Aperio AT2 DX System

K190332 · Leica Biosystems Imaging, Inc. · PSY · May 20, 2019 · Pathology

Device Facts

• Record ID: K190332
• Device Name: Aperio AT2 DX System
• Applicant: Leica Biosystems Imaging, Inc.
• Product Code: PSY · Pathology
• Decision Date: May 20, 2019
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 864.3700
• Device Class: Class 2

Intended Use

The Aperio AT2 DX System is an automated digital slide creation and viewing system. The Aperio AT2 DX System is intended for in vitro diagnostic use as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded (FFPE) tissue. The Aperio AT2 DX System is not intended for use with frozen section, cytology, or non-FFPE hematopathology specimens. The Aperio AT2 DX System is composed of the Aperio AT2 DX scanner, the ImageScope DX review application and Display. The Aperio AT2 DX System is for creation and viewing of digital images of scanned glass slides that would otherwise be appropriate for manual visualization by conventional light microscopy. It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using the Aperio AT2 DX System.

Device Story

Aperio AT2 DX System is an automated digital slide creation and viewing system for primary diagnosis. System components include an autoloader-equipped scanner (400-slide capacity), a viewing workstation, and ImageScope DX software. The scanner uses a high numeric aperture 20x objective and linear-array scanning to digitize glass slides into seamless digital images. Pathologists use the ImageScope DX software on a calibrated monitor to view, annotate, and interpret digital slides, mimicking conventional light microscopy. The system supports remote intranet access. By digitizing slides, the device enables pathologists to perform clinical assessments and make diagnostic decisions remotely or within a clinical setting, potentially improving workflow efficiency while maintaining diagnostic accuracy comparable to manual microscopy.

Clinical Evidence

Multi-center clinical study (5 sites, 2045 cases, 5849 slides) compared Whole Slide Imaging Review (WSIR) to Light Microscope Slide Review (MSR). Primary endpoint: major discordance rate difference between modalities. Observed major discordance: 3.73% (WSIR) vs 3.28% (MSR). Modeled difference: 0.44% (95% CI: -0.15%, 1.03%). Upper bound of CI was below the 4% non-inferiority margin. Study concluded WSIR is non-inferior to MSR.

Technological Characteristics

System includes an automated scanner with 400-slide autoloader, viewing workstation, and calibrated monitor (Dell MR2416). Employs linear-array scanning technique with high numeric aperture 20x objective. Software includes Console DX, Controller DX, and ImageScope DX. Connectivity via local network/intranet. System is designed for FFPE tissue slides.

Indications for Use

Indicated for use by pathologists to review and interpret digital images of surgical pathology slides prepared from FFPE tissue. Not indicated for frozen section, cytology, or non-FFPE hematopathology specimens.

Regulatory Classification

Identification

The whole slide imaging system is an automated digital slide creation, viewing, and management system intended as an aid to the pathologist to review and interpret digital images of surgical pathology slides. The system generates digital images that would otherwise be appropriate for manual visualization by conventional light microscopy.

Special Controls

A whole slide imaging system must comply with the following special controls: (1) Premarket notification submissions must include the following information: (i) The indications for use must specify the tissue specimen that is intended to be used with the whole slide imaging system and the components of the system. (ii) A detailed description of the device and bench testing results at the component level, including for the following, as appropriate: (A) Slide feeder; (B) Light source; (C) Imaging optics: (D)Mechanical scanner movement; (E) Digital imaging sensor; (F) Image processing software; (G)Image composition techniques; (H)Image file formats; (I) Image review manipulation software; (J) Computer environment; (K)Display system. (iii)Detailed bench testing and results at the system level, including for the following, as appropriate: (A)Color reproducibility; (B) Spatial resolution; (C) Focusing test; (D) Whole slide tissue coverage; (E) Stitching error: (F) Turnaround time. (iv) Detailed information demonstrating the performance characteristics of the device, including, as appropriate: (A)Precision to evaluate intra-system and inter-system precision using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included. (B) Reproducibility data to evaluate inter-site variability using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included. (C) Data from a clinical study to demonstrate that viewing, reviewing, and diagnosing digital images of surgical pathology slides prepared from tissue slides using the whole slide imaging system is non-inferior to using an optical microscope. The study should evaluate the difference in major discordance rates between manual digital (MD) and manual optical (MO) modalities when compared to the reference (e.g., main sign-out diagnosis). (D) A detailed human factors engineering process must be used to evaluate the whole slide imaging system user interface(s). (2) Labeling compliant with 21 CFR 809.10(b) must include the following: The intended use statement must include the information described in paragraph (i) (1)(i) of this section, as applicable, and a statement that reads, "It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using this device." (ii) A description of the technical studies and the summary of results, including those that relate to paragraph (1)(ii) and (1)(iii) of this section, as appropriate. (iii) A description of the performance studies and the summary of results, including those that relate to paragraph (1)(iv) of this section, as appropriate. (iv) A limiting statement that specifies that pathologists should exercise professional judgment in each clinical situation and examine the glass slides by conventional microscopy if there is doubt about the ability to accurately render an interpretation using this device alone.

