vascuCAP: Non-invasive Computer-Aided Phenotyping of Vasculopathy
Conditions: Carotid Atherosclerosis, Peripheral Arterial Disease
Sponsor: Elucid Bioimaging Inc.

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vascuCAPTM 
Q-CAMP: Quantitative CArdiovascular 
Magnetic Resonance Imaging and 
Profiling of Atherosclerotic Lesions 
Seeing Beyond the Image in Vascular Disease 
 
 
 
 
 
 
 
Program Reference Number: 0305  
Clinical Principal Investigator:  Malachi G. Sheahan III, MD 
Elucid Principal Investigator:  Andrew J. Buckler, MS 
LSUHSC-NO Institutional Review Board 
Federal Wide Assurance 00002762 Registration #  00000177 
Draft or Version Number:  2.0 
12 March 2014 

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                i 
COPYRIGHT 
Copyright © 2014 Elucid Bioimaging Inc.  All rights reserved. 
The material presented in this document and contained herein is proprietary and confidential to 
Elucid Bioimaging Inc. and its subsidiaries and is intended for Elucid Bioimaging Inc. and its 
client use only.  The material is to be used for the purpose for which it was delivered or made 
available to you subject to the terms and conditions (if any) of applicable licenses.  Each User 
shall maintain the confidentiality of the material and shall not disclose, distribute, reproduce, or 
otherwise disseminate, in whole or part, any part of this document or the information contained 
herein to any third party, without the prior written permission of Elucid Bioimaging Inc.  Any 
unauthorized use or disclosure of this document or the information contained herein, including 
any resale, reproduction, or any attempt to do so, is strictly prohibited. 
“Elucid” is a trademark of Elucid Bioimaging Inc.  All other trademarks are the property of their 
respective owners. 
 
STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the NHLBI Clinical Terms of Award.  All 
personnel involved in the conduct of this study have completed human subjects protection 
training.   

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REVISION RECORD 
Rev 
No. 
Date 
Author 
Description 
1.0 
20 Dec 
2013 
Andrew J. 
Buckler  
First version submitted for FDA review and starting point for 
filling in operational details. 
2.0 
12 Mar 
2014 
Andrew J. 
Buckler  
Formal approval copy for IRB which incorporates FDA 
feedback and fleshes out operation details for start of study. 
 

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TABLE OF CONTENTS 
 
 
PAGE 
COPYRIGHT ............................................................................................................................... I 
STATEMENT OF COMPLIANCE ................................................................................................. I 
REVISION RECORD .................................................................................................................. II 
SIGNATURE PAGE ................................................................................................................... III 
TABLE OF CONTENTS ............................................................................................................ IV 
LIST OF ABBREVIATIONS ........................................................................................................ V 
PROTOCOL SUMMARY .......................................................................................................... VII 
1 
KEY ROLES AND CONTACT INFORMATION ................................................................... 1 
2 
INTRODUCTION:  BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........ 2 
2.1 
Background Information .......................................................................................... 2 
2.2 
Rationale ................................................................................................................ 3 
2.3 
Potential Risks and Benefits ................................................................................... 4 
2.3.1 
Risks ........................................................................................................... 4 
2.3.2 
Benefits ....................................................................................................... 4 
2.3.3 
Risk to Benefit Ratio .................................................................................... 4 
2.3.4 
Therapeutic Alternatives .............................................................................. 5 
3 
OBJECTIVES ..................................................................................................................... 6 
3.1 
Study Objectives ..................................................................................................... 6 
3.2 
Study Outcome Measures ...................................................................................... 6 
4 
STUDY DESIGN ................................................................................................................ 7 
5 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................... 8 
5.1 
Subject Inclusion Criteria ........................................................................................ 8 
5.2 
Subject Exclusion Criteria ....................................................................................... 8 
5.3 
Subject Withdrawal ................................................................................................. 9 
5.4 
Premature Termination or Suspension of Study ...................................................... 9 
5.5 
Costs to Subjects .................................................................................................... 9 
6 
STUDY SCHEDULE ......................................................................................................... 10 
6.1 
Screening Visit (Day -28 to -1) .............................................................................. 10 
6.2 
Enrollment/Baseline Visit (Visit 1, Day 0) .............................................................. 10 
6.3 
Imaging Visit (Day 0-29) ....................................................................................... 11 
6.4 
Histopathology for Patients Undergoing Surgery within 30 Days of MRI ............... 12 
7 
SAFETY MONITORING ................................................................................................... 14 
7.1.1 
Unanticipated Problems ............................................................................ 14 
7.1.2 
Serious Adverse Events ............................................................................ 14 
7.2 
Reporting Procedures ........................................................................................... 15 
8 
STATISTICAL ANALYSIS ................................................................................................ 16 
8.1 
Aim I ..................................................................................................................... 16 
8.2 
Aim II .................................................................................................................... 19 
8.3 
Aim III ................................................................................................................... 20 
LITERATURE REFERENCES .................................................................................................. 21 
 

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LIST OF ABBREVIATIONS 
ADC 
Apparent Diffusion Coefficient 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CSOC 
Clinical Study Oversight Committee 
DCC 
Data Coordinating Center 
DCE 
Dynamic Contrast Enhanced 
DHHS 
Department of Health and Human Services 
DSMB 
Data and Safety Monitoring Board 
DWI 
Diffusion Weighted Imaging 
ESS 
Endothelial Shear Stress 
Fast SE 
Fast Spin Echo 
FFR 
Federal Financial Report 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
MOP 
Manual of Procedures 
MRI 
Magnetic Resonance Imaging 
N 
Number (typically refers to participants) 
NHLBI 
National Heart, Lung, and Blood Institute, NIH, DHHS 
NIH 
National Institutes of Health 
NLDR 
Non-Linear Dimensionality Reduction 
OHRP 
Office for Human Research Protections 
OHSR 
Office of Human Subjects Research 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 

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SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
SS-EPI 
Single Shot Echo Planar Imaging 
TOF 
Time of Flight 
TSE 
Turbo Spin Echo 
US 
United States 

