Microbiome meta-analysis and cross-disease comparison enabled by the SIAMCAT machine learning toolbox
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Abstract
The human microbiome is increasingly mined for diagnostic and therapeutic biomarkers using machine learning (ML). However, metagenomics-specific software is scarce, and overoptimistic evaluation and limited cross-study generalization are prevailing issues. To address these, we developed SIAMCAT, a versatile R toolbox for ML-based comparative metagenomics. We demonstrate its capabilities in a meta-analysis of fecal metagenomic studies (10,803 samples). When naively transferred across studies, ML models lost accuracy and disease specificity, which could however be resolved by a novel training set augmentation strategy. This reveals some biomarkers to be disease-specific, with others shared across multiple conditions. SIAMCAT is freely available from siamcat.embl.de .
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If spatial interdependence is ignored, localized effects may be overstated and capacity decline may be wrongly attributed only to internal stressors.
“Ignoring spatial interdependence risks overstating localized effects or misattributing capacity decline to internal stressors alone (Wirbel et al., 2021).”
From Climate Security, Water Governance, and Resilience How Climate-Induced Water Stress and Migration Challenge State Capacity (2026) · cites this paper as Wirbel et al., 2021
The Results sections on confounder analysis and advanced machine-learning workflows discuss country-related confounding and dependence among repeated microbiome samples. Neither addresses spatial interdependence, localized effects, or capacity decline attributed to internal stressors (searched those terms and close paraphrases). (LLM, conf=0.77)
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- Authors
- Wirbel, J., Zych, K., Essex, M., Karcher, N., Kartal, E., Salazar, G., Bork, P., Sunagawa, S., & Zeller, G.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Clinical Microbiomics (Denmark) (DK)
- Max Delbrück Center (DE)
- University of Trento (IT)
- SIB Swiss Institute of Bioinformatics (CH)
- Corresponding author
- Zeller, Georg
- ORCID
- Venue
- Genome Biology
- Published
- 2021-03-30
- Volume
- 22
- Issue
- 1
- Pages
- 93-93
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC8008609
- OpenAlex
- W3143324940
- Cited by
- 269
- References
- 25
- Citations by year
- 2026: 45 · 2025: 44 · 2024: 61 · 2023: 46 · 2022: 56 · 2021: 15 · 2020: 1 · 2019: 1
- FWCI
- 14.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- European Molecular Biology Laboratory
- Eidgenössische Technische Hochschule Zürich (PHRT 521)
- Bundesministerium für Bildung und Forschung (031A537B, 031L0181A)
- Deutsche Forschungsgemeinschaft (395357507)
- Helmut Horten Stiftung
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Physical Sciences › Environmental Science › Ecology › Microbial Community Ecology and Physiology
- Keywords
- human microbiome, comparative metagenomics, machine learning, training set augmentation, disease-specific biomarkers, shared biomarkers, fecal microbiota, overfitting
- MeSH terms
- Gastrointestinal Microbiome, Machine Learning, Crohn Disease, Humans, ROC Curve, Software, Meta-Analysis as Topic, Models, Statistical, Confounding Factors, Epidemiologic, Computational Biology, Databases, Genetic, Metagenome, Metagenomics, Workflow, Microbiota
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