*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must include the following information: (i) The indications for use must specify the tissue specimen that is intended to be used with the whole slide imaging system and the components of the system. (ii) A detailed description of the device and bench testing results at the component level, including for the following, as appropriate: (A) Slide feeder; (B) Light source; (C) Imaging optics; (D) Mechanical scanner movement; (E) Digital imaging sensor; (F) Image processing software; (G) Image composition techniques; (H) Image file formats; (I) Image review manipulation software; (J) Computer environment; and (K) Display system. (iii) Detailed bench testing and results at the system level, including for the following, as appropriate: (A) Color reproducibility; (B) Spatial resolution; (C) Focusing test; (D) Whole slide tissue coverage; (E) Stitching error; and (F) Turnaround time. (iv) Detailed information demonstrating the performance characteristics of the device, including, as appropriate: (A) Precision to evaluate intra-system and inter-system precision using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included. (B) Reproducibility data to evaluate inter-site variability using a comprehensive set of clinical specimens with defined, clinically relevant histologic features from various organ systems and diseases. Multiple whole slide imaging systems, multiple sites, and multiple readers must be included. (C) Data from a clinical study to demonstrate that viewing, reviewing, and diagnosing digital images of surgical pathology slides prepared from tissue slides using the whole slide imaging system is non-inferior to using an optical microscope. The study should evaluate the difference in major discordance rates between manual digital (MD) and manual optical (MO) modalities when compared to the reference ( *e.g.,* main sign-out diagnosis).(D) A detailed human factor engineering process must be used to evaluate the whole slide imaging system user interface(s). (2) Labeling compliant with 21 CFR 809.10(b) must include the following: (i) The intended use statement must include the information described in paragraph (b)(1)(i) of this section, as applicable, and a statement that reads, “It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using this device.” (ii) A description of the technical studies and the summary of results, including those that relate to paragraphs (b)(1)(ii) and (iii) of this section, as appropriate. (iii) A description of the performance studies and the summary of results, including those that relate to paragraph (b)(1)(iv) of this section, as appropriate. (iv) A limiting statement that specifies that pathologists should exercise professional judgment in each clinical situation and examine the glass slides by conventional microscopy if there is doubt about the ability to accurately render an interpretation using this device alone.

Predicate Devices

• Philips IntelliSite Pathology Solution (PIPS) (DEN160056)

Submission Summary (Full Text)

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May 20, 2019

Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text "FDA U.S. FOOD & DRUG ADMINISTRATION" on the right. The symbol on the left is a stylized representation of the Department of Health & Human Services seal. The text on the right is in blue, with "FDA" in a larger font size than the rest of the text.

Leica Biosystems Imaging, Inc. Christine Kishi Sr. RA Specialist 1360 Park Center Dr. Vista, CA 92081

Re: K190332

Trade/Device Name: Aperio AT2 DX System Regulation Number: 21 CFR 864.3700 Regulation Name: Whole slide imaging system Regulatory Class: Class II Product Code: PSY Dated: February 13, 2019 Received: February 14, 2019

Dear Christine Kishi:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate device marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801 and Part 809); medical device reporting of medical device-related adverse events) (21 CFR

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803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/CombinationProducts/GuidanceRegulatoryInformation/ucm597488.html; good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/) and CDRH Learn (http://www.fda.gov/Training/CDRHLearn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (http://www.fda.gov/DICE) for more information or contact DICE by email ([e-mail]) or phone [phone] or 301-796-7100).

Sincerely,

Yun-Fu Hu, Ph.D. Deputy Director Division of Molecular Genetics and Pathology OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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# Indications for Use

510(k) Number (if known) K190332

Device Name Aperio AT2 DX System

### Indications for Use (Describe)

The Aperio AT2 DX System is an automated digital slide creation and viewing system. The Aperio AT2 DX System is intended for in vitro diagnostic use as an aid to the pathologist to review and interpret digital pathology slides prepared from formalin-fixed paraffin embedded (FFPE) tissue. The Aperio AT2 DX System is not use with frozen section, cytology, or non-FFPE hematopathology specimens.

