. 2014 Jul; 70(1):59-73.
doi: 10.1016/j.ymeth.2014.06.015.

Digital pathology and image analysis in tissue biomarker research

Peter W Hamilton 1 Peter Bankhead 2 Yinhai Wang 2 Ryan Hutchinson 2 Declan Kieran 2 Darragh G McArt 2 Jacqueline James 2 Manuel Salto-Tellez 2 
  • PMID: 25034370
  •     55 citations


Digital pathology and the adoption of image analysis have grown rapidly in the last few years. This is largely due to the implementation of whole slide scanning, advances in software and computer processing capacity and the increasing importance of tissue-based research for biomarker discovery and stratified medicine. This review sets out the key application areas for digital pathology and image analysis, with a particular focus on research and biomarker discovery. A variety of image analysis applications are reviewed including nuclear morphometry and tissue architecture analysis, but with emphasis on immunohistochemistry and fluorescence analysis of tissue biomarkers. Digital pathology and image analysis have important roles across the drug/companion diagnostic development pipeline including biobanking, molecular pathology, tissue microarray analysis, molecular profiling of tissue and these important developments are reviewed. Underpinning all of these important developments is the need for high quality tissue samples and the impact of pre-analytical variables on tissue research is discussed. This requirement is combined with practical advice on setting up and running a digital pathology laboratory. Finally, we discuss the need to integrate digital image analysis data with epidemiological, clinical and genomic data in order to fully understand the relationship between genotype and phenotype and to drive discovery and the delivery of personalized medicine.

Keywords: Biobank; Biomarker; Digital pathology; Drug discovery; Molecular pathology; Personalized medicine; Tissue microarrays; Tumour analysis.

Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer.
Ryan A Hutchinson, Richard A Adams, +3 authors, Peter W Hamilton.
J Transl Med, 2015 Jul 08; 13. PMID: 26149458    Free PMC article.
Automated tumor analysis for molecular profiling in lung cancer.
Peter W Hamilton, Yinhai Wang, +12 authors, Manuel Salto-Tellez.
Oncotarget, 2015 Sep 01; 6(29). PMID: 26317646    Free PMC article.
Delivering a research-enabled multistakeholder partnership for enhanced patient care at a population level: The Northern Ireland Comprehensive Cancer Program.
Mark Lawler, Anna Gavin, +17 authors, David J Waugh.
Cancer, 2015 Dec 24; 122(5). PMID: 26695702    Free PMC article.
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Monika Lamba Saini, Caroline Bouzin, Birgit Weynand, Etienne Marbaix.
PLoS One, 2016 Feb 11; 11(2). PMID: 26863116    Free PMC article.
Feature-based analysis of mouse prostatic intraepithelial neoplasia in histological tissue sections.
Pekka Ruusuvuori, Mira Valkonen, +2 authors, Leena Latonen.
J Pathol Inform, 2016 Mar 10; 7. PMID: 26955503    Free PMC article.
Expression of fibroblast growth factor receptor family members is associated with prognosis in early stage cervical cancer patients.
Chel Hun Choi, Joon-Yong Chung, +2 authors, Stephen M Hewitt.
J Transl Med, 2016 May 08; 14(1). PMID: 27154171    Free PMC article.
Joint analysis of histopathology image features and gene expression in breast cancer.
Vlad Popovici, Eva Budinská, +4 authors, Rolf Jaggi.
BMC Bioinformatics, 2016 May 14; 17(1). PMID: 27170365    Free PMC article.
Embracing an integromic approach to tissue biomarker research in cancer: Perspectives and lessons learned.
Gerald Li, Peter Bankhead, +5 authors, Darragh G McArt.
Brief Bioinform, 2016 Jun 04; 18(4). PMID: 27255914    Free PMC article.
Association between nuclear expression of retinoic acid receptor alpha and beta and clinicopathological features and prognosis of advanced non-small cell lung cancer.
Saé Muñiz-Hernández, Sara Huerta-Yepez, +6 authors, Oscar Arrieta.
Int J Clin Oncol, 2016 Jun 17; 21(6). PMID: 27306217
Quantitative imaging for development of companion diagnostics to drugs targeting HGF/MET.
Fangjin Huang, Zhaoxuan Ma, +20 authors, Beatrice S Knudsen.
