Curr Gastroenterol Rep (2016) 18:30
DOI 10.1007/s11894-016-0510-4
GI ONCOLOGY (R BRESALIER, SECTION EDITOR)
Multi-Target Stool DNA Test: Is the Future Here?
Seth Sweetser 1 & David A. Ahlquist 1
# Springer Science+Business Media New York 2016
Abstract Colorectal cancer (CRC) screening reduces CRC
incidence and mortality and is widely recommended.
However, despite these demonstrated benefits, a large percent-
age of the population remains unscreened. The multi-target
stool DNA (MT-sDNA) test is a new, non-invasive option
for CRC screening that has a high accuracy rate in detection
of colorectal neoplasia and offers great opportunity to enhance
screening uptake. This review provides the current state of the
art knowledge about the use of MT-sDNA in CRC screening.
Keywords Colorectal cancer . Screening . Stool DNA
Abbreviations
CMS Center for Medicare and Medicaid Services
CRC Colorectal cancer
FDA Food and Drug Administration
MT-sDNA Multi-target stool DNA
SSP Sessile serrated polyp
Introduction
Colorectal cancer (CRC) is the third most common cancer and
fourth leading cause of cancer-related deaths in the world [1].
This article is part of the Topical Collection on GI Oncology
* Seth Sweetser
sweetser.seth@mayo.edu
1
Division of Gastroenterology and Hepatology, Mayo Clinic College
of Medicine, 200 First Street SW, Rochester, MN 55905, USA
Despite progress with screening efforts over more than three
decades, CRC remains the no. 2 cancer killer in the USA [2].
Evidence shows that screening reduces disease-specific mor-
bidity and mortality [3] and is cost-effective [4].
Although CRC screening is widely available, specific
screening programs vary across countries. In the USA,
longstanding guidelines have endorsed a panel of options [5]
including fecal immunochemical testing, flexible sigmoidos-
copy, and colonoscopy, with colonoscopy being the dominant
screening modality [6]. However, these conventional screen-
ing approaches are hampered by a number of factors. First, the
accuracy of these modalities is less than optimal. Although
colonoscopy is highly accurate when it is performed well,
colonoscopy quality is variable and operator-dependent.
Second, despite the supporting evidence, recommendations,
and availability of several screening tests, a substantial portion
of the US population is not current with screening [6]. There
are various reasons for underutilization of all the CRC screen-
ing modalities, but patients often do not want to undergo co-
lonoscopy in particular due to fear of pain, discomfort, embar-
rassment, concern of safety, or inability to take uncompensat-
ed time off from work to undergo the procedure [7]. Finally,
the recommended colonoscopic screening frequency of every
10 years may result in missed, aggressive interval lesions,
particularly in the proximal colon. Indeed, recent large cohort
studies reveal that screening colonoscopy is associated with a
substantially lower benefit in terms of reduced incidence and
mortality with proximal CRC [8, 9••]. Hence, there is substan-
tial opportunity to improve the effectiveness of CRC screen-
ing in several ways.
The multi-target stool DNA (MT-sDNA) test is a new, non-
invasive option for CRC screening that has a high accuracy
rate in detection of colorectal neoplasia, is user friendly, which
should enhance patient adherence, and is able to be distributed
via mail with improvement in screening access.
30 Page 2 of 7
Molecular Pathogenesis of Colorectal Cancer
CRC is one of the most preventable cancers because it almost
always arises from polyps, either tubular adenomas or serrated
polyps, which typically evolve into CRC over many years.
This slow polyp-cancer progression sequence offers an oppor-
tunity to detect and remove the polyps before they undergo
malignant transformation. The polyp to CRC sequence is het-
erogeneous and involves multiple different molecular path-
ways. The heterogeneity of colon polyps and CRC can be
appreciated on the basis of global DNA abnormalities (e.g.,
microsatellite instability), epigenetic alterations (e.g., CpG is-
land methylator phenotype (aka CIMP)), and specific gene
mutations. Normal epithelium transforms into invasive adeno-
carcinoma through the random accumulation of acquired ge-
netic and epigenetic changes. Because of the marked variation
in the pattern and extent of these acquired molecular changes,
there has been no single, universal genetic marker of cancer or
precancerous lesions. However, aberrant DNA methylation is
a molecular alteration that occurs during the early stages of
tumorigenesis with greater frequency and predictably than
gene mutations [10]. Several specific genes are methylated
in the majority of cancers and precancerous lesions [11].
