C T L U N G

Understanding the
ImageChecker CT Lung System
®

Version 2.0
CT Lung

Understanding the
ImageChecker® CT Lung System
Version 2.0

PN 13229 Rev A
Technical Support
Before calling R2 Technical Support, refer to the user manuals for
troubleshooting instructions. For support in North America, contact:
Toll Free: +1 866.243.2533 (866.CHECKED)
Fax: +1 408.481.5607
Email: techsupport@r2tech.com
Hours: Monday through Friday, 6:00 AM – 5:00 PM, PST
For support in Europe, South America, or Asia, contact your local dealer or
distributor.
Caution: Only service engineers certified by R2 Technology are qualified to
install or repair the system.

R2 Technology, Inc.
1195 West Fremont Avenue
Sunnyvale, CA 94087 USA
www.r2tech.com

© 2005, R2 Technology, Inc. All rights reserved. Reproduction of this document

without prior written approval is prohibited. R2 Technology reserves the right to
revise this manual. Issued July 2005.

Protected by one or more of the following U.S. Patents: 5881124, 6766043,

6909795

R2; R2 Technology; the R2 logo; ImageChecker; AutoPoint; CheckMate; Earlier.

Smarter. Better.; EmphaSize; DigitalNow; the DigitalNow logo; Gold Standard
CAD; PE; PeerView; and RightOn are trademarks and/or registered trademarks
of R2 Technology, Inc. in the United States and other countries.

Microsoft and Windows are registered trademarks of Microsoft Corporation.

This system incorporates the Interface Definition Language Compiler Front End
(IDL CFE) and Internet Inter-ORB Protocol (IIOP) technologies, provided and
licensed by Sun Microsystems. Refer to the file 3rdPartyLicenses.txt in the
c:/r2technology/imagechecker/vendor/3rdpartylic folder on the processing unit
for licensing and warranty information.

Authorized European representative: MedPass International

Limited, Windsor House, Barnett Way, Barnwood, Glouchester
GL4 3RT United Kingdom, Telephone/Fax: +44 (0)1 452 619 222

MergeCOM-3 Advanced Integrator’s Tool Kit is a product of

Merge eFilm.

ii Understanding the ImageChecker CT Lung System – PN 13229 Rev A

Contents
Part 1: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Intended Use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
AutoPoint™ Temporal Comparison Tool . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Pulmonary Artery PE™ (Patency Exam) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Available Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Symbols Used . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Warnings and Cautions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Conventions Used in this Manual . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Warnings: Radiological Interpretation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Warnings: System Operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Warnings: Installation and Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Cautions: System Operation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Cautions: Installation and Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Part 2: Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
System Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Optional Software Packages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
System Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
ImageChecker CT Lung Server . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ImageChecker CT Lung Workstation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Other Components . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Key Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Separate Image/CAD Processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
User-Controlled CAD Markers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Findings Automatically Quantified . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Flexible Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Integrated 2D and 3D Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Frontal Projection View (Lung Map) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Selection of Review Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Complementary Data Views . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
AutoPoint Temporal Comparison . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Pulmonary Artery PE (Patency Exam) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Understanding the ImageChecker CT Lung System – PN 13229 Rev A iii

Contents

Printable Summary Reports Can Include Key Images . . . . . . . . . . . . . . . . . . . . . . . . 13

Easy to Use Database Search Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Simple Database Management Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
PACS Integration and Multi-workstation Capability . . . . . . . . . . . . . . . . . . . . . . . . . 13
Controlled Access . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Queue Manager . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
CAD Algorithm Description . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
CAD Process for Pulmonary Artery PE (Patency Exam). . . . . . . . . . . . . . . . . . . . . . . 15
System Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Part 3: Scanning Protocol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Scanning Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Input Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Field of View (FOV) Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Reconstruction Filters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Support for Patient Orientations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Contrast Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Minimum Lung Z-Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Merged Exams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Gated Exams . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Number of Detectors in the Scanner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Gantry Tilt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
DICOM Fields . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Body Part Value . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Compressed Images . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Frequently Asked Questions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Part 4: Clinical Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Clinical Study Sites and Cases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Study #1 – Identification of Reference Truth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Study #2 – Accuracy Improvement Through Use of CAD . . . . . . . . . . . . . . . . . . . . . . . . . 23
Study #3 – Measurement of CAD Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

iv Understanding the ImageChecker CT Lung System – PN 13229 Rev A

Part 1: Introduction
Intended Use
Available Resources
Symbols Used
Warnings and Cautions

Intended Use
The ImageChecker® CT Lung v2.0 System is a computer-aided detection (CAD)
system designed to assist physicians in softcopy review of digital computed-
tomography (CT) images of the chest. The ImageChecker CT Lung workstation
displays composite views of 2D cross-sections and 3D volumes of chest CT images,
including findings or regions of interest identified by the physician or computer-
aided detection (CAD) findings.
The system assists physicians in the characterization, classification, and tracking of
suspicious candidate thoracic abnormalities in terms of size, dimension, shape,
density, and position, and thus aids in the patient management care decision process.
The system is intended to be used as an adjunct, alerting the physician – after an
initial reading of the scan – to regions of interest that may have been overlooked.

AutoPoint™ Temporal Comparison Tool

The optional AutoPoint temporal comparison tool consists of software that enables
physicians to view, analyze, register and compare new and previous series of thoracic
CT images. The software package assists the physicians by calculating volume change
and doubling time of selected segmented candidate thoracic abnormalities (such as
pulmonary and pleural nodules and lesions) found on these images.

Pulmonary Artery PE™ (Patency Exam)

The optional Pulmonary Artery PE (Patency Exam) tool consists of image-analysis
software that highlights low-density regions within vascular structures that may
indicate filling defects or other intravascular abnormalities, enabling physicians to
view and analyze them.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 1

Part 1: Introduction

Available Resources
The following resources are available when you are working with the ImageChecker
CT Lung System:
• Onscreen messages – The ImageChecker CT Lung System is designed to guide you
through any interaction you will need to have with the system. Informational
onscreen messages pop up when appropriate.
• R2 Technical Support and Service – For contact information, see ‘Technical
Support’ on the back of the title page of this book.
• User Manuals – Instructions for using the system are provided in this manual and
the ImageChecker CT Lung v2.0 User Manual. The user manual is a how-to guide
in the form of a simple, streamlined flip chart that describes how to use the
application. To order additional copies of the manuals, contact R2 Technical
Support. Note: The instructions in the user manual apply only when using the
ImageChecker CT Lung workstation supplied by R2 Technology, Inc.
• Algorithm Documentation – Under the Algorithm Description tab in the user
manual you will find an explanation, with examples, of how the ImageChecker CT
Lung System algorithm processes CT images. For a more general description,
without examples, see ‘CAD Algorithm Description’ on page 14 of this manual.
• DICOM Conformance Statements – The R2 Technology website
(www.r2tech.com) provides the DICOM Conformance Statements, which describe
the ImageChecker CT Lung implementation of the DICOM protocol.
• Release Notes – This document describes new product features and presents any
known issues or questions that are commonly asked.
• Customer Bulletins – We are committed to making our products safe and easy to
use. If an issue arises or new features become available, we will send you a
Customer Bulletin.
• Training – The R2 Technology Applications team is available to train your staff,
should you feel they need additional training. Contact your R2 Technology
Account Manager if you want personalized instruction.

