Determining the Accuracy of Self and Partner Anal Exams for Detecting Anal Abnormalities.
Phase: NA
Conditions: Anal Cancer
Sponsor: Medical College of Wisconsin

THE PREVENT ANAL CANCER (PAC) PALPATION STUDY 
NCT RegistraƟon Number: NCT04090060 
Protocol 4.5 Approved 12/20/2023 

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PROTOCOL 
 
THE PREVENT ANAL CANCER (PAC) PALPATION STUDY 
 
Sponsor: National Cancer Institute of the National Institutes of Health 
Official title: Determining the accuracy of self- and partner anal exams for detecting anal 
abnormalities.  
 
Grant number: 1R01CA232892-01 
NCT Registration Number: NCT04090060 
 
Principal Investigator: 
Alan G. Nyitray, Ph.D.  
Clinical Cancer Center, Center for AIDS Intervention Research  
Medical College of Wisconsin 
8701 Watertown Plank Road, Ste. 5400 
Milwaukee, WI, 53226 
Tel: 414-805-3312 
Email: anyitray@mcw.edu 
 
Co-Investigators:  
1. 
Elizabeth Chiao, MD, MPH 
Professor 
The University of Texas MD Anderson Cancer Center 
Houston, TX 
Tel: 713-792-1860  
E-Mail: eychiao@mdanderson.org 
 
2. 
John Schneider, MD, MPH 
Associate Professor 
Departments of Medicine and Public Health Sciences 
University of Chicago 
5841 S. Maryland, MC 5065 
Chicago, IL 60637 
Tel: 1-773-702-8349 
E-Mail: jschnei1@medicine.bsd.uchicago.edu  
 
3. 
Aniruddha Hazra, MD 
Assistant Professor of Medicine 
Section of Infectious Diseases and Global Health 
University of Chicago  
5841 S. Maryland, MC 5065 
Chicago, IL 60637 
Tel:1-773-795-2016 
E-mail: ahazra2@medicine.bsd.uchicago.edu  

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4. 
Ashish Deshmukh, PhD, MPH 
Assistant Professor 
The University of Texas Health Science Center at Houston School of Public Health 
Department of Management, Policy, and Community Health 
1200 Pressler Street, E-329 
Houston, TX 77030 
Tel:1-713-500-9180 
E-mail: ashish.a.deshmukh@uth.tmc.edu   
 
5. 
Michael Swartz, PhD 
Associate Professor 
The University of Texas Health Science Center at Houston School of Public Health 
Department of Biostatistics and Data Science 
1200 Pressler Street, E-815 
Houston, TX 77030 
Tel: 1-713-500-9570 
Fax: 1-713-500-9525 
E-mail: Michael.D.Swartz@uth.tmc.edu 
 
6. 
Michael Wilkerson, PhD 
Assistant Professor 
The University of Texas Health Science Center at Houston School of Public Health 
Department of Health Promotion and Behavioral Sciences 
7000 Fannin Street, Rm 2620 
Houston, TX 77030 
Tel: 1-713-500-9974 
Fax: 1-713-500-9602 
E-mail: Johnny.M.Wilkerson@uth.tmc.edu 
 
7. 
Lu-Yu Hwang, MD 
Professor 
The University of Texas Health Science Center at Houston School of Public Health 
Department of Epidemiology, Human Genetics, and Environmental Sciences 
1200 Pressler Street, E-717 
Tel: 1-713-500-9382 
E-mail: lu-yu.hwang@uth.tmc.edu  
 
 

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Contents 
PROTOCOL CHANGE HISTORY ............................................................................................... 5 
LIST OF ABBREVIATIONS ......................................................................................................... 7 
SITES PARTICIPATING IN THE STUDY .................................................................................. 7 
PROTOCOL ROSTER ................................................................................................................... 7 
Principal Investigator ................................................................................................................................ 7 
Co-Investigators ........................................................................................................................................ 8 
STUDY SYNOPSIS ....................................................................................................................... 9 
MULTI-CENTER STUDY ............................................................................................................. 9 
BACKGROUND ........................................................................................................................................... 9 
STUDY PURPOSE ....................................................................................................................... 10 
Aim 1 ....................................................................................................................................................... 10 
Aim 2 ....................................................................................................................................................... 10 
Aim 3 ....................................................................................................................................................... 10 
Exploratory aim ....................................................................................................................................... 11 
OUTCOMES................................................................................................................................. 11 
SAMPLE SIZE ............................................................................................................................. 11 
POPULATION ............................................................................................................................. 11 
DURATION OF PARTICIPANT ACTIVITIES.......................................................................... 11 
PARTICIPANT ENROLLMENT ................................................................................................ 13 
Inclusion Criteria ..................................................................................................................................... 13 
Exclusion Criteria..................................................................................................................................... 13 
Recruitment Procedures and Setting ...................................................................................................... 13 
Referral Program ........................................................................................ Error! Bookmark not defined. 
Community Advisory Board .................................................................................................................... 14 
Eligibility Procedures ............................................................................................................................... 14 
Visit 1 Overview ...................................................................................................................................... 15 
Visit 1 Detail ............................................................................................................................................ 16 
Randomization ........................................................................................................................................ 18 
Arm 1 - Practice Arm ............................................................................................................................... 18 
Arm 2 – Non-practice Arm ...................................................................................................................... 18 
Between Visit 1 and Visit 2 study procedures ........................................................................................ 19 
Preparation for Visit 2 ............................................................................................................................. 19 

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Visit 2 Study Procedures ......................................................................................................................... 20 
Data Collected from Study Participants .................................................................................................. 20 
BURDEN OF TIME ON PARTICIPANTS DOING THE ASE .................................................. 22 
STATISTICAL ANALYSIS ........................................................................................................ 23 
Aim 1 ....................................................................................................................................................... 23 
Aim 2 ....................................................................................................................................................... 24 
Aim 3 ....................................................................................................................................................... 24 
PROTOCOL FIDELITY AND QUALITY CONTROL ............................................................... 26 
HUMAN PROTECTIONS ........................................................................................................................... 27 
Overview ................................................................................................................................................. 27 
Informed Consent Process ...................................................................................................................... 28 
Use and Access of Protected Health Information (PHI) and Retention of Records ................................ 28 
Risks to the Subjects ............................................................................................................................... 29 
Alternatives to study procedures ........................................................................................................... 30 
Protections against risk ........................................................................................................................... 30 
Benefits ................................................................................................................................................... 31 
Adverse Event Reporting ........................................................................................................................ 31 
Data and Safety Monitoring Committee ................................................................................................. 31 
REPORTING TO COMMUNITIES ............................................................................................... 33 
 
 
 
 

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PROTOCOL CHANGE HISTORY 
Date 
submitted 
Date 
approved 
Version 
Revisions 
Author 
08/23/2018 
08/31/2018 1.0 
Just-in-time version 
Nyitray 
11/21/2019 
12/08/2019 1.2 
Start enrollment of 400 persons in 
Chicago 
Nyitray 
01/24/2020 
02/12/2020 3.0 
Enroll Houston version 
 
Houston 
added 
to 
Chicago 
 
Numbers 
doubled 
for 
Houston 
 
Transwomen changed to 
trans persons 
 
Timeline adjusted 
Nyitray 
05/15/2020 
06/09/2020 3.5 
Remote consenting instituted due 
to COVID-19. 
 
Consent ICF changed to reflect 
changes in the consenting process 
and subsequent changes to the 
Pre-Exam 
and 
Post-Exam 
Surveys 
 
Consent goal increased to 900 to 
accommodate no shows between 
remote consenting and Visit 1. 
 
Minor wording changes to some 
survey questions  
 
Co-Investigator Dr. Elizabeth 
Chiao worksite updated. 
 
Insurance 
requirement 
for 
Houston participants removed. 
Nyitray 
07/02/2020 
07/23/2020 3.5 
Make 
ICF 
and 
SmartForm 
consistent 
Nyitray 
09/06/2020 
09/13/2020 3.6 
Recruit 
through 
Crofoot 
appointment 
confirmation 
email/texts 
Nyitray 
10/28/2020 
11/27/2020 3.8 
Change time between Visit 1 and 
2 to six months 
Nyitray 
12/17/2020 
02/08/2021 3.9 
Update 
visit 
2 
procedures, 
recruitment section to include 
referral program. 
Nyitray 

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Move participant’s anal self-
exam (ASE)/ anal companion 
exam (ACE) at Visit 2 from in-
clinic to at-home due to COVID-
19. 
08/12/2021 
02/14/2022 4.0 
Add clinic site in Houston 
 
Dr. Chiao transitions to MD 
Anderson 
 
Thomas Street Health Center 
added as clinic site in Houston 
under purview of MD Anderson, 
 
Remove some clinicians’ names 
and replace with text that does not 
need to be altered when clinicians 
change. 
Nyitray 
03/07/2022 
05/15/2022 4.1 
Send 
participants 
notice 
of 
ANCHOR Study results 
 
Revise Protocol Change History 
table to add Date Approved 
column and modify Revisions 
column text to better identify 
amendment 
 
Remove medical records review 
activity. 
Nyitray 
05/25/2022 
05/15/2022 4.2 
Increased 
number 
to 
take 
eligibility survey to 2500. 
Nyitray 
11/02/2022 
11/12/2022 4.3 
This version accompanies  
Amendment 26160 which increases 
the number in the PROSmartForm 
of those who will take the 
eligibility survey to 3500 and 
increases the number to consent 
to 1050. Number to screen and 
number to consent do not appear 
in this protocol; thus no change 
is made to the protocol. 
Nyitray 
3/10/2023 
05/04/2023 4.4 
Sending new survey to PAC Palp 
participants 
Nyitray 
10/16/2023 
12/20/2023 4.5 
Add MUSC as getting a de-
identified dataset 
Nyitray 

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LIST OF ABBREVIATIONS 
 
 
ACE  
Anal Companion Exam 
 
ASE 
 
Anal Self-Exam 
CAB  
Community Advisory Board 
 
CASI  
Computer-Assisted Self-Interview 
 
CE 
 
Cost-effectiveness 
 
DARE  
Digital Anal Rectal Exam 
 
HRA  
High-Resolution Anoscopy 
 
HPV  
Human Papillomavirus 
 
LGBT  
Lesbian, Gay, Bisexual, and Transgender 
 
MCW  
Medical College of Wisconsin 
 
MSM  
Men Who Have Sex with Men 
 
PAC 
 
Prevent Anal Cancer 
 
TSM  
Transgender Persons Who Have Sex with Men 
 
SITES PARTICIPATING IN THE STUDY 
1. Medical College of Wisconsin in Milwaukee will act as the lead site of the study and 
coordinate the PAC Study clinics for Visit 1 and Visit 2 in Houston. 
 