Therefore, aberrantly methylated genes are particularly infor-
mative molecular markers for colorectal neoplasia. However,
given the variation in both genetic and epigenetic marker cov-
erage observed to date [12], a marker panel consisting of
complementary genetic and epigenetic targets has, to date,
been necessary to achieve highest detection of CRC and
precancerous lesions.
Stool-Based DNA Testing: Biological Considerations
There is a strong rationale to measure mutated DNA in stool.
The detection of molecular markers in stool from colorectal
neoplasms is naturally facilitated by a series of biological
events including the disproportionately copious and continu-
ous exfoliation of dysplastic cells and their constituents into
stool, the large functional surface area of neoplasms, relative
stability of dysplastic cells, and signature tumor-associated
DNA changes.
Tumor cells and their constituents are released into stool by
exfoliation from the surface of precancerous lesions and early-
stage cancers. Based on direct histological observations, ex-
foliation from colorectal neoplasms appears to be a continuous
process that occurs more frequently than exfoliation from nor-
mal epithelium [13]. In the normal colon, epithelial renewal
does not necessarily lead to exfoliation but, instead, often
involves engulfment of degenerating colonocytes by
subepithelial phagocytes [13]. In contrast, neoplasms exfoliate
or shed dysplastic cells into the lumen. The proportionately
greater exfoliation from neoplasms may be related to
Curr Gastroenterol Rep (2016) 18:30
increased proliferation, reduced cell-cell or cell-basement
membrane adhesion, and other factors. In addition, the epithe-
lial mass of a colorectal neoplasm turns over at a high rate [14]
and may replace itself every 3 days and exfoliate a substantial
discharge of dysplastic cells in the process. Furthermore, the
release of tumor-specific DNA markers into stool by the
mechanism of exfoliation is a continuous process unlike blood
loss from neoplasms which is intermittent and often absent
with precancers and early-stage CRC [15]. The mechanistic
differences in marker release allow for single stool sampling
and high neoplasm detection rates with stool DNA testing.
The amount of exfoliated tumor DNA is proportional to the
surface area of the neoplasms. Conceptually, it seems unlikely
that a single stool DNA test could reliably detect small polyps;
however, the microscopic surface area of a polyp is markedly
larger than its grossly observed surface area due to extensive
infolding of the surface epithelium. This extensive epithelial
infolding provides an actual epithelial surface area greater
than 200 times that predicted by simple gross dimensions
[16]. The disproportionate exfoliation rates and large surface
area of colorectal neoplasms explain why tumor-derived DNA
can account for more than 20 % of human DNA in stools from
patients with CRC [17].
Dysplastic cells have a survival advantage over normal
colonic cells following exfoliation. However, intraluminal ly-
sis of dysplastic cells occurs and the recovery of DNA con-
stituents released by lysis during fecal transit accounts for the
rational to test for tumor-specific cell constituents rather than
intact colonocytes to achieve the highest neoplasm detection
rates.
The Multi-Target Stool DNA Test
The multi-target stool DNA (MT-sDNA) test is an automated
test that is now available commercially in the USA
(Cologuard™, Exact Sciences, Madison, WI). The multi-
target sDNA panel consists of KRAS point mutations, aber-
rantly methylated genes (BMP3 and NDRG4), β-actin as a
control indicator of DNA quantity, and a human hemoglobin
immunochemical assay. The quantitative measurements of
each marker are then incorporated into a logistic regression
equation, with a value of 183 or more indicative of a positive
test.
Case control studies with prototype and optimized MT-
sDNA demonstrated high discrimination for early-stage
CRC and precancerous polyps at greatest risk of progression
[18, 19]. Of critical importance, the MT-sDNA detection rates
for CRC and advanced precancers were not affected by neo-
plasm site in these case-control studies; in contrast to the bias
toward distal lesion detection noted with conventional ap-
proaches, MT-sDNA was equally sensitive for proximal and
distal neoplasms.
Curr Gastroenterol Rep (2016) 18:30
In a pivotal validation study from the screening setting
[20••], MT-sDNA was prospectively compared to fecal immu-
nochemical test (FIT) in 9899 asymptomatic average-risk in-
dividuals aged 50–84 years. Colonoscopy served as the refer-
ence standard. The demographic mix of the study patients was
representative of the general US population. CRC sensitivity
was 92 % for MT-sDNA and 73 % for FIT, with respective
specificities of 87 and 95 % (when non-advanced polyps are
included in denominator). Sensitivity for advanced, precan-
cerous polyps was 42 % for MT-sDNA and 24 % for FIT.
