Direct prediction of genetic aberrations from pathology images in gastric cancer with swarm learning

Oliver Lester Saldanha, Hannah Sophie Muti, Heike I Grabsch, Rupert Langer, Bastian Dislich, Meike Kohlruss, Gisela Keller, Marko van Treeck, Katherine Jane Hewitt, Fiona R Kolbinger, Gregory Patrick Veldhuizen, Peter Boor, Sebastian Foersch, Daniel Truhn, Jakob Nikolas Kather, Oliver Lester Saldanha, Hannah Sophie Muti, Heike I Grabsch, Rupert Langer, Bastian Dislich, Meike Kohlruss, Gisela Keller, Marko van Treeck, Katherine Jane Hewitt, Fiona R Kolbinger, Gregory Patrick Veldhuizen, Peter Boor, Sebastian Foersch, Daniel Truhn, Jakob Nikolas Kather

Abstract

Background: Computational pathology uses deep learning (DL) to extract biomarkers from routine pathology slides. Large multicentric datasets improve performance, but such datasets are scarce for gastric cancer. This limitation could be overcome by Swarm Learning (SL).

Methods: Here, we report the results of a multicentric retrospective study of SL for prediction of molecular biomarkers in gastric cancer. We collected tissue samples with known microsatellite instability (MSI) and Epstein-Barr Virus (EBV) status from four patient cohorts from Switzerland, Germany, the UK and the USA, storing each dataset on a physically separate computer.

Results: On an external validation cohort, the SL-based classifier reached an area under the receiver operating curve (AUROC) of 0.8092 (± 0.0132) for MSI prediction and 0.8372 (± 0.0179) for EBV prediction. The centralized model, which was trained on all datasets on a single computer, reached a similar performance.

Conclusions: Our findings demonstrate the feasibility of SL-based molecular biomarkers in gastric cancer. In the future, SL could be used for collaborative training and, thus, improve the performance of these biomarkers. This may ultimately result in clinical-grade performance and generalizability.

Keywords: Artificial intelligence; Biomarker; Blockchain; Gastric cancer; Pathology; Swarm learning.

Conflict of interest statement

JNK declares consulting services for Owkin, France and Panakeia, UK. No other potential conflicts of interest are reported by any of the authors.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Outline of this study. A Technical setup of the swarm learning experiment. B Distribution of training and testing set for the three experiments local models (each dataset is used to independently train a model), central models (all datasets are merged), and swarm model (all datasets are used to co-train a model without merging any raw data)
Fig. 2
Fig. 2
MSI status prediction from pathology images in gastric cancer with swarm learning. A Classification performance (area under the receiver operating curve, AUROC) for prediction of MSI status on a patient level in the TCGA cohort. The results of three replicates per experiment are shown as a box plot. The box shows the median and quartiles as the whiskers expand to the rest of the distribution, with the exception of points identified as outliers. B Highly predictive image tiles for the Swarm Learning model for MSI and MSS, obtained from the first of three experiments. C Whole-slide prediction heatmaps for MSI and MSS in six patients. Abbreviations: w-chkpt weighted checkpoint of the swarm (= final swarm learning model), MSI microsatellite instable, MSS microsatellite stable
Fig. 3
Fig. 3
EBV status prediction from pathology images in gastric cancer with swarm learning. A Classification performance (area under the receiver operating curve, AUROC) for prediction of EBV status on a patient level in the TCGA cohort. The results of three replicates per experiment are shown as a box plot, obtained from the first of three experiments. The box shows the median and quartiles as the whiskers expand to the rest of the distribution, with the exception of points identified as outliers. B Highly predictive image tiles for the Swarm Learning model for MSI and MSS. C Whole-slide prediction heatmaps for EBV positivity and negativity in six patients. Abbreviations: w-chkpt weighted checkpoint of the swarm (= final swarm learning model), EBV Epstein–Barr Virus, Pos. positive, Neg. negative