Symbols Used
The following internationally recognized symbols are used with the system.

Symbol Description

Dangerous voltage

 Attention: Consult accompanying documents.

2 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 Warnings and Cautions

Warnings and Cautions

The following Warning and Cautions pertain to the use of the ImageChecker CT
Lung System workstation and the ImageChecker CT Lung CAD software.
 Caution: U.S.A. Federal law restricts the sale, distribution, and use of this device to
or on the order of a physician.

Conventions Used in this Manual

The system manuals use the following conventions to provide technical and safety
information of special interest.
 Note: Background information provided to clarify a particular step or procedure.
 Caution: An instruction that, if not followed, can result in damage to the system.
 Warning! An instruction that, if not followed, can lead to erroneous results or result
in a hazardous condition.
In this section, all precautionary information is given in a normal typeface.

Warnings: Radiological Interpretation

• The CAD software is a detection aid, not an interpretive aid. Use it only after
 you read the images. Always read first before turning on CAD. Never change
your mind about a potential finding if CAD does not mark it.

• The ImageChecker CT Lung CAD software algorithm is designed to detect nodules

that are from 4.0–30.0 mm in diameter from individual slices in the target scan
acquired at a thickness of 0.5–3.0 mm. For filling-defect analysis, the slices must be
0.5–2.0 mm.
• The CAD software does not identify all areas that are suspicious for nodules:
– If the CAD software does not mark a region identified by the physician as a
nodule, the physician should not be dissuaded from working up that finding.
– The CAD software is more sensitive for the detection of solid spherical nodules
than for nodules that are non-solid or part-solid, or have irregular shapes.
– The CAD Software is not designed to detect ground-glass opacities.
• The CAD software is not designed to detect other pulmonary parenchymal
abnormalities, such as emphysema, atelectasis, consolidation, or diffuse interstitial
disease.
• Scans should be completed during a single held breath to avoid motion artifacts
and ensure optimal processing by ImageChecker CT Lung.
• Support for spiral/helical scanners with single or dual detectors, and Electron
Beam CT (EBCT) is not available at this time.
• The CAD software marks regions with features suggestive of nodules by overlaying
a circle around those regions. These features may not represent nodules, and the
user must still use interpretative skills on items marked by the CAD software.
• The CAD software does not enhance what the user sees; rather it helps to identify
regions on CT images that should be reexamined.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 3

Part 1: Introduction

• The CAD software operates only on CT chest images that meet the technical
requirements outlined in ‘Part 3: Scanning Protocol’ and the DICOM
Conformance Statements for the ImageChecker CT Lung workstation and server.
• Image quality conditions such as underexposure or artifacts (e.g., motion artifacts
and streak artifacts caused by pacemakers or wires, for example) that diminish
radiographic contrast may also diminish CAD software sensitivity.
• Scans grossly distorted due to motion, and scans with numerous streak artifacts,
are likely to be repeated, if possible, since either condition would affect both
human and CAD performance.
• Individual practice patterns may influence the results obtained when using the
CAD software. Therefore, each facility and physician should carefully monitor the
result that this CAD software has on their practice in order to optimize its
effectiveness.
• Prior to review, ensure that multiple thoracic CT series being compared by the
software are from the same patient.
• If the automatic alignment tool fails to align the cases appropriately, the user
should use the manual alignment tools for accurate alignment.
• All comparative volumetric statistics such as volume change and doubling time
presented by the software must be assessed by the interpretative skills of the user.
• Primary diagnosis of the patient should not be based solely on volume change and
doubling time information presented, or the low-density regions highlighted by
the software.

Warnings: System Operation

• The symbol next to the power connector (shown at left) indicates a potential shock

hazard. Ensure that the system is connected to a power receptacle that is properly
grounded and provides voltage and current within the specifications of the system
to prevent the possibility of electrical shock or fire hazard.
• Do not place liquid containers on the device. In the event of a spill, shut down
power to all components prior to cleaning to prevent the possibility of electrical
shock. Do not operate the device if internal components are exposed to liquid.
Contact R2 technical support.
• This equipment has been tested and found to comply with the limits for a Class A
digital device, pursuant to Part 15 of the FCC Rules. These limits are designed to
provide reasonable protection against harmful interference when the equipment is
operated in a commercial environment. This equipment generates, uses, and can
radiate radio frequency energy and, if not installed in accordance with the
instruction manual, may cause harmful interference to radio communications.
Operation of this equipment in a residential area is likely to cause harmful
interference in which case the user will be required to correct the interference at
the user’s own expense.

4 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 Warnings and Cautions

Warnings: Installation and Maintenance

• Use of flammable cleaning solutions with power on or the system plugged in could
 cause fire.
• As with any standard computer system, use caution when moving or lifting the
components of the system to avoid possible injury.
• Protect the installation CDs that came with your system. Store them in a clean,
secure place.

Cautions: System Operation

• Operators should review the user manual and receive training as required before

 using the system.

• This product contains no user serviceable parts. To prevent damage to the system,
do not attempt to install or repair the ImageChecker CT Lung System. Only
trained personnel, authorized by R2, are qualified to install or repair the system.
For service training, contact R2 technical support.

Cautions: Installation and Maintenance

• Due to the potential for susceptibility to EMC emissions from nearby equipment,
 do not install the workstation in near proximity to MRI magnets.
• To prevent damage to the system, maintain equipment in a well-ventilated, air-
conditioned environment.
• Disconnect power cord before moving or servicing.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 5

Part 1: Introduction

6 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

Part 2: Description
System Overview
Optional Software Packages
System Components
Key Features
CAD Algorithm Description
System Maintenance

Part 2 describes the ImageChecker CT Lung System and key system features.