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PROTOCOL SUMMARY 
Title: 
Q-CAMP: QUANTITATIVE CARDIOVASCULAR MAGNETIC 
RESONANCE IMAGING AND PROFILING OF ATHEROSCLEROTIC 
LESIONS 
Précis: 
We use MRI to evaluate the extent, as well as, the structure, composition, 
and functional aspects of atherosclerotic plaques in human carotid and 
femoral arteries in patients scheduled to undergo an endarterectomy of the 
aforementioned vascular beds as part of their routine clinical care. The 
endarterectomy specimens removed at surgery will allow a direct 
comparison between the MRI information obtained prior to the surgery and 
the histopathological analyses of the arterial specimens. The vascuCAPTM 
measurements of structural and functional features of the arterial wall will 
be performed in patients undergoing endarterectomy. Measured results will 
be compared in a blinded fashion with histology to assess performance of 
plaque profiling and build a pilot prediction model for risk scoring. 
Objectives: 
Primary: 
I. 
Measure the bias, precision, and reproducibility of each of the functional 
analytes as measured by vascuCAPTM with respect to histopathologic 
results as ground truth, and assess their linear region and limits of 
quantitation. 
II. 
Establish 
performance 
characteristics 
of 
the 
structural 
and 
hemodynamic analytes, where an objective truth standard is lacking. 
Secondary: 
III. 
Classify the target lesion according to whether the analytes suggest it is 
not a plaque, or if it is, which of the 8 AHA types best fits the analyte 
profile.  Assess the accuracy of vascuCAPTM’s classification against the 
histopathology classification.   
Population: 
>=110 patients (80 carotid patients, and 30 femoral patients) scheduled for 
endarterectomy. 
Sites: 
1. West Jefferson Medical Center, 1101 Medical Center Blvd, Marrero, LA 
70072, (504) 347-5511 
2. LSU ILH, 2021 Perdido St, New Orleans, LA 70112, (504) 903-3000 
This study will be conducted within the LSU Department of Vascular 
Surgery at the above stated locations. Patients will be seen throughout the 
length of the study in both hospital and clinic settings.  
Study 
Duration: 
18 months for primary and secondary objectives. 
Estimated Time 
to Complete 
Enrollment: 
12 months 

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viii 
 
Schematic of Study Design: 
 
 
 
Up to 150 patients:  Obtain informed consent. Screen potential participants by 
inclusion and exclusion criteria; obtain history, document.
Enrolled patients will undergo pre-surgical MRI and standard of care evaluation and 
management.  Patients 1-75 further evaluated by Elucid staff using by vascuCAPTM, 
patients 76-150 evaluated using by vascuCAPTM by clinical site staff.
Operate  
within 30 
days of 
vascuCAPTM
evaluation ?
Final Assessments
I.
Bias, precision, and reproducibility of each of the 
functional analytes as measured by vascuCAPTM.
II.
Performance characteristics of the structural and 
hemodynamic analytes.
III. Accuracy of vascuCAPTM classification of target 
lesion by AHA type.
Histology will be collected and read from 75 surgical 
patients for use as a training set. 
Histology will be collected and read from >=35 surgical 
patients in a blinded fashion, with analysis and reporting 
of Aims I and II and as additional training data for Aim III
Patients who did not go to surgery within 30 days of 
vascuCAPTM evaluation will be entered into a registry
No
Yes

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1 KEY ROLES AND CONTACT INFORMATION 
LSUHSC Principal 
Investigator:   
Name: MALACHI G. SHEAHAN III, MD  Title: Program Director, 
Vascular Surgery, Associate Professor of Surgery and Radiology  
Louisiana State University Health Sciences Center New Orleans, LA 
Location:  LSHSC Phone: (504) 412-1960 
E-mail: MSHEAH@LSUHSC.EDU  
Elucid Principal 
Investigator:   
Name: ANDREW J. BUCKLER  Title: President 
Elucid Bioimaging Inc. 
Location: 225 Main Street, Wenham, MA  01984 Phone: (978) 468-
0508 
E-mail: ANDREW.BUCKLER@ELUCIDBIO.COM Fax: (978) 468-0527  
Co-Investigators: 
 
Robert Batson, M.D. , Tapash Palit, M.D. , Bruce Torrance, M.D. , Jodi 
Gerdes, M.D. , Larry Hollier, M.D.   
Institutional 
Review Board: 
LSUHSC-NO Institutional Review Board, Federal Wide Assurance 
00002762 Registration #  00000177 
Other Key 
Personnel: 
Co-investigator for Statistical Analysis: 
Name: NANCY A. OBUCHOWSKI  Title: Vice Chairman 
Quantitative Health Sciences 
Cleveland Clinic Foundation, JJN3 
Location: 9500 Euclid Ave, Cleveland, OH 44195 Phone: (216) 
217-1133 
E-mail: OBUCHON@CCF.ORG   

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2 INTRODUCTION:  BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
MRI is a safe, painless, and non-invasive way to image the body interior without harmful 
radiation. MRI provides superior information to conventional imaging studies because it can 
provide additional information regarding the chemical makeup of the atherosclerotic plaque. We 
have recently conducted imaging studies in a specialized rabbit model of atherosclerosis [1-5] 
that have served as a scientific rationale for the development of a computerized image analysis 
toolkit, vascuCAP™ [6]. 
2.1 
Background Information 
The purpose of this study is to determine the magnetic resonance imaging characteristics of 
clinically symptomatic, atherosclerotic plaques and compare them to histopathological analyses 
of arterial endarterectomy specimens obtained after surgery. Atherosclerosis is a response to 
chronic vascular injury that results in a dysregulated, vascular inflammation fundamentally 
associated with abnormalities of lipid metabolism. Current commonly employed modalities 
utilized to image atherosclerosis, such as invasive catheterization, fail to identify plaque 
components and poorly predict the likelihood of the plaque to produce acute ischemic events 
(instability). MRI provides unparalleled soft-tissue resolution non-invasively and has the 
potential to characterize plaque structural and functional components without invasive 
procedures.  
Table 1: Analytes interrogated by vascuCAPTM, understood as a multiplex assay 
Analyte 
Description 
Type and Units 
Truth Standard 
Lipid Core 
Distinguished by presence of lipids, 
intermixed with extracellular matrix 
fibers, and/or necrotic tissue. 
Expressed by burden in mm3 
and categorical variables for 
degree and uniformity using a 
0/1/2 scale. 
Histopathology 
considered as 
ground truth. 
Fibrosis 
Intimal presence of dense, 
homogeneous/organized collagen 
extracellular matrix with smooth muscle 
cells/fibroblasts embedded therein, but 
no appreciable lipid or necrotic tissue. 
Expressed by volume in mm3 
and categorical variables for 
degree and uniformity using a 
0/1/2 scale. 
Histopathology 
considered as 
ground truth. 
Intra-plaque 
hemorrhage 
Presence of erythrocytes in the deeper 
regions of the plaque, with or without 
communication to the lumen or 
neovasculature. 
Expressed by burden in mm3 
and confidence in %. 
Histopathology 
considered as 
ground truth. 
Inflammation 
Accumulations of macrophages and 
lymphocytes in the deeper regions of 
the plaque that may bridge the 
neointima, and the media of the vessel 
Expressed by burden in mm3 
and categorical variables for 
degree and uniformity using a 
0/1/2 scale. 
Histopathology 
considered as 
ground truth. 
Vascular Leak 
Composed of endothelial permeability, 
neovascularization, necrosis, and 
collagen breakdown.)  
Expressed by distribution 
volume in mm3 and categorical 
variables for degree and 
uniformity using a 0/1/2 scale. 
Histopathology 
considered as 
ground truth. 
Calcification  
Intimal/medial presence of calcification 
with osteoblasts present therein, but 
Expressed by burden in mm3 
and categorical variables for 
Histopathology 
considered as 