MT-sDNA was superior to FIT for detection of lesions with
high-grade dysplasia (69 vs 46 %, respectively) and for sessile
serrated polyps 1 cm or greater (42 vs 5 %, respectively).
Importantly, the sensitivity of MT-sDNA for detection of
high-risk adenomas and sessile serrated polyps increased in
proportion to lesion size. When MT-sDNA was normalized to
the age distribution of the general population (the multicenter
study was skewed toward older ages to increase disease prev-
alence), the adjusted specificity was 92.5 % in those with
normal colonoscopy (unpublished data). Using data from this
large, cross-sectional study, the numbers of persons who need
to be screened to detect one CRC were 154 for colonoscopy,
166 for MT-sDNA, and 208 for FIT.
In a smaller but similarly designed study [21•], MT-sDNA
was evaluated in Alaska native people, who have one of the
world’s highest rates of colorectal neoplasia. The MT-sDNA
detection rates were remarkably similar to those from the larg-
er North American study (Fig. 1). There was a higher CRC
specificity for MT-sDNA in this study of 93 % based on pa-
tients with normal colonoscopy which may be related to the
greater percentage of younger patients in the Alaska study.
Prevention of CRC is the ultimate goal of screening. To
accomplish this, a screening test must effectively detect those
precursor lesions most likely to progress. The non-invasive
approach of fecal occult blood testing to screen for CRC has
poor sensitivity for colorectal precursor lesions [22–24].
However, the detection rates of colorectal neoplasia by MT-
sDNA progressively increase with growth in adenoma size
Fig. 1 Screen detection of advanced colorectal neoplasia by multi-target
stool DNA test in the representative US population study [20••] and the
Alaska native population study [21•]. Adapted from [29]
Page 3 of 7 30
beyond 1 cm. This test feature has important implications on
precursor lesion detection by MT-sDNA testing in a screening
program (see below), as continued growth in adenoma size
>1 cm is strongly associated with progressive risk of CRC
transformation [25]. Serrated polyps, the other critical precur-
sor lesions, are detected at a much higher rate by MT-sDNA
compared to FIT [26] as shown in Fig. 2.
Multi-Target Stool DNA in Clinical Practice
The US Food and Drug Administration (FDA) approved the
MT-sDNA test for use in general CRC screening in August of
2014. Concurrently, the Center for Medicare and Medicaid
Services (CMS) ruled that the test would be covered by
Medicare at a frequency of every 3 years. Several professional
organizations, including the American Cancer Society [27],
now include stool DNA testing in their CRC screening guide-
lines. A modeling study, examining the cost-effectiveness of
MT-sDNA in the context of population screening, found that a
3-year MT-sDNA test interval provides a decrease in CRC
incidence and mortality that is only slightly lower than that
of colonoscopy every 10 years but with similar and acceptable
cost-effectiveness [28].
With the advent of this new disruptive technology for
average-risk CRC, questions must be raised regarding its per-
formance characteristics, place in clinical practice, and appro-
priate follow-up of test results. We have addressed several key
questions in the following paragraphs, and some of the text
has been excerpted from our recent clinical review [29].
Is the Sensitivity of Multi-Target Stool DNA Sufficiently
High for Screen Detection of Colorectal Cancer
and Advanced Precancer?
To have an impact on CRC mortality, a screening test must
have a high rate of detection of early-stage CRC at a single
point in time (point sensitivity). Since there is a variable rate of
stage progression to cancer, one cannot rely on cumulative
detection with repeated testing over time (program sensitivity)
Fig. 2 Sensitivity of multi-target stool DNA versus fecal immunochemical
test by SSP size. Adapted from [29]
30 Page 4 of 7
to detect missed CRC. MT-sDNA meets this criterion standard
with a high point sensitivity of 94 % for asymptomatic stage I–
II CRC [20••] which is comparable to colonoscopy [30•] and
higher than the point sensitivity of 70 % for FIT [20••].
