Randomized Controlled Trial of the Stool DNA Test to Improve Colorectal Cancer Screening Among Alaska Native People
Phase: NA
Conditions: Colorectal Cancer
Sponsor: Alaska Native Tribal Health Consortium

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RANDOMIZED CONTROLLED TRIAL OF THE STOOL DNA TEST TO IMPROVE COLORECTAL CANCER 
SCREENING AMONG ALASKA NATIVE PEOPLE (NCT04336397)
Principal Investigator: Diana Redwood, PhD MPH.1 
Consultants: Mark Thorndike, MD;2 James Tiesinga, MD; 2 John Kisiel, MD; 3 Lila Rutten, PhD; 3 
Judith Kaur, MD; 3 Peter Holck, PhD.4 
1Alaska Native Tribal Health Consortium, Anchorage AK. 
2Alaska Native Medical Center, Anchorage AK. 
3Mayo Clinic, Rochester MN and Jacksonville FL. 
4Holck Consulting, Anchorage AK 
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TABLE OF CONTENTS 
Abstract ........................................................................................................................................... 3 
1. Introduction ................................................................................................................................ 4 
1.1 Specific Aims ................................................................................................................. 5 
1.2 Rationale and Supporting Data ....................................................................................... 5 
2. Study Design and Approach ..................................................................................................... 6 
2.1 Study Team ..................................................................................................................... 6 
2.2 Theoretical Framework .................................................................................................. 7 
2.3 Study Site, Data Sources and Study Population ............................................................. 8 
2.4 Inclusion and Exclusion Criteria .................................................................................... 9 
2.5 Statistical Analysis ......................................................................................................... 9 
3. Human Subjects Protections ................................................................................................... 10 
3.1 Recruitment and Informed Consent .............................................................................. 10 
3.2 Potential Risks .............................................................................................................. 12 
3.3 Protection Against Risks .............................................................................................. 12 
3.3.1 Storage and Coding of Data ............................................................................. 13 
3.3.2 Data and Safety Monitoring Plan ..................................................................... 13 
3.4 Potential Benefits of the Research ................................................................................ 14 
3.5 Disposition of Data ....................................................................................................... 14 
3.6 Publication and Dissemination ..................................................................................... 15 
Appendix A ................................................................................................................................... 16 
Literature Cited ........................................................................................................................... 17 

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ABSTRACT 
 
Background: Only 59% of Alaska Native (AN) people have been adequately screened for colorectal 
cancer (CRC), despite having the highest reported burden of CRC in the world. A new take-home 
noninvasive screening method is now available, the multi-target stool DNA test (MT-sDNA; Cologuard) 
which includes a novel patient navigation system. However, MT-sDNA has not been tested for feasibility 
and acceptability within the Alaska tribal health care delivery system, and it is unknown whether use of 
this new test will increase AN screening rates. Addressing this unmet need will help us better understand 
what CRC screening methods work best in rural/remote tribal and underserved communities. 
 
Objective: This research study will pursue two specific aims: (1) identify patient-, provider-, and system- 
level factors associated with CRC screening preferences, uptake, and follow-up; and 2) test the hypothesis 
that multi-level high and medium intensity MT-sDNA community-based interventions, as compared with 
usual care, will increase CRC screening rates among AN people in rural/remote communities. 
 
Methods: For the first aim, focus groups and interviews of AN people who are non- or inadequately 
adherent to CRC screening guidelines and their healthcare providers will be used to identify individual, 
interpersonal (provider), and health system factors for future intervention. For the second aim, a three-arm 
cluster randomized controlled trial (high intensity with patient navigation, medium intensity with mailed 
reminders, usual care) will provide evidence on the usefulness of MT-sDNA in remote AN communities 
as well as the first data on MT-sDNA adherence rates in the AN population. 
 
Conclusion: The results of this study will help inform clinical practice and policy throughout the ATHS. 
We will gather evidence to support best practices for CRC screening implementation among AN people 
and create a baseline for future research to increase CRC screening utilization and access among AN 
people. 