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Analyte 
Description 
Type and Units 
Truth Standard 
containing no appreciable lipid or 
necrotic tissue. 
degree and uniformity using a 
0/1/2 scale. 
ground truth. 
Remodeling 
Ratio 
Calculated as the ratio of vessel area 
with plaque to reference vessel wall 
area without plaque 
Expressed with value less than 
1 for inward remodeling and 
greater than 1 for outward 
remodeling 
Calculations from 
manual contour by 
radiologist as an 
imperfect(subjective) 
reference standard  
% Stenosis 
Calculated as the 1 - (ratio of lumen 
area with plaque to reference lumen 
area without plaque) x100 
Expressed as percentage > 0 %. 
Calculations from 
manual contour by 
radiologist as an 
imperfect(subjective) 
reference standard. 
(maximum) 
Wall 
Thickness 
Calculated by measuring the largest 
thickness of wall  
Expressed in units of mm 
Calculations from 
manual contour by 
radiologist as an 
imperfect(subjective) 
reference standard 
Endothelial 
Shear Stress 
(ESS) 
Tangential stress derived from the 
friction of flowing blood on the vascular 
endothelium surface and is ESS is 
proportional to the product of the blood 
viscosity and the spatial gradient of 
blood velocity at the wall (ESS=dv/dy).  
Expressed as force/unit area 
(N/m2 or Pascal or dyne/cm2). 
Magnitude that ranges from 15 
to 70 dyne/cm2 over the cardiac 
cycle and yields a positive time 
average. 
Literature ranges to 
establish plausibility 
(no truth standard 
applied in lieu of 
independent 
measurement 
modality). 
2.2 
Rationale 
We hypothesize that in vivo MRI examinations of patients, when suitably acquired and analyzed 
with the vascuCAP™ analysis software, can provide a sufficiently accurate profile of plaque 
characteristics to provide an objective basis for patient management. 
We propose to use MRI to evaluate the extent, as well as, the structure, composition, and 
functional aspects of atherosclerotic plaques in >=110 patients (80 carotid patients and 30 
femoral patients) scheduled to undergo an endarterectomy of the aforementioned vascular beds 
as part of their routine clinical care. These patients will be undergoing endarterectomies to 
mitigate their clinical risk or symptoms for things such as strokes, claudication, and critical limb 
ischemia. The endarterectomy specimens removed at surgery will allow a direct comparison 
between the MRI information obtained prior to the surgery, and the histopathological analyses of 
the arterial specimens. All patients will undergo a MRI examination within 30 days of the 
surgical procedure. Histological samples will be analyzed to identify neovascularization, intra-
plaque hemorrhage, collagen types, necrotic core, and other hallmarks of plaque severity. 
Histology and MRI will be co-registered, step-sectioning through the endarterectomy specimen 
using the suture-marked proximal and distal ends and anterior face as the anatomical markers. 
We create ground truth maps from histology of the excised specimens with the pre-operative 
MRI. This allows for careful mapping of the precise extent of plaque from the corresponding 
pathologic lesion onto the in vivo imaging. This will allow for careful training and testing of the 
image based classifiers to identify and characterize the plaque regions. Study duration, from 

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IRB approval through analysis and close of study is expected to require approximately 18 
months, with 12 months targeted for subject enrollment and acquisition of samples, and 6 
months to complete analyses and reporting. 
2.3 
Potential Risks and Benefits 
2.3.1 
Risks  
There will be no additional risk to the patients enrolling within this study as no addition 
procedures or imaging will be required. Standard of care clinical workup, disease assessment, 
procedures, and surgical treatment will occur. Risks to patient confidentiality will be mitigated by 
de-identifying all patient data, specimens and samples. 
Although no additional MRI outside of the standard clinical workup, the 2013 American College 
of Radiology (ACR) Manual on Contrast Media stated the frequency of all acute adverse events 
after an injection of 0.1-0.2 mmol/kg of gadolinium chelate ranges from 0.07-2.4%. The vast 
majority of these reactions are mild, including coldness at the injection site, nausea with or 
without vomiting, headache, warmth or pain at the injection site, paresthesias, dizziness, and 
itching. Reactions resembling an “allergic” response are very unusual and vary in frequency 
from 0.004% to ¬0.7%. A rash hives, or urticaria are the most frequent of this group, and very 
rarely there may be bronchospasm. Severe, life-threatening anaphylactoid or nonallergic 
anaphylactic reactions are exceedingly rare (0.001% to 0.01%)  
An important severe reaction to mention is nephrogenic systemic fibrosis (NSF). NSF is a 
debilitating condition whose onset is associated with gadolinium contrast injection. Primary seen 
in patients with GFR<30 and prior gadolinium exposure. Certain agents are known to have a 
higher association with NSF and are considered higher risk when administered to patients with 
renal impairment. Incidence ranges from 36.5/100,000 to 4/100,000. 
Extravascular extravasation via infiltrated IV can occur. The incidence of extravascular 
extravasation in one series of 28,000 doses was 0.05%. Laboratory studies in animals have 
demonstrated that both gadopentetate dimeglumine and gadoteridol are much less toxic to the 
skin and subcutaneous tissues than are equal volumes of iodinated contrast media. 
Standard risk associated with the appropriate surgical procedure will be discussed with the 
patient prior to operation at the time of operation consent. Minimal to no risk will be accrued by 
the patient via pathologic examination of the removed specimen. 
2.3.2 
Benefits   
 
A direct benefit to this patient population will likely not be encountered during this study’s 
duration. Benefits will be seen in future patient populations as the vascuCAPTM imaging 
technology will be better able to identify, categorize, and score problematic vascular beds.  
2.3.3 
Risk to Benefit Ratio 
The risk to this patient population is considered minimal, while the potential benefit of 
progressing the vascuCAPTM noninvasive imaging technology could potentially allow for limited 
use of more invasive imaging techniques, such a angiography, in future patients. Accurate 
noninvasive plaque characteristics and risk scoring could also lead to individualized patient 
management based on predicted plaque stability through vascuCAPTM imaging. Future accurate 

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plaque assessment could potentially lead to noninvasive assessment of drug, example statins, 
influence on individual arterial lesions. 
2.3.4 
Therapeutic Alternatives 
Therapeutic alternatives would be limited as the MRI the patients would be set to undergo would 
be a part of their routine clinical workup. Although for select patients, alternative imaging 
strategies could include ultrasound, CT/CTA, and/or invasive angiography.    

