Evidence map›Paper›PMID 39592777›Full record

ArticleNature biotechnology2025

Recovery of biological signals lost in single-cell batch integration with CellANOVA.

Zhaojun Zhang, Divij Mathew, Tristan L Lim, Kaishu Mason, Clara Morral Martinez, Sijia Huang, E John Wherry, Katalin Susztak, Andy J Minn, Zongming Ma and 1 more

Abstract read
PubMed Publisher
In one paragraph

Article in Nature biotechnology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed.

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  8. Design, processing, and modeling for longitudinal multiomics microbiome data.Frontiers in cellular and infection microbiology · 2026
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors.

Zhaojun ZhangDepartment of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA.
Divij MathewDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Tristan L LimDepartment of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Kaishu MasonDepartment of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-0282-1190
Clara Morral MartinezDepartment of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Sijia HuangPenn Institute of Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA.
E John WherryDepartment of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0003-0477-1956
Katalin SusztakRenal, Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID http://orcid.org/0000-0002-1005-3726
Andy J MinnInstitute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Zongming Ma *Department of Statistics and Data Science, Yale University, New Haven, CT, USA. zongming.ma@yale.edu.ORCID http://orcid.org/0000-0003-2401-0177
Nancy R Zhang *Department of Statistics and Data Science, The Wharton School, University of Pennsylvania, Philadelphia, PA, USA. nzh@wharton.upenn.edu.ORCID http://orcid.org/0000-0002-0880-5749

Funding

Statistical Models for Genome Sequencing and AssociationR01HG006137 · NHGRI · UNIVERSITY OF PENNSYLVANIA · PI JI, HANLEE P, ZHANG, NANCY R · 2011 to 2022
$4.3M
Multiomic single cell and spatial interrogation of mechanisms in cellular adaptation to stressR01GM149671 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI Sydney Shaffer, Nancy R Zhang · 2024 to 2026
$1.6M
Statistical Methods for Single-Cell TranscriptomicsR01GM125301 · NIGMS · UNIVERSITY OF PENNSYLVANIA · PI LI, MINGYAO, ZHANG, NANCY R · 2017 to 2020
$1.5M
National Science Foundation (NSF) DMS/NIGMS 2245575NHGRI NIH HHS R01 HG006137NIGMS NIH HHS R01 GM125301NIGMS NIH HHS R01 GM149671U.S. Department of Energy (DOE) CSGFU.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) 5R01DK087635U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) 5R01GM125301U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) R01-HG006137U.S. Department of Health & Human Services | NIH | Center for Information Technology (Center for Information Technology, National Institutes of Health) U2C1335 CA233285
6 · The paper itself

Abstract

Data integration to align cells across batches has become a cornerstone of single-cell data analysis, critically affecting downstream results. Currently, there are no guidelines for when the biological differences between samples are separable from batch effects. Here we show that current paradigms for single-cell data integration remove biologically meaningful variation and introduce distortion. We present a statistical model and computationally scalable algorithm, CellANOVA (cell state space analysis of variance), that harnesses experimental design to explicitly recover biological signals that are erased during single-cell data integration. CellANOVA uses a 'pool-of-controls' design concept, applicable across diverse settings, to separate unwanted variation from biological variation of interest and allow the recovery of subtle biological signals. We apply CellANOVA to diverse contexts and validate the recovered biological signals by orthogonal assays. In particular, we show that CellANOVA is effective in the challenging case of single-cell and single-nucleus data integration, where it recovers subtle biological signals that can be validated and replicated by external data.

Indexed as

AlgorithmsSingle-Cell AnalysisHumans

Identifiers

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.