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1. INTRODUCTION 
Alaska Native (AN) people have among the highest rates of colorectal cancer (CRC) in the world. Both 
incidence of and mortality from CRC is twofold higher among AN people than US whites; this disparity 
has persisted for over 40 years.1 CRC is the second most frequently diagnosed cancer and the second 
leading cause of cancer-related death for ANs.2 
Preventing CRC is an important health priority of AN tribal health leaders and communities. 
Screening can prevent CRC through the identification and removal of colorectal polyps before they 
develop into cancer. Screening also allows for the detection and diagnosis of CRC at earlier stages, when 
treatment has greater likelihood of success with lower impact on quality of life.3-5 
In Alaska, CRC screening, including colonoscopy, is a covered service for AIAN beneficiaries, 
although screening-related travel is not always covered. Due to the geographic and health care delivery 
challenges of CRC screening in Alaska, only 59% of AN people have been adequately screened for CRC; 
and AN screening rates remain persistently lower than national rates.6 Efforts to increase CRC screening 
among AN people have led to some successes, but screening rates still vary substantially by Alaska Tribal 
health regions, ranging from less than 30% to 73%.7 
Complicating the ability to increase screening is that AN people have a high prevalence of 
Helicobacter pylori infection-related gastrointestinal bleeding8,9 which is associated with higher false 
positive rates for guaiac-based fecal occult blood testing (gFOBT).10 Consequently, gFOBT is not 
recommended for CRC screening in the AN population.11 The fecal immunochemical test (FIT), another 
take home stool test, is available in some regions of Alaska, but because of the high rates of precancerous 
polyps and CRC, colonoscopy has been the preferred method for CRC screening in the ATHS.11 
However, colonoscopy presents logistic and access challenges. Substantial resources, including time; 
travel expenses for the patient and a medical escort to a regional hospital or to Anchorage, usually by 
small aircraft; and specially trained personnel and facilities are required for colonoscopy within the 
ATHS.12,13 Only half of the regional Tribal hospitals offer colonoscopy year-round; the others hold 
several weeklong screening clinics per year. Furthermore, colonoscopy is biased toward detection of 
distal disease,14-20 with limited or minimal effect on incidence or mortality of proximal CRC.17,22,21 This is 
of concern as over 41% of CRCs in AN people occur in the proximal colon.2 Therefore, logistical 
barriers, endemic occult GI bleeding, and suboptimal test performance limit the value and practicality of 
current CRC screening approaches in the AN population. 
New screening methods are urgently needed to improve screening in this population. Recently, the 
take-home multi-target stool DNA test (MT-sDNA; Cologuard®, Exact Sciences, Madison, WI) has 
emerged as a viable alternative to other screening tests.22,23 Approved by the FDA and CMS for 
commercial use in 2014, the MT-sDNA test detects 11 colorectal neoplasia-associated DNA biomarkers, 
including two DNA methylation markers [NDRG4, BMP3], seven point mutations on K-ras, quantitative 
DNA using ACTB [β-actin], continuously shed in human feces or stool as well as the presence of fecal 
hemoglobin.24 MT-sDNA sensitivity for CRC is higher than other take home tests, is similar to that 
reported by colonoscopy, provides consistent detection of both left- and right-side colon cancers, and has 
the benefit of an embedded patient navigation system to help address patient and health system barriers.25- 
27,32 As with other noninvasive fecal CRC screening tests (gFOBT, FIT), a positive result may indicate the 
presence of CRC and requires follow up with a diagnostic colonoscopy. Initial MT-sDNA studies have 
shown its use increases screening adherence, including among never-screened patients, and may actually 
increase the yield and quality of follow-up colonoscopies.25-27 However, it is unknown whether the use of 
MT-sDNA would increase adherence to CRC screening among AN people and what its acceptability is 
compared to other available screening tests. 
This study will address this gap by providing a multi-level, quantitative intervention exploring use of 
the MT-sDNA test for CRC screening among AN people, complemented by qualitative evaluation of 
individual and health system CRC screening barriers reported by “never screened” and “non-adherent to 
guidelines” AN patients and their healthcare providers. 

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1.1. SPECIFIC AIMS 
Aim 1. Identify patient-, provider-, and system-level factors associated with CRC screening 
preferences, uptake, and follow-up, using a theory-based, mixed methods multi-stakeholder 
formative and process evaluation. While our prior work shows that an intervention to improve 
screening is likely to be broadly feasible and accepted, we anticipate variation in adherence between 
communities. To identify reasons for that variation we propose to: 
Sub-aim 1.a. Conduct a formative evaluation to assess community context and engage stakeholders in 
MT-sDNA intervention development including study design, protocol development, and 
implementation. 
Sub-aim 1.b. Use the Health Belief Model28,29 to evaluate patient-level factors associated with test 
preference, screening adherence, and diagnostic follow-up. 
Sub-aim 1.c. Conduct patient key informant and focus group interviews to identify factors that 
facilitate and impede screening uptake and effects among subgroups (sex, age, degree of rurality). 
Sub-aim 1.d. Conduct a brief survey and key informant interviews among community health aides, 
providers, and tribal health system administrators using validated measures of intervention feasibility, 
acceptability, and appropriateness30 to characterize provider- and system-level barriers and promotors 
to MT-sDNA implementation. 
 
Aim 2. Test the hypothesis that multi-level high and medium intensity MT-sDNA community-based 
interventions, as compared with usual care, will increase CRC screening rates among AN people in 
rural/remote communities. 
Sub-aim 2.a. Participants receiving high intensity intervention (navigated tribal health worker 
outreach, a mailed MT-sDNA kit, culturally appropriate educational material, and follow-up 
reminders) are expected to have a 20% increase in screening uptake while those receiving medium 
intensity intervention (mailed culturally appropriate educational material describing CRC screening 
options available, including MT-sDNA, and navigated follow-up outreach reminders) will have a 
10% increase in screening uptake over those receiving usual care (screening recommendation at a 
clinic visit). A sample of 770 participants in at least six communities per study arm will be recruited. 
Sub-aim 2.b. Measure the impact of sex, age, and rurality on the effect size of the intervention, MT- 
sDNA uptake compared to colonoscopy, and MT-sDNA follow up to diagnostic colonoscopy. 
Sub-aim 2.c. Measure MT-sDNA sample quality and neoplastic yield in remote AN communities. We 
anticipate that the proportion of MT-sDNA tests meeting quality control standards will be the same as 
in the general US population (96%) and that pre-cancerous polyp detection rates at diagnostic post- 
MT-sDNA colonoscopy will exceed routine clinical practice rates in the general US population (52%- 
67%). 
 