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3 OBJECTIVES 
3.1 
Study Objectives 
The vascuCAPTM measurements of structural and functional features of the arterial wall will be 
performed in patients undergoing endarterectomy for the following objectives: 
Primary: 
I. 
Measure the bias, precision, and reproducibility of each of the functional analytes as 
measured by vascuCAPTM with respect to histopathologic results as ground truth, and 
assess their linear region and limits of quantitation. 
II. 
Establish performance characteristics of the structural and hemodynamic analytes, 
where an objective truth standard is lacking. 
Secondary: 
III. 
Classify the target lesion according to whether the analytes suggest it is not a plaque, 
or if it is, which of the 8 AHA types best fits the analyte profile.  Assess the accuracy of 
vascuCAPTM’s classification against the histopathology classification.   
3.2 
Study Outcome Measures 
Measured results will be compared in a blinded fashion with histology to assess performance of 
vascuCAPTM-Profiling and build a prediction model in vascuCAPTM–Scoring according to the 
following study endpoints: 
I. 
Measure the bias, precision, and reproducibility of each of the functional analytes as 
measured by vascuCAPTM with respect to histopathologic results as ground truth, and 
assess their linear region and limits of quantitation: 
a. Plaque lipid core pool presence and volume. 
b. Plaque fibrosis volume, degree, and uniformity. 
c. Plaque inflammation burden, degree, and uniformity. 
d. Intra-plaque hemorrhage burden and confidence. 
e. Plaque vascular leak - volume, degree, and uniformity. 
f. Calcification – volume, degree, and uniformity. 
II. 
Establish performance characteristics of the structural and hemodynamic analytes, 
where an objective truth standard is lacking: 
a. Determine the interchangeability of structural measurements of wall thickness, 
remodeling ratio and luminal narrowing and hemodynamic measurements (ESS) 
with an imperfect (subjective) reference standard of manual contouring by 
radiologists.  vascuCAPTM will be evaluated under two scenarios: fully-automated 
vascuCAPTM, and a workflow where a reader will have the opportunity to review 
and adjust vascuCAPTM produced results. 
b. Assess the reproducibility under different clinical sites, scanner models, and field 
strengths (dependent variable of interest being the interchangeability for each 
analyte relative to the imperfect reference standard) and with respect to ranges 
documented in literature according to collected co-variates. 
III. 
Classify the target lesion according to whether the analytes suggest it is not a plaque, 
or if it is, which of the 8 AHA types best fits the analyte profile.  Assess the accuracy of 
vascuCAPTM’s classification against the histopathology classification.   

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4 STUDY DESIGN 
A two-phase study is proposed.  In the first phase, 75 surgical patients will be recruited as part 
of a training set; aims I-II will be evaluated with this set.  In the second phase, at least a 
minimum of 35 and as many as 75 surgical patients will be recruited (number to be set based on 
the results of a statistical analysis following the first phase). Data from the second phase will be 
used in the definitive results to be filed in a 510(k) application to the FDA documenting the 
statistical  performance of vascuCAPTM’s ability to measure functional and structural analytes 
according to Aims I and II.  Data collected in the second phase will also be used as additional 
training data for Aim III.   
vascuCAPTM’s performance in measuign functional analytes will be assessed using histology of 
specimens collected during surgery as ground truth.  vascuCAPTM’s performance in measuring 
structural analytes will be facilitated by comparing its automated segmentations against manual 
contours produced independently by two radiologists recruited for the study. The two 
radiologists will independently perform the manual contouring for all study patients, and one of 
these two radiologists will also perform the vascuCAPTM aided contouring after a sufficient 
wash-out period after the manual contouring and with appropriate blinding to their manual 
results.   
Patients are recruited, enrolled, and analyzed with vascuCAPTM. 75 patients which have been 
imaged and on which surgery was performed within 30 days of imaging will form the training set.  
An analysis will be performed and revisions to vascuCAPTM will be made, as appropriate.  The 
sample size for the Profiling will be determined at this time; we denote this as Nprofile. After 
analysis, the product configuration will be locked, and subsequent patient results are blinded.   
After Nprofile additional patients have been imaged and on which surgery was performed within 
30 days of imaging (Nprofile >35). 

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5 STUDY ENROLLMENT AND WITHDRAWAL 
Patients scheduled for MRA and endarterectomy at the LSU ILH Medical Center, New Orleans 
as well as West Jefferson Medical Center, Marrero will be recruited for the study after informed 
consent has been obtained. All patients will undergo a carotid or femoral artery MRI 
examination within 30 days of the surgical procedure. Patients will not be coerced into enrolling 
within the study. Patients will be reminded of their freedom to abstain from enrollment. Patients 
will be reminded that upon abstaining from enrollment, no objective or subjective change 
will/would occur in their care. 
Current Standard of Care and Deviation Thereof:  
Patients will be recruited, enrolled, and the vascular bed in question analyzed with MRI and the 
vascuCAPTM system. For a patient to be included within the appropriate phases as described 
previously, any vascular operation upon the vascular bed in question must take place within 30 
days of the vascuCAP TM study. MRI for carotid and femoral arterial atherosclerotic lesions is 
consistent with current standard of care [7]. Carotid and femoral lesion vessel distribution and 
percent stenosis can be accurately assessed with MRI. Thus, preoperative imagining via MRI is 
sufficient to construct an appropriate operative plan for individual patients. The MRI which will 
be required for patients to undergo will not be an addition to their clinical work up had they not 
enrolled in the study. Therefore, no additional risk will be seen by patients outside of the 
standard clinical workup for their specific disease.   
5.1 
Subject Inclusion Criteria 
Individuals must meet one of the following inclusion criteria in order to be eligible to participate 
in the study: 
a. Case subjects will be patients with documented carotid atherosclerosis, scheduled for 
magnetic resonance angiography and subsequent elective endarterectomy with 30 days 
of enrollment in the study  
b. Case subjects will be patients with peripheral arterial disease (PAD) with clinical 
symptoms, 
scheduled 
for 
magnetic 
resonance 
angiography 
and 
indicated 
endarterectomy of diseased areas of femoral arteries within 30 days of enrollment in the 
study 
5.2 
Subject Exclusion Criteria 
Individual meeting any of the following criteria will be excluded from participation in this study: 
a. Subjects with claustrophobia or inability to tolerate prior MRI studies.  
b. Subjects with metal implants that are not MRI compatible (LSU detailed checklist to be 
attached) including: Subjects with any type of bio-implant activated by mechanical, 
electronic, or magnetic means (e.g. cochlear implants, pacemakers, neurostimulators, 
biostimulators, electronic infusion pumps, etc.). Subjects with any type of ferromagnetic 
bio-implant that could potentially be displaced or damaged, such as aneurysm clips, 
metallic skull plates, etc.  
c. Subjects with a history of kidney disease or dialysis that are unable to receive 
intravenous gadolinium contrast material. 
d. Female subjects. A urine pregnancy test will be required of all female subjects of 

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childbearing potential prior to inclusion in this study. Pregnant or nursing females will be 
excluded from the study.  
e. Subjects who cannot adhere to the experimental protocol.  
f. Subjects allergic to gadolinium contrast material.  
5.3 
Subject Withdrawal 
Subjects are free to withdraw from participation in the study at any time upon request.  
An investigator may terminate a study subject’s participation in the study if: 
 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the subject. 
 
