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The Virtuoso system provides automated digital slide creation, management, analysis, and viewing. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting, review and classification of tissues and cells of clinical interest based on particular morphology, color, intensity, size, pattern and shape.

The Virtuoso™ System for IHC HER2 (4B5) is for digital read and image analysis applications. This particular Virtuoso system is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2 protein in formalin-fixed, paraffin-embedded normal and neoplastic tissue. This device is an accessory to Ventana Medical Systems, Inc. PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody. The PATHWAY® anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

NOTE: The IHC HER2 4B5 Digital Read and Image Analysis applications are adjunctive computer-assisted methodologies for the qualified pathologist in the acquisition and measurement of images from microscope glass slides of breast cancer specimens stained for the presence of HER-2/neu receptor protein. The pathologist should verify agreement with the Image Analysis software application score. The accuracy of the test results depends on the quality of the immunohistochemical staining. It is the responsibility of a qualified pathologist to employ appropriate morphological studies and controls as specified in the instructions for the PATHWAY® anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody assay used to assure the validity of the iScan System for IHC HER2 4B5 Digital Read and Image Analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established.

The Virtuoso™ System is an instrument-plus-software system designed to assist the qualified pathologist in the consistent assessment of protein expression in immunohistochemically stained histologic sections from formalin-fixed, paraffinembedded normal and neoplastic tissues. The system consists of a slide scanner (iScan), computer, monitor, keyboard, mouse, image analysis algorithms for specific immunohistochemical markers, and software with a Windows web browser-based user interface. Virtuoso is a web-based, end-to-end, digital pathology software solution that allows pathology laboratories to acquire, manage, view, analyze, share, and report digital images of pathology specimens. Using the Virtuoso software, the pathologist can view digital images, add annotations, make measurements, perform image analysis, and generate reports.

The iScan slide scanning device captures digital images of Hardware: formalin-fixed, paraffin-embedded tissues that are suitable for storage and viewing. The device includes a digital slide scanner, racks for loading glass slides, computer, scanner software, keyboard, mouse and monitor.

Software: The Virtuoso software is designed to complement the routine workflow of a qualified pathologist in the review of immunohistochemically stained histologic slides. It allows the user to select fields of view (FOVs) in the digital image for analysis and provides quantitative data on these FOVs to assist with interpretation. The software makes no independent interpretations of the data and requires competent human intervention for all steps in the analysis process.

1. Table of Acceptance Criteria and Reported Device Performance:

2. Sample Size and Data Provenance:

• Test Set Sample Size:
  • Agreement (Digital Read vs Manual): Site 1 (n = 119), Site 2 (n = 120), Site 3 (n = 118).
  • Agreement (Image Analysis vs Manual): Site 1 (n = 117), Site 2 (n = 120), Site 3 (n = 120).
  • Intra-Pathologist/Inter-Day Reproducibility: Exact number of cases not explicitly stated for individual sessions, but the confusion matrices show sums of around 40 cases for the comparisons (e.g., 40 cases for Session 1 digital read, 40 cases for Session 1 image analysis).
  • Inter-Pathologist Reproducibility: Exact number of cases not explicitly stated for individual comparisons, but the confusion matrices show sums of around 120 cases for the comparisons (e.g., 120 cases for Site 1 manual, 120 cases for Site 1 digital read, 117 cases for Site 1 image analysis).
  • Scanner Precision: A subset of 40 clinical cases from the primary study.
• Data Provenance: Not explicitly stated (e.g., country of origin). The studies appear to be prospective, as they involved pathologists reviewing cases using the Virtuoso system and comparing them to manual methods, and also involved multiple sessions for reproducibility.

3. Number of Experts and Qualifications for Ground Truth:

• Number of Experts: The study indicates that "each pathologist's Virtuoso digital read results were compared to their manual results," and also refers to "three pathologists." This suggests at least three pathologists were involved in generating the manual ground truth for the primary study.
• Qualifications of Experts: "Qualified pathologist" is mentioned. Specific years of experience or subspecialty training are not provided.

4. Adjudication Method for the Test Set:

• For the "Agreement" studies, the "Manual Method" by each pathologist served as the reference/ground truth. There is no mention of an adjudication process (e.g., 2+1, 3+1) to establish a consensus ground truth among multiple pathologists for the manual scores before comparison with the device. Each pathologist's manual read was compared to their own digital read/image analysis.
• For "Reproducibility" studies, agreement was assessed between different sessions or different pathologists, but no formal adjudication to establish a "true" score for these comparisons is described.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

• A comparative effectiveness study involving human readers with and without AI assistance is not explicitly described. The study focuses on the agreement of the AI (Virtuoso digital read and image analysis) with the manual method performed by pathologists. It also assesses inter- and intra-pathologist reproducibility of the Virtuoso system, but not a direct comparison of human performance with vs. without AI assistance. Therefore, an effect size of how much human readers improve with AI vs. without AI assistance is not provided.

6. Standalone (Algorithm Only) Performance:

• Yes, the "Image Analysis" component of the Virtuoso system represents the standalone algorithm performance. The results for "Image Analysis vs Manual Method" (Agreements of 92%, 82%, 88%) and "Intra-Pathologist Image Analysis" (100% agreement for reproducibility) and "Inter-Pathologist Image Analysis" (93%-95% agreement) and "Scanner Precision" (in excess of 90%) directly reflect the algorithm's performance. The document states that the "image analysis application is the more sensitive of the two applications, and it generates an instrument-generated HER2 score that is not affected by memory bias as would be the case with human interpretations." This confirms it as an algorithm-only evaluation.

7. Type of Ground Truth Used:

• The ground truth used was expert consensus (manual pathological assessment). The manual interpretation of HER2 protein expression by qualified pathologists using traditional microscopy was considered the "true score" against which the Virtuoso system's performance was measured.

8. Sample Size for the Training Set:

• The document does not provide the sample size for the training set. It focuses solely on the clinical validation studies (test set).

9. How the Ground Truth for the Training Set Was Established:

• The document does not provide information on how the ground truth for any potential training set was established.

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