1.2 RATIONALE AND SUPPORTING DATA 
MT-sDNA represents a potential addition to CRC screening among AN people; it is accurate, easy to use, 
unencumbered by diet/medication restrictions, and may be accessible from low resource, underserved 
sites. However, MT-sDNA has not been tested in the ATHS practice setting. In addition, our study design 
will allow us to separate the effects of different technology: mailed reminders with small media health 
communication vs. telephone outreach by a patient navigator. We will also gain important new insight 
and qualitative data on the “never” and “rarely screened” population to identify strategies to improve 
screening in these vulnerable groups, as recommended in the 2017 American Indian and Alaska Native 
Collaborative CRC Screening Strategic Framework.31 
 
In Specific Aim 2, we will evaluate (using a three-arm randomized controlled trial (RCT) design) the 
efficacy of graded intensity interventions for increasing CRC screening uptake as well as determine the 
MT-sDNA repeat adherence rate among AN people. Because the MT-sDNA test has only been available 
commercially since 2014, there are no published data available on repeat adherence to screening using 

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MT-sDNA. Adherence to guidelines is a critical component of the success of screening programs: failure 
to screen at appropriate intervals or follow up on abnormal results within a timely manner have been 
associated with substantially increased odds of CRC mortality.32 By determining MT-sDNA adherence to 
screening, this study will contribute to the evidence base for this new screening test, which has 
implications for system workloads and patient outcomes. The design of the intervention arms: high 
intensity patient navigation and medium intensity AN-specific health education materials, compared with 
usual clinical practice, was chosen based on our previous work13,33 and that of others34-38 demonstrating 
the benefit of these methods in increasing screening adherence. 
 
The qualitative data collected in Specific Aim 1 will complement the RCT intervention by determining 
promoters and barriers to CRC screening practices among screening non-adherent AN patients and their 
healthcare providers in the ATHS. This will provide a patient- and provider-centered viewpoint on 
reasons for non-adherence to CRC screening that will lead to new areas for screening promotion. 
Screening test acceptability is an important factor for increasing CRC screening rates.39 
 
Patient willingness and ability to complete tests at home as well as provider recommendation are major 
factors in the effectiveness of a stool test-based CRC screening program.40-44 Many barriers and 
facilitators are screening test-specific such as fear of pain associated with colonoscopy, or discomfort 
with collecting stool samples.45 Even when cost is removed as a barrier, there are still issues for patients 
that remain.46 There may also be specific Tribal and cultural barriers to CRC screening, including lack of 
AIAN healthcare providers or patient navigators, health education materials that are not culturally 
relevant, or health literacy issues and English as a second language among AIAN elders.47,48 To begin to 
understand these barriers from the AN perspective, we will conduct a series of focus groups and key 
informant interviews with screening non-adherent and inadequately adherent AN patients from 
Anchorage and rural areas. These will be supplemented by a series of key informant interviews with 
healthcare providers from across the ATHS that are involved in the promotion and delivery of CRC 
screening. Interviewees may range from Community Health Aides/Practitioners that provide primary 
healthcare in rural villages, to surgical staff at ANMC. Ultimately, identifying areas for system 
improvement through our quantitative analysis will have little impact if proposed solutions are infeasible 
or unacceptable to the population served. Thus, the goal of this Specific Aim is to identify culturally 
appropriate, AN-identified opportunities for screening promotion that enhance the chances of successful 
implementation and CRC screening uptake. 
 
The field of behavioral economics shows us that there is sometimes a considerable gap between what 
people say they will do versus what they actually do.49,50 This intervention will demonstrate which 
outreach practices actually lead to increased screening, and whether the addition of MT-sDNA 
substantially increases screening rates in the AN population. This intervention trial is specifically 
designed to address CRC screening barriers identified through our previous work, while also laying the 
foundation for interventions in the future. In summary, this research will address a health disparity of 
established community concern, and generate data that will have broad-reaching clinical and policy 
outcomes for the ATHS. This study will advance scientific knowledge and clinical practice by revealing 
strategies that work to increase screening among the AN population and help curb the extreme, disparate 
morbidity and mortality due to CRC in this population. 
 
2. STUDY DESIGN AND APPROACH 
2.1 STUDY TEAM 
Key Personnel: 
Study PI: Diana Redwood, PhD 
Senior Epidemiologist, ANTHC 
 
Consultants: 
Clinical Consultant: Mark Thorndike, MD 
Chief of Surgery, ANMC 

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Clinical Consultant: James Tiesinga, MD 
Pathology Lab Director, ANMC 
Consultant: Lila Rutten, PhD 
Professor, Mayo Clinic 
Consultant: John Kisiel, MD 
Gastroenterologist, Mayo Clinic 
Consultant: David Ahlquist, MD 
Gastroenterologist, Mayo Clinic 
Consultant: Judith Kaur, MD 
Professor, Mayo Clinic 
Biostatistician: Peter Holck, PhD 
Consultant, Holck Consulting 
 
Other Personnel: 
Qualitative Data Expert 
ANTHC EpiCenter Staff 
Statistician/Data Manager 
ANTHC EpiCenter Staff 
Study Coordinator 
ANTHC EpiCenter Staff 
Research Assistant 
ANTHC EpiCenter Staff 
Media Specialist 
ANTHC EpiCenter Staff 
 
2.2 THEORETICAL FRAMEWORK. 
The theoretical basis for our intervention is the 
CDC’s CRC Control Program Social Ecological 
Model (SEM, Figure 4),51,52 supplemented by the 
Health Belief Model.28,29 We have successfully 
applied these in our previous work.34,53 Health 
behavior constructs include perceived severity, 
perceived susceptibility, perceived benefits, 
perceived barriers, and self-efficacy. These beliefs 
may interact with system-level factors, including 
the healthcare delivery system’s approach to CRC 
screening.54,55 Our study is designed to examine 
individual, interpersonal, and organizational level 
predictors associated with CRC screening. Our study will have a sequential explanatory mixed methods 
design.56,57 This will include a randomized controlled trial complemented by qualitative focus groups and 
key informant interviews. The qualitative findings will be used to help explain and triangulate the 
quantitative results; however, the quantitative and qualitative data will be kept analytically distinct. 
Statistical techniques will be used to analyze screening adherence data while thematic analysis will be 
used to analyze interview data. In this way, the integrity of each method will be preserved while 
capitalizing on the potential for enhanced understanding from combining the two sets of findings.56 
 
This study will also use the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) 
Framework58 to inform the study design and implementation activities (see Figure 2). 
Figure 1. Study Social Ecological Model. 