The subject meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation.   
5.4 
Premature Termination or Suspension of Study 
This study may be suspended or prematurely terminated if there is sufficient reasonable cause.  
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party.  If the study is prematurely terminated or 
suspended, the principal investigator will promptly inform the IRB and will provide the reason(s) 
for suspension or termination. Circumstances that may warrant termination include, but are not 
limited to: 
 
Early attainment of statistical significance;  
 
Continuation of enrollment due to positive trend; and  
 
Determination of unexpected, significant, or unacceptable risk to subjects. 
 
Insufficient adherence to protocol requirements. 
 
Data that are not sufficiently complete and/or evaluable.  
 
Determination of futility. 
5.5 
Costs to Subjects   
All research related procedures and/or medications will be provided at no charge to the subject 
and will not be billed to the insurance carrier. 

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6 STUDY SCHEDULE 
6.1 
Screening Visit (Day -28 to -1) 
 
Obtain and document consent from potential participant on the consent form. 
 
Review medical/dental history to determine eligibility based on inclusion/exclusion 
criteria. 
 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
 
Perform medical/dental examinations as needed to determine eligibility. 
 
Schedule study visits for individuals who are eligible and available for the duration of the 
study.   
 
Provide potential participants with instructions needed to prepare for first study visit. 
6.2 
Enrollment/Baseline Visit (Visit 1, Day 0) 
 
Review and confirm informed consent. 
 
Verify inclusion/exclusion criteria.   
 
Update any changes in demographic information, medical/dental history, medication 
history, alcohol and tobacco use history.  
 
Record results of physical and dental examinations. 
 
Collect blood/urine/saliva/other specimen. 
 
A single blood sample will be collected via antecubital venipuncture by a phlebotomist 
prior to MR imaging, 10-15 ml blood collected. The blood sample will be collected after 
verification of negative urine pregnancy test in women of childbearing potential.  
 
All patients will undergo a comprehensive baseline clinical assessment including 
evaluation of their cardiovascular risk factor profile. The specific information that will be 
collected is seen in the table below. 
Table 2: Clinical Assessment Parameters to be Collected 
Demographics 
Antecedent CV Hx & 
Risk Factors 
Clinical 
Parameters 
Current 
Medications 
Clinical 
Biochemistry 
Ultrasound 
Findings 
Age-Years 
Sex-% male 
Race 
Body Mass 
Index – kg/m2 
Alcohol use 
Tobacco Use 
Smoking 
T2D 
Hypertension 
Hypercholesterolemia 
 
Heart Rate 
Systolic BP 
Diastolic BP 
Ankle-
brachial 
index 
Aspirin 
Clopidogrel 
Statin 
 blocker 
ACE/ARI 
Calcium 
channel 
blocker 
Other anti- 
hypertensives 
Oral nitrates 
Total Cholesterol 
HDL-C, LDL-C 
VLDL 
Triglyerides 
Creatinine 
BUN 
AST 
ALT 
Bilirubin 
hsCRP 
Uric Acid 
Salivary cortisol 
Thickness of 
anterior and distal 
wall of artery with 
lesion.  
Assessment of flow 
restriction 
 

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6.3 
Imaging Visit (Day 0-29) 
 
Subjects, meeting inclusion and exclusion criteria, will be contacted by research 
assistant or physician in person or by telephone to complete pre-MRI consent screening 
by use of the MRI safety checklist. After confirming consent to study protocol, those 
willing to participate will be scheduled to a 1-hour time-slot to appear at the Department 
of Radiology to undergo an MRI. 
 
At the appointed time, subjects will be met by a research assistant or physician and will 
be oriented. Consent will be confirmed both for the MR imaging as well as the pathology 
specimen (carotid endarterectomy specimen after surgery in carotid artery patients and 
peripheral arterial specimen in PAD patients) and the MRI safety checklist repeated. 
Subjects will change into hospital scrubs (provided) and remove any jewelry, watches, 
etc. 
 
The subject should be asked if he or she had a permanent coloring technique (i.e., 
tattooing) applied to any part of the body. This includes cosmetic applications such as 
eyeliner, lip-liner, lip coloring, as well as decorative designs. 
 
The subject should be informed of the risks associated with the site of the tattoo. 
 
The subject should be advised to immediately inform the MRI technologist regarding any 
unusual sensation felt at the site of the tattoo in association with the MR procedure. 
 
As a precautionary measure, a cold compress (e.g., ice bag) may be applied to the 
tattoo site during the MR procedure. 
 
Women of childbearing potential will be asked to provide a urine sample for a urine 
pregnancy test before each MRI study. If the test is negative, the patient may continue to 
participate. A positive pregnancy test will exclude further participation. 
 
Subjects will then be escorted by a research assistant/ physician into the MRI scan room 
and asked to lie on the imaging table. The patient will undergo MRI imaging of the 
specific arterial target, which is to include post-gadolinium contrast enhanced images. 
The total scan duration will be less than 60 minutes. All equipment for monitoring (ECG 
and respiration) and imaging is approved for human clinical use. 
Table 3: Image acquisition sequences used in the protocol 
 Contrast 
T1 
T2 
TOF 
Gadolinium 
Diffusion 
Phase 
Contrast 
Imaging 
BB 
T2 weighting 
MRA 
DCE 
DWI 
Q-flow 
Sequence 
2D-TSE 
or FAST 
SE 
2D-TSE or 
FAST SE 
T1-FFE or 
FLASH or 
SPGR 
T1-TFE 
THRIVE or 
VIBE or 
FGRE 
SE-EPI 
T1-FFE or 
FLASH or 
SPGR 
Acquisition Before 
and after 
contrast 
inf; Fat 
Sat 
Long TR, 
long TE; Fat 
Sat; inflow 
suppression 
Fat Sat; 
inflow 
suppression 
T1 weighted; 
Fat Sat 
B values 
at 0, 500, 
and 1000 
s/mm2 
Choosing 
in phase 
and out of 
phase TEs 

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 
Carotid Artery. All carotid MR axial image acquisitions will have a FOV of maximum 140×120mm, a 
slice thickness of maximum 4mm, and an acquisition matrix of at least 280×256, and a longitudinal 
coverage of at least 30mm. The MR imaging will be centered on the bifurcation of the symptomatic 
carotid arteries, defined as the arteries responsible for the neurological symptoms.  
 
