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Hardware and Software in Whole Slide Imaging Lessons Learned to Assist in FDA Validation FDA Panel - Wednesday, October

Hardware and Software in Whole Slide Imaging Lessons Learned to Assist in FDA Validation FDA Panel - Wednesday, October 21 st , 2009 . Michael J. Becich, MD PhD – becich@pitt.edu Chairman, Department of Biomedical Informatics University of Pittsburgh Medical School

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Hardware and Software in Whole Slide Imaging Lessons Learned to Assist in FDA Validation FDA Panel - Wednesday, October

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  1. Hardware and Software in Whole Slide ImagingLessons Learned to Assist in FDA ValidationFDA Panel - Wednesday, October 21st, 2009 Michael J. Becich, MD PhD – becich@pitt.edu Chairman, Department of Biomedical Informatics University of Pittsburgh Medical School Professor of Biomedical Informatics, Pathology, Information Sciences & Telecommunications Professor of Clinical and Translational Science Department of Biomedical Informatics - http://dbmi.pitt.edu Slide 1

  2. Disclosures by MJB • Corporate Support for API and APIII • 550K projected for 2009 [Cerner, Misys, GE, IBM, IMPAC - Cisco, Verizon, CAP Today - Aperio, Apollo, Applied Imaging, De-ID Corp, GE Medical Systems/Triple G, Nikon, Olympus, SCC Soft, Sysmex, SNOMED, PSA, ThermoFisher, Zeiss others] • Corporate Sponsored Research Agreements • 200K in 2009 [Amgen and General Electric] • Startup/Public Companies (Royalties - MJB): • Omnyx – Joint Venture with UPMC and GE (http://www.omnyx.com) • Consultancy • ThermoFisher – Physician Advisory Board (paid) • GE Global Vision and Lab Vision (speaker honorarium) • Pathology Education Consortium (PEC) with Bruce Friedman (volunteer) • Cancer Center Consulting - Moffit Cancer Center, Univ Med Dent NJ, Univ Colorado (honorarium) • CTSA Consulting - Penn State, U MN, UAB, Northwestern U, UC Davis, Wash U (honorarium) Slide 2

  3. Intro to Digital Imaging in Pathology • Numerous situations where digital imaging in pathology has provided useful solutions to pathologists: • Digital Imaging (digital cameras / “snapshot” imaging) – mid 1990 • Gross room – documentation of resected specimens and requisitions • Microscopic signout – documentation of rare lesions, consults, etc… • Conference support – cheaper, faster, much more efficient • Telepathology (digital and video cameras) – late 1990 / early 2000 • Dynamic telepathology – requires real time “live’ dedicated connection • Static telepathology – cheaper, asynchronous, sub-sampling issues • Web based – cheaper even yet, also asynchronous but doesn’t have to be • Whole Slide Imaging – Virtual Microscopes / Virtual Slides - today • Newest technology images entire slide – like radiology PACS • Allows glass slides to be dealt with like digital files and shared at multiple locations simultaneously – collaborative telemicroscopy • Dropping costs for network, storage and CPUs make this possible • Huge implications for the practice of pathology – major efficiency gains Slide 3

  4. Digital Pathology Timeline at Pittsburgh Slide 4

  5. Digital Pathology Volumes at Pittsburgh (w/o Gross) * In Neuropathology at Pitt, 25% of all frozen section volume is done via telepathology Slide 5

  6. Why is Whole Slide Imaging (WSI) on the rise? • WSI as the basis for digital pathology is helping to address several problems with convential light microscopy, including: • Eliminating the inefficiencies of “snapshot” imaging • Difficulty sharing slides across distances • Access to experts, irrespective of patient location • Ability to share cases multiple peers simultaneously • Prioritization of case load • Reallocation of cases across a network (experts doing expert work and generalists doing general pathology) • Immediate access of archived images • Reduces/eliminates slide couriers/filers/consult issues Slide 6

  7. Will WSI Improve the Quality of Care? • Any new technology introduced to medical practice should improve the quality of care delivered. • Physician’s Hippocratic Oath “…To practice to the best of my ability for the good of my patients, and to try to avoid harming them…” • If WSI is safe and effective than many other applications are possible • The basic ability to capture the digital image faithfully must be validated before further applications can be developed • Let’s take a look at validation studies to date Slide 7

  8. WSI and Primary Diagnosis Gilbertson JR, et al. BMC Clinical Pathology 2006 • 3 Subject Pathologists signed out 25 cases (31 Parts) • Real cases (Genitourinary and DERMatopathology) • Misdiagnoses (2 cases) • DERM cases (lack of DERM experience) • Lesion missed (3 occurrences in 2 cases) • Lesion visible but not seen by pathologist and therefore not reported • WSI contain enough information for diagnostic use • Consensus DX matched original glass DX’s • WSI is not as good as a microscope • Focus was imperfect in almost all WSI • Also blur from over-compression • Physical Characteristics of WSI used in study • Device type – 1st generation line scanner • Resolution – 0.47 microns/pixel • Objective Used – 20X • Monitor Used – no control – whatever available • Monitor Resolution – no control – whatever available • Light Microscopes – no control for field of view, color, light intensity, focusing objectives or illumination – used whatever was available Slide 8

