Cited by 181Bioinformatics and Genomic NetworksGene expression and cancer classificationGenomics and Phylogenetic Studies

The DOI matches its Crossref record; 137 of the 148 references it cites were found in a registry or an index; none of the 80 sources its claims cite is checked for support yet.

Missing data in multi-omics integration: Recent advances through artificial intelligence

Open access
Flores, Javier E., Claborne, Daniel M., Weller, Zachary D., Webb-Robertson, Bobbie-Jo M., Waters, Katrina M., Bramer, Lisa M.·2023·Frontiers in Artificial Intelligence

Abstract

Biological systems function through complex interactions between various ‘omics (biomolecules), and a more complete understanding of these systems is only possible through an integrated, multi-omic perspective. This has presented the need for the development of integration approaches that are able to capture the complex, often non-linear, interactions that define these biological systems and are adapted to the challenges of combining the heterogenous data across ‘omic views. A principal challenge to multi-omic integration is missing data because all biomolecules are not measured in all samples. Due to either cost, instrument sensitivity, or other experimental factors, data for a biological sample may be missing for one or more ‘omic techologies. Recent methodological developments in artificial intelligence and statistical learning have greatly facilitated the analyses of multi-omics data, however many of these techniques assume access to completely observed data. A subset of these methods incorporate mechanisms for handling partially observed samples, and these methods are the focus of this review. We describe recently developed approaches, noting their primary use cases and highlighting each method's approach to handling missing data. We additionally provide an overview of the more traditional missing data workflows and their limitations; and we discuss potential avenues for further developments as well as how the missing data issue and its current solutions may generalize beyond the multi-omics context.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review surveys recent AI/ML multi-omics integration methods that explicitly handle partially observed data, either by joint imputation within the model or by optimization masking of missing components. It also summarizes traditional missing-data workflows and discusses limitations, especially sample-size demands, limited coverage of mass-spectrometry omics, and interpretability.

Key findings

  • Missing data are pervasive in omics: proteomics can have 20–50% of possible peptide values unquantified, and the human proteome project estimates ~20% of genes yield protein products not detected by mass spectrometry.
  • The review groups missing-data-robust integration methods into joint-imputation approaches (e.g., FBM, iMODA, MOFA/MOFA+, BIDIFAC+) and optimization-masking approaches (e.g., TiMEG, COMBI, MVAE, DeepMF, MvNE, DeepIMV, JACA, SUMO, NEMO, MSNE, MONET), across early, middle, and late integration categories.
  • Reported performance varies with missingness: FBM prediction RMSE increased with missing percentage, most prominently when both gene expression and methylation had 30% missingness; iMODA power decreased with 50% and 30% missingness; MOFA imputation had lower MSE than feature-wise mean, SoftImpute, and KNN across ~10–80% missingness; DeepMF identified simulated MCAR sample/feature subgroups with perfect accuracy at 10%, 50%, and 70% missingness; SUMO slightly outperformed NEMO except at extreme missingness (80% and greater).
  • BIDIFAC+ enables bi-dimensional integration across omics and sample cohorts, but took nearly 24 h to converge on a combined TCGA dataset, and assumes shared structures are present across integrated matrices.

Methods

  • Narrative review of AI/ML and statistical-learning approaches for multi-omics integration that accommodate missing data, plus background on traditional missing-data mechanisms (MCAR, MAR, MNAR) and imputation/complete-case workflows.
  • Methods are categorized by integration strategy (early/concatenation, middle/transformation-based, late/model-based) and by missing-data handling strategy (joint-imputation vs. optimization-masking).
  • Table 1 summarizes each reviewed method’s integration approach, missing-data approach, compatible omics platforms, primary use case, application dataset characteristics, and software availability.