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2.3 STUDY SITE, DATA SOURCES AND STUDY POPULATION 
Study design: Under Aim 1, the study will employ focus groups and key informant interviews to learn 
about factors associated with screening response. Under Aim 2, the study will employ a cluster- 
randomized design, in which twelve communities within 1-2 Tribal health regions will be randomized to 
one of the two study intervention conditions (16 communities per intervention), matched by community 
size (Figure 3). Clinic staff (front desk, Community Health Aides, midlevel providers) in intervention 
communities will be informed that a CRC outreach project is occurring in case they are contacted by 
community members but not which arm their community is in. All AN adults aged 45-75 within each 
community will be offered the same intervention. This design will reduce the likelihood of study 
contamination from having individuals in a small community be offered different screening options, as 
well as be more culturally acceptable to AN people.59 The high intensity intervention will include 
navigated outreach, a mailed MT-sDNA kit, 
mailed culturally appropriate educational 
material describing CRC screening options 
available and follow-up reminders (Study 
Group 1). The medium intensity 
intervention will include mailed culturally 
appropriate educational material describing 
CRC screening options available, including 
MT- sDNA, and navigated follow-up 
outreach reminders (Study Group 2). All 
other communities in the participating 
Tribal health region will serve as the 
reference group (Study Group 3) receiving 
usual care (i.e., screening recommendation 
at a clinic visit). 
 
Study outcomes: The primary outcome measure as determined by electronic medical record review by a 
study team member blinded to randomization assignment will be completion of an incident CRC 
screening episode. This will be defined as having at least one of the following within 1 year of follow-up 
after randomization and intervention: colonoscopy; MT-sDNA with a negative result; or MT-sDNA with 

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a positive result followed by a colonoscopy within 90 days. Due to the COVID-19 pandemic preventive 
screening was postponed for a time, which created a backlog of patients who need screening, including 
screening for CRC. To adjust for this delay, additional medical record review will be conducted to assess 
for any incident CRC screening episode within 18-months after randomization and intervention. A 
secondary outcome measure will include the rate of positive MT-sDNA test follow up to diagnostic 
colonoscopy. We anticipate that positive MT- sDNA tests will have higher follow-up rates to colonoscopy 
within 90 days than other studies have reported of positive FIT/gFOBT (55.6% followed up with 
colonoscopy)54 due to the patient navigation system included in the MT-sDNA test model. We will also 
compare incident CRC and advanced adenoma [adenomatous polyp ≥1 cm or containing >25% villous 
component or high-grade dysplasia, or sessile serrated adenoma/polyp ≥1 cm] detection between the three 
arms. We will also incorporate into our secondary analyses measures from the process evaluation (e.g., 
patient satisfaction with MT-sDNA vs colonoscopy, provider attitudes and beliefs) as well as other 
moderating factors to determine their roles in explaining the magnitude and direction of the results we 
find. 
 
Specific data elements collected on CRC screening clinical care will be pulled from tribal electronic 
medical records (EMR) and the ANMC CRC 1st Degree Relatives database, as well as data from the 
Alaska Native Tumor Registry (ANTR). Variables included in the EMR include: age, sex, race/ethnicity, 
history of CRC screening; personal or family history of CRC or polyps; test adherence; indication for 
test(s) (screening, surveillance, diagnostic); clinical diagnosis; biopsy/polypectomy performed; bowel 
preparation adequacy; cecum reached; recommended follow-up procedure(s); histology, size and number 
of polyp/lesions; follow-up surgery details; final diagnosis; recommended next screening/surveillance test 
and time interval; recurrent cancers; and status and date of cancer treatment. Variables collected will 
include those previously mentioned above, although there may be missing data for some of these 
variables in regional EMRs. Data included in the ANTR will only be used to fill in missing data to 
include cancer diagnosis and treatment dates, clinical information regarding the cancer (e.g., size, 
histology, morphology, laterality), and cancer treatment information (first course of treatment only). Data 
included in the CRC 1st Degree Relatives database will only be used to determine if a 1st degree relative 
with prior CRC was diagnosed at age 60 or younger if not available in the medical record. 
 
2.4 INCLUSION AND EXCLUSION CRITERIA 
QUANTITATIVE STUDY. Inclusion Criteria: The study will include AN adults ages 45-75 eligible to 
receive health care through the Alaska Tribal Health System that are active users (at least one Alaska 
Tribal Health System visit in the previous three years) and have contact information on file. Exclusion 
criteria: Participants will be ineligible if they have a history of familial adenomatous polyposis, 
hereditary non-polyposis CRC, previous colonoscopic evidence of inflammatory bowel disease, Crohn’s 
disease, colorectal adenomas, CRC, presence of a 1st degree relative with prior CRC diagnosed at age 60 
or younger, or positive fecal occult blood test in the last 6 months as these patients are not eligible for the 
MT-sDNA test. Patients adherent to screening (colonoscopy within 10 years, sigmoidoscopy within five 
years, or fecal occult blood testing within preceding 12 months) will also be excluded from the 
intervention trial. 
 