J Pathol Clin Res, 2016 Oct 28; 2(4). PMID: 27785366    Free PMC article.
Construction and analysis of tissue microarrays in the era of digital pathology: a pilot study targeting CDX1 and CDX2 in a colon cancer cohort of 612 patients.
Sarah Nolte, Inti Zlobec, +6 authors, Tilman T Rau.
J Pathol Clin Res, 2017 Feb 01; 3(1). PMID: 28138402    Free PMC article.
An Assessment of Imaging Informatics for Precision Medicine in Cancer.
C Chennubhotla, L P Clarke, +9 authors, A Sharma.
Yearb Med Inform, 2017 Oct 25; 26(1). PMID: 29063549    Free PMC article.
Time for change: a new training programme for morpho-molecular pathologists?
David A Moore, Caroline A Young, +4 authors, Manuel Salto-Tellez.
J Clin Pathol, 2017 Nov 09; 71(4). PMID: 29113995    Free PMC article.
Morphomolecular pathology: setting the framework for a new generation of pathologists.
J Louise Jones, Karin A Oien, Jessica L Lee, Manuel Salto-Tellez.
Br J Cancer, 2017 Nov 11; 117(11). PMID: 29123262    Free PMC article.
Molecular Subtypes and Local-Regional Control of Breast Cancer.
Simona Maria Fragomeni, Andrew Sciallis, Jacqueline S Jeruss.
Surg Oncol Clin N Am, 2017 Nov 15; 27(1). PMID: 29132568    Free PMC article.
QuPath: Open source software for digital pathology image analysis.
Peter Bankhead, Maurice B Loughrey, +10 authors, Peter W Hamilton.
Sci Rep, 2017 Dec 06; 7(1). PMID: 29203879    Free PMC article.
Highly Cited.
Advances in the computational and molecular understanding of the prostate cancer cell nucleus.
Neil M Carleton, George Lee, Anant Madabhushi, Robert W Veltri.
J Cell Biochem, 2018 Jun 21; 119(9). PMID: 29923622    Free PMC article.
Artificial intelligence in digital pathology - new tools for diagnosis and precision oncology.
Kaustav Bera, Kurt A Schalper, +2 authors, Anant Madabhushi.
Nat Rev Clin Oncol, 2019 Aug 11; 16(11). PMID: 31399699    Free PMC article.
Highly Cited. Review.
Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression.
Fabián Segovia-Miranda, Hernán Morales-Navarrete, +14 authors, Marino Zerial.
Nat Med, 2019 Dec 04; 25(12). PMID: 31792455    Free PMC article.
Deep Learning for Whole Slide Image Analysis: An Overview.
Neofytos Dimitriou, Ognjen Arandjelović, Peter D Caie.
Front Med (Lausanne), 2019 Dec 12; 6. PMID: 31824952    Free PMC article.
Digital Microscopy, Image Analysis, and Virtual Slide Repository.
Famke Aeffner, Hibret A Adissu, +8 authors, Kristin Wilson.
ILAR J, 2018 Dec 12; 59(1). PMID: 30535284    Free PMC article.
Feasibility of fully automated classification of whole slide images based on deep learning.
Kyung-Ok Cho, Sung Hak Lee, Hyun-Jong Jang.
Korean J Physiol Pharmacol, 2020 Jan 08; 24(1). PMID: 31908578    Free PMC article.
Automated Identification and Quantification of Signals in Multichannel Immunofluorescence Images: The SignalFinder-IF Platform.
Daniel Barnett, Johnathan Hall, Brian Haab.
Am J Pathol, 2019 Apr 27; 189(7). PMID: 31026417    Free PMC article.
Beyond the H&E: Advanced Technologies for in situ Tissue Biomarker Imaging.
Lauren E Himmel, Troy A Hackett, +7 authors, Kelli L Boyd.
ILAR J, 2018 Nov 22; 59(1). PMID: 30462242    Free PMC article.
The use of digital pathology and image analysis in clinical trials.
Robert Pell, Karin Oien, +6 authors, UK National Cancer Research Institute (NCRI) Cellular-Molecular Pathology (CM-Path) quality assurance working group.
J Pathol Clin Res, 2019 Feb 16; 5(2). PMID: 30767396    Free PMC article.