References

    1. Laleh NG, Muti HS, Loeffler CML, Echle A, Saldanha OL, Mahmood F, et al. Benchmarking weakly-supervised deep learning pipelines for whole slide classification in computational pathology. Med Image Anal. 2022;79:102474. doi: 10.1016/j.media.2022.102474.
    1. Heinz CN, Echle A, Foersch S, Bychkov A, Kather JN. The future of artificial intelligence in digital pathology - results of a survey across stakeholder groups. Histopathology. 2022;80(7):1121–1127. doi: 10.1111/his.14659.
    1. Shmatko A, GhaffariLaleh N, Gerstung M, Kather JN. Artificial intelligence in histopathology: enhancing cancer research and clinical oncology. Nat Cancer. 2022;3:1026–1038. doi: 10.1038/s43018-022-00436-4.
    1. Bera K, Schalper KA, Rimm DL, Velcheti V, Madabhushi A. Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology. Nat Rev Clin Oncol. 2019;16:703–715. doi: 10.1038/s41571-019-0252-y.
    1. Muti HS, Heij LR, Keller G, Kohlruss M, Langer R, Dislich B, et al. Deep Learning for diagnosis of microsatellite instable and Epstein–Barr-Virus-associated gastric cancer. Lancet Digital Health. 2021 [cited 21 Jun 2022]. Available:
    1. Kather JN, Pearson AT, Halama N, Jäger D, Krause J, Loosen SH, et al. Deep learning can predict microsatellite instability directly from histology in gastrointestinal cancer. Nat Med. 2019;25:1054–1056. doi: 10.1038/s41591-019-0462-y.
    1. Echle A, Laleh NG, Schrammen PL, West NP, Trautwein C, Brinker TJ, et al. Deep learning for the detection of microsatellite instability from histology images in colorectal cancer: a systematic literature review. ImmunoInformatics. 2021;3–4:100008. doi: 10.1016/j.immuno.2021.100008.
    1. Kather JN, Schulte J, Grabsch HI, Loeffler C, Muti H, Dolezal J, et al. Deep learning detects virus presence in cancer histology. bioRxiv. 2019 doi: 10.1101/690206.
    1. Bilal M, Raza SEA, Azam A, Graham S, Ilyas M, Cree IA, et al. Development and validation of a weakly supervised deep learning framework to predict the status of molecular pathways and key mutations in colorectal cancer from routine histology images: a retrospective study. Lancet Digit Health. 2021;3:e763–e772. doi: 10.1016/S2589-7500(21)00180-1.
    1. GhaffariLaleh N, Ligero M, Perez-Lopez R, Kather JN. Facts and hopes on the use of artificial intelligence for predictive immunotherapy biomarkers in cancer. Clin Cancer Res. 2022 doi: 10.1158/1078-0432.CCR-22-0390.
    1. Kacew AJ, Strohbehn GW, Saulsberry L, Laiteerapong N, Cipriani NA, Kather JN, et al. Artificial intelligence can cut costs while maintaining accuracy in colorectal cancer genotyping. Front Oncol. 2021 doi: 10.3389/fonc.2021.630953.
    1. Echle A, GhaffariLaleh N, Quirke P, Grabsch HI, Muti HS, Saldanha OL, et al. Artificial intelligence for detection of microsatellite instability in colorectal cancer—a multicentric analysis of a pre-screening tool for clinical application. ESMO Open. 2022;7:100400. doi: 10.1016/j.esmoop.2022.100400.
    1. Muti HS, Heij LR, Keller G, Kohlruss M, Langer R, Dislich B, et al. Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study. Lancet Digital Health. 2021 doi: 10.1016/S2589-7500(21)00133-3.
    1. Cifci D, Foersch S, Kather JN. Artificial intelligence to identify genetic alterations in conventional histopathology. J Pathol. 2022 doi: 10.1002/path.5898.
    1. Lu MY, Chen RJ, Kong D, Lipkova J, Singh R, Williamson DFK, et al. Federated learning for computational pathology on gigapixel whole slide images. Med Image Anal. 2022;76:102298. doi: 10.1016/j.media.2021.102298.
