Integrating deep learning and unbiased automated high-content screening to identify complex disease signatures in human fibroblasts.

Journal: Nature communications
PMID: 35338121

Abstract

Drug discovery for diseases such as Parkinson's disease are impeded by the lack of screenable cellular phenotypes. We present an unbiased phenotypic profiling platform that combines automated cell culture, high-content imaging, Cell Painting, and deep learning. We applied this platform to primary fibroblasts from 91 Parkinson's disease patients and matched healthy controls, creating the largest publicly available Cell Painting image dataset to date at 48 terabytes. We use fixed weights from a convolutional deep neural network trained on ImageNet to generate deep embeddings from each image and train machine learning models to detect morphological disease phenotypes. Our platform's robustness and sensitivity allow the detection of individual-specific variation with high fidelity across batches and plate layouts. Lastly, our models confidently separate LRRK2 and sporadic Parkinson's disease lines from healthy controls (receiver operating characteristic area under curve 0.79 (0.08 standard deviation)), supporting the capacity of this platform for complex disease modeling and drug screening applications.

Authors

  • Lauren Schiff
    Google Research, Mountain View, CA, USA.
  • Bianca Migliori
    Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School; Tech4Health and Neuroscience Institutes, NYU Langone Health.
  • Ye Chen
    1 Department of Urology, First Affiliated Hospital of Soochow University, Suzhou, China.
  • Deidre Carter
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Caitlyn Bonilla
    Google Research, Mountain View, CA, USA.
  • Jenna Hall
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Minjie Fan
    1 Google, LLC, Mountain View, CA, USA.
  • Edmund Tam
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Sara Ahadi
    Google Research, Mountain View, CA, USA.
  • Brodie Fischbacher
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Anton Geraschenko
    1 Google, LLC, Mountain View, CA, USA.
  • Christopher J Hunter
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Subhashini Venugopalan
    Google Inc, Mountain View, California2Department of Computer Science, University of Texas, Austin.
  • Sean DesMarteau
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Arunachalam Narayanaswamy
    Google Inc, Mountain View, California.
  • Selwyn Jacob
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Zan Armstrong
    1 Google, LLC, Mountain View, CA, USA.
  • Peter Ferrarotto
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Brian Williams
    1 Google, LLC, Mountain View, CA, USA.
  • Geoff Buckley-Herd
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Jon Hazard
    1 Google, LLC, Mountain View, CA, USA.
  • Jordan Goldberg
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Marc Coram
    Google Inc, Mountain View, California.
  • Reid Otto
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Edward A Baltz
    Google Research, Mountain View, CA, USA.
  • Laura Andres-Martin
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Orion Pritchard
    Google Research, Mountain View, CA, USA.
  • Alyssa Duren-Lubanski
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Ameya Daigavane
    Google Research, Mountain View, CA, USA.
  • Kathryn Reggio
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Phillip C Nelson
    Google Research, Mountain View, CA, USA.
  • Michael Frumkin
    Google Research, Mountain View, CA, USA.
  • Susan L Solomon
    The New York Stem Cell Foundation Research Institute, New York, New York, USA.
  • Lauren Bauer
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Raeka S Aiyar
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Elizabeth Schwarzbach
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Scott A Noggle
    The New York Stem Cell Foundation Research Institute, New York, New York, USA.
  • Frederick J Monsma
    The New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • Daniel Paull
    The New York Stem Cell Foundation Research Institute, New York, New York, USA.
  • Marc Berndl
    Google Inc., 1600 Amphitheatre Pkwy, Mountain View, CA, 94043, USA.
  • Samuel J Yang
    Google Inc, Mountain View, CA, USA. samuely@google.com.
  • Bjarki Johannesson
    The New York Stem Cell Foundation Research Institute, New York, NY, USA. johannesson.bjarki@gmail.com.

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