Validation of the prognostic value of NF-κB p65 in prostate cancer: A retrospective study using a large multi-institutional cohort of the Canadian Prostate Cancer Biomarker Network.
Andrée-Anne Grosset, Véronique Ouellet, +18 authors, Canadian Prostate Cancer Biomarker Network.
PLoS Med, 2019 Jul 03; 16(7). PMID: 31265453    Free PMC article.
Quality assurance guidance for scoring and reporting for pathologists and laboratories undertaking clinical trial work.
Max Robinson, Jacqueline James, +12 authors, UK National Cancer Research Institute (NCRI) Cellular-Molecular Pathology (CM-Path) clinical trials working group.
J Pathol Clin Res, 2018 Nov 09; 5(2). PMID: 30407751    Free PMC article.
Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.
Mohamed Amgad, Elisabeth Specht Stovgaard, +66 authors, International Immuno-Oncology Biomarker Working Group.
NPJ Breast Cancer, 2020 May 16; 6. PMID: 32411818    Free PMC article.
Current status of pathological image analysis technology in pharmaceutical companies: a questionnaire survey of the Japan Pharmaceutical Manufacturers Association.
Tsuyoshi Yoshikawa, Yasushi Horai, +4 authors, Masaharu Tanaka.
J Toxicol Pathol, 2020 May 20; 33(2). PMID: 32425346    Free PMC article.
Characterization of RNA-Binding Motif 3 (RBM3) Protein Levels and Nuclear Architecture Changes in Aggressive and Recurrent Prostate Cancer.
Neil M Carleton, Guangjing Zhu, +3 authors, Robert W Veltri.
Cancer Rep (Hoboken), 2020 Jun 27; 3(3). PMID: 32587951    Free PMC article.
Twenty Years of Digital Pathology: An Overview of the Road Travelled, What is on the Horizon, and the Emergence of Vendor-Neutral Archives.
Liron Pantanowitz, Ashish Sharma, +3 authors, Joel Saltz.
J Pathol Inform, 2019 Jan 05; 9. PMID: 30607307    Free PMC article.
Automated macrophage counting in DLBCL tissue samples: a ROF filter based approach.
Marcus Wagner, René Hänsel, +6 authors, Wolfram Klapper.
Biol Proced Online, 2019 Jul 16; 21. PMID: 31303867    Free PMC article.
Empiric Methods to Account for Pre-analytical Variability in Digital Histopathology in Frontotemporal Lobar Degeneration.
Lucia A A Giannini, Sharon X Xie, +7 authors, David J Irwin.
Front Neurosci, 2019 Jul 25; 13. PMID: 31333403    Free PMC article.
A Regulatory Science Initiative to Harmonize and Standardize Digital Pathology and Machine Learning Processes to Speed up Clinical Innovation to Patients.
Hetal Desai Marble, Richard Huang, +14 authors, Jochen K Lennerz.
J Pathol Inform, 2020 Oct 13; 11. PMID: 33042601    Free PMC article.
Immune contexture analysis in immuno-oncology: applications and challenges of multiplex fluorescent immunohistochemistry.
Reshma Shakya, Tam Hong Nguyen, Nigel Waterhouse, Rajiv Khanna.
Clin Transl Immunology, 2020 Oct 20; 9(10). PMID: 33072322    Free PMC article.
Prediction of clinically actionable genetic alterations from colorectal cancer histopathology images using deep learning.
Hyun-Jong Jang, Ahwon Lee, +2 authors, Sung Hak Lee.
World J Gastroenterol, 2020 Nov 13; 26(40). PMID: 33177794    Free PMC article.
Prediction of relapse-free survival according to adjuvant chemotherapy and regulator of chromosome condensation 2 (RCC2) expression in colorectal cancer.
Christian H Bergsland, Jarle Bruun, +13 authors, Ragnhild A Lothe.
ESMO Open, 2020 Nov 22; 5(6). PMID: 33219056    Free PMC article.
WHO/ISUP classification, grading and pathological staging of renal cell carcinoma: standards and controversies.
Anne Y Warren, David Harrison.
World J Urol, 2018 Aug 21; 36(12). PMID: 30123932    Free PMC article.
A novel computational method for automatic segmentation, quantification and comparative analysis of immunohistochemically labeled tissue sections.
Elena Casiraghi, Veronica Huber, +6 authors, Barbara Vergani.
