Who is the manufacturer of OMNYX IDP FOR HER2 MANUAL APPLICATION?

Omnyx, LLC filed the 510(k) submission for OMNYX IDP FOR HER2 MANUAL APPLICATION (K131140).

What is the FDA product code for OMNYX IDP FOR HER2 MANUAL APPLICATION?

OEO. It is classified under 21 CFR 864.1860 as a Class 2 device in the Hematology panel.

What is the regulatory pathway for OMNYX IDP FOR HER2 MANUAL APPLICATION?

510(k) clearance (submission type: Traditional).

What are the predicate devices for OMNYX IDP FOR HER2 MANUAL APPLICATION?

ScanScope® XT System for HER2 (k071671).

Who can help prepare an FDA 510(k) submission like OMNYX IDP FOR HER2 MANUAL APPLICATION?

Innolitics — a medical-device software consultancy — provides regulatory and engineering support for FDA 510(k) submissions. See https://innolitics.com/services/510ks/ or contact https://innolitics.com/contact.

OMNYX IDP FOR HER2 MANUAL APPLICATION

K131140 · Omnyx, LLC · OEO · Apr 1, 2014 · Hematology

Device Facts

Record ID	K131140
Device Name	OMNYX IDP FOR HER2 MANUAL APPLICATION
Applicant	Omnyx, LLC
Product Code	OEO · Hematology
Decision Date	Apr 1, 2014
Decision	SESE
Submission Type	Traditional
Regulation	21 CFR 864.1860
Device Class	Class 2

Intended Use

The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for in vitro diagnostic use as an aid to pathology professionals for creating, managing, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalin-fixed, paraffin-embedded (FFPE) tissue sections stained with the Dako HercepTest™. The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in digital images of FFPE breast cancer tissue immunohistochemically stained with the Dako HercepTest™ and viewed on a computer monitor. The Dako HercepTest™ is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered.

Device Story

System captures, manages, and displays digital whole slide images (WSI) of FFPE breast cancer tissue stained with Dako HercepTest™. Components include VL4 scanner (LED light source, tile sensor technology), data/workflow infrastructure, and histology/pathology workstations. Pathologists use high-resolution monitors to view digital images, annotate, measure, and manually score HER2 expression based on Dako HercepTest™ package insert instructions. System facilitates digital pathology workflow, replacing traditional manual microscopy for HER2 scoring. Benefits include digital storage, retrieval, and remote review capabilities. Pathologists perform scoring; system provides the digital environment for this clinical decision-making process.

Clinical Evidence

Method comparison study (n=200 FFPE breast cancer specimens) compared manual microscopy (MM) to digital manual read (M-WSI) across 4 sites. Overall percent agreement for binary scores ranged from 89.4% to 93.0%. Intra-pathologist/inter-day precision study (n=40 slides, 3 reads) showed trichotomous agreement ranging from 62.5% to 97.5%. Inter-scanner precision study (n=80 ROIs, 3 scanners) showed trichotomous agreement between 88.8% and 95.0%.

Technological Characteristics

System uses VL4 scanner with LED light source and tile sensor technology. Scans at 40x magnification (0.275 µm/pixel). Components include high-resolution monitors, workstations, and networked digital pathology software. Calibration required at installation and every 1300 hours. Software manages image acquisition, stitching, compression, and viewing.

Indications for Use

Indicated for use as an aid to pathology professionals in the detection and semi-quantitative measurement of HER2/neu in digital images of FFPE breast cancer tissue stained with Dako HercepTest™ for patients being considered for HERCEPTIN® treatment.

Regulatory Classification

Identification

Immunohistochemistry test systems (IHC's) are in vitro diagnostic devices consisting of polyclonal or monoclonal antibodies labeled with directions for use and performance claims, which may be packaged with ancillary reagents in kits. Their intended use is to identify, by immunological techniques, antigens in tissues or cytologic specimens. Similar devices intended for use with flow cytometry devices are not considered IHC's.

Special Controls

(2) Class II (special control, guidance document: “FDA Guidance for Submission of Immunohistochemistry Applications to the FDA,” Center for Devices and Radiologic Health, 1998). These IHC's are intended for the detection and/or measurement of certain target analytes in order to provide prognostic or predictive data that are not directly confirmed by routine histopathologic internal and external control specimens. These IHC's provide the pathologist with information that is ordinarily reported as independent diagnostic information to the ordering clinician, and the claims associated with these data are widely accepted and supported by valid scientific evidence. Examples of class II IHC's are those intended for semiquantitative measurement of an analyte, such as hormone receptors in breast cancer.