System Overview
The ImageChecker CT Lung System is an advanced thoracic 3D application designed
to assist physicians in the detection of thoracic abnormalities during review of multi-
slice CT (MSCT) exams of the chest. It is to be used as an adjunctive reader,
providing the physician with ‘a second set of eyes’ with which to find, assess, and
track abnormalities that may represent clinically significant disease.
The system does this by applying proprietary signal processing CAD algorithms to the
large digital datasets generated during scanning. These algorithms analyze the
complete set of images and search for findings with features suggestive of thoracic
abnormalities such as pulmonary nodules. The system conveys information regarding
candidate nodules of current and prior studies to the application for consideration by
the reader, including a marker noting each candidate nodule’s location.
The system provides fast, interactive nodule segmentation and volume measurement,
coronal 3D lung projection with stack navigation and nodule localization, as well as a
lung 3D view port that displays views of nodules and related anatomy with automatic
vessel, airway, and chest wall segmentation. After performing the initial read of the
exam, the user activates the display of the markers to review the computer-identified
findings.
The system facilitates case analysis by providing a complete toolkit for the measure-
ment and management of candidate nodules. Findings and measurements are
summarized in a database for subsequent review. This summary can be printed to any
Windows-compatible printer. The key images in the summary can be exported as
separate graphics files.
The system reduces the chance of performance lapses by the reader due to fatigue,
distraction, satisfaction of search, or other recognized causes of a suboptimal review;
it thereby increases the likelihood of identifying a clinically significant abnormality at
an earlier, more treatable stage.
Note that the ImageChecker CT Lung System is not intended to be used principally in
a screening environment, where the vast majority of scans would be expected to be

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 7

Part 2: Description

free of clinically significant disease. Rather, it is intended as a ‘back-up’ identification

and reporting system for physicians reading everyday diagnostic chest CT scans,
many of which will have other pathologic processes competing for their attention.
 Warning! When working with the ImageChecker CT Lung System, always read
unaided by CAD first. Once you evaluate the CAD results, never change your mind about
a judgment of actionability of a nodule because CAD fails to mark it. CAD is a tool –
always rely primarily on your unaided judgment.

Optional Software Packages

Optional software packages for the ImageChecker CT Lung System provide
additional tools such as temporal comparison and pulmonary artery patency exam to
aid in diagnosis. These additional tools are available only with the workstation
provided by R2 Technology, Inc.

AutoPoint Temporal Comparison Tool

The optional AutoPoint temporal comparison tool provides enables the physician to
compare the current study to a prior study in order to assess volume change and
doubling time of any candidate nodule.

Pulmonary Artery PE (Patency Exam) Tool

The optional Pulmonary Artery PE software package highlights areas of CT volume
data sets of the chest containing regions of low density within segmented, contrast-
opacified vessels. The tool is intended for use as an adjunctive device that aids the
physician in assessing the significance of low-density regions.

8 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 System Components

System Components
The ImageChecker CT Lung System consists of two computers, a review workstation
and a server. The workstation may either be provided by R2 Technology or be any
DICOM compliant PACS workstation. The graphic shows the principal system
components and actions.
After the initial study acquisition by the scanner, images typically are sent to a PACS
archive (1). Then, the ImageChecker CT Lung application either queries the PACS
archive for images (at which point the images are routed to the ImageChecker CT
Lung server for CAD processing) or the images are automatically routed from the
PACS archive to the ImageChecker CT Lung server (2).
After the server processes the image data and completes the CAD segmentation
processing, it sends the results to the workstation in the form of a DICOM structured
report. You can then choose to display the CAD findings (suspected nodules and/or
filling defects) (3), and use the application’s many tools to assist in your review. In
addition, when configured to do so, the system can store a secondary series of images
with CAD findings or an overlay of CAD findings to the PACS archive for later
retrieval by a PACS workstation. (4)
When you complete your review, the system makes a summary report available that
lists any findings and measurements associated with the study. You can print this
summary as well as any key images (5).
When configured to do so, the application archives the DICOM structured report
along with any key image series for nodules, pulmonary emboli, measurements and
3D captures (6).

ImageChecker CT Lung Data Flow

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 9

Part 2: Description

ImageChecker CT Lung Server

The ImageChecker CT Lung server operates in the background, automatically
accepting studies from the scanner (or PACS archive) and sending structured reports
to the review workstation. You do not need to directly interact with the server on a
regular basis. You only need to interact with it directly during periodic maintenance
by authorized service personnel or to manage the case queue when working with a
non-R2 workstation. The server has no display or external input devices (e.g.,
keyboard).
The server provides optional multi-workstation capability, enabling several
workstations to work with one ImageChecker CT Lung server.
The server does the following:
• Receives Exams – The server receives computed tomography (CT) exams via
DICOM from either a scanner or a PACS archive.
• Segments Anatomical Structures (CAD Process) – The processing application
takes the CT images and segments different anatomical structures into normal
structures (for example, vessels) and other composite features. Most cases will
have more than 100 composite features, consisting of any group of adjacent voxels
(volume elements) that have similar characteristics according to an established set
of criteria.
• Performs CAD – The processing application then applies the CAD algorithm and
searches for suspicious candidate thoracic abnormalities such as nodules. In
addition, if the exam was performed with intravenous contrast agents, the
algorithm also searches for low-density regions within vascular structures that may
indicate filling defects or other intravascular abnormalities.
• Provides DICOM Structured Report – The processing application stores the
location and characteristics of the segmented composite features in a DICOM
Structured Report and sends the CAD results to workstations via DICOM.
• Sends CAD Findings to PACS – The server may be configured to send its results to
a PACS archive via DICOM as a secondary capture series (with CAD marks and
information burned into images) or as a DICOM GSPS (grayscale softcopy
presentation state) overlay for later retrieval.

ImageChecker CT Lung Workstation

The ImageChecker CT Lung workstation application provides the interface between
the clinical user and the ImageChecker CT Lung System. It includes a high-resolution
LCD monitor, keyboard, and mouse. The application does the following:
• Receives CT exams via DICOM – The software either accepts CT exams from
acquisition devices or allows the user to execute a query via DICOM, usually to a
PACS archive.
• Presents a study list – The list contains the exams available for review and can
include prior studies. The individual study entries contain patient demographic
and study information that ensure the unambiguous identification of an exam.
The entries also indicate whether or not the study has been processed yet by the
server.