2. University of Chicago will provide clinical guidance and advice, recruitment, and coordinate 
and conduct the PAC Study clinics for Visit 1 and Visit 2 in Chicago. 
 
3. Crofoot Clinic will provide clinical guidance and advice, clinic space, education and health 
care provider exams for PAC Study clinics at Visit 1 and Visit 2 in Houston. 
 
4. University of Texas Health Sciences Center School of Public Health will provide cost-
effectiveness analysis, development of a qualitative interview, and recruitment in Houston. 
 
5. The University of Texas MD Anderson Cancer Center will provide clinical guidance and 
advice and a weekly study clinic at Thomas Street Health Center, conducting the same 
activities as Crofoot Clinic but under MD Anderson IRB purview. 
PROTOCOL ROSTER 
 
Principal Investigator: 
Alan G. Nyitray, Ph.D.  
Center for AIDS Intervention Research and Clinical Cancer Center 
Medical College of Wisconsin 
8701 Watertown Plank Road, Ste. 5400 
Milwaukee, WI, 53226 
Tel: 414-805-3312 
Email: anyitray@mcw.edu 
Role: Epidemiologist  

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Co-Investigators:  
Elizabeth Chiao, MD, MPH  
Medical Oncologist 
John Schneider, MD, MPH 
 
Infectious Disease Specialist 
Aniruddha Hazra, MD 
 
Infectious Disease Specialist 
Ashish Deshmukh, PhD, MPH 
Cost-Effectiveness and Decision Scientist 
Michael Swartz, PhD  
 
Biostatistician 
Michael Wilkerson, PhD 
 
Behavioral Scientist 
Lu-Yu Hwang, MD 
 
 
Infectious Disease Specialist 
 
 

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STUDY SYNOPSIS 
This is a clinical trial of the sensitivity and specificity of anal self-exams and anal companion 
exams to detect early invasive anal cancer among Chicago and Houston HIV-positive and HIV-
negative men who have sex with men (MSM) and transgender persons who have sex with men 
(TSM). 
 
MULTI-CENTER STUDY 
Medical College of Wisconsin (MCW) is the lead agency in the study. MCW will coordinate 
activities among study sites and receive all study data. Data will be coded, collected and shared 
with co-Investigators using REDCap (Vanderbilt University).  
 
1) The University of Chicago (UChicago) staff/faculty will have participant contact during 
recruitment and when participants come for clinic visits at UChicago.  
2) Staff of the Crofoot Clinic in Houston will have participant contact during recruitment 
and when participants come for clinic visits at Crofoot Clinic.  
3) Staff/faculty of The University of Texas Health Science Center at Houston School of 
Public Health (UTHealth) will have participant contact during recruitment, when 
participants come for clinic visits at Crofoot Clinic and when analyzing qualitative data. 
4) Staff/faculty of MD Anderson will have participant contact during recruitment and when 
participants come for clinic visits at Crofoot Clinic or Thomas Street Health Center and 
when faculty view study procedures at the Crofoot Clinic for quality control purposes. 
5) MCW staff/faculty will have participant contact during recruitment and when participants 
come for clinic visits at UChicago, the Crofoot Clinic, and Thomas Street Health Center. 
 
All study data will be collected and sent to MCW which will aggregate and analyze the data to 
complete Aims 1 and 2. UTHealth will analyze these same data for completion of Aim 3. 
 
BACKGROUND 
Anal cancer is a common cancer among gay, bisexual and other men having sex with men 
(MSM).1,2 Its annual incidence is approximately 50-fold and 5-fold higher among HIV-positive 
MSM and HIV-negative MSM, respectively, compared to the rest of the general population.2 
Like cervical cancer, it is primarily caused by human papillomaviruses (HPV).3 Unlike cervical 
cancer, there is no efficacious treatment for anal precancers as there is for cervical precancers.4 
To date, randomized clinical trials have failed to find an efficacious treatment although other 
trials continue;4-7  thus, professional societies recommend an annual Digital Anal Rectal Exam 
(DARE) for detection of anal abnormalities, including small tumors, among all MSM.8-11 But 
DARE is underutilized, e.g., most persons, regardless of HIV do not receive an annual 
DARE12,13 and most HIV physicians do not perform the exam.14 Therefore, alternative methods 
for early detection are needed because early detection of small tumors is associated with >85% 
5-year survival.15-17 
 
To increase detection of anal canal tumors, our NCI-funded phase II pilot study in Houston, 
Texas determined it was feasible to teach MSM to palpate their own, or their companion’s, anal 
canal.18 Acceptability was 94% among 148 individuals doing the exam on themselves (anal self-
exam, ASE) and 92% among 52 couples doing the exam on their companion (anal companion 

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exam, ACE). There was 93% concordance between the clinician’s gold-standard DARE and the 
participants’ ASE or ACE for any anal canal abnormality.  
 
STUDY PURPOSE 
The long-term goal of the Prevent Anal Cancer (PAC) Palpation Study is to decrease morbidity 
and mortality from anal cancer by increasing detection of anal canal tumors through self- or 
partner-palpation of the anal canal.  
 
Having established feasibility among MSM to detect an anal abnormality, next steps are to 
derive robust estimates of accuracy for both ASE and ACE (e.g., increased sample size in the 
current study), assess if another clinic can replicate the R21 finding (i.e., UChicago), and assess 
cost-effectiveness of these exams. In this protocol, “accuracy” is a general term for test operating 
performance and predictive value. It includes our outcomes of concordance, sensitivity, 
specificity, positive predictive value, and negative predictive value.19 
 
Our central hypothesis is that both ASE and ACE at Visit 1 will have ≥70% sensitivity and 
≥90% specificity compared to the clinician DARE gold standard; thus, we believe this study will 
demonstrate that MSM can recognize when disease is present. We will test the hypothesis with 
three specific aims: 
 
AIMS 
Aim 1: Estimate ASE and ACE sensitivity and specificity.  
 
Hypothesis: ASE and ACE sensitivity will be ≥ 70% and ≥78%, respectively, at Visit 1; 
specificity will be ≥ 90% on both exams, and there will be no difference in ASE 
sensitivity between Houston and Chicago clinics.  
 
Objective: Our objective in this aim is to compare the men’s ASE or ACE result with the 
clinician gold-standard DARE to determine sensitivity and specificity for each exam at 
two time points. 
 
Aim 2: Determine independent factors associated with ASE and ACE concordance.  
 
Hypothesis: We postulate that practicing the ASE or ACE between visits will be 
associated with concordance between the ASE/ACE and DARE at Visit 2.  
 
Objective: Using regression analysis, determine factors associated with ASE and ACE 
concordance. 
 
Aim 3: Determine the impact of ASE, ACE, and DARE on survival and quality of life, and 
evaluate the cost-effectiveness of these strategies among HIV-positive and HIV-negative 
MSM.  
 

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Hypothesis: We hypothesize that initiating training to perform annual ASE or ACE as 
early as age 30 will lead to cost-effective use of health care resources and will have long-
term health benefits relative to no ASE or ACE.  
 
Objective: Complete an economic and survival analysis of ASE, ACE, and DARE using 
mathematical modeling. 
 
Exploratory aim: Collect qualitative data at Visit 1 from all persons with a false-positive, false-
negative, or true-positive result and a 5% random sample of true-negatives to explore 
participants’ feelings about the ASE/ACE including anxiety among persons with discordant 
results and any needed support. 
 
OUTCOMES 
Our expected outcomes for aims 1 and 2 are sensitivity, specificity and identification of clinical 
and behavioral factors associated with concordance. The outcomes of aim 3 will be the 
computation of incremental cost-effectiveness ratios and net monetary benefits to assess the 
economic viability of ASE, ACE, and DARE. Data on these outcomes are necessary to provide 
options for anal cancer screening given underutilization of DARE, no proven precancer 
treatment efficacy, poor infrastructure for a Pap cytology-based precancer screening protocol, 
and stigma-related barriers that delay clinic attendance for anogenital examinations. Data from 
the proposed study could propel the development of a patient-centered intervention for rapid 
dissemination to a population with extremely high anal cancer incidence and no currently proven 
screening options. 
 