Predicate Devices

ScanScope® XT System for HER2 (k071671)

Related Devices

K130021 — PHILIPS HERCEPTEST DIGITAL SCORE · Philips Medical Systems Nederland B.V. · Sep 19, 2013
K071671 — SCANSCOPE XT SYSTEM · Aperio Technologies · Dec 28, 2007
K111914 — VIRTUAL SLIDE SYSTEM, OLYMPUS VS800 SYSTEM · Olympus America Inc. / Scientific Equipment Group · Aug 21, 2012
K071128 — SCANSCOPE XT SYSTEM · Aperio Technologies · Oct 10, 2007

Submission Summary (Full Text)

{0}------------------------------------------------ K13/140 APR 0 1 2014 # 510(k) Summary for the Omnyx, LLC. Omnyx Manual Read of the Digital HER2 Application #### SUBMITTER/510(K) HOLDER 1. Omnyx, LLC 1251 Waterfront Place Pittsburgh, PA 15222 Contact Person: Michael C. Montalto, Ph.D. Telephone: 732-457-8135 #### CONSULTANT/CONTACT 2. Aptiv Solutions 62 Forest Street Suite 300 Marlborough, MA 01752 Telephone: (main) 508-597-6000 (direct) 508-835-1688 508-597-5789 Facsimile: Primary Contact: Gail E. Radcliffe, Ph.D. Date Prepared: April 19, 2012 #### DEVICE NAME 3. | Proprietary Name: | Omnyx Manual Read of the Digital HER2 Application | |--------------------|----------------------------------------------------------------| | Common/Usual Name: | Digital Pathology Device | | Classification: | Class II | | Product Code: | OEO (automated digital image manual interpretation microscope) | #### PREDICATE DEVICES 4. - · Aperio ScanScope XT System (K071671) - · Virtuoso™ IHC HER2 (K111543) {1}------------------------------------------------ # 5. DEVICE DESCRIPTION The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended to aid pathology professionals in creating, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalin-fixed, paraffin-embedded (FFPE) tissue sections stained with the Dako HercepTest™. The system is composed of the following components: - · VL4 Scanner: A hardware device that captures and compresses bright field images of tissue samples. - · Data and Workflow Infrastructure: A set of networked applications which enables case data entry, acquisition, indexing, storage and acceptance of digital images, workflow management, and retrieval of case and image data. - · Histology Workstation: The application which permits the histologist to review or enter case data and check quality of scanned images. - · Pathology Workstation: The application which allows the pathologist to retrieve case data and review and annotate slide images. # Hardware: The Omnyx™ VL4 scanner is an automated imaging system that can be loaded with up to 4 slides at a time. The VL4 Scanner outputs its images and metadata to the Omnyx Digital Archive, which receives and stores the images and data. ## Software: The Omnyx software is composed of 1) the VL4 scanner software which performs tissue identification, scan planning, focusing, image acquisition, stitching and compression of digital slide images and sends them to the Digital Archive and 2) the DPS software that manages the Histologist and Pathologist workstation functions, image viewer, workflow service, database, interface engine, APLIS service, digital archive, image store and the administrator client application. {2}------------------------------------------------ ## Principles of Operation: FFPE tissue sections are stained with the Dako HercepTest™ according to the package insert. Slides are then scanned and digitized using the Omnyx VL4 Scanner. Whole slide images are transferred automatically to the Omnyx Digital Archive (DA) where they are indexed and stored. The Workflow Server contains patient information. These files are then accessed using the Histology Workstation or the Pathologist Workstation. The Histology Workstation is used by histologists or