An ideal screening test for CRC prevention would accu-
rately detect the precancerous polyps most likely to progress
to cancer, as the large majority of polyps do not evolve into
CRC. The precancerous polyps that are most likely to progress
include advanced adenomas and sessile serrated polyps >1 cm
[31]. However, the degree of CRC risk applicable to these
lesion subgroups remains controversial [32]. Using radiologic
data from the precolonoscopic era [33], many colorectal
polyps ≥1 cm at baseline appear to remain stable or regress
over time, but 2.5 % develop cancer at the index polyp site
after 5 years, 8 % after 10 years, and >20 % after 20 years.
High-grade dysplasia represents the most advanced precancer-
ous lesion and the critical link between benign and malignant
disease [34, 35]. Furthermore, the large majority of high-grade
dysplasia occurs in polyps >2 cm in diameter [19, 36]. It is
therefore logical that from a prevention standpoint, it is most
important to detect polyps with high-grade dysplasia and large
polyps at greatest risk of containing high-grade dysplasia.
In contrast to CRC, there is a long dwell time of precancer-
ous lesions [33] that permits detection of high-risk polyp co-
horts by repeat testing. As such, cumulative sensitivity with
repeated testing over time (program sensitivity) is most rele-
vant. Based on point sensitivities from the screen setting [20••],
MT-sDNA is estimated to achieve high program sensitivities
for those polyps at greatest risk of progression. For example,
cumulative sensitivity for HGD is estimated to increase to
93 % by the second screen, and for a cohort of 1–2-cm ade-
nomas, it is estimated to rise to 88–98 % by the third screening
round. Thus, the program sensitivity of MT-sDNA performed
at a frequency of every 3 years may compare favorably to
colonoscopy done every 10 years.
It is important to note that high test sensitivity is not the
single feature responsible for effective lesion detection in
population-level screening. Rather, effective detection is the
product of sensitivity, compliance, and access. All three fac-
tors must be high to achieve effective screen detection in the
population. In this regard, MT-sDNA can potentially achieve
high effective detection rates by positively affecting each of
these three factors (Table 1). In addition to high test sensitivity,
MT-sDNA may improve CRC screening uptake due to its
user-friendly features and high accessibility by mail
distribution.
Is the Specificity of Multi-Target Stool DNA Acceptable
for Population Screening?
High specificity is a desirable feature of a screening test in
order to minimize false-positive results that trigger costly
and unnecessary diagnostic procedures. Some have expressed
Curr Gastroenterol Rep (2016) 18:30
Table 1 Elements for effective detection by MT-sDNA and factor
influences
Elements for effective detection by MT-sDNA Factor influences
High sensitivity for CRC and greatest-risk precancer Sensitivity
Less affected by tumor site Sensitivity
Operator independent (automated) Sensitivity
Non-invasive Compliance
No bowel preparation Compliance
No diet or medication restriction Compliance
Off-site collection Access
Widely accessible Access
concern over the specificity of MT-sDNA. However, most
important in a screening application is the cumulative false-
positive rate over time, which is influenced by both point
specificity and testing frequency. Because of its high sensitiv-
ity for CRC, MT-sDNA will be performed initially every
3 years. Using the lower point specificity of 87 % for MT-
sDNA, compared to 95 % for FIT, the performance of MT-
sDNA within a screening program will be favorable. For ex-
ample, MT-sDNA done every 3 years yields roughly 4 % false
positives/year (13 % divided by 3) compared to 5 % false
positives/year by annual FIT.
The point specificity of MT-sDNA is likely higher than the
reported 87 % [20••] for several reasons. First, in the large
seminal study [20••], non-advanced polyps were considered
false-positives; in this Bfalse-positive^ group as defined in the
study, 40 % had non-advanced adenomas, 23 % had hyper-
plastic or non-neoplastic polyps, and 37 % had no biopsies
taken. Therefore, it is likely that the 40 % with non-advanced
adenomas would have a change in surveillance recommenda-
tions and would not be treated in practice as false positives.
Second, at least 10 % of advanced neoplasms are missed by
colonoscopy and would have been considered MT-sDNA
false positives. Lastly, unlike the blinded study [20••],
endoscopists in practice will be aware of the MT-sDNA-
positive results prior to their diagnostic examination, which
may improve yield and reduce the likelihood of overlooked
lesions. A preliminary study (unpublished) demonstrated that
an endoscopists’ knowledge of a positive MT-sDNA en-
hanced colonoscopy performance as measured by longer
withdrawal time and significant increases in the number of
detected serrated and adenomatous polyps.