10 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 System Components

• Aids image review – The application presents a single screen that shows various
display representations:
2D Review Window – The original 2D axial images (slices). You will be able to
perform functions that are commonly available in other review workstations,
such as Window and Level, Pan, Zoom, Manual paging through the images,
and distance measurements. You can also choose to switch this view to a thick
slice or maximum intensity projection (MIP) view of the data.
Lung Map (Frontal Projection View) – An anterior-posterior coronal
projection view with the mediastinum and chest wall removed automatically.
You can interact with this image, which acts like a localizer. When your cursor
touches a point on the map, the 2D Review Window will display the slice from
the corresponding location.
3D Review Window – A neighborhood around a point that is selected by the
user in an axial slice. This 3D image presents an image that shows lungs, vessels,
airways and other objects within the lung parenchyma. You can rotate and
magnify this image to further analyze a suspicious finding.
• Allows region of interest and finding selections by user – This phase can occur in
conjunction with the image review or immediately after. During this phase, the
physician reviews the 2D axial images (slices) and selects a point considered to be a
region of interest. If this point is part of a composite feature found during the
preprocessing stage, the characteristics of the region (e.g., volume, average density)
are displayed. Based on experience, the reviewer can decide to mark the region as a
finding. If the selected point is not part of a composite feature, the reviewer can
perform distance measurements on it as well as obtain density values. This
information may help the reviewer decide whether or not to mark the feature as a
finding.
• Permits temporal comparison – With the optional AutoPoint temporal
comparison tool, the application displays the current and selected prior study
simultaneously and aligned. This screen provides all the 2D review tools, enables
you to link, either manually or automatically, the findings from the current and
prior, as well as add and discard findings.
• Aids in detection of pulmonary arterial filling defects – With the optional
pulmonary artery PE (Patency Exam) tool, the application highlights regions of
low density within the vasculature of the lung when the image is enhanced through
the use of contrast media. The screen presentation provides 2D and 3D review
tools plus reporting capability.
• Creates a summary – After reviewing the exam, the physician can review the
summary of the findings. Depending on the optional software packages you have,
this summary can include the summary of any temporal comparison or
pulmonary arterial filling defect detection performed. A physician or other user
can review all of the findings in a tabular form that includes all measurements
made for that point. For each finding you can also see the corresponding axial
image (slice) with an indicator showing the finding. You can print the summary
report on paper and attach it to the exam record or save the summary on the
workstation for later review.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 11

Part 2: Description

Other Components
The ImageChecker CT Lung System also comes with the following:
• Documentation (user and service)
• Licensing keys (one for each computer received from R2 Technology)
• Ethernet cables (for connecting the system to the LAN)

Key Features
While this section provides a list of the most prominent system features, it is not
exhaustive. For information on how to use the features described below, refer to the
ImageChecker CT Lung System User Manual.

Separate Image/CAD Processing

The system uses a separate CAD server that performs the CAD segmentation
processing of cases, allowing you to review other cases on the workstation during
processing. After the server computes the results, they are automatically forwarded to
the workstation, which displays all available cases and indicates their processing
status.

User-Controlled CAD Markers

By default, the application hides the CAD-generated markers until you are ready to
view them. When you finish your initial reading, you can turn the CAD markers on
and verify your own findings, or focus on areas you may have overlooked. Editing
tools let you confirm or discard the CAD markers. In addition, you can add and
delete user-defined findings.

Findings Automatically Quantified

The CAD processor automatically quantifies findings (with linear and volume
measurements) to help you make decisions about the finding’s clinical significance.

Flexible Algorithm
The R2 Technology CAD algorithm supports multiple multi-detector row computed
tomography vendors and acquisition protocols.

Integrated 2D and 3D Environment

To ease the interpretation of images, the user interface design provides an integrated
environment for 2D and 3D views.

Frontal Projection View (Lung Map)

You can also view a computed frontal (coronal) projection of the lungs that provides
an unobstructed view of the airways, lung vasculature, lung tissue, and any CAD
findings at a glance.

Selection of Review Tools

A wide range of 2D and 3D review tools, e.g., window leveling and Cine animation,
also make your job of viewing and interpreting the images easier.

12 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 Key Features

Complementary Data Views

The additional display modes enable the reader to switch between thin, thick, and
maximum intensity projection (MIP) views of the axial slices.

AutoPoint Temporal Comparison

This optional tool automatically selects and loads the most recent prior study to
compare to the current. Images can be synchronized manually or automatically, and
are presented together in a comparison screen. The system analyzes the images and
provides measurement data to allow you to assess volume change and doubling time.
The system provides a summary of the comparative data for all findings, and you can
print these or save them for future review.

Pulmonary Artery PE (Patency Exam)

The optional Pulmonary Artery PE (Patency Exam) tool analyzes the images and
provides indicators, upon physician request, to help identify possible filling defects of
the lung vasculature. The system provides a summary of the filling defects for all
findings as a column on the overall summary, and you can print these or save them
for future review.

Printable Summary Reports Can Include Key Images

The ImageChecker CT Lung System produces annotated summary reports that show
key images as well as the detected findings and their associated measurements. You
can print these reports and forward them to other care providers or save them for
future reference. You can also choose whether or not to include the key images on the
printed summary.

Easy to Use Database Search Tools

The ImageChecker CT Lung System provides you with a complete set of tools that
allow you to search and filter the local database, as well as any remote databases the
system is configured to recognize (e.g., an archive). You can also search for prior
reports both locally and on remote databases.

Simple Database Management Tools

An indicator shows you how much space is left on your local hard disk and a delete
button allows you to remove selected older, or unwanted studies.

PACS Integration and Multi-workstation Capability

A single ImageChecker CT Lung server can function with multiple R2-validated
workstations. In addition, the server can send the CAD results to a PACS archive as a
secondary series of images (DICOM SC) or as an overlay (DICOM GSPS). This
allows access to CAD results from all PACS workstations, which is essential for the
efficient workflow of clinicians.

Controlled Access
Everyone who uses the application must have a user ID and password in order to log
on to the workstation. This is a security measure to ensure that only authorized
personnel can use the application enhancing patient privacy.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 13

Part 2: Description

Queue Manager
The ImageChecker CT Lung server provides a queue manager that enables clinical
staff to monitor and manage the CAD segmentation processing of studies. You can
reprioritize, resend, and delete studies. The queue manager is available on the
workstation Study List, Server View screen.