QUALITATIVE STUDY: We will recruit never or inadequately screened AN patients ages 45-75 and Alaska 
tribal health system providers to participate in either focus groups (patients only) or key informant 
interviews (patients and providers). We will recruit AN patients who have not been screened according to 
their tribal medical records at ANMC and at participating rural Tribal health organizations (THOs). 
Inadequately screened will be defined as patients who are not up-to-date with recommended screening. 
Clinical staff will be recruited based on their involvement in the provision of CRC screening at the 
participating organizations. During and following the graded intensity intervention, we will survey 
samples of patients to evaluate their awareness and response to the CRC intervention. The survey will 
be conducted by the Patient Navigator and/or the study Evaluation Consultant. They will need to know 
which screening test the patient had (colonoscopy or stool DNA test) so they can ask the survey 

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questions about how the patient felt about using that specific test, and why they chose that test over the 
other one. It is important they also know the test result so they can anticipate any questions the patient 
might have, especially if there was an abnormal finding. We will also conduct a semi-structured open-
ended telephone survey with intervention participants who requested the MT-sDNA test for CRC 
screening, were sent a test kit but did not complete and return it to the laboratory for analysis within the 
12-month post intervention period. The purpose of the survey is to learn about the underlying barriers 
and reasons patients did not complete this screening method. Similarly, we will survey patients who 
chose to complete screening with a colonoscopy, scheduled an appointment, but never completed a 
procedure to assess barriers to patients completing the procedure even after it was scheduled. A study 
staff member at ANTHC will contact patients and conduct the surveys. We will verify patients’ address 
and phone number at the time of the surveys to assess whether we sent the kit to the correct address, 
which could relate to non-adherence of screening with the MT-sDNA test as well as update YKHC 
medical records with patients’ current contact information. We will use IRB- and tribally-approved 
study flyers and information sheets located at the Alaska Native Medical Center in Anchorage, AK and 
participating rural THOs to further recruit participants per IRB and tribal review. 
 
2.5 STATISTICAL ANALYSIS. 
Although this study will use a cluster-randomized design with the community as the unit of analysis, our 
research experience in rural Alaska communities indicates minimal within community influence on an 
individual's personal health decisions. Because an intra-class correlation near zero approaches a simple 
random sample design, for clarity in our power calculations we have approximated our design as a simple 
random sample.60 The sample size allocation for this study is based on a pre-specified ability to detect an 
expected difference of 10% or more in screening participation rates for usual care vs any intervention as 
well as a difference of 10% or more in screening for high intensity vs medium intensity outreach. Given 
these expected improvements in screening rates, and the expected non-intervention screen rate of 59% 
based on current rates among AN people, we anticipate more than 80% power to detect a statistically 
significant difference between screening rates in our medium and high interventions, at alpha of 0.05. 
To achieve this, we will recruit a sample of 775 or more persons per study arm. An intent-to-screen 
principle will be used to analyze all eligible patients for the primary outcome: screening participation. All 
eligible communities will be randomly assigned to an intervention arm at baseline. Group assignment will 
not be shared because all patients will be randomized at the same time point. Outreach patients will be 
blinded to the presence of alternate interventions; usual care patients will be blinded to the presence of 
group assignment altogether. 
We will compare demographic characteristics (sex, age) between those screened using MT-sDNA and 
colonoscopy, as well as by intervention status (high intensity, medium intensity, usual care) in simple 
frequency tables. We will use multivariable models to assess the role of intervention status in determining 
screening rates, adjusting for potential confounders such as age, sex, and other demographic 
characteristics. Because our primary response is the proportion of persons screened (or the screening rate) 
we will utilize logistic and/or Poisson regression in our multivariable linear models. For Sub-aim 2.b we 
will examine how effectiveness of the interventions may vary by sex, age, and rurality using frequency 
tables and crossing outcome proportions by levels of sex, age, and rurality. Examination of interaction 
terms (sex by intervention, age by intervention, etc.) in multivariable models, as well as subset analysis as 
appropriate to illuminate such differences, will allow us to evaluate differences across these covariates in 
effectiveness of the intervention arms. For Sub-aim 2.c we will obtain an estimate of the sample quality 
under each of the three intervention conditions and also an estimate of the sample quality likely to result 
when these interventions are deployed to the larger population and compare those to national sample 
quality estimates (96%). 
3 HUMAN SUBJECTS PROTECTION 

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3.1 RECRUITMENT AND INFORMED CONSENT 
Quantitative Study: After obtaining Alaska Area Institutional Review Board (IRB) and appropriate Tribal 
review and clearance, a list of eligible patients will be drawn from each participating THOs electronic 
medical record (EMR) system. Each healthcare system in the ATHS uses comprehensive EMRs and 
administrative databases that will be used to collect contact information (e.g., phone number(s) and 
mailing address), demographic information (e.g., age, sex, and race and ethnicity), identify patients due 
for screening, provider orders, screening test completion, and pathology results. Prior history of CRC 
screening, including time since the last screening, will be retrospectively collected from EMRs. Current 
Procedural Terminology, Healthcare Common Procedure Coding System, and laboratory codes will be 
used to ascertain receipt of screening and screening method, regardless of indication. See Appendix A for 
list of variables to be collected. All variable data collected for this study will be stored in REDCap 
(Research Electronic Data Capture), a secure HIPAA compliant database system.  
 
Communities will be randomized to one of two interventions: high intensity or medium intensity. The 
high intensity intervention will include navigated outreach, a mailed MT-sDNA kit, mailed culturally 
appropriate educational material describing CRC screening options available, and follow-up reminders 
(Study Group 1). The medium intensity intervention will include mailed culturally appropriate 
educational material describing CRC screening options available, including MT-sDNA, and navigated 
follow-up outreach reminders (Study Group 2). Participants will be recruited by mail and phone calls, 
depending on the intervention arm. All remaining communities in the region served by that THO will 
receive usual care and will not have direct outreach. 
 