    1. Warnat-Herresthal S, Schultze H, Shastry KL, Manamohan S, Mukherjee S, Garg V, et al. Swarm learning for decentralized and confidential clinical machine learning. Nature. 2021;594:265–270. doi: 10.1038/s41586-021-03583-3.
    1. Saldanha OL, Quirke P, West NP, James JA, Loughrey MB, Grabsch HI, et al. Swarm learning for decentralized artificial intelligence in cancer histopathology. Nat Med. 2022 doi: 10.1038/s41591-022-01768-5.
    1. Dislich B, Blaser N, Berger MD, Gloor B, Langer R. Preservation of Epstein-Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer. Histopathology. 2020;76:740–747. doi: 10.1111/his.14059.
    1. Hayashi T, Yoshikawa T, Bonam K, SueLing HM, Taguri M, Morita S, et al. The superiority of the seventh edition of the TNM classification depends on the overall survival of the patient cohort: comparative analysis of the sixth and seventh TNM editions in patients with gastric cancer from Japan and the United Kingdom. Cancer. 2013;119:1330–1337. doi: 10.1002/cncr.27928.
    1. Kohlruss M, Grosser B, Krenauer M, Slotta-Huspenina J, Jesinghaus M, Blank S, et al. Prognostic implication of molecular subtypes and response to neoadjuvant chemotherapy in 760 gastric carcinomas: role of Epstein–Barr virus infection and high- and low-microsatellite instability. Hip Int. 2019;5:227–239.
    1. The Cancer Genome Atlas Research Network The cancer genome atlas research network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202–209. doi: 10.1038/nature13480.
    1. GhaffariLaleh N, Truhn D, Veldhuizen GP, Han T, van Treeck M, Buelow RD, et al. Adversarial attacks and adversarial robustness in computational pathology. Nat Commun. 2022;13:1–10.
    1. Muti HS, Loeffler C, Echle A, Heij LR, Buelow RD, Krause J, et al. The Aachen protocol for deep learning histopathology: a hands-on guide for data preprocessing. 2020. Zenodo. 10.5281/ZENODO.3694994.
    1. Macenko M, Niethammer M, Marron JS, Borland D, Woosley JT, Xiaojun Guan, et al. A method for normalizing histology slides for quantitative analysis. In: 2009 IEEE international symposium on biomedical imaging: from nano to macro. IEEE: Piscataway; 2009. p. 1107–1110.
    1. Wang X, Du Y, Yang S, Zhang J, Wang M, Zhang J, et al. RetCCL: clustering-guided contrastive learning for whole-slide image retrieval. Med Image Anal. 2022 doi: 10.1016/j.media.2022.102645.
    1. Saldanha OL, Loeffler CML, Niehues JM, van Treeck M, Seraphin TP, Hewitt KJ, et al. Self-supervised deep learning for pan-cancer mutation prediction from histopathology. bioRxiv. 2022 doi: 10.1101/2022.09.15.507455.
    1. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang T-H, et al. The immune landscape of cancer. Immunity. 2018;48:812–830.e14. doi: 10.1016/j.immuni.2018.03.023.
    1. Mathiak M, Warneke VS, Behrens H-M, Haag J, Böger C, Krüger S, et al. Clinicopathologic characteristics of microsatellite instable gastric carcinomas revisited: urgent need for standardization. Appl Immunohistochem Mol Morphol. 2017;25:12–24. doi: 10.1097/PAI.0000000000000264.
    1. Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, et al. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open. 2019;4:e000470. doi: 10.1136/esmoopen-2018-000470.
    1. Schirris Y, Gavves E, Nederlof I, Horlings HM, Teuwen J. DeepSMILE: Contrastive self-supervised pre-training benefits MSI and HRD classification directly from H&E whole-slide images in colorectal and breast cancer. Med Image Anal. 2022;79:102464. doi: 10.1016/j.media.2022.102464.
    1. Chen RJ, Lu MY, Williamson DFK, Chen TY, Lipkova J, Noor Z, et al. Pan-cancer integrative histology-genomic analysis via multimodal deep learning. Cancer Cell. 2022;40:865–878.e6. doi: 10.1016/j.ccell.2022.07.004.

Source: PubMed

3
Prenumerera