CAD Algorithm Description

The CAD algorithm used by the ImageChecker CT Lung server is designed to assist
physicians in the detection of pulmonary nodules during review of multi-slice
(MSCT) examinations of the chest, by looking for and identifying solid, parenchymal
nodules in the lung tissue. The algorithm also identifies pleural-based nodules,
provided they project significantly into the lung.
The algorithm generally defines solid, parenchymal nodules as focal densities,
approximately spherical in shape, with smooth, lobulated, or spiculated boundaries
and with density near that of water. The algorithm also recognizes that although
pleural-based nodules are not, in general, spherical, their shape usually approximates
that of a portion of a sphere.
The algorithm does not look for non-nodular abnormalities (e.g., scars, atelectasis,
bronchiectasis) nor does it look for nodules or other abnormalities outside of the lung
parenchyma (e.g., in the mediastinum or in the chest wall).
Although, on any given slice, a nodule may appear to be a blood vessel, by also
considering a series of slices in proximity to the suspect slice, the algorithm can
measure and report the volume of any mass it finds. It also can differentiate between
nodules and blood vessels, based on shape, density, size, texture, connectivity
(between the slices), and other properties. This is a task that otherwise can be very
time consuming for a physician.
Shape analysis is almost exclusively performed in three dimensions. This means that
an object that appears very circular in a particular 2D axial slice may not be marked,
because in 3D it is very flat (i.e., sheet-like) or elongated (i.e., linear or tube-like).
The algorithm ranks its findings by likelihood and then segments those regions above
a fixed threshold of likelihood.
The algorithm is tuned to detect nodules that are at least 4 mm in diameter (although
under some circumstances, CAD will find and mark smaller nodules). Individual
slices in the target scan must be acquired at a thickness 0.5–3.0 mm. Slice thicknesses
outside this range can cause unpredictable results.
In addition, note that the algorithm relies on accurate segmentation in order to
process images properly. Factors affecting segmentation can result in a failure of the
ImageChecker CT Lung server to process images. Factors can include extreme diffuse
lung disease, field-of-view problems, foreign objects in the lung field, or any gross
deviation from normal anatomical appearance. For Pulmonary Artery Patency Exams
(described next), factors include poor contrast quality, interference with the ability to
detect the bifurcation of the bronchial tube, and severe respiratory or other motion
artifacts.

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 System Maintenance

For more details about the algorithm, see ‘Part 3: Scanning Protocol’ and the
Algorithm Description tab in the ImageChecker CT Lung User Manual.

CAD Process for Pulmonary Artery PE (Patency Exam)

The identification of low-density regions begins with a simple segmentation process.
The process first segments the pulmonary vascular trees using anatomical
information derived from segmentations of the lungs, mediastinum, airways, ribs and
other normal structures. The vascular segmentation uses morphological information
to ensure that nonvascular structures such as nodules, scars, and infiltrates are not
incorrectly classified as vascular. The algorithm attempts to distinguish pulmonary
arteries from veins in order to reduce the occurrence of findings on poorly-enhanced
pulmonary veins.
Following the standard segmentation of the vessels, the degree of contrast
enhancement is adaptively estimated from the image data and used with shape and
position information to identify regions of lower density than is expected of contrast-
enhanced blood. These low-density regions are further segmented into discrete
objects to produce a final set of regions of probable low density that may represent
filling defects.

System Maintenance
The ImageChecker CT Lung System is a software system and as such does not require
regular maintenance. On a regular basis, summary files are automatically saved to the
configured default archive.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 15

Part 2: Description

16 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

Part 3: Scanning Protocol
Scanning Specifications
Frequently Asked Questions

 Note: The specifications in Part 3 are subject to change as new applications are
available and/or the ImageChecker CT Lung System supports additional acquisition
protocols.
The ImageChecker CT Lung System consists of a processing unit server and a
software application for image display on a workstation. The system provides
flexibility in the acquisition of MSCT chest exams acceptable for processing and
visualization. The flexibility includes:
• Support of chest CT scans from multiple MSCT vendors with four or more
detectors.
• Support for a range of high-resolution CT protocols (see parameters below).
• Support of exams performed without or with intravenous contrast agents.
• For use with all indications for chest CT studies.
• Most MSCT chest exams can be reviewed on the workstation as soon as they are
completed/processed.

Scanning Specifications
The following statements define the acceptable acquisition protocol for applying the
CAD algorithms for lung-nodule detection and filling-defect analysis. Exceptions are
noted.

Input Data
ImageChecker CT Lung can display a wide range of chest CT exams, but to be eligible
for CAD processing, the acquisition protocols must meet the following requirements:
• Images acquired with a 4- or more detector MSCT scanner.
• Collimation of 3 mm or less that results in image reconstruction with slice
thickness of 3 mm or less (2 mm or less for filling-defect analysis) as reported by
DICOM Slice Thickness parameter (0018, 0050).
• Image spacing less than or equal to slice thickness (image overlap is acceptable, but
gaps are not).
• Slice thickness is the same throughout the series.
• Slice spacing is the same throughout the series.
• Tube voltage no less than 20 keV.
• Exposure no less than 15 mAs.
• Series containing lung should not have more than 1,000 images.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 17

Part 3: Scanning Protocol

• Minimal FOV is 18 cm.

• An input series must contain a single volumetric MSCT reconstruction;
scanograms or multiple reconstructions within a single series are not supported.
• Scans should be completed during a single held breath to avoid motion artifacts
and ensure optimal processing by ImageChecker CT Lung.

Field of View (FOV) Issues

• Whether the FOV is a square or a circle, it should not ‘clip’ the lung anatomy. If
this occurs, ImageChecker CT Lung will not preprocess the case.
• The entire intrathoracic cavity must be included, even if the patient has had prior
lung surgery (e.g., lobectomy, pneumonectomy).
• At this time ImageChecker CT Lung does not preprocess a lung case where the
targeted reconstruction shows only one lung.
• Cases with chest tubes, large amounts of fluid, or other gross abnormalities may
result in unexpected results in processing.

Reconstruction Filters
ImageChecker CT Lung accepts MSCT exams acquired with common acquisition
protocols. In particular, GE ‘Standard’, ‘Bone’ and ‘Lung’ reconstruction algorithms
(and their equivalent for other manufacturers) are allowed.
When comparing studies, always compare series that have been processed with the
same reconstruction filter, as automatic volume measurements may vary with
different filters.
Preliminary investigation has shown that the reconstruction algorithm does not affect
the CAD sensitivity; however the false-positive marker rate may vary with edge-
enhancing reconstruction algorithms

Support for Patient Orientations

ImageChecker CT Lung supports DICOM data that present images with the DICOM
Patient Position attribute (0018,5100) values HFS (Head First Supine) or FFS (Feet
First Supine); DICOM Image Orientation (Patient) attribute (0020,0037) has a non-
NULL value; and the DICOM Image Position (Patient) attribute (0020,0032)
indicates images stored in a Head First Supine format. Other values are not supported
at this time and the exams will not be accepted by the workstation for review or
preprocessing.