other lab professionals to perform quality checks on scanned slides, confirm that IHC slides/case associations are correct and order re-cuts and re-stains. It also enables the histologist to enter case data manually. The Pathologist Workstation enables the pathologist to flag significant cases and regions of interest. It also allows the pathologist to review the digital HercepTest™ IHC whole slide image (WSI) via the Omnyx Image Viewer and is used by the pathologist for functions such as annotating images and making measurements. # 6. INDICATIONS FOR USE/ INTENDED USE The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for in vitro diagnostic use as an aid to pathology professionals for creating, managing, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalinfixed, paraffin-embedded (FFPE) tissue sections stained with the Dako HercepTest™. The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in digital images of FFPE breast cancer tissue immunohistochemically stained with the Dako HercepTest™ and viewed on a computer monitor. The Dako HercepTest™ is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered. {3}------------------------------------------------ # 7. SUMMARY OF TECHNOLOGICAL CHARACTERISTICS COMPARED TO THE PREDICATE DEVICES The following table summarizes the similarities and differences between the Omnyx Manual Read of the Digital HER2 Application and the predicate devices Aperio ScanScope XT System and Virtuoso™ IHC HER2. | | Proposed Device | Predicate | Predicate | |--------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------| | | Omnyx Manual Read of the | Aperio ScanScope XT System | Virtuoso™ IHC HER2 | | Comparators | Digital HER2 Application | (K071671) | (K111543) | | Intended use | The Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for in vitro diagnostic use as an aid to pathology professionals for creating, receiving, managing, storing, annotating, measuring, and viewing digital Whole Slide Images (WSI) from formalin-fixed, paraffin- embedded (FFPE) tissue sections stained with the Dako HercepTest™. | The ScanScope system is an automated digital slide creation, management, viewing and analysis system. It is intended for in vitro diagnostic use as an aid to the pathologist in the display, detection, counting and classification of tissues and cells of clinical interest based on particular color, intensity, size, pattern and shape. | This device is intended for in vitro (IVD) use. The Virtuoso System provides automated digital slide creation, management, analysis, and viewing. It is intended for IVD 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 Omnyx Manual Read of the Digital HER2 Application on the Omnyx IDP System is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in digital images of FFPE breast cancer tissue immunohistochemically stained with the Dako HercepTest™ and viewed on a computer monitor. Dako HercepTest™ is indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered. | The IHC HER2 Manual Read of a Digital Slide application is intended for use as an aid to the pathologist in the detection and semi-quantitative measurement of HER2/neu (c-erbB-2) in formalin-fixed, paraffin- embedded normal and neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor. HER2 results are indicated for use as an aid in the management, prognosis and prediction of therapy outcomes in breast cancer. | 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 the 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 | | | | The IHC HER2 Manual Read of a Digital Slide application is intended for use as an accessory to the Dako HercepTest™ to aid in the detection and semi- quantitative measurement of HER2/neu (c-ebB-2) in formalin- fixed, paraffin-embedded normal and neoplastic tissue immunohistochemically stained for HER-2 receptors on a computer monitor. When used with the Dako HercenTest, it is | specimens stained for the presence of | | | Proposed Device | Predicate | Predicate | | | Omnyx Manual Read of the | Aperio ScanScope XT System | Virtuoso™ IHC HER2 | | Comparators | Digital HER2 Application | (K071671) | (K111543) | | | | indicated for use as an aid in the assessment of breast cancer patients for whom HERCEPTIN® (Trastuzumab) treatment is being considered. Note: The actual correlation of the Dako HercepTest™ to Herceptin® clinical outcome has not been established. | 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 Digital Read and Image Analysis scores. The actual correlation of PATHWAY® anti-HER-2/neu (4B5) to clinical outcome has not been established. | | Specimen Type | Formalin-fixed, paraffin- embedded normal and neoplastic tissue immunohistochemically stained | Same | Same | | Device Components | Automated digital slide scanner, computer, color monitor, keyboard, and digital pathology information management software | Automated digital microscope slide scanner, computer, color monitor, keyboard and digital pathology information management software | BioImagene (now Ventana) iScan slide scanner, computer, color monitor, proprietary software for HER2 (4B5) | | Image Acquisition | Tile sensor technology | Line scanning technology | Same | | Light Source | LED | Tungsten light | Same | | Primary Antibody (Assay) Reagent | Dako Reagents for HER2 (HercepTest™) | Same | Ventana PATHWAY HER2 (4B5) (P990081 S003) | | Interpretation ( Modes of Operation) | Interpretation is performed by the pathologist ( Manual digital read) | Same | Manual and Automated | # Similarities/Differences of Omnyx Manual Read of the Digital HER2 Application with Predicate Devices Omnyx, LLC Traditional 510(k) K131140 Manual Read of the Digital HER2 Application on the Omnyx IDP System {4}------------------------------------------------ . , i {5}------------------------------------------------ 8. SUMMARY OF NON-CLINICAL AND CLINICAL PERFORMANCE TESTING AS BASIS FOR SUBSTANTIAL EQUIVALENCE ### CLINICAL COMPARISON TO MANUAL MICROSCOPY Each of the four (4) pathologists read 200 breast cancer cases, comprising of both the controls and specimen slides stained with the Dako HercepTest™, using a conventional manual microscope (MM) and the Omnyx™ IDP (M-WSI), separated by at least a 2 week washout period. Three (3) VL4 scanners were installed in separate laboratories, with each scanner associated with a different scanner technician. Each pathologist reviewed WSIs obtained from different VL4 scanners, although two (2) of the pathologists received WSIs from the same VL4 scanner. The pairwise percent agreement between all pathologist on both MM and M-WSI modalities (inter-reader/intra-modality) was determined for both binned (0/1+ = neg; 1+/2+ = pos) and trichotomous (0/1+, 2+, 3+) score categories. Furthermore, in order to determine how well each pathologist could recapitulate a slide score for each slide when read on each modality, an analysis of the percent agreement between MM vs. M-WSI (inter-modality/intra-reader) for each pathologist was determined. | Inter-Reader/ Intra-Modality (MM) | Pathologist 2 | | | | Pathologist 3 | | | | Pathologist 4 | | | | Pathologist 3 | | | | Pathologist 4 | | | | Pathologist 4 | | | | | |-----------------------------------------|---------------|-----------------|----|----|---------------|-----------------|----|----|---------------|-----------------|----|----|---------------|-----------------|----|----|---------------|-----------------|----|----|---------------|-----------------|----|----|----| | | 