Many factors that may influence DNA marker levels in
stool have been studied [37]. Increasing age is the only factor
that significantly influences DNA marker levels in stool [20••,
38], which may be due to an increasing polyp burden or ac-
cumulated background field changes with age over 65 years.
Other variables including sex, race, smoking, alcohol, medi-
cations, body mass, or diabetes mellitus do not affect the test
Curr Gastroenterol Rep (2016) 18:30
specificity. These findings are of critical importance to CRC
screening compliance, as patients using MT-sDNA do not
need to make lifestyle or medication adjustments.
In summary, while the point specificity of MT-sDNA is less
than that of FIT, the program specificity of MT-sDNA may be
equal to or better than that of FIT when screening with MT-
sDNA at every 3-year intervals. MT-sDNA should generate
fewer unnecessary colonoscopies over time than with FIT
done annually when comparing their program specificities.
Longitudinal studies are needed to determine the clinical sig-
nificance of MT-sDNA-positive results in those with negative
colonoscopy findings.
Indications for Multi-Target Stool DNA
MT-sDNA is FDA approved for general screening of those at
average risk for CRC. MT-sDNA has a higher sensitivity for
larger precancerous polyps over fecal blood testing ap-
proaches, and it achieves high point sensitivity for CRC, sim-
ilar to that of colonoscopy. MT-sDNA has potential to im-
prove effectiveness of CRC screening through impacts of its
high accuracy for neoplasm detection, user-friendly features
on patient compliance, and easy mail-out distribution on test
access.
Potential Evolving Indications of Multi-Target Stool
DNA
While the initial approval of MT-sDNA is for average-risk
screening of CRC in general population, other indications
may evolve including interval testing between screening co-
lonoscopy, follow-up of an inadequately prepared or incom-
plete colonoscopy, and surveillance in low CRC populations.
In the common scenarios below, use of MT-sDNA may rep-
resent a rational complement or a resource-saving approach.
Screening colonoscopy is less effective at reducing the in-
cidence and mortality from right-sided CRC [9••, 38] with
interval cancers being disproportionately right-sided [30•,
39]. In addition, colonoscopy is operator-dependent with wide
variability in adenoma and sessile serrated polyp detection
between endoscopists [40, 41]. Furthermore, the effectiveness
of colonoscopy in CRC prevention is dependent upon the skill
of the endoscopist [42••, 43]. Finally, while the point sensitiv-
ity of colonoscopy for CRC is very high, the long interval of
every 10 years as conventionally practiced may not accom-
modate for the variable progression rates of neoplastic polyps
to CRC and may miss more aggressive lesions. Some have
recommended the use of fecal blood testing for interval
screening between colonoscopies to compensate for program
deficiencies of colonoscopy [44], but fecal blood tests have
suboptimal sensitivity for both CRC and adenomas,
Page 5 of 7 30
particularly for right-sided lesions [22, 23]. Importantly, fecal
blood tests do not detect sessile serrated polyps [20••, 45],
lesions that are also often missed by colonoscopy and may
help to explain its lesser effect of colonoscopy on proximal
disease [46]. For these reasons, interval testing with MT-
sDNA may be more logical and effective.
Suboptimal bowel preparation occurs in up to 25 % of
colonoscopies, resulting in substantial miss rates of advanced
neoplasia [47], and the rates of complete colonoscopy to the
cecum are variable across endoscopists and practice groups
[31, 48]. For individuals with a poor preparation or incomplete
colonoscopy, MT-sDNA testing may be a reasonable follow-
up alternative to repeat colonoscopy or other imaging
methods, particularly among individuals who refuse to under-
go repeat bowel preparation and invasive testing.
Some groups undergoing surveillance colonoscopy are not
at particularly increased risk of future colorectal neoplasia.
The risk of metachronous colorectal neoplasia is relatively
low following removal of a single small adenoma, and CRC
risk may not be higher than average among those with a pos-
itive family history of sporadic CRC following a negative
initial surveillance colonoscopy [31]. In these scenarios and
in those refusing colonoscopy, surveillance for colorectal neo-
plasia by MT-sDNA is rational and should be evaluated.