The Aperio AT2 DX System is composed of the Aperio AT2 DX scanner, the ImageScope DX review application and Display. The Aperio AT2 DX System is for creation and viewing of digital images of scanned glass slides that would otherwise be appropriate for manual visualization by conventional light microscopy. It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the interpretation of images obtained using the Aperio AT2 DX System.

Type of Use (Select *one* or *both*, as applicable)X Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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Image /page/3/Picture/0 description: The image shows the logo for Leica Biosystems. The word "Leica" is written in a stylized red font. Below the word "Leica" is the word "BIOSYSTEMS" written in a sans-serif font.

## 510(k) Summary Aperio AT2 DX System

#### I. Submitter

Leica Biosystems Imaging, Inc 1360 Park Center Dr. Vista, CA 92081

#### II. Contact Person

Christine Kishi Sr. Regulatory Affairs Specialist 1360 Park Center Dr. Vista, CA 92081 [e-mail] Phone: [phone] Fax: [phone]

#### III. Device

Proprietary Name of the Device: Aperio AT2 DX System Classification Name: Whole Slide Imaging System Regulation Number: 21 CFR Part 864.3700 Regulatory Class: Class II Product code: PSY

#### IV. Predicate Device

Philips IntelliSite Pathology Solution (PIPS) DEN160056

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#### Device Description V.

Clearance of this premarket application will enable the Aperio AT2 DX System comprised of a scanner and a viewing station for the primary diagnosis of formalin-fixed paraffin-embedded tissue.

## System:

The Aperio AT2 DX System is an automated digital slide creation and viewing system. The system is comprised of an Aperio AT2 DX scanner instrument and a Viewing Workstation with a computer and a calibrated monitor executing ImageScope DX viewer software. The system capabilities include digitizing microscope slides at diagnostic resolution, retrieving and displaying digital slides, including support for remote intra-net access over computer networks, providing tools for annotating digital slides, entering data associated with digital slides and displaying the scanned slide images for primary diagnoses by Pathologists.

## Image Acquisition:

The Aperio AT2 DX has a 400 glass slides capacity via an autoloader. High numeric aperture 20x objective, as found on conventional microscopes, is used to produce high-quality images. The Aperio AT2 DX digital slide scanner employs a linear-array scanning technique that generates images and accounts for merging scan stripes along the scanning axis. The result is seamless digital slide images.

The image acquisition software components include Console DX and Controller DX. The Console DX application is a user-interface for the operator. It allows users to initiate scanning and select appropriate slide areas to scan. The Controller DX application is a software subsystem that runs on the Aperio AT2 DX scanner Control PC.

## Image Viewing:

The remote image viewing capabilities of the ImageScope DX software subsystem supports reading digital slides on a calibrated monitor, enabling Pathologists to make clinically relevant decisions analogous to those they make using a conventional microscope. ImageScope DX includes support for locally or intranet connected image Viewing Workstation computers, which run digital slide viewing. The software includes elements to support data confidentiality and integrity.

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#### VI. Intended Use

The Aperio AT2 DX System is an automated digital slide creation and viewing system. The Aperio AT2 DX System is intended for in vitro diagnostic use as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded (FFPE) tissue. The Aperio AT2 DX System is not intended for use with frozen section, cytology, or non-FFPE hematopathology specimens.

The Aperio AT2 DX System is composed of the Aperio AT2 DX scanner, the ImageScope DX review application and Display. The Aperio AT2 DX System is for creation and viewing of digital images of scanned glass slides that would otherwise be appropriate for manual visualization by conventional light microscopy. It is the responsibility of a qualified pathologist to employ appropriate procedures and safeguards to assure the validity of the interpretation of images obtained using the Aperio AT2 DX System.

