Artificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease.

Journal: Nature communications
Published Date: Jul 12, 2021

Abstract

Modeling human diseases as networks simplify complex multi-cellular processes, helps understand patterns in noisy data that humans cannot find, and thereby improves precision in prediction. Using Inflammatory Bowel Disease (IBD) as an example, here we outline an unbiased AI-assisted approach for target identification and validation. A network was built in which clusters of genes are connected by directed edges that highlight asymmetric Boolean relationships. Using machine-learning, a path of continuum states was pinpointed, which most effectively predicted disease outcome. This path was enriched in gene-clusters that maintain the integrity of the gut epithelial barrier. We exploit this insight to prioritize one target, choose appropriate pre-clinical murine models for target validation and design patient-derived organoid models. Potential for treatment efficacy is confirmed in patient-derived organoids using multivariate analyses. This AI-assisted approach identifies a first-in-class gut barrier-protective agent in IBD and predicted Phase-III success of candidate agents.

Authors

  • Debashis Sahoo
    Department of Pediatrics, University of California San Diego, San Diego, CA, USA. dsahoo@ucsd.edu.
  • Lee Swanson
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • Ibrahim M Sayed
    Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiu, Egypt.
  • Gajanan D Katkar
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • Stella-Rita Ibeawuchi
    Department of Pathology, University of California San Diego, San Diego, CA, USA.
  • Yash Mittal
    Department of Medicine, University of California San Diego, San Diego, CA, USA.
  • Rama F Pranadinata
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • Courtney Tindle
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • Mackenzie Fuller
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • Dominik L Stec
    Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA, USA.
  • John T Chang
    Department of Medicine, University of California San Diego, San Diego, CA, USA.
  • William J Sandborn
    University of California San Diego, La Jolla, California.
  • Soumita Das
    Department of Pathology, University of California San Diego, San Diego, CA, USA. sodas@ucsd.edu.
  • Pradipta Ghosh
    Rebecca and John Moore Comprehensive Cancer Center, University of California San Diego, San Diego, CA, USA. prghosh@ucsd.edu.

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