0+ | 1+ | 2+ | 3+ | 0+ | 1+ | 2+ | 3+ | 0+ | 1+ | 2+ | 3+ | 0+ | 1+ | 2+ | 3+ | 0+ | 1+ | 2+ | 3+ | 0+ | 1+ | 2+ | 3+ | | | Pathologist 1 | 0+ | 46 | 9 | 1 | 0 | 50 | 6 | 0 | 0 | 46 | 9 | 0 | 0 | | | | | | | | | | | | | | | 1+ | 7 | 18 | 8 | 1 | 7 | 22 | 6 | 0 | 1 | 30 | 3 | 0 | | | | | | | | | | | | | | | 2+ | 0 | 7 | 28 | 4 | 1 | 6 | 32 | 0 | 0 | 23 | 15 | 0 | | | | | | | | | | | | | | | 3+ | 1 | 0 | 6 | 63 | 0 | 0 | 11 | 59 | 0 | 0 | 12 | 56 | | | | | | | | | | | | | | Pathologist 2 | 0 | | | | | | | | | | | | | 50 | 3 | 1 | 0 | 43 | 9 | 1 | 0 | | | | | | | 1+ | | | | | | | | | | | | | 7 | 23 | 4 | 0 | 3 | 30 | 2 | 0 | | | | | | | 2+ | | | | | | | | | | | | | 1 | 7 | 34 | 1 | 1 | 22 | 19 | 0 | | | | | | | 3+ | | | | | | | | | | | | | 0 | 0 | 10 | 58 | 0 | 1 | 8 | 56 | | | | | | Pathologist 3 | 0 | | | | | | | | | | | | | | | | | | | | | 46 | 11 | 0 | 0 | | | 1+ | | | | | | | | | | | | | | | | | | | | | 1 | 32 | 1 | 0 | | | 2+ | | | | | | | | | | | | | | | | | | | | | 0 | 19 | 26 | 2 | | | 3+ | | | | | | | | | | | | | | | | | | | | | 0 | 0 | 3 | 54 | | % Agreement (95% CI) (Trichotomous) | | 85.9% (80%-90%) | | | | 88.0% (83%-92%) | | | | 80.5% (74%-85%) | | | | 87.9% (83%-92%) | | | | 82.1% (76%-87%) | | | | 87.2% (82%-91%) | | | | Inter-Reader/Intra-Modality on Glass (MM) between four (4) pathologists - Trichotomous score categories {6}------------------------------------------------ | Inter-Reader/ Intra-Modality | | | Pathologist 2 | | | | | | | | | | | | | | | | | | | | | | | |----------------------------------------|----|----|-----------------|----|------|----|----|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----|----|------|----|----|----|----|----|------|----|----|----|----|----|----|----|------| | (M-WSI) | | 04 | 1+ | 2+ | 34 | 04 | 14 | 2+ | 34 | 0+ | 14 | 24 | 3+ | 0+ | 1+ | 24 | ਤੇ + | 04 | 1+ | 24 | 34 | 04 | 1+ | 2+ | 34 | | | 0 | 48 | હ | O | 0 | 28 | 21 | ટ | 0 | 29 | 22 | 0 | 0 | | | | | | | | | | | | | | | 1+ | শ | 22 | 11 | 1 | 1 | 11 | 23 | 3 | 0 | તે વ | ਤੇ | 0 | | | | | | | | | | | | | | Pathologist 1 | 24 | 0 | 7 | 26 | ર | ਹੈ | 0 | Pathologist 4 Pathologist 3 Pathologist 4 Pathologist 4 Pathologist 3 20 16 । 19 19 1 2 રવ ୧୧ ﻠ 7 0 21 0 28 20 1 28 ﻠﺴﺎ র্ব 1 2 12 20 1 ਤੇ ਤੋ 0 0 0 0 22 । ਰੇ 20 22 2 0 3 64 ತಿ ട ટે પે 0 0 0 25 ന 0 0 26 0 0 4 1 40 8 0 7 18 1 64.4% (57%-71%) 73.4% (67%-79%) 82.4% (76%-87%) 74.4% (68%-80%) 83.5% (78%-88%) | | | | | | | | | | | | | | | | | | | | 34 | 1 | 0 | 7 | દર્ભ | 0 | 0 | | | | | | | | | | | | | | | | | | | | | 0 | | | | | | | | | | | | | | | | | | | | | | | | | | Pathologist 2 | 1+ | | | | | | | | | | | | | | | | | | | | | | | | | | | 2+ | | | | | | | | | | | | | | | | | | | | | | | | | | | 34 | | | | | | | | | | | | | | | | | | | | | | | | | | | 0 | | | | | | | | | | | | | | | | | | | | | | | | | | | 1+ | | | | | | | | | | | | | | | | | | | | | | | | | | Pathologist 3 | 2+ | | | | | | | | | | | | | | | | | | | | | | | | | | | 3+ | | | | | | | | | | | | | | | | | | | | | | | | ટર્ટ | | % Agreement (95% Cl) (Trichotomous) | | | 83.4% (78%-88%) | | | | | | | | | | | | | | | | | | | | | | | Inter-Reader/Intra-Modality on Digital (M-WSI) between four (4) pathologists – Trichotomous score categories To calculate the negative & positive percent agreements, the 4x4 binary agreements are binned into a 2x2 table with 0/1+ (Negative) combined and 2+/3+ (Positive) combined. Since neither pathologist can be considered a reference in each pairwise reader comparison, analysis for negative and positive score categories is provided as Average Negative Agreement (ANA) and Average Positive Agreement (APA). | Inter-Reader/ Intra-Modality (MM) | | | Pathologist 2 | | Pathologist 3 | | Pathologist 4 | | Pathologist 3 | | Pathologist 4 | | Pathologist 4 | | |-------------------------------------------|-----|--------------------|---------------|--------------------|---------------|--------------------|---------------|--------------------|---------------|--------------------|---------------|--------------------|---------------|--| | | | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | | | Pathologist 1 | Neg | 80 | 10 | 85 | 6 | 86 | 3 | | | | | | | | | | Pos | 8 | 101 | 7 | 102 | 23 | 83 | | | | | | | | | Pathologist 2 | Neg | | | | | | | 83 | 5 | 85 | 3 | | | | | | Pos | | | | | | | 8 | 103 | 24 | 83 | | | | | Pathologist 3 | Neg | | | | | | | | | | | 90 | 1 | | | | Pos | | | | | | | | | | | 19 | 85 | | | Overall Percent Agreement (95% CI) | | 91.0% (86%-94%) | | 93.5% (89%-96%) | | 86.7% (81%-91%) | | 93.5% (89%-96%) | | 86.2% (81%-90%) | | 89.7% (85%-93%) | | | | Average Positive Agreement (95% CI) | | 89.9% (85%-94%) | | 92.9% (88%-96%) | | 86.9% (81%-91%) | | 92.7% (88%-96%) | | 86.3% (81%-90%) | | 90.0% (85%-93%) | | | | Average Negative Agreement (95% CI) | | 91.8% (87%-95%) | | 94.0% (90%-96%) | | 86.5% (81%-91%) | | 94.1% (90%-96%) | | 86.0% (80%-90%) | | 89.5% (84%-93%) | | | Inter-Reader/Intra-Modality on Glass (MM) between four (4) pathologists - Binary score categories {7}------------------------------------------------ | Inter-Reader/ Intra-Modality (M-WSI) | Pathologist 2 | | Pathologist 3 | | Pathologist 4 | | Pathologist 3 | | Pathologist 4 | | Pathologist 4 | | |--------------------------------------------|--------------------|-----|--------------------|-----|--------------------|-----|--------------------|-----|--------------------|-----|--------------------|-----| | | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | | Pathologist 1 | 80 | 12 | 61 | 31 | 85 | 3 | | | | | | | | Pathologist 1 | 8 | 99 | 1 | 106 | 22 | 78 | | | | | | | | Pathologist 2 | | | | | | | 62 | 26 | 83 | 1 | | | | Pathologist 2 | | | | | | | 0 | 111 | 24 | 80 | | | | Pathologist 3 | | | | | | | | | | | 58 | 0 | | Pathologist 3 | | | | | | | | | | | 49 | 81 | | Overall Percent Agreement (95% CI) | 89.9% (85%-93%) | | 83.9% (78%-88%) | | 86.7% (81%-91%) | | 86.9% (82%-91%) | | 86.7% (81%-91%) | | 73.9% (67%-80%) | | | Average Positive Agreement (95% CI) | 88.9% (83%-93%) | | 79.2% (72%-85%) | | 87.2% (82%-91%) | | 82.7% (76%-88%) | | 86.9% (81%-91%) | | 70.3% (63%-77%) | | | Average Negative Agreement (95% Cl) | 90.8% (86%-94%) | | 86.9% (82%-91%) | | 86.2% (80%-90%) | | 89.5% (85%-93%) | | 86.5% (81%-91%) | | 76.8% (71%-82%) | | Inter-Reader/Intra-Modality on Digital (M-WSI) between four (4) pathologists - Binary score categories The inter-modality/intra-reader agreement results evaluating glass vs. digital (MM vs. M-WSI) for all four (4) pathologists are shown below. The washout period between the glass and digital reads was a minimum of 2 weeks. | Inter-Modality/Intra-Reader (MM vs. M-WSI) | Glass (MM) | | | | | | | | | | | | | | | | |-----------------------------------------------|------------|---------------|----|---------------|----|---------------|----|---------------|----|----|----|----|----|----|----|----| | Digital (M-WSI) | | Pathologist 1 | | Pathologist 2 | | Pathologist 3 | | Pathologist 4 | | | | | | | | | | | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | | 0 | 50 | 4 | 0 | 0 | 47 | 3 | 2 | 1 | 29 | 1 | 0 | 0 | 29 | 0 | 2 | 0 | | 1+ | 6 | 26 | 6 | 0 | 5 | 25 | 5 | 0 | 25 | 7 | 0 | 0 | 16 | 54 | 5 | 0 | | 2+ | 0 | 5 | 32 | 2 | 0 | 7 | 30 | 7 | 4 | 24 | 21 | 0 | 0 | 6 | 20 | 0 | | 3+ | 0 | 0 | 1 | 67 | 2 | 0 | 6 | 60 | 0 | 2 | 28 | 58 | 0 | 0 | 3 | 5 | Intra-Reader/Inter-Modality