SAMPLE SIZE 
800 participants completing Visit 1: 400 in Chicago and 400 in Houston 
 
POPULATION 
We will recruit MSM and TSM, aged 25 years and over, who acknowledge sex with men in the 
last five years or have a minority sexual orientation, have no unresolved health care provider’s 
diagnosis of anal condyloma, hemorrhoids or anal cancer, speak either English or Spanish, have 
not had a DARE in the prior 3 months, have no plans to move in the following 6 months, and 
have access to medical care for any needed referral and treatment that may be discovered during 
the study. 
 
DURATION OF PARTICIPANT ACTIVITIES 
6 months 
 
 

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Study Timeline 
 
2018 
2019 
2020 
2021 
2022 
2023 
Quarter 
q3 
q4 
q1 
q2 
q3 
q4 
q1 
q2 
q3 
q4 
q1 
q2 
q3 
q4 
q1 
q2 
q3 
q4 
q1 
q2 
Human subjects approvals 
  
  
  
  
  
Initiate/meet with CABs 
  
  
  
  
  
  
  
  
  
  
Complete protocol/build CE models 
  
  
  
  
Pilot full protocol & adjust 
  
Train clinicians and observe  
 
 
 
 
 
 
 
 
 
 
 
Visit 1 clinics 
  
  
  
  
  
  
Interim ASE/ACE practice reminders 
  
  
  
  
  
Visit 2 clinics 
  
  
  
  
  
  
Data cleaning & analyses (Aims 1, 2) 
  
  
  
  
CE analyses (Aim 3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submit abstracts & manuscripts 
  
  
  
  

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PARTICIPANT ENROLLMENT 
Participants in each city must meet all stated eligibility criteria.  
 
Inclusion Criteria 
• Be ≥25 years old 
• Acknowledge sex with men in the past five years or identify with a minority sexual 
orientation 
• Identify as a male or transgender person who has sex with men 
• Spanish or English speakers/readers 
• Is HIV-positive or HIV-negative 
• Is HPV vaccinated or unvaccinated 
 
 
Exclusion Criteria 
• Have a primary residence that is not in the Chicago or Houston metro areas 
• Have had a DARE in the prior 3 months 
• Have unresolved health care provider’s diagnosis of anal condyloma, hemorrhoids or anal 
cancer 
• Have plans to move in the following 6 months 
• Is unable to give informed consent 
 
Recruitment Procedures and Setting 
Chicago and Houston staff will use five strategies:  
1) Social media advertisements to reach persons not accessing clinics and thus more 
vulnerable to late presentation of disease (e.g., Growlr, Scruff, Jack’d, and Facebook); 
2) Face-to-face encounters in clinics serving HIV-positive and HIV-negative persons; 
3) Communication that markets the study within appointment confirmation emails/texts sent 
by Crofoot Clinic (Houston only) 
4) Telephone calls to clinic patients; 
5) CAB-associated peer leader recruitment of friends; 
6) Pamphlet and flyer distribution at clinic sites and in businesses (e.g., bars), non-profits, 
and LGBT events. 
7) Referral Program 
The PAC Referral Program will help direct qualified candidates to the study by incentivizing 
participants to refer partners, friends and family to be a part of the PAC Study. Specifically: 
1) Study staff will provide already-consented participants with information about the 
referral program: 
a. The referral program is designed to spread the word about PAC Study recruitment 
to men who have sex with men and transgender persons who have sex with men.  
b. The referral program and the study are entirely voluntary.  
c. If study participants want to help recruit, they can pass along up to five coupons 
to their partners, friends and family.  

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2) Each coupon is stamped with a unique number. Staff members will record which coupon 
numbers were given to which participants. 
3) Participants can distribute a digital image or hard copy of the coupons to refer persons to 
the PAC Study Eligibility Survey in REDCap. 
4) The referred persons then engage in study activities as anyone else with the exception 
that they will provide the coupon code to a staff person when attending a consenting 
session. Study team members will ask ‘how did you hear about us?’ or ‘who can we 
thank for referring you to the study?” 
5) The participant who referred the person and provided a coupon to person will receive $20 
for each coupon redeemed up to a maximum of five coupons or a total of $100. Form of 
payment, e.g., debit card, gift card or cash app, is up to local site. Sites may decide to pay 
the referrer after each coupon is received or at regular intervals (e.g., bimonthly).   
The study will recruit individuals in each city over 27 months. We will record data on 
recruitment activities, number of calls and website hits, number who decline, ineligibles, and 
those not keeping appointments. 
 
Houston. In 2015, 2,084,981 males, aged 25-79 lived in the Houston metropolitan area. If 6.3% 
of these are MSM, then more than 130,000 MSM live in the metro area. Key recruitment sites 
are the Crofoot Clinic (i.e., the primary clinic site in Houston), Thomas Street Health Center 
(TSHC), Legacy Community Health Services (all of which are neighborhood clinics with annual 
caseloads from 2495 to 5000 MSM), the Montrose Center with multiple projects serving lesbian, 
gay, bisexual, and transgender people (LGBT), and LGBT businesses and non-profits. 
 
Chicago. In 2015, 3,073,639 males, aged 25-79 lived in the Chicago metropolitan area. If 6.8% 
of these are MSM, then more than 200,000 MSM live in the metro area. Key recruitment sites 
are the Chicago Center for HIV Elimination (over 1500 MSM visits in 2014-2015), Connect 
Health (a sexual health clinic housed in the Infectious Disease department at UChicago, the 
UChicago HIV prevention and treatment clinic, and two Federally Qualified Health Centers 
where UChicago providers see patients for HIV treatment and prevention. These sites serve a 
high proportion of African-American MSM on Chicago’s South Side.  
 
Community Advisory Board 
In both Houston and Chicago, we will rely on a 10-member community advisory board (CAB) in 
each city for overall guidance. Comprised of both HIV-positive and HIV-negative MSM and 
TSM and agency representatives who serve them, we will partner with the CAB to ensure study 
materials are culturally competent for middle-aged, older, and racial and ethnic minority MSM 
and TSM. After training on study objectives, anal cancer, and the pilot study, the CABs will 
provide guidance on culturally competent recruitment, educational material design, participant 
follow-up, and results interpretation. The CAB in Houston will convene for an inaugural dinner 
during the first 6 months with regular meetings thereafter. The CAB in Chicago already exists 
and is ongoing. 
 
Eligibility Procedures 
Interested persons will click on a link in recruitment adds or material (or scan a QR code). 
Persons may also act on recruitment material with telephone calls to study staff. The link will 

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take them to a short description of the study in REDCap and then, if interest remains, a short 
survey will assess eligibility. Once eligibility is determined, the person will be asked to provide 
name, email, and phone number in REDCap. Once the person has submitted initial contact 
information, REDCap will notify study staff in the person’s city that a prospective participant 
has been deemed eligible and has provided contact information.  
 
Remote Consenting Appointment 
Staff will go into REDCap to get the contact information and then contact the person to set up a 
virtual appointment for remote consenting through an electronic meeting like WebEx or a smart 
phone call (see detailed consenting procedure below). For persons without this technology, face-
to-face consenting will be an option.  
 
Once consenting is complete, staff will collect other contact information (e.g., address, alternate 
email and phone numbers). Then, staff will set an appointment for Visit 1. The person will be 
provided directions and asked not to have receptive anal sex for 24 hours before the scheduled 
visit and not to douche or do extra cleaning of the anus on the day of the appointment. Persons 
will also be asked to trim their fingernails short.  
 
To end the Remote Consenting Appointment, participants will complete an online Pre-Exam 
Survey in either English or Spanish (all public-facing material will be bilingual in Houston and 
only in English in Chicago) in REDCap. The Pre-Exam survey will collect the person’s 
demographics, co-morbid conditions, and EQ-5D quality of life data, in addition to, knowledge, 
attitudes, beliefs and behaviors regarding anal cancer, self-examinations, sexuality, and COVID-
19.  
 
Once the participant clicks “Submit” for the survey, the Remote Consenting Appointment ends. 
 
Visit 1 
Before the Visit 1 appointment, reminder emails/texts/calls will be made. Eligibility can be done 
in person at Visit 1 if preferred for persons calling rather than using the online eligibility survey. 
 
Visit 1 Overview 
With identical protocols in Houston and Chicago, persons will receive a short didactic 
presentation on anal anatomy, practice on pelvic mannequins, and get instructions on doing an 
ASE or ACE (figure 1). The clinician will then swab the anal canal of each participant, and 
perform a DARE, without disclosing the results, before leaving participants in private to perform 
their ASE or ACE. Participants will record their results (as either “normal” or “abnormal”) and 
then get the clinician’s DARE result along with any needed referrals; thus, the participant result 
will be judged against the clinician gold standard. Participants will then complete the post-exam 
computer-assisted self-interview. At the end of Visit 1, persons will be randomized to a condition 
of encouraged practice of the ASE (or ACE) or a condition of neither encouragement nor 
discouragement from practice. Persons will have Visit 2 in 6 months when concordance of self- 
and companion exam with a clinician DARE will again be assessed. Data collected during these 
visits will be analyzed to complete the aims. 

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Visit 1 Detail 
 
After assessment for COVID-19 symptoms/signs, 
participant weight, height, and waist circumference will be 
measured followed by rooming the participant with 1-3 
other persons in the training room. For this group, the 
study coordinator will provide anal anatomy/disease 
education and ASE/ACE instruction. The study 
coordinator will use pelvic mannequin 1 which has a 
healthy anal canal and mannequin 2 with a 0.6 cm x 1.0 
cm tumor on the anal canal wall (Kyoto Kagaku Co., 
Kyoto, Japan). The study coordinator will demonstrate on 
the mannequins how to palpate for an anal canal tumor 
and ask each participant to practice on the mannequins and 
then identify the mannequin with the tumor. The study 
coordinator will then review the ASE/ACE pictorial 
instructions with participants. Key elements of ASE and 
ACE education are first viewing the perianus region (with 
a mirror or phone selfie), finding a comfortable position, 
and making sure the full 360º of the anal canal is palpated.  
 