  9. WSI & QA in Surgical Pathology Ho J, et al. Human Pathology 2006 • 24 Full GU cases • 47 Parts; 391 Slides • Cases selected using normal QA procedures • Two independent reviews: Glass and WSI • Nearly equivalent • Time consideration (WSI possibly slower 8 cases >45 minutes • 5 Clinically insignificant discrepancies • 2 glass; 3 WSI • Disagreement of atypia • Glass reviewer found one subtle carcinoma (prostate core BX) that was missed by both original pathologist and by WSI reviewer • Physical Characteristics of WSI used in study • Device type – 1st generation line scanner • Resolution – 0.47 microns/pixel • Objective Used – 20X • Monitor Used – no control – whatever available • Monitor Resolution – no control – whatever available • Light Microscopes – no control for field of view, color, light intensity, focusing objectives or illumination – used whatever was available Slide 9

  10. WSI and Immunohistochemistry Fine JL, et al. Human Pathology, 2008 • 30 Difficult Prostate BX foci were studied • Not full cases; foci which had required IHC for original dx • Non-subject pathologist identified foci from reports and by observing dots on glass slides • 5 subject pathologists; 1 outside expert • Review of WSI Stains (with H&E available) • Review of Glass Stains (with H&E) • Simulate workflow with glass slide review as a QA step • Kappa Statistic for Interobserver Agreement • Substantial (3 pairs of subjects, both) • Moderate (7 pairs glass; 5 pairs WSI) • Fair (2 pairs WSI) • Consensus vs. Outside Expert • Almost Perfect (kappa = 0.817) • Interpretations • Pathologists saw the same thing but disagreed on how to interpret it • Image quality • One WSI case w/ difficult seeing nucleoli • Physical Characteristics of WSI used in study • Device type – 1st generation line scanner • Resolution – 0.47 microns/pixel • Objective Used – 20X • Monitor Used – no control – whatever available • Monitor Resolution – no control – whatever available • Light Microscopes – no control for field of view, color, light intensity, focusing objectives or illumination – used whatever was available • NOTE: Identical properties were used in all 3 studies.

  11. WSI and Immunohistochemistry Fine JL, et al. Human Pathology, 2008 • 30 Difficult Prostate BX foci were studied • Not full cases; foci which had required IHC for original dx • Non-subject pathologist identified foci from reports and by observing dots on glass slides • 5 subject pathologists; 1 outside expert • Review of WSI Stains (with H&E available) • Review of Glass Stains (with H&E) • Simulate workflow with glass slide review as a QA step • Kappa Statistic for Interobserver Agreement • Substantial (3 pairs of subjects, both) • Moderate (7 pairs glass; 5 pairs WSI) • Fair (2 pairs WSI) • Consensus vs. Outside Expert • Almost Perfect (kappa = 0.817) • Interpretations • Pathologists saw the same thing but disagreed on how to interpret it • Image quality • One WSI case w/ difficult seeing nucleoli • Physical Characteristics of WSI used in study • Device type – 2nd generation line scanner • Resolution – 0.47 microns/pixel • Objective Used – 20X • Monitor Used – no control – whatever available • Monitor Resolution – no control – whatever available • Light Microscopes – no control for field of view, color, light intensity, focusing objectives or illumination – used whatever was available

  12. Lessons Learned from Early “Validation” Studies Image capture or hardware “lessons learned” • Results from early studies were “first generation” imaging robots using line scanning • Image quality “good enough” (focus group consensus) from IHC study (Fine et al, 2008) • For interpretation • To recognize a hard case (“defer to glass”) • 2008 studies based on later generation line scanning robots • Agreement rates similar to those reported in literature for other tasks (Gleason grading; evaluation colon biopsies using digital images; etc.) (Fine et al, 2008) Digital Pathology Workflow or software “lessons learned” • Lack of digital slide box (in this software) (Gilbertson et al, 2006) • Can’t “preview” a case prior to opening slides (Gilbertson et al, 2006) • Low/medium magnification scanning clumsy/slow (Gilbertson et al, 2008) • Not enough monitor “real estate” (Gilbertson et al, 2008) • Integration of Anatomic Pathology Lab Info System is key (Gilbertson et al, 2008) Slide 12