Femoral Artery: The femoral artery will be scanned employing a standard leg coil placed around the 
thigh and conventional prospective ECG triggering. All femoral MR axial image acquisitions will have 
a FOV of maximum 140×120mm, a slice thickness of maximum 4mm, and an acquisition matrix of at 
least 280×256, and a longitudinal coverage of at least 15 cm. The MR imaging will start at the femoral 
bifurcation and continuing through the adductor canal.  
Gadolinium intravenous injection (0.1mmol/kg) will take place in between the MRI scans while 
the subject is lying in the scanner. A physician will be present at all times. During the imaging 
procedure, subjects will be monitored physiologically by the ECG and respiration monitoring 
devices, and also observed by closed circuit television. Further, they will have an attached 
emergency call button in-hand to activate voice communication. Following completion of the 
imaging study, subjects will be excused and their participation in the study complete.  
6.4 
Histopathology for Patients Undergoing Surgery within 30 Days of MRI 
At the time of surgical excision, a suture will be placed at the anterior aspect of the proximal end 
(closest to the heart) of each endarterectomy specimen and at least 1 additional suture placed 
on the anterior aspect of the specimen to allow for proper orientation of the specimen during 
embedding and sectioning of the specimen so that the sections obtained can be aligned with the 
MR images. After endarterectomy during surgery, the excised plaque specimens will be sent to 
the hospital’s pathology lab to be analyzed by two board-certified pathologists. Established 
hospital histopathology protocols will be used for the histology processing. The specimens will 
be fixed in standard fashion in 10% buffered neutral formalin, decalcified, and then processed 
routinely to obtain paraffin blocks. Samples will be step-sectioned to obtain four (10 µm thick) 
sections every 2.0 mm throughout the length of the endarterectomy specimen and stained 
(Hematoxylin-Eosin, Masson’s trichrome, Verhoeff van Gieson and Picrosirius red). The H&E 
and Masson’s Trichrome will be used to identify morphological and structural features for 
categorizing according to the proposed modified AHA classification scheme [8]. Picrosirius Red 
Staining is used to identify demarcations of the connective tissue and the extent and type of 
fibrotic tissue (collagen) present in the intimal regions of the lesions [9]. The sections will be 
stained with Masson’s trichrome (Sigma Aldrich) for cellular components [SMC-pink, red blood 
cells (RBC)-red], fibrous tissue (blue), fibrin and platelet-rich thrombus (deep purple). Picrosirius 
red (Electron Microscopy Sciences, Hatfield, PA) staining is used to identify the type of collagen 
fibers (type I-old fibers stain yellow-orange and type III-new fibers stain green). The Verhoeff’s 
van Giesen stained sections will be used to identify the internal (IEL) and external elastic 
laminae (EEL) which delineate the boundaries of the intima and media (IEL) and the media and 
adventitia. The lipid core is evaluated by use of all four sections, and defined as the negative 
staining area that may contain inflammatory cells, collagen and elastin fibers, The presence and 
area of classic cholesterol clefts will also be assessed. Atherosclerotic plaques will be 
categorized into early (types II and III) and advanced (types IV, Va, Vc and VI) plaques 
according to a proposed modified American Heart Association (AHA) classification. Type VI 
plaques were further subdivided into VI-ruptured and VI-eroded to discriminate whether thrombi 
were associated with demarcation of the endothelial layer of the intima or not. Rupture was 
defined as a discontinuity of the endothelium resulting in a contact of the thrombus with the 
underlying lipid core. Erosion was identified when the thrombus is attached to an intima that 
lacked endothelium and an underlying myointimal region that is rich in SMC and proteoglycans. 
Plaques types VII (calcification) and VIII (fibrotic) are proposed as two forms of regression of 

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plaques that may be associated with intensive lipid lowering drug regimens [10]. Calcification 
and fibrosis will be identified with the H&E and Masson’s Trichrome stains. 
 
 
Figure 1:  Endartectomy Specimen Orientation and Process Map 
 

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7 SAFETY MONITORING 
The investigator will be responsible for study oversight, including monitoring safety, ensuring 
that the study is conducted according to the protocol and ensuring data integrity.  The PI will 
review the data for safety concerns and data trends at regular intervals, and will promptly report 
to the IRB and NHLBI any Unanticipated Problem (UP), protocol deviation, or any other 
significant event that arises during the conduct of the study.   
Safety monitoring for this study will focus on unanticipated problems involving risks to 
participants, including unanticipated problems that meet the definition of a serious adverse 
event. 
7.1.1 
Unanticipated Problems  
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to subjects or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria: 
 
unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved 
research protocol and informed consent document; and (b) the characteristics of the 
subject population being studied; 
 
related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.1.2 
Serious Adverse Events  
A serious adverse event (SAE) is one that meets one or more of the following criteria: 
 
Results in death 
 
Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred) 
 
Results in inpatient hospitalization or prolongation of existing hospitalization 
 
Results in a persistent or significant disability or incapacity 
 
Results in a congenital anomaly or birth defect 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
the event may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 

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7.2 
Reporting Procedures 
Incidents or events that meet the OHRP criteria for unanticipated problems require the creation 
and completion of an unanticipated problem report form.  OHRP recommends that investigators 
include the following information when reporting an adverse event, or any other incident, 
experience, or outcome as an unanticipated problem to the IRB: 
 
Appropriate identifying information for the research protocol, such as the title, 
investigator’s name, and the IRB project number; 
 
A detailed description of the adverse event, incident, experience, or outcome;  
 
An explanation of the basis for determining that the adverse event, incident, experience, 
or outcome represents an unanticipated problem;  
 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the unanticipated problem. 
 
Additional information required by the IRB as listed in Section 4.7 of the LSUHSC IRB 
Policies and Procedures Guidebook will also be provided in a timely manner.  
To satisfy the requirement for prompt reporting, unanticipated problems will be reported using 
the following timeline:  
 
Unanticipated problems that are serious adverse events will be reported to the IRB and 
to NHLBI within 1 week of the investigator becoming aware of the event.  
 
Any other unanticipated problem will be reported to the IRB and to NHLBI within 2 weeks 
of the investigator becoming aware of the problem.  
 