In brief, the study coordinator will describe a 5-step 
ASE/ACE: 1) view the perianus, 2) after gloving and 
adding lube, touch the anal opening and feel for an 
abnormality, 3) put a finger in to the first knuckle, try to 
feel 360° around for an abnormality, and then push in to 
the second knuckle and feel again, 4) pull finger out and then re-insert to perform the procedure 
again, and 5) (for individuals only) switch hands (or fingers) and repeat to feel 360° of the canal. 
The full 360° palpation will be emphasized when practicing on the mannequin by showing the 
participant that the full circumference is hard to palpate with only one finger. Participants will 
likely need to switch hands although it may be possible to use the index finger first and then 
opposable thumb on the same hand to palpate the full anal canal. The manner used by the 
participant is less important than full palpation of the anal canal. The study coordinator will 
emphasize that it is not important to distinguish between diseases: any abnormality should be 
noted. This will end the training session. 
 
After each participant is put in a private exam room, a highly-experienced clinician will collect 
anal canal exfoliated cells from the participant using a swab. The clinician will follow the 
Darragh swabbing protocol (e.g., twirling the swab and slowly removing the swab while 
counting slowly to ten, and applying pressure to the anal canal walls).20 The clinician will insert 
the swab into a prelabeled vial with 2 mL of STM, write the date on the vial, and then place the 
vial in a cooler. Onsite processing of the specimen will occur at the end of each clinic which 
consists of logging the specimen in REDCap, vortexing for 45 seconds and then aliquoting the 
liquid into 3 cryovials that are then stored in a -80C freezer. On a monthly basis, the study 
coordinator will overnight specimens in styrofoam containers to the Medical College of 
Coordinator provides anal cancer education,  
mannequin practice, and ASE/ACE instruction 
Clinician performs DARE, without providing results 
Individuals perform ASE and partners perform ACE, 
and record results 
Participants complete post-exam CASI,  
receive DARE result/safety check from clinician,  
and then are randomized  
Figure 1. 
Participants neither 
encouraged nor 
discouraged to practice 
Participants encouraged 
to practice 
Participants conduct ASE/ACE 24hrs before visit 
Clinician provides DARE and DARE result; 
participants complete post-exam CASI 
At Visit 2 
The Day Before Visit 2 

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Wisconsin Tissue Bank laboratory where each specimen will be recorded in a logbook with 
participant ID# and date. These specimens will be archived and made available for testing of 
candidate molecular biomarkers. These results may provide further information on the role of 
ASE, ACE, and DARE in detecting anal abnormalities. The PI will observe the swabbing 
protocol of the first 5 participants in each clinical site and re-observe on a quarterly basis. 
 
After collection of the anal canal exfoliated cells, the clinician will then perform a DARE 
without disclosing results to the participant; however, the clinician will describe to the 
participant the process of the DARE as the DARE is performed (e.g., “I am first looking at the 
area around your anus to see if there is anything that doesn’t look normal.” And “I am now 
feeling all the way around your anal canal to make sure I don’t miss any part of it.”).  The 
clinician will be trained to not provide inadvertent cues on DARE results. After completing the 
DARE, the clinician will then leave the exam room and record the DARE results for both 
perianus and anal canal according to published guidance.21 If an abnormality was observed, the 
clinician will note its location, size in diameter, appearance and color (if perianal) and other 
notable characteristics. The duration of the anal canal swabbing and DARE will be noted to 
inform cost-effectiveness analysis.  
 
The first 40 persons in each city will receive a second DARE done by another experienced 
clinician immediately after the first DARE done by the primary clinician. The clinicians will be 
kept separate for the two DAREs and not disclose their findings to each other. The second 
DARE is done to assess the reliability and repeatability of the primary clinician’s DARE. 
 
Once the clinician leaves the exam room, participants will remain and conduct the ASE/ACE. 
Participants will be trained to stop the procedure if pain is felt. The participant will record on a 
form the ASE/ACE result: either normal or abnormal. The participant will inform staff that the 
ASE/ACE is complete. If the participant detects an abnormality, staff will ask if the abnormality 
was at the perianus and/or anal canal, what it felt like, (i.e., hard or soft) and its size (using 
varying sizes of circles on paper). Persons will then complete a Post-Exam CASI in the exam 
room (one member of a couple will do the CASI in another room to give each participant 
privacy). The couples’ protocol mirrors the individuals’ protocol except that each partner will 
ask the other for consent before performing the ACE. Prostate and distal rectal palpation will 
neither be taught nor expected.  
 
The Visit 1 post-exam CASI requires ~20 minutes to complete and asks about ASE/ACE 
acceptability and self-efficacy, in addition to intentions-to-seek subsequent care, body 
positioning for the exam, history of anal self-exams, alcohol use, recent sexual behavior (type 
and frequency), and anogenital hygiene. Questions to support cost effectiveness analysis are 
included.22  
 
While the participant completes the post-exam CASI, the study coordinator will use REDCap to 
randomize the participant (Arm 1 – practice or Arm 2 – control); if the person is a true negative 
(the coordinator will possess both participant and clinician results at this point) the study 
coordinator will check REDCap to determine if this true negative will receive a qualitative 
interview. 
 

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After the post-exam CASI, participants will remain in the exam room (couples will be reunited) 
and receive DARE results. If the screening result is a true negative (either for an individual, or, 
for couples, both partners), the study coordinator will provide the results, e.g., “You reported that 
your anus felt and looked normal and that’s what the clinician said too. So now you know what 
your anus is like when it’s completely normal. If something changes, you’ll be better able to 
notice there’s a difference.” If the result is a true positive, false positive or false negative, then 
the clinician will provide the result.  
 
If there is a finding of an abnormality on DARE, then standard clinical practices will be 
followed. If needed, clinicians will treat limited external disease, triage other disease, and ask the 
participant to call if there are any concerns in the following week. If the result is a false positive 
or false negative, the clinician will request to immediately perform a second DARE for 
adjudication of the discordant result. All participants with referrals due to abnormal DAREs will 
be followed to assess care-seeking behavior and outcome. 
 
An exploratory aim of this study is to collect qualitative data at Visit 1 from all persons with a 
false-positive, false-negative, or true-positive result and a 5% random sample of true-negatives 
(~65 persons in each city based on pilot data, or ~1 per clinic week over 2 years). Each will be 
invited to participate in an individual interview of up to 15-minutes conducted by a member of 
the project team at each clinical site. Interviews will explore anxiety among persons with 
discordant results and any needed support. Faculty will train staff to use a semi-structured guide 
for interviews.  
 
Randomization 
At the end of Visit 1, all participants will be randomized to one of two conditions: Arm 1 
(practice) or Arm 2 (no practice). One-half of participants in each city will be randomly selected 
and encouraged to practice the ASE/ACE 3 months before Visit 2. Persons randomized to the 
control arm will neither be encouraged nor discouraged from practicing the ASE/ACE. 
 
Arm 1 - Practice Arm 
Persons in the practice arm will pick a date three months after Visit 1. The study coordinator will 
record the date and provide participants written ASE/ACE instructions. Participants who report 
more than minimal pain associated with ASE/ACE at Visit 1, or otherwise have 
contraindications based on DARE results, will be asked to not to practice if randomized to the 
practice Arm. However, all persons will be asked to attend Visit 2 to engage in study activities 
that are not contraindicated at the time of Visit 2. Participants will be reminded that we will 
schedule a Visit 2 appointment and that we will also contact them in 3 months and periodically 
to keep in touch to support study retention. 
 
Arm 2 – Non-practice Arm 
Persons in the non-practice arm will be reminded that we will schedule a Visit 2 appointment and 
that we will also contact them periodically to keep in touch to support study retention. Persons in 
the non-practice arm will be neither encouraged to practice nor discouraged from practice. If 
asked about practice, study staff will reply that the participant is not expected to practice since 
the ASE/ACE is not known at this time to be beneficial. The PAC Palpation Study is trying to 
determine if it’s beneficial. 

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After end-of-Visit 1 study staff will provide a $50 incentive and also tell the participants about 
the Referral Program for recruitment. Anticipated visit duration is about 75 and 90 minutes for 
individuals and couples, respectively.  
 
Between Visit 1 and Visit 2 study procedures 
Arm 1 – Practice.  
If participant had a normal DARE at Visit 1, OR if participant had an abnormal DARE at Visit 1 
that required no referral (e.g., a scar or non-prolapsed hemorrhoids), study staff will make 
reminder calls (or emails/texts) and follow-up calls for the scheduled practice session. At the 
follow-up calls, study staff will record the participant’s result for the self/companion exam and 
the level of anxiety and pain, if any, associated with the exam. If the participant reports more 
than minimal pain and anxiety, they will be asked to return to the clinic for an HCP exam. 
 
If a new abnormality is detected by the participant, i.e., an abnormality not recorded at Visit 1,  
the study coordinator will request they return to the study clinic site for a clinical examination. 
While requesting they return to the clinic, staff will record the participant description of the 
abnormality, and their level of anxiety and pain associated with the ASE/ACE practice. When 
the participant returns to the clinic, staff will record medical outcomes for each person.  
 