  13. Lessons Learned from Early “Validation” Studies Validation Study Design Considerations: • Need diagnostic standards & better design of study conditions for head to head comparison of light and WSI – currently lacking in studies to date • We must consider intraobserver discrepancies and identify the causes • Many times these discrepancies are not image quality related • Subject pathologists sign out cases they are accustomed to signing out • General pathologists sign out general cases, whereas subspecialized pathologists sign out subspecialty cases only. • This needs to be considered when proposing retrospective validation studies • Subject pathologists see slides scanned from histo labs that they are accustomed to seeing slides from. • Different histo labs have different cutting and staining protocols • Things that vary the usual workflow of pathologists will lead to artificial discrepancies • No considerations paid to software used to present whole slides • May have a profound impact on not only speed (cited as a problem in all studies to date) but effectiveness of presentation of diagnostic areas

  14. Lessons Learned from Early “Validation” Studies Physical Characteristics of Hardware and Software need to be considered in study design • Device type – line scanner vs point scanner • Resolution – control for microns/pixel resolution • Objective Used – will be hard to match WSI scanning at one objective with multiple objectives used in conventional light microscopy (LM) • Monitor Used – need to control for this aspect as well as viewing conditions • Monitor Resolution – need to “match” image file resolution capabilities • Light Microscopes – we need to consider the effect of: • Field of view (wide field vs. narrow) • Color • Light intensity • Focusing objectives (a specialize objective available on light microscopes) • Illumination • Software – how do you control for this in head to head LM/WSI comparisons? • Once proven that workflow software enhances the pathologist’s effectiveness and patient safety, can we afford to have LM only environments? Slide 14

  15. WSI does not eliminate the glass slide • Pathologist will be relied on to determine when the glass slide is needed: • Concept of “glass/microscope plus WSI” environment • In instances that the glass slide is not available and the pathologist needs more to make a decision then he/she should deferring the dx. • Scope of Discussion today: • Digitization Process - Glass to Digital Image – Whole Slide Imaging (Hardware) and Digital Capture Methods • Workflow Tools – Digital Image to Diagnosis – Digital Glass Slide Diagnostics (Software) • Out of Scope for Discussion: • Histology lab processing including fixation, sectioning, staining and coverslipping • For WSI and convention light microscopy both will be the same. Slide 15

  16. WSI & Software Innovations Not Possible Today • Retrieval of previous biopsy images using the computer • Major safety issue currently not “standard of care” – should be a major goal of surgical pathology • Facilitating increased informal consultation via digital workflows • This is one of the mainstays of high quality surgical pathology • Distribution of routine work (may be as much as 80% of all surgical pathology) so more time can be spent on more challenging and patient critical material • Not possible to easily and efficiently do with glass slides • Facilitating quality control and quality improvement with digital glass • Time consuming and costly uncompensated but critical part of any practice Slide 16

  17. Final Points – WSI has limitations that are important to recognize • Cytology type preparations (including some heme) should not be considered for WSI today due to three dimensional nature of the clinical material • Z-axis scanning is coming but there are still technical barriers to address, but this technology is rapidly maturing • Oil immersion microscopy (100X) is rarely used in surgical pathology practice and will not be replaced by the current commercially available Digital Pathology systems • Less than 0.1% of all light microscopy diagnostics • Special (shared area) microscopes are usually used for this in most practice settings • In this same class of exceptions are “polarization” Slide 17

  18. Final Points – Comparing light microscopy to WSI will be problematic • The “reference” or “gold standard” for light microscopy use doesn’t exist today (analog world) • Tremendous surgical pathology practice variability in: • Objectives • Illumination • Color fidelity/optimization • Field of view • Focus • Some commonality in both methods (WSI and light microscopy) use objective lens from microscopes • Conclusion: Perhaps we should focus on ability to diagnose and resolve histologic structure irrespective of the method of image presented? • Analogous to lessons learned from Radiology Slide 18

  19. Final Points – Imaging Reference Standards Favor a diagnostic “yardstick” for validating WSI • Since a “reference” or “gold standard” doesn’t exist, we favor the development of a diagnostic “yardstick” of pertinent features for WSI • What are the 20 features that any system (light or digital) would have to detect in a statistically reliable way for validation and approval • FDA suggests: • cancer invasion of basement membrane, • cytoplasmic vacuoles, • cross striations in sarcoma cytoplasm, • micro-calcification in breast tissue, • Others should include perhaps: • gram-stain and other chemical stained organisms, • immunohistochemistry • chromagen in situ hybridization (CISH) • eosinophilic and basophilic granules, • nucleoli detection, • mitotic figures, • platelet clumps, • prostate cancer crystalloids, • microvilli, • nuclear invaginations • Might also consider a hybrid feature and imaging characteristics based approach and include: • color • refractive properties • size • resolution • contrast Slide 19

  20. Development of Reference Standards – Phantoms for WSI • Phantoms (as pioneered by Radiology) are an interesting concept worth exploring and would require extensive testing and vetting with the Pathology community (perhaps a worthy long term goal?) • I propose a “grand challenge” like with Natural Language Processing challenges in the Medical Informatics community for patient clinical records • There are pathology, imaging and informatics communities that would help to accomplish this goal: • Advancing Practice Instruction and Innovation through Informatics (APIII) • American Medical Informatics Association (AMIA) • Association for Pathology Informatics (API) • College of American Pathologists (CAP) & Futurescape • Digital Pathology Association (DPA) & Pathology Visions • Society for Imaging Informatics in Medicine (SIIM) • United States and Canadian Academy of Pathology (USCAP) • Many if not all are aligned and interested in a dialogue on this!!!