### Comparison of technological characteristics with the predicate VII. device

| Item | Predicate Device<br>Philips IntelliSite Pathology Solution<br>(PIPS) (DEN160056) | Candidate Device<br>Aperio AT2 DX System |
|-----------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Intended Use/<br>Indications<br>for Use | The Philips IntelliSite Pathology<br>Solution (PIPS) is an automated digital<br>slide creation, viewing, and<br>management system. The PIPS is<br>intended for in vitro diagnostic use as<br>an aid to the pathologist to review and<br>interpret digital images of surgical<br>pathology slides prepared from<br>formalin-fixed paraffin embedded<br>(FFPE) tissue. The PIPS is not<br>intended for use with frozen section,<br>cytology, or non-FFPE<br>hematopathology specimens.<br>The PIPS comprises the Image<br>Management System (IMS), the Ultra<br>Fast Scanner (UFS) and Display. The<br>PIPS is for creation and viewing of<br>digital images of scanned glass slides<br>that would otherwise be appropriate<br>for manual visualization by<br>conventional light microscopy. It is the<br>responsibility of a qualified | The Aperio AT2 DX System is an<br>automated digital slide creation<br>and viewing system. The Aperio<br>AT2 DX System is intended for in<br>vitro diagnostic use as an aid to<br>the pathologist to review and<br>interpret digital images of surgical<br>pathology slides prepared from<br>formalin-fixed paraffin embedded<br>(FFPE) tissue. The Aperio AT2<br>DX System is not intended for use<br>with frozen section, cytology, or<br>non-FFPE hematopathology<br>specimens.<br>The Aperio AT2 DX System is<br>composed of the Aperio AT2 DX<br>scanner, the ImageScope DX<br>review application and Display.<br>The Aperio AT2 DX System is for |
| Item | Predicate Device<br>Philips IntelliSite Pathology Solution<br>(PIPS) (DEN160056) | Candidate Device<br>Aperio AT2 DX System |
| | pathologist to employ appropriate<br>procedures and safeguards to assure<br>the validity of the interpretation of<br>images obtained using PIPS. | creation and viewing of digital<br>images of scanned glass slides that<br>would otherwise be appropriate<br>for manual visualization by<br>conventional light microscopy. It<br>is the responsibility of a qualified<br>pathologist to employ appropriate<br>procedures and safeguards to<br>assure the validity of the<br>interpretation of images obtained<br>using the Aperio AT2 DX System. |
| Specimen<br>type | Surgical pathology slides prepared<br>from formalin-fixed, paraffin-<br>embedded tissue | Same |
| Principle of<br>operation | The technician loads the slides into the<br>WSI scanner. The scanner scans the<br>slides and generates WSI image for<br>each slide. The technician performs<br>Quality Control (QC) on scanned WSI<br>images and rescan the slide when QC<br>is failed. The acquired WSI images are<br>stored in an end user provided image<br>storage attached to the local network.<br>During review, the pathologist opens<br>WSI images acquired with the WSI<br>scanner from the image storage,<br>performs further QC and reads WSI<br>images of the slides to make a<br>diagnosis. | Same |
| Device<br>Components | WSI scanner (PIPS Ultra Fast<br>Scanner), Image Management System<br>and color monitor display | Same (Aperio AT2 DX scanner,<br>ImageScope DX application, and<br>color monitor display) |

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| Differences | | |
|--------------------------------|-----------------------------------------------------------------|--------------------------------------------------------------|
| Item | Device | Predicate |
| Whole Slide Imaging<br>Scanner | Aperio AT2 DX scanner<br>with loading capacity of<br>400 slides | Ultra Fast Scanner with<br>loading capacity of 300<br>slides |
| Graphical User Interface | ImageScope DX | Image Management<br>System |
| Monitor Display | Dell MR2416 monitor | PS27QHDCR |

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# VIII. Performance Data

The performance testing was conducted via a series of studies that included Accuracy, Intra-System, Inter-System/Site. Within-Pathologist and Between-Pathologist precision.

The accuracy was evaluated by analyzing the concordance of the diagnoses made using the Aperio AT2 DX System (also known as WSIR diagnosis) with the gold standard reference diagnoses (the original sign-out pathologic diagnosis), and the concordance of traditional light microscope slide review (MSR) diagnoses with the gold standard reference diagnoses. Accuracy was assessed by analyzing major discrepancy rates for each study modality versus the gold standard reference diagnosis and calculating the difference between the major discrepancy rates for WSIR diagnosis and MSR diagnosis. Major discrepancy was defined as a difference in diagnoses that resulted in a clinically important difference in patient management.

The acceptance criteria were as follows:

- The upper bound of the two-sided 95% CI of the difference between the overall major discrepancy rates of WSIR diagnoses and MSR diagnoses is <4%.
- The upper bound of the two-sided 95% CI of the overall major discrepancy . rate of the WSIR diagnoses is <7%.

The precision of the Aperio AT2 DX System was evaluated in 3 studies.

- For the Intra-System Precision study, the objective was to assess precision within each of three independent systems, and overall within system precision.
- . For the Inter-System/Site Precision study, the objective was to assess precision between systems/sites (three independent systems at three different sites) and overall between system/site precision.
- For the Within- and Between-Pathologist Precision study, the objective was to . assess precision within and between pathologists (using images generated from a single system), overall within pathologist precision, and overall between pathologist precision.

The Precision was considered acceptable if the lower bounds of the 2-sided 95% confidence intervals (CIs) of the overall agreements for each precision component (e.g. intra-system, inter-system/site) were ≥ 85%.