Participants not wanting to return to the clinic will be provided referrals by the health care 
provider at the clinic. Efforts will be made to contact persons once each week for up to four 
weeks to encourage a return to the study clinic or completing of the referral elsewhere.  
 
If participant had an abnormal DARE at Visit 1 that required referral (e.g., condyloma or 
suspicious lesion), the person can still participate in practice unless the clinician advises that the 
ASE/ACE is contraindicated due to the Visit 1 abnormality, or the person reported more than 
minimal anxiety or pain due to the ASE/ACE at Visit 1. During follow up, staff will ask about 
referral completion, resolution of the abnormality, and practice ASE/ACE results. If referral has 
still not been completed, staff will again encourage completion of referral or coming back to an 
upcoming study clinic for another DARE. 
 
Participant activity and results between Visit 1 and Visit 2 will be documented in REDCap.  
 
Preparation for Visit 2 
Two weeks before the six-month anniversary of Visit 1, staff will contact participant to confirm 
the Visit 2 appointment time, give instructions for the pre-visit ASE/ACE, and how to report the 
result. Regardless of prior results, all persons will be asked to return for Visit 2. Persons with a 
prior contraindication for ASE/ACE will not be asked to complete the Visit 2 ASE/ACE until 
cleared by a clinician. To reduce loss to follow up, staff will contact participants two days before 
Visit 2 to encourage attendance. 
 
Participants will complete the Visit 2 pre-exam computer-assisted self-interview before coming 
to the clinic for Visit 2. The Visit 2 pre-exam CASI will add questions to the Visit 1 pre-exam 
CASI to assess 1) knowledge retention about how to do an ASE/ACE, 2) use of ASE/ACE 
between visits, 3) health-seeking behavior if a participant detected an abnormality between 

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Version 4.5  
visits,4) social desirability bias23 (to assess response bias related to being compliant about 
practicing), and social support questions.  
 
After the pre-exam CASI, participants will be asked to do the ASE/ACE at home within 24 hours 
before the Visit 2 in-clinic visit. ASE/ACE instructions will be provided upon request. The 
person will then complete an ASE/ACE, record results as either normal or abnormal, and text the 
result to the study staff as soon as they’re done with the anal exam. Persons in the control arm 
will be asked about performing the ASE/ACE between visits, technique, and frequency to 
control for potential confounding. Moving the ASE/ACE to a home-based exam will shorten the 
participant’s time in the clinic which, regarding nosocomial infections like coronavirus, supports 
a safer clinic visit for participants and may encourage more participants to attend the visit. 
 
Participants will complete an online COVID-19 symptoms survey within 24 hours of  Visit 2. 
 
Visit 2 Study Procedures 
During Visit 2, study staff will confirm the participant’s ID, measure their weight and waist 
circumference, and then room the participant in a private room.  
 
The clinician will collect an anal canal swab using a procedure identical to Visit 1 and provide a 
DARE. The clinician will immediately give DARE results (with results recorded using the same 
form from Visit 1) before participants take the post-exam CASI which will explore participant 
responses to knowledge of false-positive, false-negative, true-positive and true-negative results, 
e.g., how does a false-positive result impact intention to perform the procedure in the future? 
 
After completion of the post-exam CASI, persons will be paid $80. They then can leave. 
 
If the health care provider found an abnormality at Visit 2 during DARE that required referral, 
we will maintain contact with the person to record health seeking behavior, treatment received, if 
any, and the outcome. 
 
Persons who initially entered the study with a partner, but are no longer partnered at Visit 2, can 
switch from an ACE to an ASE. These changes will be noted and accounted for in analyses. 
Persons who conducted an ASE at Visit 1 will be asked to conduct an ASE at Visit 2. 
 
To determine the proportion of consented persons who would be interested in a follow-up anal cancer 
study, all persons who consented to the parent study using a UChicago ICF or an MCW ICF will be 
contacted near study end.  Persons will be contacted by the email or phone number provided by them in 
the parent study. If necessary, non-respondents will be contacted up to 3 times starting with their 
preferred method of contact for the first two contacts and switching to another method for the third 
contact. After asking the one question in this effort (see Renewal Survey file), we will record a Yes or No 
in the appropriate REDCap field to record their interest in a future study. 
Data Collected from Study Participants 
For all data collected in the study, personal health information in items 1-6 below will be kept at 
the Medical College of Wisconsin (MCW) on a secure internet-based server that meets Health 
Insurance Portability and Accountability Act privacy standards for health records. 

21 
Version 4.5  
 
1. For each participant, the study coordinator will document completion of study forms and 
activities (e.g., consents and anal swabbing) and record height, weight, and waist 
circumference.  
2. The health care provider will record on hard copy the results of DARE on participants. 
These results may be retained in the clinic and then extracted from the participant record 
by study staff.  
3. Participants will use a one-page form in the clinic to record their detection or non-
detection of perianal and anal canal abnormalities at Visit 1. Participant will text their 
result to a staff member after completing the in-home ASE/ACE. 
4. The study coordinator will record the participant’s understanding about the location and 
size of the abnormality. 
5. In addition to the eligibility CASI before consenting, participants will complete 4 CASIs 
during the study, both pre-ASE/ACE/DARE CASIs and post-ASE/ACE/DARE CASIs at 
each visit. 
6. Qualitative interviews will collect some participants’ reactions to the ASE/ACE results at 
Visit 1, participants’ suggestions on needed resources after doing the ASE/ACE, and 
suggestions for modification of training. 
7. Staff will collect data between Visit 1 and Visit 2, e.g., practice documentation, 
ASE/ACE results, and referral completion. 
8. Participants consenting with a UChicago or MCW ICF will be contacted to determine 
their interest in a follow-up anal cancer study. 
 

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Version 4.5  
BURDEN OF TIME ON PARTICIPANTS DOING THE ASE 
Activity 
Duration 
Pre-Visit 1 - Consenting. 
12 min 
Pre-Exam Online Survey 
8 min 
Visit 1 
 
1. Appointment greeting and photo ID check 
1 min 
2. Body measurements and COVID-9 symptom check 
3 min 
3. Anal anatomy and pathology and self-/companion exam education (Visit 1 only) 
10 min 
4. Anal swab 
2 min 
5. DARE 
2 min 
6. Anal-self exam or Anal companion exam 
10 min 
7. Post-Exam CASI  
20 min 
8. Results including referral or schedule for treatment if needed 
7 min 
Total time 
 75 min 
Other: for first ~40 persons in each city, second DARE (QA and reliability study) 
2 min 
Other: estimated 28 persons in each city will have discordant result and clinician will offer to give 
participant another DARE to adjudicate 
2 min 
Other: for an estimated 65 persons in each city, a qualitative interview will be done 
15 min 
 
Note. Persons in couples doing the ACE at Visit 1 will require about 90 minutes for the visit. For Visit 2, 
persons will not receive the anal anatomy/pathology and ASE/ACE face-to-face education. Rather, they 
will be given instructions and asked to do the exam without benefit of a training session with study staff; 
then the clinician will do a DARE and provide results and any needed referrals during the same face-to 
face. 
 
 
Activity 
Duration 
Immediately before Visit 2 
 
1. Pre-Visit 2 Pre-Exam Online Survey  
10 min 
2. Anal-self exam or Anal companion exam  
8 min 
3. COVID-19 Symptom Online Survey 
3 mins 
 
 
During Visit 2 
 
4. Appointment greeting, body measurement [weight and waist circumference] ID confirmation 
3 min 
5. Anal swab, DARE and results with clinician including referral or schedule for treatment if 
needed 
5 min 
6. Post-Exam CASI  
20 min 
Total clinic time 
28 min 
Other: estimated 25 persons will have discordant result and clinician will offer to give participant 
another DARE to adjudicate 
 
 
 

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STATISTICAL ANALYSIS 
Aim 1 
The central hypothesis is that both ASE and ACE at Visit 1 will have ≥70% sensitivity and 
≥90% specificity using the clinician DARE as the gold standard. We will test our central 
hypotheses at Visit 1 by comparing ASE and ACE sensitivity and specificity to random guessing 
(i.e., sensitivity and specificity=50%) using a one-sample test for proportion. We will then 
conduct a test of equivalence using two, one-sided likelihood score tests to compare ASE 
sensitivity in Houston vs Chicago clinics to determine if the ASE performance is equivalent in 
each city; thus, we will assess the homogeneity of Houston and Chicago sensitivity before 
combining results. We focus on sensitivity since this factor performed worse than specificity in 
the pilot study and had wide confidence limits. Sensitivity will also be stratified by other factors, 
for example location (anal canal vs perianal) and co-morbidities, to determine the effect on 
sensitivity. Tests will be two-sided with a 0.05 alpha. We will estimate percent agreement, 
positive predictive value, negative predictive value and perform receiver operating characteristic 
(ROC) curve analysis for a binary outcome. 
 
To test our central hypothesis, our pilot data indicate 1) 11% of persons will have condyloma, 
hemorrhoids, skin tags, scars, or malignant tumors at Visit 1 at the anal canal or perianal region, 
and 2) a sensitivity of ≥70% on ASE and 78% on ACE and specificity ≥90% for both at Visit 1. 
Given a null value for sensitivity and specificity of 50% (since we seek to rule out accuracy due 
only to chance), our power to detect sensitivity ≥70% among 600 individuals is 0.90 and 0.81 
among 200 couples. Power to detect specificity ≥90% among both individuals and couples is 
>0.90. For multiple comparisons we will use the False Discovery Rate. Using a test of 
equivalence, our hypothesis of no difference in ASE sensitivity between Houston and Chicago 
assumes that a difference of less than 0.15 constitutes equivalent sensitivity given that a smaller 
difference may have little practical relevance for adjusting the protocol in either city. Under this 
definition of equivalence, we have at least 0.87 power to detect a lack of equivalence in 
sensitivity between the cities if the actual observed difference ranges from 0 to 0.05. Power was 
assessed with PASS13. 
 