Contrast Support
ImageChecker CT Lung accepts exams with and without intravenous contrast media.
The CAD algorithms perform equally well in exams with and without intravenous
contrast media. Note that contrast medium is required for Perfusion Exam analysis.

Minimum Lung Z-Range

In order to preprocess the case for 3D or for CAD, the exam needs to include a
minimum of 3 cm of lung in the z-axis direction.

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 Scanning Specifications

Merged Exams
ImageChecker CT Lung supports continuous volumetric reconstructions. It does not
support series that are the result of merging two acquisitions that result in two or
more slices on the same location or nonuniform image spacing.

Gated Exams
ImageChecker CT Lung does support MSCT exams acquired with cardiac gating.
CT lung scans should be completed during a single held breath to avoid motion
artifacts and ensure optimal processing.

Number of Detectors in the Scanner

ImageChecker CT Lung has been qualified for input data acquired with MSCT
scanners with four or more detectors. Support for Spiral/Helical scanners with single
or dual detectors is not available at this time. This applies to Electron Beam CT
(EBCT) as well.

Gantry Tilt
Indications for chest MSCT exams with gantry tilt are rare and ImageChecker CT
Lung will reject such exams for processing or review.

DICOM Fields
ImageChecker CT Lung will reject exams where the following DICOM fields are
empty. This is an uncommon scenario for patient scanning but the customer is
reminded that these fields must be filled in either by the technologist or by the
scanner:

Tag Name Tag ID

Patient Name 0010,0010
Patient ID 0010,0020
Modality 0008,0060
Referring Physician 0008,0090
Photometric Interpretation 0028,0004
Bits Allocated 0028,0100
Samples Per Pixel 0028,0002
Patient Position 0018,5100
Slice Thickness 0018,0050
Image Orientation (Patient) 0020,0037
Image Position (Patient) 0020,0032

The DICOM conformance statements for the R2 ImageChecker CT Lung workstation

and server contain information about acceptable values for the DICOM attributes
supported.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 19

Part 3: Scanning Protocol

Body Part Value

ImageChecker CT Lung supports the following Body Part Examined DICOM
attribute values: CHEST, ABDOMEN, BREAST, THORAX, MEDIASTINUM or if the
Body Part Examined attribute has a NULL value.

Compressed Images
ImageChecker CT Lung does not accept images that have been subjected to
compression (lossy or lossless).

Frequently Asked Questions

What happens when one of the above conditions is not met?
The ImageChecker CT Lung System consists of software, a preprocessor server, and
display workstation (the workstation may be provided by R2 Technology or an R2-
approved third-party partner). Usually the display workstation software is very
flexible and will accept the exam, and the user is able to use all review tools as the user
would in a scanner console or review station. However, segmentation information or
CAD results will not be available.

Can a CTA exam be used for CAD lung nodule detection in ImageChecker CT Lung?
Yes. The presence of intravenous contrast media is taken into consideration by the
CAD algorithm in the automatic detection process as long as the other scanning
protocol criteria are met.

Can ImageChecker CT Lung be used with MSCT lung cancer screening exams?
Yes, as long as the exams meet the input parameters described above.

Are there limitations if the study contains localizers (scanograms)?

These cases can be accepted for processing and review.

What about patients with staples or other metallic objects in the thorax or
mediastinum?
These cases are acceptable for review and will be preprocessed for 3D and CAD if they
are acquired with scanning techniques that minimize the presence of artifacts.

What is the minimum vessel diameter in which the CAD algorithm will detect
filling defects?
Four (4) mm

Are any of the limitations subject to change?

We are continuously evaluating the use of ImageChecker CT Lung and the evolving
nature of the acquisition protocols. Based on customer feedback, we will consider
making changes in subsequent releases to accommodate newer clinical applications.

20 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

Part 4: Clinical Studies
Objectives
Clinical Study Sites and Cases
Study #1 – Identification of Reference Truth
Study #2 – Accuracy Improvement Through Use of CAD
Study #3 – Measurement of CAD Algorithm

Part 4 describes the clinical studies submitted to the United States Food and Drug
Administration (FDA) for approval of the ImageChecker CT Lung System.

Objectives
R2 Technology, Inc. has conducted three pivotal clinical studies to evaluate the safety
and effectiveness of the ImageChecker CT Lung System. The studies were based on a
retrospective case collection project involving multiple clinical sites in various regions
across the United States. The clinical studies had the following objectives:
• The first study was designed to generate a ‘truth’ set of cases containing solid
pulmonary nodules, as well as cases with no nodules, to be used as a reference
truth for subsequent studies.
• The second study, conducted in two phases, was an Observer/ROC (Receiver
Operating Characteristic) Study designed to measure the performance
enhancement of radiologists using the system.
• The third study was a retrospective study to characterize the stand-alone sensitivity
of the CAD software.
The clinical studies did not attempt to assess the effectiveness of the device on an
asymptomatic lung cancer screening population. The applicability of this device to
such a CT screen population has not been established.

Clinical Study Sites and Cases

Five (5) regionally diverse sites contributed 151 cases to the studies: two sites in the
northeast states and one site each from the South, Midwest, and West. Of these sites,
three were private imaging centers and two were academic medical centers (see
Table 1).
All cases were acquired consecutively from the sites’ digital archives according to the
inclusion and exclusion criteria identified in the case collection protocols.
The nodule-present cases collected included only those in which a diagnosis of
cancer, either primary lung cancer or an extrathoracic neoplasm, had been
documented. Other coexisting disease processes resulting in the formation of nodules
(e.g., TB, histoplasmosis, rheumatoid lung) were allowed, as were cases containing
other underlying pathology such as lobar pneumonia, emphysema, and heart failure.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 21

Part 4: Clinical Studies

A total of 63 nodule-present cases dating from November 2001 through December

2002 were included in the studies. The study population consisted of 56% females
and 44% males, with a median age of 66 (range 20–86). The malignancies consisted of
primary lung cancer in 24 (38%) of these cases, and documented extra-thoracic
primary cancer with suspected metastatic disease of the lung in the remaining 39
(62%) cases. Forty-six percent (46%) of the exams were performed following
injection of intravenous contrast media.
The nodule-absent cases collected were those in which no nodules were deemed to be
present by the principal investigator at each site. In all, 88 nodule-absent cases dating
from June 2002 through December 2002 were included. This group consisted of 53%
females and 47% males, with a median age of 55 (range 18–85). Other disease
processes could be present, including the presence of pulmonary masses larger than
3 cm. Patients with histories of cancer, radiation therapy, or even previous
thoracotomy, were allowed. Fifty-two percent (52%) of the exams included
intravenous contrast media.

