo·2023·Nature Methods

Abstract

Generative pre-trained models have achieved remarkable success in various domains such as natural language processing and computer vision. Specifically, the combination of large-scale diverse datasets and pre-trained transformers has emerged as a promising approach for developing foundation models. Drawing parallels between linguistic constructs and cellular biology — where texts comprise words, similarly, cells are defined by genes — our study probes the applicability of foundation models to advance cellular biology and genetics research. Utilizing the burgeoning single-cell sequencing data, we have pioneered the construction of a foundation model for single-cell biology, scGPT, which is based on generative pre-trained transformer across a repository of over 33 million cells. Our findings illustrate that scGPT, a generative pre-trained transformer, effectively distills critical biological insights concerning genes and cells. Through the further adaptation of transfer learning, scGPT can be optimized to achieve superior performance across diverse downstream applications. This includes tasks such as cell-type annotation, multi-batch integration, multi-omic integration, genetic perturbation prediction, and gene network inference. The scGPT codebase is publicly available at https://github.com/bowang-lab/scGPT .

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

scGPT is a generative pretrained transformer foundation model for single-cell biology, pretrained on over 33 million human scRNA-seq cells and fine-tuned for cell-type annotation, integration, perturbation prediction, and gene network inference. It reports state-of-the-art or competitive performance across these tasks and identifies a scaling law where larger pretraining data improves downstream fine-tuning.

Key findings

  • Pretraining used 33 million normal human scRNA-seq cells from CELLxGENE, spanning 51 organs/tissues and 441 studies; UMAP of a 10% subset showed cell types separated into distinct clusters despite over 400 studies.
  • Cell-type annotation: scGPT achieved high precision (>0.8) for most hPancreas cell types except rare types, around 0.85 accuracy on multiple sclerosis, and ≥0.7 precision for most tumor-infiltrating myeloid cell types; it outperformed TOSICA and scBert on Accuracy, Precision, Recall, and MacroF1.
  • Perturbation prediction: scGPT achieved the highest correlation on both Adamson and Norman datasets versus GEARS and CPA; in reverse perturbation prediction it identified 71.4% correct perturbations (5/7 test cases) within top 5 predictions, a 95.2% speedup over random tryouts (105.5 average attempts out of 210).
  • Integration and GRN: PBMC 10K AvgBIO was 0.821, 5–10% higher than compared methods; ASAP PBMC AvgBATCH was 0.951 versus scMoMaT’s 0.916; scGPT uniquely identified 22 Reactome pathways, 14 immune-related, and attention analysis found all top 20 DDIT3-influenced genes and 19/20 BHLHE40-influenced genes as ChIP-Atlas targets.

Methods

  • Design: two-stage generative pretraining and fine-tuning of a transformer that jointly learns cell and gene embeddings; a specialized attention mask enables generative prediction on non-sequential gene expression, with fine-tuning objectives including GEP, GEPC, ECS, DAR, and CLS.
  • Data: pretraining on 33 million normal human scRNA-seq cells from CELLxGENE; downstream datasets included hPancreas, multiple sclerosis, myeloid, Adamson, Norman, COVID-19, PBMC 10K, Perirhinal Cortex, 10X Multiome PBMC, BMMC, ASAP PBMC, and Immune Human.
  • Analysis: benchmarks against TOSICA, scBert, GEARS, CPA, scVI, Seurat, Harmony, scGLUE, and scMoMaT; metrics included Accuracy, Precision, Recall, MacroF1, Pearson correlation and corr(Δ), AvgBIO, AvgBATCH, Overall, and Reactome pathway enrichment.

Limitations

  • Stated: the scaling law appeared to saturate after 3M pretraining cells; the authors hypothesize larger model sizes could improve performance at 33M and beyond but leave larger model sizes to future work.
  • Stated: future work plans larger-scale, more diverse pretraining including multi-omic, spatial omics, diseased conditions, perturbation and temporal data, broader biological validation, and in-context instruction learning.
  • Evident: this is a bioRxiv preprint not certified by peer review; results are computational benchmarks, and the text does not report prospective wet-lab validation of predictions.

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Crossref · 10.1101/2023.04.30.538439

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  • Probably not a substantial claim. 26
  • It may state two separate claims as one. 17
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43 of 43
  • The paper relies on this without support.

    The COVID-19 dataset comprises diverse cellular compositions, making it suitable for evaluating in-context pre-training effects.

    “The COVID-19 dataset serves as an ideal task for this investigation, as it comprises diverse412 cellular compositions.”
  • The paper relies on this without support.

    Adaptive immune populations exist in the fine-tuning datasets.

    “This is concordant with the fact that adaptive immune populations342 exist in the fine-tuning datasets.”
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Research works printed but not linked: 6

  1. 2019, In: Chinese Computational Linguistics: 18th China National Conference, CCL 2019, Kunming, China, October 18–20, 2019, Proceedings, 18, 194
  2. National Library of Medicine. Bhlhe40 basic helix-loop-helix family, member e40 [Mus mus-culus (house mouse)]. https://www.ncbi.nlm.nih.gov/gene/20893. Online; accessed 29 May 2023. 2023.
  3. 2019, Language models are unsupervised multitask learners, In: OpenAI blog, 1, 9
  4. 10.1186/S13059-020-02000-8/FIGURES/6 · DOI
  5. 2013, Auto-encoding variational bayes, In: arXiv
  6. 2021, Joint probabilistic modeling of single-cell multi-omic data with to-talVI, In: Nature methods, 18, 272

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Metadata

Authors
Cui, H., Wang, C., Maan, H., Pang, K., Luo, F., & Wang, B.
Affiliations
  • University Health Network (CA)
  • University of Toronto (CA)
Corresponding author
Wang, Bo
Venue
Nature Methods
Publisher
openRxiv
Published
2023-05-01
Volume
21
Issue
8
Pages
1470-1480
ISSN
1548-7091 (ISSN-L)
OpenAlex
W4392168151
Cited by
1,694
References
98
Citations by year
2026: 918 · 2025: 521 · 2024: 234 · 2023: 19
FWCI
186.38
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Nature Methods (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (submittedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • University Health Network
  • Canadian Network for Research and Innovation in Machining Technology, Natural Sciences and Engineering Research Council of Canada (DGECR-2020-00294, RGPIN-2020-06189)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
Keywords
scGPT, single-cell multi-omics, foundation models, generative pre-trained transformer, single-cell RNA sequencing, cell type annotation, multi-omics integration, perturbation response prediction, gene network inference, transfer learning, single-cell biology
MeSH terms
Multiomics, Algorithms, Artificial Intelligence, Humans, Computational Biology, Gene Regulatory Networks, Single-Cell Analysis

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