Qualitative data at Visit 1 will be analyzed with concurrent mixed-methods design, i.e., a 
participant’s study ID number will link qualitative to quantitative data. Demographic 
characteristics and summary statistics from the CASIs involving quantitative cognitive and 
affective responses to the ASE/ACE of the ~125 persons getting a qualitative interview will be 
imported into Atlas.ti (Scientific Software Development GmbH, Berlin, Germany). During 
qualitative analysis, the imported quantitative data will be used to stratify the 125 persons by 
demography or other categorical data. Qualitative data will be analyzed as it is collected, per the 
constant-comparative method.24 Specifically, as interviews are completed, transcripts will be 
entered into Atlas.ti for analysis within ~72 hours. Faculty and a graduate research assistant team 
will independently code the data, meet to compare codes, and resolve discrepancies by 
collapsing and reorganizing codes to arrive at a common codebook. The researchers will then use 
axial coding to identify relationships between codes. To arrive at an explanatory model, the team 
will compare findings and recommendations to the existing literature,18,25 and consult CAB 
members for interpretation. The final explanatory model will aid in understanding how anal 
cancer knowledge and perceived risk for anal cancer affects ASE/ACE performance. In 
particular, we will explore anxiety among persons with false-positive results because the false-

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Version 4.5  
positivity rate was 14% among persons in the pilot study who said anal cancer concerned them 
“a lot,” while among persons who had no, little, or some concern, the false positivity rate was 
5% (p=0.58) suggesting that anxiety may play a role in false-positive results. 
 
Aim 2 
There is one primary outcome for Aim 2: the association between practice and concordance at 
Visit 2. Concordance is binary and equals 1 when both participant and clinician identify an 
abnormality or agree on its absence; thus, the statistical analysis is premised on detecting an anal 
abnormality, not a cancer. We postulate that practicing the ASE or ACE between visits will be 
associated with ASE/ACE and DARE concordance at Visit 2. To derive unbiased estimates in 
multivariable modeling for the association between practice and concordance, we will use 
directed acyclic graphs to identify potential confounders to include in models (e.g., age, 
ethnicity, race, city, anxiety, chronic disease, and, for ACE, co-teaching and reported familiarity 
with a companion’s body) and intermediate variables to exclude from multivariate modeling; 
however, given successful randomization, bias, including confounding, should be minimized. 
Both intent-to-treat and per-protocol analyses will be conducted (we expect a similar proportion 
of persons in the practice and non-practice arms to switch arms of their own accord, i.e., 
crossover, between visits). The association will be assessed with logistic regression. After 
univariate analyses, variables where p≤0.25, and which are not intermediate variables, will be 
added to a multivariable model using backward selection with binary practice (yes/no) retained 
in the model. After adjustment for potential confounders, factors where p<0.05 (two-sided) will 
be considered statistically significant. Adjusted and un-adjusted odds ratios will be reported with 
95% confidence intervals. We will use a similar approach to derive unbiased estimates in 
multivariable modeling for the association between continuous waist size and concordance; 
however, we will also use ROC curves to ascertain the potential for a threshold effect of waist 
circumference size on concordance. We will also assess the full set of other study data and their 
potential associations with concordance. For multiple comparisons we will use the False 
Discovery Rate. Finally, we will investigate effect modification by age and individual/couple 
status. 
 
For the Aim 2 hypothesis, that practice will be associated with concordance in all persons at 
Visit 2, sample size will be adjusted downward by dropouts and non-resolving abnormalities 
from Visit 1. We expect 11% of persons (n=88) to have an abnormality at Visit 1 (based on pilot 
data) with most of these being hemorrhoids and condyloma. We conservatively expect 50% of 
hemorrhoids and condyloma to resolve in 9 months; thus, there will be a minimum of 44 non-
resolving events from Visit 1 and another 10% of persons will dropout (800-44=756; 756-76 = 
680). We have 80% power to detect an odds ratio of at least 1.55 or larger if concordance is 85% 
and n=680.  
 
Aim 3 
All data used in Aim 3 come from literature, our previously published studies, and data collected 
in Aim 2 and Aim 3. For example, CASI and DARE results will provide data on screening test 
characteristics, screening test costs, and quality of life scores. The parameters required to 
structure the decision-analytic model will be derived from these sources. 
 

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For comparative cost-effectiveness analysis, we will consider these strategies: no screening, 
ASE, ACE, and clinician DARE. In addition, we will evaluate the optimal interval for 
performing these tests (annual, biennial, or triennial) and optimal age to initiate training MSM to 
perform the test.  
 
For the analysis, we will develop an individual-level state-transition (i.e., micro-simulation) 
model (STM). They also enable screening interval evaluation, and appropriate screening ages. 
The model will be programmed in TreeAge Pro 2016 software (TreeAge Software, Inc., 
Williamstown, MA). 
 
The starting (hypothetical) cohort will be comprised of MSM in the US distributed in health 
states based on the baseline prevalence of anal HPV infection and anal dysplasia among HIV-
positive persons. Patient profiles will be defined based on history/diagnosis of anal 
abnormalities, HIV disease status (i.e., current and nadir CD4 count of CD4>500, CD4 200-500, 
or CD4<200), HPV vaccination status, and receipt of antiretroviral therapy (yes or no). We 
identified these characteristics as they might impact long-term outcomes including survival, 
quality-adjusted life years (QALYs), and anal cancer mortality risk. Baseline age will be 
assigned according to the age distribution of MSM in the US. The cycle length (i.e., the amount 
of time represented by each model simulation step) will be 12 months which seems appropriate 
(1) since persons in our pilot study were willing to screen at least every few months, (2) given 
recommendations of an annual DARE, and (3) given a higher likelihood that more frequent 
exams will detect anal tumors at an earlier stage. 
 
Health quality of life scores will be assigned for each health state using utility scores (i.e., quality 
of life weights) ranging from 0.0 to 1.0. This assignment will be computed as the mean EQ-5D 
score associated with each participant who is classified in each health state. 
 
Direct costs of performing ASE, ACE, and DARE (e.g., cost of gloves and lubricant) will be 
determined using a “micro-costing” approach with data on resources used coming from Aim 1. 
Clinician time cost for performing DARE will be obtained from the Medicare fee schedule 
(using HCPC S code G0102). We will also include direct non-health-related costs, for example, 
individual and/or couple time cost for performing ASE/ACE (collected in the R21 pilot study). 
Previously, our group estimated the cost of anal cancer care in the US and clinical and cost-
effectiveness of treating early stage anal cancer. We have also identified the costs of care for 
HIV, condyloma, and hemorrhoids. 
  
The accuracy of our decision-analytic model will be evaluated by performing extensive model 
validation that will compare model-predictions to the outcomes reported in the literature. For 
instance, we will compare age-specific cumulative risk of anal cancer among HIV-positive MSM 
to the cumulative risk reported in a recent analysis of the HIV/AIDS Cancer Match Study. 
Similarly, we will compare model-predicted mortality among HIV-positive persons to the 
mortality risk estimated independently using databases from SEER-Medicare (>3,500 HIV-
positive men with 33 anal cancer cases) and NA-ACCORD (>100,000 HIV-positive persons 
(>50% MSM) with 245 squamous cell anal carcinoma cases). We will assume an average DARE 
utilization rate of 23% in the US.  If the predicted model outcomes fall outside the 95% 

26 
Version 4.5  
confidence intervals of the reported data, we will calibrate the parameters such that the model 
outcomes are within the limits. 
 
The microsimulation allows us to perform calculations of the expected economic costs and 
clinical outcomes of life expectancy and long-term quality of life and estimate stochastic 
uncertainty with confidence intervals for each strategy. When executed, an individual transitions 
from one state to another according to the transition probabilities, participant physiologic 
characteristics, and prior health history. As an individual passes through each health state, the 
utility value is accumulated for a period of time equal to the cycle length of the microsimulation 
model (i.e., 12 months). By accumulating utilities over the lifetime of the model, we will obtain 
the quality-adjusted life expectancy for each strategy. The same methodology applies to 
determining the expected costs for the strategies. We will discount costs and QALYs by 3%. 
 
Cost-effectiveness using societal- and health care-sector perspectives will be evaluated in terms 
of incremental cost-effectiveness ratios (i.e., the ratio of difference in costs between 2 
alternatives to the difference in effectiveness between the same 2 alternatives), comparing each 
strategy in sequence from lowest expected cost to most expensive. Issues of strong and weak 
dominance of clinical strategies will be considered. We will use the commonly accepted 
willingness-to-pay (WTP) threshold of $100,000/QALY to determine the most-cost-effective 
strategy. As per the guidelines from the second panel on cost-effectiveness analysis, we will also 
estimate net monetary benefits (i.e., the linear combination of costs and effects expressed in US 
dollars). Other long-term health outcomes will be estimated in terms of lifetime risk of 
developing anal cancer among individuals who performed ASE or ACE relative to no screening, 
lifetime anal cancer mortality risk among those individuals, and life expectancy gained attributed 
to screening using anal examinations.  
 