Patients who requested MT-sDNA for CRC screening, received a kit, but did not return it will be 
contacted to assess reasons for non-adherence. Survey data will be collected verbally by phone by an 
ANTHC study team member and stored in REDCap, a secure HIPAA compliant database system. 
This data will be stored with identifying information such as name and phone number, which is 
needed to contact patients for the phone survey but no personally identifying information will be 
included in the reporting of the non-adherence data analysis. 
Waiver of Consent: As individuals will be selected for each trial arm based on their randomized 
community, we requested a waiver of informed consent for eligibility and group assignment from the 
Alaska Area IRB as well as the Alaska Native Tribal Health Consortium (ANTHC) and the ANTHC and 
SCF Privacy Officers, who have given approval for the waiver of consent. We will also request a waiver 
of informed consent from participating THOs prior to study implementation. 
 
The rationale for the waiver of consent is that the study will randomize by community (cluster 
randomization) so that everyone who is eligible for CRC screening in that community will be offered the 
same intervention (or usual care). The disclosure of the study purpose as part of the consent process to 
individuals would bias the research so that the results will not be meaningful, since the study is trying to 
determine on a community level how much offering these different types of CRC screening interventions 
would help increase overall community screening rates. The purpose of the waiver of informed consent is 
to avoid potential selection/volunteer bias. Additionally, if participants are consented, they will know 
which intervention community they are in, and so there might be bias resulting from that as well. Patients 
who did not return their mt-sDNA kit for CRC screening and those that scheduled a colonoscopy but 
never completed it will be contacted for a phone survey and fall under this waiver of consent. These are 
patients who participated in the intervention and are being followed up with to assess why they chose to 
screen with mt-sDNA or colonoscopy, but ultimately did not return their kit or complete a procedure to 
complete screening.  
 
To help address potential concerns raised by this type of study design, the regional THOs and their 
Privacy Officers will be asked to approve the waiver of consent prior to study implementation. Clinic 
staff (front desk, Community Health Aides, midlevel providers) in intervention communities will be 

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informed that a CRC outreach project is occurring in case they are contacted by community members but 
not which arm their community is in. Lastly, since the risks posed by this intervention do not exceed the 
threshold of minimal risk, an independent monitoring committee (Data and Safety Monitoring 
Committee; DSMC) is not required. However, to provide additional safeguards for this study, we will 
engage a DSMC to provide study oversight and consultation (see 3.3.2. Data and Safety Monitoring 
Plan). 
 
Qualitative Study: We will recruit never or inadequately screened patients and Alaska tribal health 
system providers to participate in either focus groups (patients only) or key informant interviews (patients 
and providers) to identify barriers to receipt of CRC screening, as well as explore opportunities to 
increase screening using the MT-sDNA test. We will recruit Alaska Native patients who have not been 
screened or are not currently adherent to screening recommendations (colonoscopy within 10 years, 
sigmoidoscopy within five years, or FIT/FOBT within preceding 12 months) according to their tribal 
medical records at ANMC and at 1-2 participating regional THOs. Clinical staff will be recruited based 
on their involvement in the provision of CRC screening at the participating organizations. 
 
Recruitment for focus groups will be conducted by Hays Research Group LLC to increase our chance of 
successfully recruiting the required number of AN people to participate in the focus groups. Hays 
Research Group LLC has extensive experience recruiting for and conducting health-related focus groups 
with AN people and has previously conducted focus groups for the EpiCenter and others within the 
ATHS. We will also use IRB- and tribally-approved study flyers and information sheets located at the 
Alaska Native Medical Center in Anchorage, AK and participating rural THOs to recruit for the study. 
 
Upon recruitment, we will explain the purpose of the qualitative study to participants, and thoroughly 
review the consent with each participant individually (including for focus group participants). All focus 
group participants and key informants will sign an informed consent form that describes the focus 
group/interview, how the information that they provide will be used, and how their confidentiality will be 
protected. No names of participants will be associated with notes or transcriptions. We will have a 
translator available for those participants who have difficulty with the consent forms, or who would like 
further clarification in their Native language. Per Alaska Area IRB requirements, all consent forms and 
study documents will be written at grade 8 reading level or lower. All documents will be reviewed and 
approved by the IRB and necessary THOs. 
There will be a short, anonymous questionnaire distributed before the focus group or interview to collect 
some general demographic information about the participants (age, gender, community). Focus groups 
will last approximately 2 hours and will be stratified by gender. Interviews are expected to take 
approximately 30-45 minutes of staff time. Focus groups may be completed using the Zoom platform 
which is a HIPAA compliant web and video conferencing platform. In this case, focus groups will still be 
recorded so they can be transcribed and participant names will be excluded from the transcripts. Focus 
group guides have been created for both in-person and virtual focus groups and the appropriate guide will 
be utilized depending on the method we use. The focus groups and interviews will be tape-recorded and 
the tapes transcribed by a private transcription service (temi.com) to ensure no voice recognition by the 
transcriber. The analysis, interpretation, and reporting will be done by EpiCenter staff trained in research 
and with current CITI certifications on file with the AAIRB. Qualitative computer software (ATLAS.ti) 
may be used for analysis as needed. 
Focus group and interview participants will be given a thank you gift for their time. This will be a gift 
card, at a value to be determined in collaboration with our THO partners, and after approval from the 
Alaska Area IRB. In addition to gift certificates for focus group participants we will have $25 taxi cab 
and $25 childcare vouchers to help people be more readily able to participate in the focus groups. These 
will be offered to all in-person focus group participants in THO regions where we conduct in-person 

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focus groups. Our previous studies have provided $25 for interviews and $50 for focus group 
participation. We do not anticipate the need for additional retention strategies, as interviews and focus 
groups will be one-time, and will occur soon after recruitment (ideally <7 days). 
 
