Deep-learning methods for computational pathology require either manual annotation of gigapixel whole-slide images (WSIs) or large datasets of WSIs with slide-level labels and typically suffer from poor domain adaptation and interpretability. Here we report an interpretable weakly supervised deep-learning method for data-efficient WSI processing and learning that only requires slide-level labels. The method, which we named clustering-constrained-attention multiple-instance learning (CLAM), uses attention-based learning to identify subregions of high diagnostic value to accurately classify whole slides and instance-level clustering over the identified representative regions to constrain and refine the feature space. By applying CLAM to the subtyping of renal cell carcinoma and non-small-cell lung cancer as well as the detection of lymph node metastasis, we show that it can be used to localize well-known morphological features on WSIs without the need for spatial labels, that it overperforms standard weakly supervised classification algorithms and that it is adaptable to independent test cohorts, smartphone microscopy and varying tissue content.
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The TCGA diagnostic whole-slide data (NSCLC, RCC) and corresponding labels are available from the NIH genomic data commons (https://portal.gdc.cancer.gov). The CPTAC whole-slide data (NSCLC) and the corresponding labels are available from the NIH cancer imaging archive (https://cancerimagingarchive.net/datascope/cptac). Metastatic-lymph-node data are publicly available from the CAMELYON16 and CAMELYON17 website (https://camelyon17.grand-challenge.org/Data). We included links to all public data in Supplementary Table 20. All reasonable requests for academic use of in-house raw and analysed data can be addressed to the corresponding author. All requests will be promptly reviewed to determine whether the request is subject to any intellectual property or patient-confidentiality obligations, will be processed in concordance with institutional and departmental guidelines and will require a material transfer agreement.
All code was implemented in Python using PyTorch as the primary deep-learning library. The complete pipeline for processing WSIs as well as training and evaluating the deep-learning models is available at https://github.com/mahmoodlab/CLAM and can be used to reproduce the experiments of this paper. All source code has been released under the GNU GPLv3 free software license.
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The authors thank A. Bruce for scanning internal cohorts of patient histology slides at BWH; J. Wang, K. Bronstein, L. Cirelli and S. Sahai for querying the BWH slide database and retrieving archival slides; M. Bragg, S. Zimmet and T. Mellen for administrative support; and Z. Noor for developing the interactive demo website. This work was supported in part by internal funds from BWH Pathology, the NIH National Institute of General Medical Sciences (NIGMS) grant no. R35GM138216A (to F.M.), a Google Cloud Research Grant and the Nvidia GPU Grant Program. R.J.C. was additionally supported by the NSF Graduate Research Fellowship and NIH National Human Genome Research Institute (NHGRI) grant no. T32HG002295. The content is solely the responsibility of the authors and does not reflect the official views of the National Institute of Health, National Institute of General Medical Sciences, National Human Genome Research Institute and the National Science Foundation.
The authors declare no competing interests.
Peer review information Nature Biomedical Engineering thanks Anant Madabhushi, Geert Litjens and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Lu, M.Y., Williamson, D.F.K., Chen, T.Y. et al. Data-efficient and weakly supervised computational pathology on whole-slide images. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-020-00682-w