comparing agreement between glass and digital (MM vs. M- WSI) for each of the four (4) pathologists . Trichotomous score categories To calculate the negative & positive percent agreements, the 4x4 binary agreement tables are binned into a 2x2 table with 0/1+ (Negative) combined and 2+/3+ (Positive) combined. Since the glass scores for each pathologist is used as their respective reference, the analysis is provided as Negative Percent Agreement (NPA) and Positive Percent Agreement (PPA), with the glass reads as the imperfect reference. {8}------------------------------------------------ | | Glass (MM) | | | | | | | | |-----------------------------------------------|--------------------|-----|--------------------|-----|--------------------|-----|--------------------|-----| | Inter-Modality/Intra-Reader (MM vs. M-WSI) | Pathologist 1 | | Pathologist 2 | | Pathologist 3 | | Pathologist 4 | | | | Neg | Pos | Neg | Pos | Neg | Pos | Neg | Pos | | Digital (M-WSI) Neg | 86 | 8 | 80 | 8 | 62 | 0 | 99 | 7 | | Digital (M-WSI) Pos | 5 | 75 | 9 | 103 | 30 | 107 | 6 | 75 | | Overall Percent Agreement (95% CI) | 92.5% (88%-96%) | | 91.5% (87%-95%) | | 89.4% (79%-89%) | | 93.0% (88%-96%) | | | Negative Percent Agreement (95% CI) | 94.5% (88%-98%) | | 89.9% (82%-95%) | | 67.4% (57%-76%) | | 94.3% (88%-97%) | | | Positive Percent Agreement (95% CI) | 90.4% (82%-95%) | | 92.8% (86%-96%) | | 100% (97%-100%) | | 91.5% (83%-96%) | | Intra-Reader/Inter-Modality comparing agreement between glass and digital (MM vs. M- WSI) for each of the four (4) pathologists - Binary score categories The pairwise inter-reader/intra-modality percent agreements do not differ significantly between MM and M-WSI. Additionally, there are high percent agreements between MM and M-WSI for each pathologist when examined by binary or trichotomous score category. ### PRECISION & REPRODUCIBILITY ### INTRA-READER/INTER-DAY In order to compare the intra-reader variability on digital M-WSI, three (3) pathologist performed three (3) independent readings of a set of the HercepTest™ stained slides (n=40) using the M-WSI modality. Each of the three reads was separated by a minimum one week wash out, with the inclusion of wildcards. The results are presented as both trichotomous and binary analysis, with additional negative and positive percent agreements (NPA and PPA). | Intra-Reader/Inter-Day (M-WSI) | | Read 2 | | | | Read 3 | | | | Read 3 | | | | |----------------------------------------|----|-----------------|----|----|----|-----------------|----|----|----|-----------------|----|----|----| | | | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | | Read 1 | 0 | 6 | 3 | 1 | 0 | 8 | 2 | 0 | 0 | | | | | | | 1+ | 0 | 3 | 11 | 0 | 0 | 8 | 6 | 0 | | | | | | | 2+ | 0 | 0 | 4 | 3 | 0 | 0 | 4 | 3 | | | | | | | 3+ | 0 | 0 | 0 | 9 | 0 | 0 | 0 | 9 | | | | | | Read 2 | 0 | | | | | | | | | 6 | 0 | 0 | 0 | | | 1+ | | | | | | | | | 2 | 4 | 0 | 0 | | | 2+ | | | | | | | | | 0 | 6 | 10 | 0 | | | 3+ | | | | | | | | | 0 | 0 | 0 | 12 | | % Agreement (95% CI) (Trichotomous) | | 62.5% (47%-76%) | | | | 77.5% (62%-88%) | | | | 85.0% (71%-93%) | | | | Intra-Reader/Inter-Day on Digital (MM) for Pathologist 1 – Trichotomous score categories {9}------------------------------------------------ | Intra-Reader/Inter-Day (M-WSI) Pathologist 1 | | Read 2 | | Read 3 | | Read 3 | | |----------------------------------------------------|-----|-----------------|-----|-----------------|-----|-----------------|-----| | | | Neg | Pos | Neg | Pos | Neg | Pos | | Read 1 | Neg | 12 | 12 | 18 | 6 | | | | | Pos | 0 | 16 | 0 | 16 | | | | Read 2 | Neg | | | | | 12 | 0 | | | Pos | | | | | 6 | 22 | | Overall % Agreement (95% CI) | | 