3.2 POTENTIAL RISKS 
We will collect information on CRC screening clinical care including in tribal electronic medical record 
(EMR), as well as data from the Alaska Native Tumor Registry (ANTR). There is a small risk of loss or 
accidental release of personally identifiable information during data extraction. Risk associated with this 
occurrence is expected to be minimal, as personally identifiable information will not be included in the 
study database. The research team will have access to personally identifiable information only for the 
purpose of medical chart review. The Alaska Native Health Campus is a Covered Entity; all electronic 
data will be stored in the secure, password-protected campus network system and only the study research 
team designated in the Alaska Area IRB-approved protocol have access to the data. Any paper recorded 
(e.g., informed consent documentation) will be stored in locked cabinets in the Alaska Native 
Epidemiology Center office. Access to this area is restricted to keycard holders only; only the PI and 
Study Coordinator will have direct access to this key. 
 
It is possible that there may be the potential for stigmatization of or concern from the Alaska Native 
community regarding findings from the analyses. We believe the risk of this to be small, due to 
collaboration with and oversight by tribal review entities (see below). 
 
As with all scientific studies, it is possible that we will not generate results that will have direct 
therapeutic or preventive benefit to Alaska Native people. This possibility is not likely to cause adverse 
effects. 
 
3.3 PROTECTION AGAINST RISK 
Every effort will be made to maintain the confidentiality of the participants’ personal information. Files 
and computers are accessible only to the Study’s research team. Care will be taken to ensure that 
information is collected and presented in such a way that individuals cannot be identified. For example, 
no personally identifiable information will be included in the study database used for analysis. The 
research team will have access to personally identifiable information only for the purpose of medical 
chart review to determine CRC screening completion and outcomes. 
 
All research team members have been trained in HIPAA, confidentiality and medical record compliance 
standards, as appropriate. Furthermore, all ANTHC research staff sign a Confidentiality Statement as a 
condition of employment, which is reviewed annually and includes a clause indicating a break in 
confidentiality is grounds for immediate dismissal. All members of the research team have verification of 
Collaborative Institutional Training Initiative (CITI) human subject protections training. All investigators 
and staff members involved in the project will sign confidentiality and data use agreements to avoid 
misuse or accidental release of data. Access to research data will be strictly limited to study staff directly 
involved in data analysis and interpretation, under the direction of the PI and Study Coordinator. 
 
Access to research data will be strictly limited to study staff directly involved in data analysis and 
interpretation, under the direction of the PI. Study staff will only be given access to the minimum 
necessary information to complete their assigned tasks. For example, the Research Assistant will have 
access to limited personally identifiable information for a limited period of time, in order to complete 
medical chart review as described above. Any data that is shared with investigators external to ANTHC 
will be shared only with completion of a signed ANTHC Data Use Agreement. Only aggregated, de- 
identified data will be shared with other consultants, and any other individuals who may assist in the data 
interpretation process (e.g., tribal health leaders, ANTHC Research Consultation Committee). 
 
We will work closely with ANTHC and regional tribal researchers and review boards to ensure that all 

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results are presented in a culturally appropriate, respectful way. All dissemination materials will present 
data in aggregate or summary form and in no way will identify individual participants. This protocol, and 
all materials designed to disseminate information or results from this study, will undergo ANTHC and 
regional THO tribal review and clearance. 
 
3.3.1. Storage and Coding of Data 
ANTHC data files are managed, processed, and stored in a secure environment (e.g., lockable computer 
systems with passwords, firewall system in place, virus/malicious intruder protection) and by controlling 
access to digital files with encryption and/or password protection. Necessary data security and storage 
mechanisms will be used as required by applicable laws to protect personal health information as per 
ANTHC policy. Login permissions to the shared folder are managed by ANTHC IT Administrators or the 
designated Data Manager. The Data Manager will also be responsible for naming conventions, version 
control, folder structures, and data dictionaries (as needed). The Data Manager will assign each individual 
in the linked database with a unique study ID that will be associated with the participant’s information. 
The study PI will be responsible for ensuring that all data are kept secure and that the data management 
plan is reviewed annually. 
 
3.3.2. Data and Safety Monitoring Plan 
This is no more than a minimum risk study with a CRC screening intervention. Because the risks posed 
by this intervention do not exceed the threshold of minimal risk, an independent monitoring committee 
(Data Safety Monitoring Committee; DSMC) is not required. However, to provide additional safeguards 
for this study with AN people, we will engage a DSMC to provide study oversight and consultation. The 
DSMC for this clinical trial will consist of three (3) experts who are independent of this protocol. Ms. 
Dana Diehl, Director of Wellness & Prevention at ANTHC will be asked to chair the DSMC. The other 
DSMC members who will be invited to participate will include Dr. Timothy Thomas, Director of 
Research and Clinical Services at ANTHC, and Dr. Steven Vindigni, clinical gastroenterologist at the 
Alaska Native Medical Center. Dr. Thomas oversees ANTHC’s Research Department and is the PI for a 
clinical intervention trial currently underway at ANTHC. Dr. Vindigni is a clinical gastroenterologist at 
the Alaska Native Medical Center. A representative of the participating regional THOs will be invited to 
join the committee if they would like to be involved. 
 
The DSMC will review data on such aspects as participant enrollment, site visits, study procedures, data 
quality, and other measures of adherence to protocol. The DSMC will review data and individual reports 
related to unanticipated problems and adverse (AEs) and serious adverse events (SAEs). They will 
provide recommendations to the PI regarding problems and safety concerns. They will provide periodic 
reports to the PI indicating whether they see any reasons for change and document all their actions. The 
data manager will prepare tables with data to be reviewed by the DSMC at least annually. 
 
All reportable AE, SAE and unanticipated problems experienced by participants will be reported to the 
AAIRB in addition to any adverse or serious adverse events in compliance with their Adverse Event 
Reporting Policy requirements. Within 72 hours after a reportable AE, SAE or unanticipated problem has 
been reported by the participant, it will be graded by the PI, forwarded to the study’s DSMC for review, 
and then will be submitted by the PI to the AAIRB. In addition, all cumulative reportable AE, SAE and 
unanticipated problems included in the DSMC reports will be submitted to the AAIRB in the PI’s Annual 
Progress Reports. 
 