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| | Number of | Number of | Agreement Rate and 95% CI* | | | |
|----------|------------------------|---------------------|----------------------------|-------|-------|--|
| System | Pairwise<br>Agreements | Comparison<br>Pairs | 0/0<br>Agreement | Lower | Upper | |
| System 1 | 193 | 201 | 96.0% | 91.0% | 100% | |
| System 2 | 201 | 201 | 100% | 98.2% | 100% | |
| System 3 | 199 | 204 | 97.5% | 93.6% | 100% | |
| Overall | 593 | 606 | 97.9% | 95.9% | 99.5% | |

## Table 1. Intra-System Study: Agreement Within Systems

* A bootstrap approach was used to calculate 95% CIs with the following exception. When the agreement estimate was 100%, the Arcsine (variance stabilizing transformation) approach that corrected for the continuity was used to calculate CIs (Pires and Amado, 2008).

## Table 2. Inter-System/Site Study: Agreement Between Systems

| | Number of<br>Pairwise<br>Agreements | Number of<br>Comparison<br>Pairs | Agreement Rate and 95%<br>CI* | | |
|----------------------|-------------------------------------|----------------------------------|-------------------------------|--------------|--------------|
| System | | | %<br>Agreement | Lower | Upper |
| System 1 vs System 2 | 195 | 202 | 96.5% | 94.1% | 99.0% |
| System 1 vs System 3 | 194 | 202 | 96.0% | 93.1% | 98.5% |
| System 2 vs System 3 | 193 | 202 | 95.5% | 92.6% | 98.0% |
| <b>Overall</b> | <b>582</b> | <b>606</b> | <b>96.0%</b> | <b>93.6%</b> | <b>98.2%</b> |

*A bootstrap approach was used to calculate 95% CIs.

## Table 3. Within/Between -Pathologist Study: Agreement Within Pathologists

| | Number of | Number of | Agreement Rate and 95% CI* | | | |
|---------------|------------|------------|----------------------------|-------|-------|--|
| Pathologist | Pairwise | Comparison | % Agreement | Lower | Upper | |
| | Agreements | Pairs | | | | |
| Pathologist 1 | 561 | ୧୦୧ | 92.6% | 89.6% | 95.7% | |
| Pathologist 2 | રેતેર | ୧୦୧ | 98.2% | 96.3% | 99.7% | |
| Pathologist 3 | 571 | ୧୦୧ | 94.2% | 91.4% | 96.9% | |
| Overall | 1727 | 1818 | 95.0% | 92.9% | 96.8% | |

*A bootstrap approach was used to calculate 95% CIs.

Table 4. Within- and Between-Pathologist Study: Agreement Between Pathologists

| Pathologist<br>Comparison | Number of<br>Pairwise<br>Agreements | Number of<br>Comparison<br>Pairs | Agreement Rate and 95% CI* | | |
|-----------------------------------|-------------------------------------|----------------------------------|----------------------------|-------|-------|
| Pathologist 1 vs<br>Pathologist 2 | 572 | 606 | 94.4% | 91.6% | 96.9% |

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| Pathologist 1 vs<br>Pathologist 3 | 562 | 606 | 92.7% | 89.9% | 95.4% |
|-----------------------------------|------|------|-------|-------|-------|
| Pathologist 2 vs<br>Pathologist 3 | 579 | 606 | 95.5% | 93.1% | 97.7% |
| Overall | 1713 | 1818 | 94.2% | 91.7% | 96.4% |

*A bootstrap approach was used to calculate 95% CIs.

Table 5. Overall Major Discrepancy Rates for the WSIR and MSR Modalities and the Difference Between the Overall Major Discrepancy Rates

| | WSIRD Major<br>Discrepancy* | | | MSRD Major<br>Discrepancy* | | | Difference in Major<br>Discrepancy Rates<br>(WSIRD minus<br>MSRD) | |
|----------|-----------------------------|-------------|-----------------|----------------------------|-------------|-----------------|-------------------------------------------------------------------|-----------------|
| | Total<br>Reads | Rate<br>(%) | Model<br>95% CI | Total<br>Reads | Rate<br>(%) | Model<br>95% CI | % | Model<br>95% CI |
| Observed | | 3.73 | - | | 3.28 | - | 0.45 | - |
| Model | 7509 | 3.64 | (3.21,<br>4.12) | 7522 | 3.20 | (2.80,<br>3.65) | 0.44 | (-0.15%, 1.03%) |

MSRD = MSR diagnosis, WSIRD = WSIR diagnosis

#### IX. Conclusions

The clinical study results demonstrate that AT2 DX System is substantially equivalent to the predicate device.