To evaluate robustness of the outcomes, we will perform comprehensive sensitivity analysis on 
all model parameters. We will perform one-way sensitivity analyses, varying model parameters 
(e.g., screening accuracy, treatment efficacy, costs, etc.) to look for consistent patterns in the 
results. Decision uncertainty will be evaluated using probabilistic sensitivity analysis (PSA).  For 
PSA, we will perform 10,000 runs of Monte Carlo simulation using two nested simulation loops 
where the inner loop will evaluate the outcomes across the simulated population and the outer 
loop will sample those parameters to reflect the uncertainty in the model parameters. The 
outcomes of PSA will be presented in the form of a cost-effectiveness acceptability curve, which 
plots the probability that an intervention is cost-effective against various willingness-to-pay 
thresholds. 
 
Exploratory analysis of de-identified data may also be done by collaborators including the 
Medical University of South Carolina. The Safe Harbor method will be used to de-identify the 
data https://www.hhs.gov/hipaa/for-professionals/privacy/special-topics/de-
identification/index.html#standard. 
 
 
PROTOCOL FIDELITY AND QUALITY CONTROL 
Protocol activities will be documented with a checklist. To ensure identical protocols in each 
location, qualified clinicians will conduct clinical exams of participants after being trained in the 

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study protocol by Dr. Nyitray and after being trained in the study's clinical procedures by either 
Dr. Hazra, Dr. Schneider, Dr. Chiao, or Nurse Practitioner Maggie White. 
 
At study start and semi-annually, the PI will observe all procedures for two individuals in both 
Houston and Chicago sites and provide critique to prevent drift in study protocol. Houston co-I 
Dr. Chiao and Chicago co-I Dr. Schneider will attend five initial Visit 1 appointments in 
Houston and Chicago, respectively, to observe the clinician’s DARE technique and protocol. 
 
To document the repeatability of the NP DARE results (which was 95% in the pilot), a second 
clinician at each clinic will perform a second DARE on ~40% of persons in each study site in the 
first six months of enrollment (i.e., 40 in each city). The secondary NPs will also be trained in 
study protocol and DARE. 
 
HUMAN PROTECTIONS 
Overview 
The principles of Institutional Review Board (IRB) approval and informed consent described in 
the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 56) and Department 
of Health and Human Services (DHHS) regulations for the Protection of Human Subjects 
regulations (45 CFR Part 46)] must be followed. IRB approval of the protocol and the informed 
consent form must be given in writing. 
 
The Investigator(s) must receive a copy of the letter of approval from the IRB, which specifically 
approves the protocol and informed consent, before participant enrollment. The IRB must also 
approve any significant changes to the protocol and documentation sent to the Investigator(s). 
The IRB must review the research project at least once every 365 days during the project. 
Continuing approval of the project must be given in writing and provided to the Investigator(s). 
  
Records of all study review and approval documents must be kept on file by the Investigator and 
are subject to inspection during or after completion of the study. Adverse events must be 
reported to the IRB according to local procedures. The IRB should receive notification of 
completion of the study and final report within 3 months of study completion and termination. 
The Investigator will maintain an accurate and complete record of all submissions made to the 
IRB, including a list of all reports and documents submitted. The Investigator will grant 
monitor(s) and auditor(s) from the NCI and regulatory authorities access to the participants’ data. 
Participants confidentiality will be maintained and will not be made publicly available to the 
extent permissible by the applicable laws. 
 
As detailed below 
 
• Persons must have provided informed consent to participate in the study; 
• All participant data must be handled and stored securely;  
• Study risks will be reduced with adequate protections from risks; 
• Participants will be monitored for adverse events; 
• A Data and Safety Monitoring Board will monitor participant welfare. 
 

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Version 4.5  
Institutional Review Boards (IRB) at UChicago, UTHealth, and MD Anderson will receive 
approval for their protocols and consents and then submit those approved documents to the 
Principal Investigator who will include these documents in an IRB application at MCW. Once 
MCW has approved the full study protocol, recruitment can begin. All persons working with 
participants or participant data will have relevant human protections training.  
 
Informed Consent Process   
The process for obtaining informed consent will use a video conference or a phone call to a 
person with a smart phone. Persons who do not have access to this technology will be consented 
in person. 
 
At the beginning of the electronic consent meeting (pre-arranged by appointment), staff will ask 
participant to confirm email address and name and then use REDCap to send the person a link by 
email or text (depending upon technology used by the person). Person will click on the received 
link to open the ICF in REDCap. Receipt of the unsigned ICF on the computer/tablet or smart 
phone, will be confirmed by the participant before beginning the consent session. With delivery 
of REDCap electronic versions of the ICF, both study staff and participant will now be viewing 
the study ICF. Study staff will explain study procedures, risks, benefits, confidentiality. Prior to 
signature, the staff member will ask the participant if they have any questions and, if not, to 
briefly review their understanding of their participation to be sure the information was clearly 
understood. The person obtaining consent will emphasize that participation is voluntary and that 
participants can choose to join or, if they do join, leave the study at any point without any 
repercussions. Study staff will frequently refer to pages, headings or some other marker in the 
ICF to make sure the participant is following along. 
 
Persons agreeing to provide consent will sign the ICF as follows: a. Touch screen - persons will 
use finger or mouse to sign; b. No touch screen - persons will use a mouse to sign. After signing, 
person will submit by clicking on/touching the “Submit” button on the REDCap screen 
displaying the ICF. REDCap has two settings to send signed ICFs to participants and both will 
be employed to allow participants to have their choice of either downloading a pdf of the signed 
ICF or receiving an email with signed ICF attached. 
 
For consents in person, the participant's identification is checked when coming to the consent 
face-to-face meeting. When a participant appears for an appointment, they will be thoroughly 
informed of all study procedures, potential risks, benefits, and that one can discontinue 
participation in the study at any time without risk to subsequent care at the place(s) where health 
care is received, etc. 
 
Participants in couples must both consent to the study to be enrolled as partners. They can be 
consented together. 
 
Use and Access of Protected Health Information (PHI) and Retention of Records 
The primary platform for collection of all study data is REDCap (REDCap, Vanderbilt 
University) which will store data on a secure internet-based server. REDCap meets Health 
Insurance Portability and Accountability Act privacy standards for health records. Study PCs 
will have passwords and strong data encryption installed as per requirements at MCW.  

29 
Version 4.5  
 
Staff will collect participant contact information such as email address, telephone number, and 
mailing address to send study reminders and to share study-related updates. Staff will also collect 
information about secondary contacts to support study retention if initial contact information is 
no longer valid. Staff will not collect social security numbers. 
 
All other study data will be coded only with a Study ID.  Personal identifiers such as name, 
address and phone number will be removed from clinical results. The computer-assisted self-
interviews will be identified only by ID number and do not contain personal identification 
information. Information linking the participants’ identity to the study code will be kept in a 
Linking Log on a secure server. Separate cabinets will contain informed consents. 
 
CASI data will be delivered directly from tablets and PCs in Chicago and Houston to MCW 
servers using REDCap. Clinician and participant data from clinic visits will be collected in hard 
copy and then entered into REDCap. Qualitative interview data will be collected in hard copy 
and by audio recordings on study computers. Audio recordings will be transcribed with both 
recordings and transcriptions stored on MCW servers. Original hard copies of all data will be 
stored in locked file cabinets separate from linking logs and consents. 
 
After all study queries and analyses are completed, the data/PHI will not be destroyed but will be 
archived in a secure long-term storage site to keep an accurate record of screened and enrolled 
subjects for the sponsor and potential audit purposes only specific for this study. No information 
that could lead to personal identification of participants will be included in any of the reports or 
given to any non-authorized person. Staff will store the identified information for 10 years after 
study completion, as required by the NIH. Staff will destroy all personal identifiers after analyses 
are completed.    
 
Risks to the Subjects 
The risks to participants can be divided into four groups: a) risks during the health care provider 
DAREs, b) risks during collection of anal canal exfoliated cells, c) risks during the ASE/ACE, 
and d) concerns about disclosure of confidential, sensitive information. 
 
a) Each health care provider will perform a DARE on the participant which will entail inserting a 
gloved finger into the anal canal. While this is a common and safe procedure, it may be mildly 
uncomfortable or embarrassing for some participants.  
 
b) Collection of anal canal cells: Some persons may feel embarrassed about a health care 
provider inserting a swab into the anal canal. The swab can be uncomfortable, and occasionally 
there can be some bleeding. Justification: Currently there is no acceptable anal cancer biomarker. 
These specimens will be archived and then available for testing of candidate biomarkers. 
 
c) The participant will perform an ASE/ACE which will entail the participant looking at the 
perianal region (individuals will use a mirror or selfie) and then inserting a gloved finger into 
their own anal canal or that of their partner. While it is common for a person to insert a finger 
into the anus or the anus of another while having sex or engaging in exploration or self-hygiene, 
it may be uncomfortable or embarrassing for some participants. Partners will ask each other for 

30 
Version 4.5  
consent before performing the procedure. If an anal fissure is present, finger insertion could be 
more painful. It is also possible that a participant will palpate a mass which may induce anxiety, 
e.g. if the participant imagines that the mass could be a malignant tumor. This risk is justifiable 
because the participant will, at the same visit, meet with a health care provider who completes a 
DARE on the participant and who can explain the results and support onsite treatment or referral 
for treatment if needed. 
 
d) This study will ask sensitive questions about sexual behavior and disease status. Some people 
may fear that unauthorized persons, who may discriminate, might obtain this information or 
otherwise cause a change in the participant’s social status or access to benefits to which 
participants would otherwise be entitled. In addition, some persons who do a qualitative 
interview may feel uncomfortable talking about their ASE/ACE experience. This information is 
needed to better understand how to modify instruction in the procedures to reduce false-
negatives and false-positives, and how to support health care engagement for true-positives. The 
study team will do everything possible to protect subjects’ confidentiality. 
 