Table 1: Sites Contributing CT Chest Cases

Number of Nodule- Number of Non-
Present Cases Used Nodule Cases Used Total
Name State in Studies in Studies Cases
Atlantic Medical Imaging NJ 11 10 21
MRI & CT Diagnostics VA 15 23 38
South Jersey Radiology NJ 14 35 49
University of Iowa IA 18 9 27
UC San Francisco CA 5 11 16
Total 63 88 151

Study #1 – Identification of Reference Truth

The objective of this study was to generate a ‘truth’ set of unanimous actionable
nodules, as identified by a panel of three experienced radiologists (‘Reference Truth
Panel’), to serve as a reference truth for all subsequent studies.
To achieve this objective, multiple panel sessions were scheduled in which three
radiologists independently read a variable number of cases (minimum 12,
maximum 25) until all 151 study cases had been independently interpreted by all
three readers.
The Reference Truth Panel identified a total of 142 findings in the 151 cases that met
the size (4–30 mm) and peak density (greater than –100 HU) requirements, and
which all three panelists agreed were actionable. We define this set of findings as solid
actionable nodules. The presence or absence of at least one of these findings in a
quadrant was used as the reference truth for Study #2 below.
The findings ranged in size from 4–28 mm. The majority of were between 4–8 mm in
diameter (46%, 66/142), with the largest categories being the 5–6 mm (15%, 21/142)
and 6–7 mm (15%, 22/142) findings.

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 Study #2 – Accuracy Improvement Through Use of CAD

Study #2 – Accuracy Improvement Through Use of CAD

The objective of this study was to demonstrate that review of CAD output improves
performance of radiologists reviewing MSCT with respect to their ability to accurately
identify actionable nodules. The study employed a receiver operating characteristic
(ROC) methodology.
Ninety (90) cases were randomly selected from the 151 cases in a stratified manner.
The cases were divided into four quadrants, yielding 360 regions for evaluation. Each
of 15 radiologists independently reviewed the 360 quadrants, first without computer-
aided detection (CAD) and then immediately with CAD. The results of this study
were used for all of the final analyses of the data.
Each reader rated each quadrant on a 0–100 ‘actionability scale’ as to his or her level
of confidence that the quadrant contained at least one actionable nodule. Ratings
were provided both before and after viewing the CAD marks.
For purposes of measuring reader performance, quadrants were defined as
‘actionable’ if the Reference Truth Panel described in Study #1 unanimously agreed
that at least one of the findings in the quadrant was (1) a solid lung nodule and (2)
actionable (i.e., required intervention or short-term follow-up). Otherwise, the
quadrant was defined as non-actionable for the purpose of ROC analysis.
Before describing the statistical analysis, one example case is given. The following
figure shows a case where the CAD software identified a nodule that was initially
missed by four radiologists.

Pos –221.3 Pos –223.3 Pos –225.3

Case Example of a Missed Nodule Where CAD Reduced Misses

The patient was a 67-year-old male, with a history of bladder cancer. A small 4.4 mm
noncalcified nodule was present in the right lung, in the lower quadrant, marked by
the CAD algorithm. Only eleven of the 15 radiologists rated that quadrant as
containing an actionable nodule in their initial review, whereas three more
radiologists increased their ratings after viewing the CAD marks.
The area under the receiver operator curve (AUC) was computed for each of the 15
radiologists before and after using CAD. The average curve of all 15 radiologists is
shown below for the 90-case study. The AUC increased with the use of CAD. If the
full plot is viewed as a unit square, the area separating the two curves in the Phase II
study is 0.024.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 23

Part 4: Clinical Studies

Average ROC Curve Showing Pre-CAD (dashed line) and Post-CAD (solid line)

The primary analysis of statistical significance was based on the Dorfman-Berbaum-

Metz (DBM) ANOVA-after-jackknife approach1 (adapted for the fact that the
quadrants represent ‘clustered’ data). The results are presented in Table 2.
The average reader improvement in AUC (estimated using the ANOVA-after-
jackknife) was 0.0240 ± 0.0077 (p = 0.0033) with a 95% confidence interval of
(0.0084, 0.0395). Thus, the study showed that use of CAD resulted in a statistically
significant improvement in the area under the ROC curve.
Secondary analyses of statistical significance were conducted to determine the
dependence of the study results on the use of the consensus reference truth from
Study #1 for ROC evaluation. This was done since a reference truth based on a
consensus panel assessment of actionability is weaker than one based on biopsy.
The first of these variations in the reference truth involved using the findings
identified by at least two of the three members of the Reference Truth Panel in
Study #1 (n = 310 findings). The ANOVA-after-jackknife analysis was recomputed,
producing the results shown in Table 2. The average reader improvement in AUC was
again statistically significant.
To further examine the effect of variability in the unanimous three-panelist Reference
Truth Panel, three-, two-, and single-panelist reference truths were constructed from
the data collected in Study #1. Implementing this variable truth is difficult within the
framework of the ANOVA-after-jackknife analysis; therefore the secondary analysis
employs a bootstrap analysis.2 The bootstrap is a computationally intensive non-
parametric method that allows complex analyses to be repeated many times using
different randomly generated datasets (all based on the original data) to approximate
the variability that would occur if the entire study was repeated many times. As a test

1. Dorfmann DD, Berbaum KS and Metz, CE. Receiver Operating Characteristic Rating
Analysis. Invest Radiol 1992; 27: 723-731.
2. Rutter, C. Bootstrap Estimation of Diagnostic Accuracy with Patient-Clustered Data. Acad
Radiol 2000; 7: 413-419.

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 Study #2 – Accuracy Improvement Through Use of CAD

of the validity of the bootstrap mechanism, the analysis was performed first using the
unanimous reference truth. As shown in Table 2, the results of the primary ANOVA-
after-jackknife analysis and the bootstrap analysis using the unanimous reference
truth are very similar.