Limitations

  • The paper states that many reviewed methods implicitly require relatively large sample sizes, as their application datasets contain hundreds to thousands of observations, which may be prohibitive for rare diseases or small studies.
  • The paper states that many methods were motivated by or evaluated on sequencing-based omics, with few considering metabolomics, proteomics, or lipidomics, where mass-spectrometry-specific batch effects, missingness mechanisms, and identification uncertainty may violate model assumptions.
  • The paper notes that only FBM and iMODA describe how correlation structure is modeled or affects results among joint-imputation approaches, and that many middle-integration methods are black-box with limited interpretability; evident from the text, this is a review rather than an independent benchmark, so performance claims are drawn from original publications and simulations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/frai.2023.1098308

Cites

137 of 137 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

54 Not checked yet · 36 Own interpretation · 14 No basis given

Verify all 80 references — free account

Show all 46 claims

  • It may state two separate claims as one. 41
  • Probably not a substantial claim. 30
58 of 58
  • The paper relies on this without support.

    Existing multi-omics data integration review articles either do not address or only briefly mention methods for handling missing observations.

    “Despite the importance of considering methods for handling missing observations, this topic is either not addressed or is only briefly mentioned in existing multi-omics data integration review articles.”
  • The authors state this as an assumption.

    The iBAG approach assumes completely observed data.

    “The iBAG approach assumes completely observed data, and to remedy this, the FBM approach introduces a third, imputation layer that models missing gene expression and methylation data through multivariate normal distributions.”
  • The authors state this as an assumption.

    The FBM model assumes gene-gene and methylation-methylation independence, and imputed values reflect this assumption.

    “Also worth noting is that the FBM model assumes gene-gene and methylation-methylation independence and imputed values reflect this assumption accordingly.”
  • The authors state this as an assumption.

    MVAE assumes that data views are independent from one another, given a shared latent representation.

    “One key assumption made by this approach is that data views are independent from one another, given a shared latent representation.”
  • The authors state this as an assumption.

    BIDIFAC+ assumes that shared structures are present across the integrated matrices.

    “Lock et al. (2022) note that BIDIFAC+ assumes that shared structures are present across the integrated matrices, an assumption that may be violated in practice.”
  • The paper relies on this without support.

    The known causal hierarchy across biomolecules is that genotype affects omic expression, which influences phenotype.

    “The proposed framework is aligned with the known causal hierarchy across these biomolecules, i.e., genotype affects ‘omic expression which influences phenotype.”
  • The paper relies on this without support.

    Gene expression is known to be affected by changes to the DNA sequence.

    “For example, gene expression is known to be affected by changes to the DNA sequence.”
7 of 7

Claims other papers make about this one

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Citations

Cites

Show all 148 references

Research works printed but not linked: 3

  1. Achille, 2017, Emergence of invariance and disentanglement in deep representations, J. Machine Learn. Res., 19, 1, 10.48550/arxiv.1706.01350 · DOI
  2. A variational information bottleneck approach to multi-omics data integration,15131521 LeeC. van der SchaarM. International Conference on Artificial Intelligence and Statistics2021
  3. Sindhwani, 2005, A co-regularization approach to semi-supervised learning with multiple views,

Cited by

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Metadata

Authors
Flores, J. E., Claborne, D. M., Weller, Z. D., Webb-Robertson, B.-J. M., Waters, K. M., & Bramer, L. M.
Affiliations
Pacific Northwest National Laboratory (US)
Corresponding author
Bramer, Lisa M.
Venue
Frontiers in Artificial Intelligence
Published
2023-02-09
Volume
6
Pages
1098308-1098308
ISSN
2624-8212 (ISSN-L)
OpenAlex
W4319759388
Cited by
181
References
148
Citations by year
2026: 55 · 2025: 77 · 2024: 38 · 2023: 11
FWCI
4.78
Type
journal article
Language
en
Open access
Locations
  • Frontiers in Artificial Intelligence (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
Funders
Pacific Northwest National Laboratory
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
Keywords
missing data, multi-omics integration, artificial intelligence, statistical learning, missing data imputation, data heterogeneity, biological systems

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