3.4 POTENTIAL BENEFITS OF THE RESEARCH 
Individuals whose data will be included in this research will not receive any direct benefit from their 
participation in the research study. However, there are several societal benefits to AN people: 
 
1. The primary goal of this research is to understand whether the use of MT-sDNA, as well as high and 
medium intensity interventions, help increase CRC screening among Alaska Native people. The 

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results of this study may be incorporated into Alaska Tribal Health System policies and procedures 
and lead to more sustainable screening infrastructure and screening services access in the future. 
2. This study will also identify barriers to CRC screening experienced by “never” and “rarely screened” 
Alaska Native people to identify additional strategies to increase screening in these groups, who have 
among the highest rates of CRC in the world. The benefit of this research is in our improved 
understanding of screening and access patterns, as well as potential improvements that can be made to 
the Alaska Tribal Health System to reduce this health disparity. 
3. This research hopes to serve as an example of how to conduct research in a culturally appropriate and 
respectful manner, and will provide a basis for ongoing discussion around healthcare delivery 
research among AN people. Translational and healthcare delivery research is proving informative 
regarding best practices for care, including cancer, in other populations, yet has been underexplored 
for its potential to be informative regarding cancer prevention and control among AN people. 
Working closely with tribal stakeholders to develop and conduct this research, we hope to identify 
strategies and policies that can be implemented in the tribal health system to improve AN healthcare. 
Our goal is that by working with AN tribal health leaders and community members in this way, this 
study will join in other current cutting edge science being conducted at the AN Health Campus and 
pave the way for future research programs that could benefit the health of AN people. 
 
3.5 DISPOSITION OF THE DATA 
Per standard scientific practice, data will be retained, on a secure network drive within the ANTHC 
firewall, at the completion of the study. Per NIH data sharing policies, data may be made available to 
investigators for additional analyses beyond those proposed herein, given that all tribal and IRB processes 
are adhered to. Should additional analyses be considered as part of the existing project, an IRB 
modification will be submitted. Should external investigators wish to conduct additional secondary 
analyses on the linked database, they will apply to work in collaboration with existing study investigators, 
and a new protocol will be submitted for tribal and IRB review. Data will be retained by Study 
Investigators for a period of six years past the publication of the final manuscript resulting from this work. 
This period of time is to ensure that Study Investigators are able to answer any questions arising from the 
publication of results. The Study PI will be responsible for handling ClinicalTrials.gov requirements for 
this project. Study results will be reported within one year of final collection of data through 
ClinicalTrials.gov. Results information will include participant flow, demographic and baseline 
characteristics, outcomes and statistical analyses, adverse events, the protocol and statistical analysis plan, 
and administrative information. 

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3.6 PUBLICATION AND DISSEMINATION 
The results generated by this research project will be shared across the ATHS in order to affect policy and 
systems change for AIAN people throughout Alaska. Our results will be interpreted in consultation with 
statewide and regional tribal health leaders, as well as the ANTHC Research Consultation Committee. 
Findings will be disseminated to members of the clinical community through forums such as Ground 
Rounds, which are broadcast statewide for attendees from our THO partners. Results will be shared with 
the wider community using culturally appropriate formats such as local and regional newspapers or radio 
interviews. All community dissemination materials will be developed at an appropriate level of health 
literacy, in collaboration with the ANTHC Research Consultation Committee. 
 
We will share these results with the scientific community through a series of scientific publications and 
presentations at scientific meetings. All manuscripts, abstracts, and community dissemination materials 
resulting from this research will be approved by ANTHC and appropriate THOs before any publication or 
presentation. 

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APPENDIX A. POTENTIAL VARIABLES TO BE COLLECTED FROM THE MEDICAL RECORD 
1. Contact Information 
a. Telephone number(s) 
b. Mailing address 
2. Demographics: 
a. Gender 
b. Date of birth 
c. Race(s) 
d. Hispanic or Latino origin 
e. Town and state of residence 
f. County/census area 
 
3. CRC Clinical Data Elements: 
a. History of CRC screening 
b. Personal history of CRC or polyps 
c. Family history of CRC 
d. Currently experiencing CRC symptoms (rectal bleeding, blood in stool, etc.) 
e. Test appointment date schedules, or fecal kit distributed 
f. Screening adherence (test performed, pending, not performed) 
g. Indication for test(s) (screening, surveillance, diagnostic) 
h. Type of test(s) performed (colonoscopy, flexible sigmoidoscopy, DCBE, etc.) 
i. 
Date of test(s) 
j. 
Result of test(s) clinical diagnosis 
k. Was a biopsy/polypectomy performed 
l. 
Was the bowel preparation adequate 
m. Was the cecum reached during colonoscopy 
n. Test(s) outcome complete 
o. Recommended follow-up procedure(s) 
p. Additional test(s) required? Type 
q. Histology of the most severe polyp/lesion 
r. Total number of adenomatous polyp/lesion 
s. Size of largest adenomatous polyp/lesion 
t. 
Histology from surgical resection 
u. Date surgery performed 
v. Status of final diagnosis 
w. Final diagnosis 
x. Date of final diagnosis 
y. Recommended next screening/surveillance test 
z. Indication for next test(s) (screening, surveillance) 
aa. Recommended time interval till next test 
bb. Recurrent cancers 
cc. Status and date of cancer treatment 
dd. Tumor Registry data: diagnosis, histological type, behavior, primary site, AJCC stage, 
tumor size, CS-derived SS2000 

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