Table 2: Study analyses of the significance of the improvement in area under ROC curve
when reference truth or statistical methods were varied.
Estimated
Improvement
Analysis Method in AUC p-value 95% CI
Primary: ANOVA-after-jackknife, 0.0240 0.003 (0.0084, 0.0395)
with unanimous reference truth
Secondary: ANOVA-after-jackknife, 0.0213 0.001 (0.0097, 0.0329)
with 2/3 majority reference truth
Secondary: Bootstrap with 0.0246 <0.001 (0.0089, 0.0446)
unanimous reference truth
Secondary: Bootstrap with random 0.0224 <0.001 (0.0076, 0.0403)
3-panel reference truth
Secondary: Bootstrap with random 0.0216 0.002 (0.0077, 0.0387)
2-panel reference truth
Secondary: Bootstrap with random 0.0209 <0.001 (0.0080, 0.0370)
1-panel reference truth

Several approaches were used, based on the bootstrap resampling approach, to

incorporate random reference truths for the random cases against which the random
readers’ performance could be estimated. Based on varying the reference truth in this
way, the average reader improvement in AUC (estimated using the 1000 bootstrap
samples with variability in the reference truth) ranged from 0.0209–0.0224, as shown
in Table 2. Thus again, the results with the varied random reference truth showed a
statistically significant improvement in the area under the ROC curve with the use of
CAD.
An additional secondary analysis was performed to determine if the effect of the
presence or absence of intravenous contrast in the cases affected the overall study
results. The ROC primary ANOVA-after-jackknife analysis (based on the unanimous
Reference Truth Panel findings) was redone, stratifying the 90 cases into those that
included contrast and those that did not. Analysis of both the 45 no-contrast and 45
contrast media cases showed improvement with CAD (delta AUC for each set of cases
was greater than 0.02).

Finally, an analysis at the patient level, rather than at the quadrant level, was
conducted to determine if there was evidence to show a positive effect of the use of
CAD using a methodology closer to the clinical use of the product.
Each case in the study was assigned to one case cohort based on what truth nodules
were present (depending on the definition of the ‘truth’ reference standard). For
example, cases that contained at least one unanimous actionable nodule were placed
in a case cohort that would be considered true nodule-present cases. Each case was
also assigned a rating of ‘actionable’ if at least one quadrant had a rating of 50 or
greater (on our 0–100 scale). A threshold of 50 was chosen based on the way the

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Part 4: Clinical Studies

readers were instructed to use the scale (a rating of 50 was ‘indeterminate’) and the
actual ratings data showed a bimodal distribution, with most ratings clearly above 50
or below 50. Thus, we can calculate the effect of CAD at the patient level in terms of
reduction in observational oversights (i.e., the number of times a patient had a rating
change from below 50 pre-CAD to above 50 post-CAD in a case that contained a
truth nodule) and change in the false-positive rate (the same ratings change for a
patient with no nodules). This analysis showed that, at the case level, there were 22
corrections of 86 oversights (25.6%) and an increase in the false-positive rate (8
increases in 57 cases; 14.0%).
In summary, the primary analysis of the ImageChecker CT Lung System study shows
a statistically significant improvement in the AUC for an ROC analysis for detecting
solid pulmonary nodules between 4–30 mm in diameter. This result is robust when
different reference truth definitions are used in the analysis.

Study #3 – Measurement of CAD Algorithm

The objective of this study was to test that the ImageChecker CT Lung System can
mark solid pulmonary nodules equal to or greater than 4 mm in size with a high level
of sensitivity and a low number of false marks per normal case. The CAD software is
designed to specifically identify solid, spherical nodules whereas radiologists identify
many other actionable findings (e.g., ground-glass opacities), some of which were
included in the set of 142 nodules from Study #1.
To evaluate the performance, all 142 unanimous actionable solid nodules arising
from Study #1 were first independently shown to a new panel of five radiologists (the
‘Nodule Classification Panel’), each with a minimum of six months experience
reading MSCT of the chest. The radiologists were asked to categorize each finding
according to its three-dimensional appearance, and how closely that appearance
approximates a classic pulmonary nodule. The definition of ‘nodule’ was taken from
a standard text3, and the term ‘classic’ was as pictured in the same text4. Again, the
descriptor ‘solid’ referred to a nodule with a peak density greater than –100 HU.
After all 142 reference truth nodules were reviewed by the Nodule Classification
Panel; each candidate nodule was then categorized based on how many of the five
Nodule Classification Panel radiologists rated it as classic. The subset of pulmonary
nodules deemed to be classic in appearance (‘classic nodules’) by at least 4 of the 5
readers (n = 64) was defined as the primary target population for testing purposes.
All 151 cases were analyzed by the ImageChecker CT Lung System, and an automatic
scoring tool matched the CAD marks with the locations of the nodules. The CAD
sensitivity results are shown in Table 3. The accompanying false marker rate, as
measured on cases with no reference truth nodules, was a median of two marks per
case.

3. Fraser RS, Muller NL, Colman N, Paré PD, Eds. Fraser and Paré’s Diagnosis of Diseases of
the Chest, Fourth Edition, Volume 1. W.B. Saunders, Philadelphia, 1999: page xxxv. The
definition is: ‘Round opacity, at least moderately well marginated and no greater than 3 cm
in maximum diameter.’
4. ibid, Figure 18–31, page 458.

26 Understanding the ImageChecker CT Lung System – PN 13229 Rev A

 Study #3 – Measurement of CAD Algorithm

Table 3: CAD Stand-alone sensitivity numbers for nodules based on classic ratings.
Nodule Classification
Panel Members Rating # of CAD 95% Lower 95% Upper
Nodule as Classic Nodules Sensitivity* Limit Limit
4/5, 5/5 ‘classic’ 64 83% 73% 92%
3/5 13 69% 44% 94%
0/5, 1/5, 2/5 65 32% 21% 44%

*CAD Sensitivity is defined as the number of nodules marked by CAD divided by the total
number of nodules in each category.

A further analysis of the case sensitivity for cases with and without intravenous
contrast media showed consistent results in the cases with contrast compared to the
cases without contrast. The sensitivity for the classic nodules in cases with contrast
was 94% (16/17, 95% CI 83–100%) and for the classic nodules without contrast was
79% (37/47, 95% CI 67–90%). The sensitivity for the solid nodules in cases with
contrast was 55% (34/62, 95% CI 43–67%), and in cases without contrast was 61%
(49/80, 95% CI 51–72%). The false-marker rate measured on the nodule-absent cases
was the same in both groups and the same as the summary numbers above.
These results confirm that the ImageChecker CT Lung System performs at a high
level of sensitivity for classic pulmonary nodules, with low false-marker rates per
normal case.

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 27

Understanding the ImageChecker CT Lung System – PN 13229 Rev A 28
R2 Technology
1195 West Fremont Avenue
Sunnyvale, CA 94087 USA
www.r2tech.com PN 13229 Rev A