  21. Conclusions and Future Directions - WSI and Digital Pathology • WSI does not eliminate the glass slide • Pathologist will be relied on to know when to use glass slides • Does not in any way replace Pathologist’s critical judgment • WSI will not be utilized in cytology type (3D) preparations and “oil” immersion diagnostics today, but WSI is maturing rapidly • There are other areas of diagnostics that should be excluded but an WSI Pathologist will know when to go to glass • WSI may improve the quality of care, improve patient safety and aide the evolution of surgical pathology • In my opinion, adding Digital Pathology tools to the workflow has significant advantages over conventional light microscopy alone • Reference gold standards for light microscopy do not exist today hence comparison to WSI will require new solutions • Development of a diagnostic “yardstick” seems appropriate • “Grand Challenge” for diagnostic phantoms for pathology could be facilitated by the clinical, academic and informatics communities who care • Welcome input by this esteemed panel and presenters Slide 21

  22. Key Publications by Our Team – NOTE: Please e-mail me at becich@pitt.edu if you want PDFs – Validation studies in red • Horbinski C, Wiley CA. Comparison of telepathology systems in neuropathological intraoperative consultations. Neuropathology. 2009 Apr 21. [Epub ahead of print] PubMed PMID: 19422534 • Fine JL, Grzybicki DM, Silowash R, Ho J, Gilbertson JR, Anthony L, Wilson R, Parwani AV, Bastacky SI, Epstein JI, and Jukic DM. Evaluation of whole slide image immunohistochemistry interpretation in challenging prostate needle biopsies. Hum Pathol, 39(4):564-72. 2008. • Horbinski C, Fine JL, Medina-Flores R, Yagi Y, Wiley CA. Telepathology for Intraoperative Neuropathologic Consultations at an Academic Medical Center: A 5-Year Report. J Neuropathol Exp Neurol, 66(8):750-9. 2007. • Raab SS, Grzybicki DM, Condel JL, Stewart WR, Turcsanyi BD, Mahood LK, Becich MJ. Effect of lean method implementation in the histopathology section of an anatomic pathology laboratory. J Clin Pathol. 2008 Nov;61(11):1193-9. Epub 2007 Aug 3. PMID: 17675533 • Mohanty SK, Parwani AV, Crowley RS, Winters S, Becich MJ. The Importance of Pathology Informatics in Translational Research. Adv Anat Pathol. 2007 Sept;14(5):320-322. • Ho J, Parwani AV, Jukic DM, Yagi Y, Gilbertson JR. Use of whole slide imaging in surgical pathology quality assurance: design and pilot validation studies. Hum Pathol, 37(3):322-31. 2006. • Gilbertson JR, Ho J, Anthony L, Jukic DM, Yagi Y, Parwani AV. Primary histologic diagnosis using automated whole slide imaging: a validation study. BMC Clin Pathol, 6:4. 2006. • Becich, MJ, Patel AA, Juki DM. The digital future of histopathology: where we are today and where we are heading. The Bulletin of The Royal College of Pathologists July Issue 131(27-31) 2005. • Grzybicki DM, Turcsanyi B, Becich MJ, Gupta D, Gilbertson JR, Raab SS. Database construction for improving patient safety by examining pathology errors. Am J Clin Path 2005 Oct;124(4):500-9. • Becich, M.J. Patel A.A. and Jukic D.M. A Diagnostic Virtual Microscope System for Whole Slide Robotic Imaging: The Value of Virtual Slides for the Practice of Pathology. Gu, J. and Ogilvie, R.W., Eds., Virtual Microscopy and Virtual Slides in Teaching, Diagnosis and Research, Taylor & Francis, Boca Raton, 2005;19; 297-312. • Becich MJ, Gilbertson JR, Gupta D, Grzybicki DM and Raab, SS. Patient Safety and Healthcare Research: The Critical Role of Path Informatics in Error Reduction and Quality Initiatives. Clin Lab Med. 2004 Dec;24(4):913-43.

  23. End of Talk – e-mail me at becich@pitt.edu if you have questions/clarifications not covered in the discussion.NOTE: Please e-mail me if you want PDFs of articles or presentation. Thank you for the invitation to participate in the FDA Panel Slide 23

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