BMC Bioinformatics, 2018 Oct 28; 19(Suppl 10). PMID: 30367588    Free PMC article.
High Oct4 expression: implications in the pathogenesis of neuroblastic tumours.
Ezequiel Monferrer, Rebeca Burgos-Panadero, +3 authors, Rosa Noguera.
BMC Cancer, 2019 Jan 05; 19(1). PMID: 30606139    Free PMC article.
Quantitative pixel intensity- and color-based image analysis on minimally compressed files: implications for whole-slide imaging.
Douglas J Taatjes, Nicole A Bouffard, +3 authors, Filip Braet.
Histochem Cell Biol, 2019 Apr 15; 152(1). PMID: 30982111
Computerized Image Analysis of Tumor Cell Nuclear Morphology Can Improve Patient Selection for Clinical Trials in Localized Clear Cell Renal Cell Carcinoma.
In Hwa Um, Lindesay Scott-Hayward, +9 authors, David J Harrison.
J Pathol Inform, 2020 Dec 22; 11. PMID: 33343995    Free PMC article.
Quantitative immuno-mass spectrometry imaging of skeletal muscle dystrophin.
David P Bishop, Mika T Westerhausen, +8 authors, Jonathan Wanagat.
Sci Rep, 2021 Jan 15; 11(1). PMID: 33441839    Free PMC article.
Deep Convolutional Neural Network-Based Lymph Node Metastasis Prediction for Colon Cancer Using Histopathological Images.
Min Seob Kwak, Hun Hee Lee, +4 authors, Ha Il Kim.
Front Oncol, 2021 Feb 02; 10. PMID: 33520727    Free PMC article.

;. PMID: 33574288
QuPath: The global impact of an open source digital pathology system.
M P Humphries, P Maxwell, M Salto-Tellez.
Comput Struct Biotechnol J, 2021 Feb 19; 19. PMID: 33598100    Free PMC article.
Elevated Expression of Glycerol-3-Phosphate Phosphatase as a Biomarker of Poor Prognosis and Aggressive Prostate Cancer.
Mohamed Amine Lounis, Veronique Ouellet, +7 authors, Fred Saad.
Cancers (Basel), 2021 Apr 04; 13(6). PMID: 33805661    Free PMC article.
Next-Generation Digital Histopathology of the Tumor Microenvironment.
Felicitas Mungenast, Achala Fernando, +4 authors, Rupert C Ecker.
Genes (Basel), 2021 May 01; 12(4). PMID: 33917241    Free PMC article.
Artificial Intelligence in Pathology: From Prototype to Product.
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J Pathol Inform, 2021 May 21; 12. PMID: 34012717    Free PMC article.
Automated gleason grading on prostate biopsy slides by statistical representations of homology profile.
Chaoyang Yan, Kazuaki Nakane, +6 authors, Jun Xu.
Comput Methods Programs Biomed, 2020 May 30; 194. PMID: 32470903    Free PMC article.
Dissecting the Business Case for Adoption and Implementation of Digital Pathology: A White Paper from the Digital Pathology Association.
Giovanni Lujan, Jennifer C Quigley, +16 authors, Doug Bowman.
J Pathol Inform, 2021 Jul 06; 12. PMID: 34221633    Free PMC article.
Digital pathology and artificial intelligence will be key to supporting clinical and academic cellular pathology through COVID-19 and future crises: the PathLAKE consortium perspective.
Lisa Browning, Richard Colling, +6 authors, Clare Verrill.
J Clin Pathol, 2020 Jul 06; 74(7). PMID: 32620678    Free PMC article.
Selection of high-producing clones by a relative titer predictive model using image analysis.
Weihong Tao, Waqas Ahmed, +3 authors, Rongxiu Li.
Ann Transl Med, 2021 Aug 26; 9(14). PMID: 34430585    Free PMC article.
Analysis of Image Feature Characteristics for Automated Scoring of HER2 in Histology Slides.
Ramakrishnan Mukundan.
J Imaging, 2019 Mar 10; 5(3). PMID: 34460463    Free PMC article.
Digital pathology and artificial intelligence in translational medicine and clinical practice.
Vipul Baxi, Robin Edwards, Michael Montalto, Saurabh Saha.
Mod Pathol, 2021 Oct 07;. PMID: 34611303    Free PMC article.