Alternatives to study procedures 
The only alternative screening for anal cancer is an anal pap test and high-resolution anoscopy; 
however, this screening modality is not a standard practice at the current time, nor one widely 
recommended or available, especially for HIV-negative men who have sex with men who are 
nevertheless at increased risk for anal disease. The infrastructure for high-resolution anoscopy is 
limited so that even persons with HIV who have abnormal anal Pap tests may wait months before 
getting an appointment. This is one reason that expert opinion recommends DARE for HIV-
negative and HIV-positive MSM. 
 
Protections against risk 
When the nurse practitioner performs a DARE on the participant, standard medical practice for a 
DARE will be used including gloving, use of lubricant, and a few seconds of hesitation while the 
finger is on the anal os to allow sphincter muscles time to relax. The nurse practitioner will 
visually inspect the perianal region before performing the DARE. If the nurse practitioner sees 
an anal fissure, anal fistula, or other condition that is a contraindication for a DARE, the nurse 
practitioner will discontinue the clinical visit and provide treatment and/or referral to the 
participant. The participant will be allowed to rejoin the study after the condition heals. 
Confidential, sound-proofed exam rooms are provided for all exams. 
 
When giving DARE results at the end of the visit, the nurse practitioner will treat found anal 
disease (if appropriate), provide any necessary referrals, and ask to be notified if a participant has 
any anus-related concerns in the following week. If any participant reports an abnormal outcome 
between Visit 1 and Visit 2, the nurse practitioner will ask the participant to return to the clinic 
for a DARE and any necessary treatment (and/or referral to a colorectal surgeon if treatment at 
the study clinic is not possible). If any participant reports an adverse event, the nurse practitioner 
will immediately provide necessary treatment (and/or referral to a colorectal surgeon if treatment 
at the study clinic is not possible). The nurse practitioner will also document the event and 
forward the document to the PI and co-Investigators within 24 hours. The event will then be 
reported to the NIH, as appropriate, to ensure safety of participants. 
 

31 
Version 4.5  
Study staff will be instructed to perform the ASE/ACE with gloved hands, use of lubricant, and 
hesitation before finger insertion to allow sphincter muscles time to relax. ASE/ACE training 
provided by the coordinator or educator will emphasize proper gloving technique to reduce the 
potential for delivery of pathogens into the anal canal or for receipt of pathogens already resident 
in the anal canal. In addition, the study coordinator will emphasize that a fissure at the anal os 
may make inserting a finger painful for the recipient. If this occurs the study staff will advise that 
the ASE/ACE be stopped and that the participant may need to seek medical attention. Finally, 
the coordinator will emphasize that palpation of a mass does not mean a person has cancer since 
there are a number of conditions that may create a mass. 
 
Computer-assisted self-interviewing will be used so participants can confidentially report 
sensitive behaviors while minimizing feelings of shame or embarrassment discussing sexual 
histories.  
 
Names will be kept separate from coded identifiers according to standards set for PHI. All 
computers will require a password to access files.  
 
Benefits 
The benefit of the research to participants is that they will learn about anal conditions common 
among MSM and TSM who have sex with men. In addition, they will receive two examinations 
of their anal canal by a highly experienced nurse practitioner and thus potentially learn of an anal 
condition or disease and need for treatment. Thus, the risk of mild discomfort during study 
procedures (either physical discomfort during clinical procedures or psychological discomfort 
due to sensitive survey questions) are reasonable within the context of important educational and 
personal health information gained by the participant. 
 
The knowledge gained by this research will benefit society by determining the viability of the 
ASE and ACE for persons at high risk for anal cancer and other anal conditions. This 
information is necessary given increasing disease incidence, the lack of infrastructure for anal 
cancer screening, and declining DARE use by clinicians. Data from the proposed study will 
propel the development of a patient-centered intervention that could be rapidly disseminated to 
communities with high anal cancer incidence and no currently accepted screening options; thus, 
the risks to participants is reasonable given the information we may learn that could help reduce 
anal cancer incidence. 
 
Adverse Event Reporting 
Expected and unexpected adverse events will be reviewed by the research team on a weekly 
basis. We expect this study to be of minimal risk since all activities are already commonplace 
and routinely used in clinics globally.  
 
Data and Safety Monitoring Committee  
The MCW Cancer Center’s Data and Safety Monitoring Committee (DSMC) will monitor this 
study. The DSMC will help ensure the safety of the participants by monitoring adverse outcomes 
throughout the study and by reviewing outcome data for possible harm. The DSMC will pay 
particular attention to the potential for severe anxiety in participants who believe they may have 
palpated a malignant disease in their anus.  

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Version 4.5  
 
The table below specifies which adverse events (AEs) and serious adverse events (SAEs) should 
be reported to the DSMC and when they should be reported. An SAE is defined as an adverse 
event that (1) results in death, (2) is life-threatening, (3) requires inpatient hospitalization or 
prolongation of existing hospitalization, (4) results in persistent or significant 
disability/incapacity, (5) results in a congenital anomaly/birth defect, or (6) is an important 
medical event that jeopardizes the subject or requires medical intervention to prevent one of 
outcomes listed above. Adverse events will be graded according to CTCAE v5. 
 
Please note that the above guidelines are for the DSMC only. SAEs also need to be reported to 
the IRB, and participating sites should follow their IRB’s institutional guidelines for reporting.  
 
A running log of deviations should be kept and reported to the DSMC at time of scheduled 
monitoring. Any deviations requiring immediate reporting to the IRB should also be reported to 
the DSMC immediately. 
 
Any other events requiring immediate reporting to the IRB (e.g., Unanticipated Problems 
Involving Risk to Subject or Other) should also be reported to the DSMC immediately. 
 
A summary of the MCWCC DSMC activities are as follows:  
 Review the clinical trial for data integrity and safety.  
 Review any adverse events as specified above, as well as deviations.  
 Submit a summary of any recommendations related to study conduct to the PI.  
 Terminate the study if deemed unsafe for participants.  
Attribution 
SAE 
AE 
Grade 1, 2, and 3 
Grade 4 and 5 
Grade 3 
Grade 4  
Expected 
Unexpected 
Expected 
Unexpected 
Unexpected 
Expected 
Unexpected 
Possible 
Probable 
Definite 
Not 
required 
to be 
reported 
Within 5 
calendar 
days1 
Within 5 
calendar 
days1 
Within 5 
calendar 
days1 
Routine 
reporting2 
Within 5 
calendar 
days1 
Within 5 
calendar 
days1 
Unrelated 
Unlikely 
Not required to be reported to DSMC 
1For expedited (within 5 calendar days) DSMC reporting, the study coordinator must notify 
the DSMC via email including the subject ID, date of event, grade, relatedness, 
expectedness, and a short narrative. The event should also be entered on the Adverse 
Event Log.  
2For routine reporting, events should be entered onto the Adverse Event Log for review at 
the time of DSMC scheduled monitoring.  
 

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The committee will review the study for scheduled monitoring after completion of 100 of 
participant visits and at six-month intervals thereafter (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary. Any available 
DSMC letters will be submitted to the IRB of record as required. 
REPORTING TO COMMUNITIES 
At the time of publication of study results, public presentations to members of lay communities 
involved in the study will be scheduled. Study results will be published in per-reviewed journals 
and presented at conferences. 
 
 

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References 
 
1. 
Colon-Lopez V, Shiels MS, Machin M, et al. Anal cancer risk among people with HIV infection in 
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Silverberg MJ, Lau B, Justice AC, et al. Risk of anal cancer in HIV-infected and HIV-uninfected 
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Chaturvedi AK. Beyond cervical cancer: Burden of other HPV-related cancers among men and 
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Macaya A, Munoz-Santos C, Balaguer A, Barbera MJ. Interventions for anal canal intraepithelial 
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4, 2017. 
 
 
 

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APPENDIX I: INFORMED CONSENT 
APPENDIX II: INSTRUCTIONS FOR ASE AND ACE 
APPENDIX III: PROTOCOL FOR CLINICAL SWABBING 
APPENDIX IV: PROTOCOL FOR SPECIMEN PROCESSING 
APPENDIX V: VISIT 1 PRE-EXAM CASI 
APPENDIX VI: VISIT 1 POST-EXAM CASI 
APPENDIX VII: VISIT 2 PRE-EXAM CASI 
APPENDIX VIII: VISIT 2 POST-EXAM CASI 
APPENDIX IX: SEMI-STRUCTURED QUALITATIVE INTERVIEW GUIDES 
 
True Negative 
 
True Positive 
 
False Positive 
 
False Negative 
APPENDIX X: SCRIPTS 
Setting an appointment 
Clinic Session: Anal Anatomy, Pathology, and ASE/ACE Procedures 
APPENDIX X1: COORDINATOR FORMS 
 
Clinic Activity Checklist 
 
Abnormal ASE Finding Detail 
 
Abnormal ACE Finding Detail 
APPENDIX X11: CLINICIAN FORMS 
 
DARE and Swabbing 
APPENDIX X111: PARTICIPANT FORMS 
 
ASE Finding 
 
ACE Finding 
 
Anal Medical History 

37 
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APPENDIX XIV: KYOTO MODEL (INSERT Kyoto sales flyer)