Comprehensive tissue deconvolution of cell-free DNA by deep learning for disease diagnosis and monitoring.

Journal: Proceedings of the National Academy of Sciences of the United States of America
PMID: 37399400

Abstract

Plasma cell-free DNA (cfDNA) is a noninvasive biomarker for cell death of all organs. Deciphering the tissue origin of cfDNA can reveal abnormal cell death because of diseases, which has great clinical potential in disease detection and monitoring. Despite the great promise, the sensitive and accurate quantification of tissue-derived cfDNA remains challenging to existing methods due to the limited characterization of tissue methylation and the reliance on unsupervised methods. To fully exploit the clinical potential of tissue-derived cfDNA, here we present one of the comprehensive and high-resolution methylation atlas based on 521 noncancer tissue samples spanning 29 major types of human tissues. We systematically identified fragment-level tissue-specific methylation patterns and extensively validated them in orthogonal datasets. Based on the rich tissue methylation atlas, we develop the supervised tissue deconvolution approach, a deep-learning-powered model, , for sensitive and accurate tissue deconvolution in cfDNA. On the benchmarking data, showed superior sensitivity and accuracy compared to the existing methods. We further demonstrated the clinical utilities of with two potential applications: aiding disease diagnosis and monitoring treatment side effects. The tissue-derived cfDNA fraction estimated from reflected the clinical outcomes of the patients. In summary, the tissue methylation atlas and enhanced the performance of tissue deconvolution in cfDNA, thus facilitating cfDNA-based disease detection and longitudinal treatment monitoring.

Authors

  • Shuo Li
    Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Weihua Zeng
    Department of Radiology, 117752Xiangtan Central Hospital, Xiangtan, PR China.
  • Xiaohui Ni
    EarlyDiagnostics Inc., Los Angeles, CA 90095.
  • Qiao Liu
    MOE Key Laboratory of Bioinformatics; Bioinformatics Division and Center for Synthetic & Systems Biology, TNLIST; Department of Automation, Tsinghua University, Beijing 100084, China.
  • Wenyuan Li
  • Mary L Stackpole
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Yonggang Zhou
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Arjan Gower
    Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095.
  • Kostyantyn Krysan
    Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095.
  • Preeti Ahuja
    Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • David S Lu
    Department of Radiological Sciences, University of California Los Angeles, 300 UCLA Medical Plaza, Suite B119, Los Angeles, CA, 90095, USA.
  • Steven S Raman
    Department of Radiologic Sciences David Geffen School of Medicine, University of California Los Angeles CA.
  • William Hsu
    Medical & Imaging Informatics, Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90024, USA.
  • Denise R Aberle
    Department of Radiological Sciences, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Clara E Magyar
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Samuel W French
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Steven-Huy B Han
    Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095.
  • Edward B Garon
    Department of Medicine, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095.
  • Vatche G Agopian
    Department of Surgery, Dumont-UCLA Transplant and Liver Cancer Centers, University of California at Los Angeles, Los Angeles, California, United States.
  • Wing Hung Wong
    Department of Statistics, Stanford University, Stanford, CA 94305, USA.
  • Steven M Dubinett
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.
  • Xianghong Jasmine Zhou
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095.

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