70.0% (55%-82%) | | 85.0% (71%-93%) | | 85.0% (71%-93%) | | | Negative % Agreement (95% CI) | | 66.7% (50%-80%) | | 85.7% (72%-93%) | | 80.0% (63%-90%) | | | Positive % Agreement (95% CI) | | 72.7% (58%-84%) | | 84.2% (70%-93%) | | 88.0% (76%-94%) | | Intra-Reader/Inter-Day on Digital (MM) for Pathologist 1 - Binary score categories | Intra-Reader/Inter-Day (M-WSI) | | Read 2 | | | | | Read 3 | | | | | Read 3 | | | | |----------------------------------------|----|--------|----|-----------------|----|---|------------------|----|----|---|------------------|--------|----|--|--| | | | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | | | | Read 1 | 0 | 8 | 0 | 0 | 0 | 8 | 0 | 0 | 0 | | | | | | | | | 1+ | 0 | 8 | 1 | 0 | 1 | 8 | 0 | 0 | | | | | | | | | 2+ | 0 | 1 | 10 | 0 | 0 | 1 | 10 | 0 | | | | | | | | | 3+ | 0 | 0 | 0 | 12 | 0 | 0 | 0 | 12 | | | | | | | | Read 2 | 1 | | | | | | | | | 8 | 0 | 0 | 0 | | | | | 1+ | | | | | | | | | 1 | 8 | 0 | 0 | | | | | 2+ | | | | | | | | | 0 | 1 | 10 | 0 | | | | | 3+ | | | | | | | | | 0 | 0 | 0 | 12 | | | | % Agreement (95% CI) (Trichotomous) | | | | 95.0% (83%-99%) | | | 97.5% (87%-100%) | | | | 97.5% (87%-100%) | | | | | Intra-Reader/Inter-Day on Digital (MM) for Pathologist 2 - Trichotomous score categories | Intra-Reader/Inter-Day (M-WSI) Pathologist 2 | | Read 2 | | Read 3 | | Read 3 | | |----------------------------------------------------|---------------------------------|-----------------|-----|------------------|-----|------------------|-----| | | | Neg | Pos | Neg | Pos | Neg | Pos | | Read 1 | Neg | 16 | 1 | 17 | 0 | | | | Read 1 | Pos | 1 | 22 | 1 | 22 | | | | Read 2 | Neg | | | | | 17 | 0 | | | Pos | | | | | 1 | 22 | | | Overall % Agreement (95% CI) | 95.0% (83%-99%) | | 97.5% (87%-100%) | | 97.5% (87%-100%) | | | Negative % Agreement (95% CI) | | 94.1% (81%-98%) | | 97.1% (85%-99%) | | 97.1% (85%-99%) | | | Positive % Agreement (95% CI) | | 95.7% (85%-99%) | | 97.8% (88%-100%) | | 97.8% (88%-100%) | | Intra-Reader/Inter-Day on Digital (MM) for Pathologist 2 - Binary score categories {10}------------------------------------------------ | Intra-Reader/Inter-Day (M-WSI) | | Read 2 | | | | Read 3 | | | | Read 3 | | | | |----------------------------------------|----|--------|----|-----------------|----|--------|----|-----------------|----|--------|----|-----------------|----| | | | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | 0 | 1+ | 2+ | 3+ | | Read 1 | 0 | 5 | 0 | 0 | 0 | 5 | 0 | 0 | 0 | | | | | | | 1+ | 3 | 3 | 0 | 0 | 1 | 5 | 0 | 0 | | | | | | | 2+ | 0 | 1 | 15 | 3 | 0 | 0 | 15 | 4 | | | | | | | 3+ | 0 | 0 | 0 | 10 | 0 | 0 | 0 | 10 | | | | | | Read 2 | 1 | | | | | | | | | 5 | 3 | 0 | 0 | | | 1+ | | | | | | | | | 1 | 2 | 1 | 0 | | | 2+ | | | | | | | | | 0 | 0 | 14 | 1 | | | 3+ | | | | | | | | | 0 | 0 | 0 | 13 | | % Agreement (95% CI) (Trichotomous) | | | | 90.0% (77%-96%) | | | | 90.0% (77%-96%) | | | | 95.0% (83%-99%) | | Intra-Reader/Inter-Day on Digital (MM) for Pathologist 3 - Trichotomous score categories | Intra-Reader/Inter-Day (M-WSI) Pathologist 3 | | Read 2 | | Read 3 | | Read 3 | | |----------------------------------------------------|----------------------------------|--------|------------------|--------|-------------------|------------------|-----| | | | Neg | Pos | Neg | Pos | Neg | Pos | | Read 1 | Neg | 11 | 0 | 11 | 0 | | | | | Pos | 1 | 28 | 0 | 29 | | | | Read 2 | Neg | | | | | 11 | 1 | | | Pos | | | | | 0 | 28 | | | Overall % Agreement (95% CI) | | 97.5% (87%-100%) | | 100.0% (91%-100%) | 97.5% (87%-100%) | | | | Negative % Agreement (95% CI) | | 95.7% (79%-99%) | | 100.0% (85%-100%) | 95.7% (79%-99%) | | | | Positive %…

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