All unanticipated problems should be reported to appropriate institutional officials (as 
required by an institution’s written reporting procedures), the supporting agency head (or 
designee), and OHRP within one month of the IRB’s receipt of the report of the problem 
from the investigator. 
All unanticipated problems will be reported to NHLBI’s centralized reporting system via Rho 
Product Safety: 
 
Product Safety Fax Line (US):  1-888-746-3293 
 
Product Safety Fax Line (International):  919-287-3998 
 
Product Safety Email:  rho_productsafety@rhoworld.com 
General questions about SAE reporting can be directed to the Rho Product Safety Help Line 
(available 8:00AM – 5:00PM Eastern Time):   
 
US:  1-888-746-7231 
 
International: 919-595-6486   

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8 STATISTICAL ANALYSIS 
A two-phase study is proposed.  In the first phase, 75 surgical patients will be recruited as part 
of a training set; aims I-III will be evaluated with this set.  In the second phase, at least 35 
surgical patients will be recruited (possibly more, depending on the results of the first phase). 
Data from the second phase data will be used in the 510(k) application (i.e. Report of the results 
of the performance of the functional and structural analytes) and as additional training data for 
Aim III.   
Two radiologists will be recruited for the study. The two radiologists will independently perform 
the manual contouring for all study patients, and one of these two radiologists will also perform 
the vascuCAPTM aided contouring after a sufficient wash-out period after the manual contouring 
and with appropriate blinding to their manual results.   
8.1 
Aim I 
The first study aim is to estimate the bias and precision of each of the following functional 
analytes, which will be measured for each target lesion by both vascuCAPTM and 
histopathology:  
a. Plaque lipid   
b. Plaque fibrosis  
c. Plaque inflammation 
d. Intra-plaque hemorrhage burden and confidence. 
e. Plaque vascular leak  
f. Calcification 
For each of these functional analytes, three measurements will be evaluated for a total of 18 
measurements per target lesion: volume in mm3, and degree and uniformity both measured on a 
three-point ordinal scale.  The same measurements will be taken via histopathology, where the 
volume of each analyte will be measured using the same units (i.e. mm3); however, degree and 
uniformity are graded subjectively on histopathology by the pathologist.   
We anticipate that each patient will have at least one target lesion and some patients, especially 
the PAD patients, will have two target lesions, on average.  There will be no replicate 
measurements (i.e. all of the measurements are obtained objectively by the algorithm so 
multiple runs should not produce different results).   
For volume measurements for each analyte for each site (i.e. neck and leg), we will plot the 
value measured by histopathology vs. the difference between the value measured by 
vascuCAPTM and the value measured by histolopathology. Any analyte not measurable will also 
be indicated on the plot using a different plotting character.  The resulting plot will be inspected 
visually for the following:  
1. Limits of vascuCAPTM’s quantitation;  
2. Associations between the magnitude of the histopathology measurement and bias; and  
3. Associations between the magnitude of the histopathology measurements and 
heteroscedasticity in the vascuCAPTM measurements.  

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If the plots of carotid and femoral entarterectomies have similar distributions, then the data from 
these sites will be pooled; otherwise, separate analyses will be performed.   
A linear model will be fit (for all of the data or for a subset of histopathology values, depending 
on the findings from the plot) where the dependent variable is the vascuCAPTM measurement 
(X) and the independent variable is the histopathology value (Y). Generalized estimating 
equations (GEEs) (to account for the fact that some patients will have more than one target 
lesion) will be used to estimate the linear function:  ( | )        . An unstructured working 
covariance will be used.  We will construct a 95% CI for the intercept    using a t-statistic as the 
pivotal statistic.  CIs not containing 0 indicate fixed bias. We will also construct a 95% CI for the 
slope   . CIs not containing 1 indicate proportional bias [11].  
The precision of the vascuCAPTM measurements will be estimated by the standard deviation: 
√ 
   ∑
(       ̅) 
 
   
 where  ̅ is the sample mean of the differences,  ̅  
 
 ∑
(     )
 
   
 [1].  
We will construct a 95% CI for the precision using bootstrap methods.   
We will plot the bias profile (plot of bias of measurements for various ranges of histopathology 
values vs. the histopathology value) and precision profile (plot of standard deviation of 
vascuCAPTM measurements from patients with similar histopathology values vs. the 
histopathology value) as visual summaries of vascuCAPTM performance for the bias and 
precision components, respectively [12]. 
In addition to reporting these technical performance characteristics of the volume 
measurements, we will also report i) the coverage probability (CP) and ii) a discrimination index 
[11].  The CP is the probability that the absolute difference between the value measured by 
vascuCAPTM and the value measured by histology is less than d0, i.e.      (|   |    ).  We 
will plot the CP for a range of values for d0.  The discrimination ability of the measurements, i.e. 
the ability of vascuCAPTM to discriminate between different magnitudes of histopathology 
values, will be measured using the area under the ROC curve for continuous measures [13].  
95% CIs for the CP and ROC area will be constructed using methods for clustered binary data 
[14] and clustered ROC data [15], respectively.   
The volume measurements are considered the most critical because they will be used to 
construct a score to predict rupture risk.  Thus, we considered the width of 95% confidence 
intervals for the bias and the between-subject variance as a function of sample size (see Tables 
1 and 2).  The following assumptions were made: 1) the volume measurements are normally 
distributed; 2) carotid artery patients contribute one target lesion each, while PAD patients 
contribute two target lesions each; 3) target lesions from the same patient are moderately 
correlated (r=0.5); 4) one-quarter of all patients will be PAD patients; 5) results from femoral and 
carotid target lesions can be pooled; 6) the average volume of an analyte is 25mm3; and 6) the 
precision of the vascuCAPTM measurements is 10-20% of the volume of analyte.   
From Table 4, if the SD was 15% of the mean volume, then we expect to be able to construct a 
95% CI for the bias of total width of 10% with n=35.  If the SD was 20%, then with n=35 we 
expect to construct a 95% CI of total width of 14%.  Similarly, from Table 5, if the SD was 15% 
of the mean volume, then with n=35 we expect to be able to construct a 95% CI for the 
precision of total length 8%; if the SD was 20%, then we expect to be able to construct a 95% CI 
for the precision of total length 11%.  We plan to recruit 75 patients (55 carotid artery patients 
and 20 PAD patients) in phase one to account for the fact that the estimates of bias and 