Clinical Follow-Up of Multi-Target Stool DNA Test
Results
The MT-sDNA test is reported as either negative or positive. If
the MT-sDNA is negative, then the risk of harboring advanced
colorectal neoplasia is extremely low and MT-sDNA should
be repeated in 3 years with the recognition that the test is most
effective in the programmatic setting. A positive MT-sDNA
test result should be followed by a diagnostic colonoscopy
with colorectal neoplasia treated as clinically indicated. An
area of heightened concern is the MT-sDNA test-positive pa-
tient with normal colonoscopy findings. In instances of such
discordance, it is imperative to ensure that the colonoscopy
was complete to the cecum and the bowel preparation was of
high quality. If there is doubt regarding the completeness or
quality of the bowel preparation, then colonoscopy should be
repeated. The available data have not permitted the establish-
ment of an evidence-based algorithm to direct management of
the test-positive patient with a high-quality normal colonosco-
py. The current assessment is based on expert opinion, but
lessons learned from conventional algorithms will help direct
future evaluations. Patients with a positive MT-sDNA result
go onto diagnostic colonoscopy, while those with a negative
test result have the option of continuing with MT-sDNA
screening every 3 years. In instances where the initial MT-
sDNA result is positive but high-quality colonoscopy (i.e.,
meticulous examination of cecum to rectum with good-to-
30 Page 6 of 7
excellent bowel preparation) is negative, a repeat MT-sDNA
test is suggested. If the repeat MT-sDNA test is negative, then
this may indicate that the initial positive result could have
been due to a technical error or short-lived bleeding and that
the likelihood of missed advanced colorectal neoplasia is low;
in such cases, patients would have the option to return to every
3-year screening with MT-sDNA. If the repeat MT-sDNA
remains positive, a high-quality colonoscopy should be re-
peated to assess for an overlooked colorectal lesion. If either
the first or second colonoscopy reveals a colorectal neoplasm
or a bleeding lesion (as the MT-sDNA also has a fecal immu-
nochemical test component within its panel), the patient is
treated accordingly and may subsequently be routed to a sur-
veillance arm. However, should the second colonoscopy also
be normal, it is not clear if further diagnostic evaluation is
needed, because the risk of upper aerodigestive neoplasia is
likely very low. MT-sDNA has been configured and opti-
mized for detection of colorectal neoplasia. In preclinical stud-
ies with earlier-generation stool DNA tests, upper endoscopy
and CT scanning performed on 60 consecutive patients with a
positive stool DNA test and negative colonoscopy revealed no
neoplastic pathology [49]. Clinical judgment will be required
for decision-making in such instances until additional longi-
tudinal clinical data are available with MT-sDNA.
The MT-sDNA test has two major components, a
quantitative molecular assay and a hemoglobin immuno-
assay. As currently configured, the MT-sDNA test result
is generated with the use of a logistic regression algo-
rithm with a predefined cutoff value to provide a di-
chotomous Bpositive^ or Bnegative^ test result. By using
this logistic regression algorithm approach, the MT-
sDNA test has higher sensitivity without loss in speci-
ficity compared to using only a marker-specific cutoff
and scoring a test as negative or positive if one or more
markers exceeded a threshold [19]. When a MT-sDNA
test is positive, it is unclear how much the molecular
assay versus FIT component contributes to this positive
result. In clinical practice, the hemoglobin immunoassay
component of the MT-sDNA may lead to a Bfalse-
positive^ result by detecting non-neoplastic bleeding le-
sions within the colorectum. Studies are underway to
examine this important issue.
Conclusions
MT-sDNA is FDA-approved for average-risk CRC screening
and CMS-approved for every 3-year screen frequency. It is a
non-invasive screening option that has high sensitivity for
CRC and large polyps. MT-sDNA has the greatest potential
to prevent CRC via program detection of the highest-risk
precancers. Its user-friendly and distributable features could
improve compliance and access to CRC screening. Future
Curr Gastroenterol Rep (2016) 18:30
applications of stool DNA testing might include its use as an
interval test between screening colonoscopy and for surveil-
lance of populations, at low risk for CRC, or for higher-risk
persons refusing to undergo invasive testing.
Compliance with Ethics Guidelines
Conflict of Interest SS and DAA’s employer, Mayo Clinic, has li-
censed technology to Exact Sciences that was used in the development
of Cologuard. As an inventor on this licensed technology, DAA shares in
royalties from Exact Sciences to Mayo Clinic. DAA is also a scientific
advisor and research collaborator with Exact Sciences.
Human and Animal Rights and Informed Consent All reported
studies/experiments with human or animal subjects performed by the
authors have been previously published and were in compliance with
all applicable ethical standards (including the Helsinki declaration and
its amendments, institutional/national research committee standards, and
international/national/institutional guidelines).
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