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precision may need to be reported in strata based on the magnitude of the histopathology 
volume and/or by anatomic location.  In phase two we plan to recruit at least the minimum of 35 
(25 carotid artery patients and 10 PAD patients) and possibly more depending on the results of 
the training set.   
Table 4: Width of 95% CIs for Bias Based on Total Sample Size (n)* 
 
n=10 
n=20 
n=30 
n=40 
n=50 
n=60 
SD=2.5 (10%) 
+1.72 
+1.12 
+0.90 
+0.77 
+0.68 
+0.62 
SD=3.75 (15%) 
+2.58 
+1.69 
+1.34 
+1.15 
+1.02 
+0.93 
SD=5.0 (20%) 
+3.44 
+2.25 
+1.79 
+1.54 
+1.37 
+1.24 
*The effective sample size, m, is calculated as m=(3/4)n+(1/4)n(2/[1+(s-1)0.5]), where s=2.  
Then the half-width of the 95% CI for bias is  (   )  
  (   √ ).   
Table 5: Estimated 95% CIs for SD Based on Total Sample Size (n)* 
 
n=10 
n=20 
n=30 
n=40 
n=50 
n=60 
SD=2.5 
[1.80,4.77] 
[1.98,3.81] 
[2.08,3.51] 
[2.11,3.29] 
[2.16,3.20] 
[2.19,3.14] 
SD=3.75 
[2.70,7.16] 
[2.97,5.71] 
[3.11,5.26] 
[3.17,4.94] 
[3.24,4.80] 
[3.29,4.71] 
SD=5.0 
[3.60,9.54] 
[3.96,7.61] 
[4.15,7.02] 
[4.22,6.59] 
[4.31,6.40] 
[4.38,6.29] 
*The effective sample size, m, is calculated as m=(3/4)n+(1/4)n(2/[1+(s-1)0.5]), where s=2.  
Then the 95% CI for the SD is  √
(   )  
  
  (   )
 
 √
(   )  
 (   
 ) (   )
 
 .   
For degree and uniformity measurements for each analyte for each site (i.e. neck and leg), we 
will tabulate the histopathology value vs. the vascuCAPTM value.  Any analyte not measurable 
will also be indicated in the table. In the distributions in the tables are similar, then the data from 
the two sites will be pooled.  
The coverage probability (CP) will be reported which is the probability that the absolute 
difference between the value measured by vascuCAPTM and the value measured by histology is 
less than d0, i.e.      (|   |    ).  We will report the CP for values for d0 of 0 and 1.  95% 
CIs for the CP will be constructed using methods for clustered binary data [6].   
For volume, degree, and uniformity of the six functional analytes, we will estimate the 
reproducibility of the measures at different institutions (two sites), and under different scanner 
models and field strengths (1.5 and 3.0) and with respect to ranges documented in the literature 
according to collected patient characteristics. Multiple variable linear and logistic regression 
models will be built, where the dependent variable is the difference between the measured 
functional analyte and the true value, and the independent variables are institution, scanner 
model, field strengths, and patient characteristics.  We will test whether the independent 
variables in the model are predictors of bias using F-tests, and Wald tests, respectively.   

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8.2 
Aim II  
The second study aim is to establish performance characteristics of each of the following 
structural analytes, which will be measured for each target lesion by both vascuCAPTM and two 
radiologists’ performing manual contouring:  
a. Remodeling ratio 
b. Percent Stenosis  
c. Maximum wall thickness  
This study aim also applies similar analysis to the hemodynamic analyte endothelial shear 
stress since even though the computational method differs, yet it still depends on the location of 
contours 
The vascuCAPTM measurements will be made under two scenarios: vascuCAPTM fully 
automated (fully automated mode) and vascuCAPTM followed by adjustments by a radiologist 
(semi-automated mode).  
In the neck and leg, for each structural analyte, we will first visually compare vascuCAPTM’s 
measurements to the median of the two radiologists’ measurements.  We will plot the 
radiologists’ median value vs. the value measured by vascuCAPTM in each vascuCAPTM mode. 
Any analyte not measurable will also be indicated on the plot using a different plotting character.  
The resulting plot will be inspected visually for the following:  
1. Limits of vascuCAPTM’s quantitation;  
2. Associations between the magnitude of the analyte and the magnitude of the 
discrepancy between vascuCAPTM and the radiologists’ measurements; and  
3. Associations between the magnitude of the analyte and heteroscedasticity in the 
vascuCAPTM measurements.  
If the plots of neck and leg have similar distributions, then the data from these sites will be 
pooled; otherwise, separate analyses will be performed.  Since the radiologists’ manual 
contouring has both bias and measurement error, rather than assessing agreement, we will 
estimate the interchangeability of vascuCAPTM’s structural measurements with the manual 
contouring by radiologists.  The individual equivalence criterion [16, 17] will be estimated as 
follows:  
   
̂  √∑
(      ) 
 
   
  √∑
(       ) 
 
   
 
where    is the measurement for the i-th case by vascuCAPTM,     is the measurement for the i-
th case by the first radiologist using manual contouring, and     is the measurement for the i-th 
case by the second radiologist using manual contouring.  IEC is a measure of the expected 
difference between vascuCAPTM’s measurements and a radiologist’s measurements with 
manual contouring, after adjusting for the expected difference between two radiologists’ 
measurements with manual contouring.  IEC will be estimated for both vascuCAPTM fully-

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automated and vascuCAPTM semi-automated. 95% bootstrap CIs will be constructed for the 
IEC.   
For each of the structural analytes, we will estimate the reproducibility of the measures for 
different factors: different institutions, different scanner models, different field strengths, and with 
respect to ranges documented in the literature according to collected patient characteristics. We 
will estimate the IEC for these different factors, and we will construct CIs for the difference 
between the IECs using bootstrap simulations.    
8.3 
Aim III  
The vascuCAPTM measurements will be used to classify the target lesions according to whether 
the analytes suggest it is not a plaque, or if it is, which of the 8 AHA types best fits the analyte 
profile.  The data from the first phase will be used to build the classifier, and the data from 
second phase will be used as a first assessment of the accuracy of the classifier.  This is 
considered a pilot study for the classifier and will not be included in the Profiling product release 
until sufficient statistical significance for all outputs is demonstrated.   
With the limited sample size for the assessment of the classifier, we will not attempt to model 
the results.  Rather, we will simply report the 9x9 table of AHA types by histopathology vs. AHA 
types by vascuCAPTM’s classifier.  In addition, for each of the AHA types according to 
histopathology, we will report:  
1. the frequency with which vascuCAPTM’s classification agrees with histopathology,  
2. the frequency with which vascuCAPTM’s classification is within an acceptable range (see 
Table 6), and  
3. the frequency with which vascuCAPTM’s classification is not within an acceptable range.   
Table 6: Penalty Matrix for Evaluating vascuCAPTM AHA Plaque Type Classifier 
  
Truth 
Classification 
0 
1 
2 
3 
4 
5 
6 
7 
8 
0 
A 
1 
A 
A 
2 
NA 
A 
A 
3 
NA 
NA 
A 
A 
4 
NA 
NA 
NA 
A 
A 
5 
NA 
NA 
NA 
NA 
NA 
A 
6 
NA 
NA 
NA 
NA 
NA 
NA 
A 
7 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
A 
8 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
A 
A=acceptable 
NA=not acceptable 

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ELUCID CONFIDENTIAL/PROPRIETARY INFORMATION-NOT FOR PUBLIC DISSEMINATION 
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