EDITORIAL
Challenges for colorectal cancer screening decision
modeling
Colorectal cancer (CRC) screening is effective, but only
if it is completed. One of the giants of CRC screening and
surveillance, Sidney Winawer, would often say: “The best
CRC screening test is the one that gets done.” Is there a
“best” CRC screening test? The answer is not known,
because few head-to-head studies have been performed.
Few comparative studies have measured CRC incidence,
mortality, life-years gained, and cost for more than one
screening program. Such studies are difficult and costly.
There is clearly an information gap.
Decision models can simulate what might happen in real
life and can enable us to determine the merits of more than 1
screening program. Such models rely on inputs that may be
assumed, not known. Therefore, models can reveal truths,
but they may lack precision to create sharp realities. “Real
life” is messy and hard to simulate. The CRC screening mi-
crosimulation by Deibel et al1 reinforces this point by
modeling different screening tests with 100% adherence
and then with “real-world” adherence. The authors
describe screening tests based on efficacy and outcomes.
An efficient test is defined by high sensitivity for CRC and
advanced adenomas, and an effective test is defined by
outcomes including CRC incidence, mortality, life-years
gained, and cost. The authors conclude that a less efficient
test could have better outcomes if adherence is better
than a more efficient, but less adherent, test. This is a pro-
found statement, because we are often focused on what hap-
pens when test adherence is 100%. However, perfect
adherence is never the case in real life.
Decision modeling can provide some important insights
into the performance of clinical tests by showing us how
manipulation of variables can affect key outcomes. But de-
cision modeling has its limits. In this commentary, I will
raise several issues that may have an impact on CRC
screening test performance and may not be fully consid-
ered in various decision models.
PROGRAMMATIC PERFORMANCE
Programmatic performance of CRC screening requires
adherence at several steps, which are challenging to model.
Four of the programs discussed in this microsimulation
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require 3 levels of adherence. First is completion of the initial
test when provided to a patient. This is relatively easy to
model, and the authors make real-life assumptions based
partly on existing literature. The assumptions made for urine
and serum tests are derived from non-CRC screening, and
they may or may not be valid. The second level of adherence
is the appropriate follow-up of a positive test result. The au-
thors assume that 82% of patients will receive colonoscopy
follow-up for positive test results, but the medical literature
suggests that the range could be from <50% to 85%.2 None
of the noninvasive programs will be effective if patients
with positive test results do not receive colonoscopy, so
It is easy to model a patient who has a positive
noninvasive screening test result, receives a
colonoscopy, is found to have an advanced ad-
enoma, and enters colonoscopy surveillance
because of the higher risk of CRC. What about
a patient who undergoes a colonoscopy for a
positive noninvasive test result, but the result
of colonoscopy is negative?
this is a crucial metric in any screening program. It is quite
possible that these tests might differ in adherence to
colonoscopy follow-up. For example, a test that detects an in-
direct marker of risk (blood or metabolomics) may have
lower rates of colonoscopy than a test that may detect a ge-
netic abnormality. The third level of adherence is the
follow-up of a negative screening test result at the appro-
priate interval. This is important because none of these
noninvasive programs has 100% sensitivity for one-time
testing. Two of the testsdfecal immunochemical test (FIT)
and Epi proColon (Epigenomics, Berlin, Germany)drequire
annual testing, and 2 of the tests require retesting at 3-year
intervals (mt-sDNA and PolypDx [Metabolomic Technolo-
gies Inc, Edmonton, Alberta, Canada]).
If the authors model the same adherence for repeated
testing as for initial testing, the model is likely to be flawed.
Studies of multiple rounds of FIT have demonstrated a
decline in adherence after the first round of testing.3
Moreover, there is a strong possibility of intermittent
variable adherence. For example, the patient may be
adherent in round 1, miss rounds 2 and 3, and then
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Editorial
resume in round 4. This gap may be especially important
for a test performed at 3-year intervals because the gap
in screening may be quite long. This latter effect of vari-
ability is very challenging to model, and this is why most
models have used a 100% adherence rate as a baseline
and then picked some other rate for “real life.” Arguably,
real life is messy, and rates will not be consistent over
the 25- to 30-year period (age 45 to 75) for screening.
PATIENT PREFERENCE
A second issue to consider is the impact of patient pref-
erence on screening test choice and adherence. A test that
can detect advanced adenomas is fundamentally different
from a test that primarily detects early-stage cancer. Each
of the noninvasive tests in this model detects <50% of pa-
tients with advanced adenomas, which may be cancer pre-
cursors. These tests are less likely to result in cancer
prevention than is colonoscopy. If informed decision mak-
ing is conducted and patients are fully informed of the dif-
ferences in these tests, some may opt for a test more likely
to lead to cancer prevention if they are provided a choice.
Therefore, patient choice could affect the outcomes. This
is an issue of patient preference, not test performance.
The conclusion of this microsimulation analysis is still valid.
A test with lower efficiency with good adherence may be
more effective than a test with excellent efficiency but
poor adherence.
What if patients are not happy with the screening pro-
cess? This could result in future nonadherence. Here is
an example. When the Affordable Care Act was passed, it
created incentives for preventive screening by waiving
any copayments. However, when patients have a positive
noninvasive test result (currently FIT and mt-sDNA), colo-
noscopy is designated as a diagnostic examination, and co-
pays may be billed to patients. Anecdotally, some patients
regard this as a bait and switch, become resentful, and
decline to have further screening. Model assumptions
that patients may stick with the program they start with
may not be correct.
PROGRAM QUALITY
A third issue for models is program quality. The nonin-
vasive programs depend on the 3 levels of adherence
noted above. These quality metrics of adherence should
be monitored (and improved) to achieve an effective pro-
gram. Colonoscopy quality is crucial to each screening pro-
gram. Decision models depend on published data from
clinical trials, which often represent the colonoscopy re-
sults of experts. In clinical practice, metrics such as bowel
preparation quality, cecal intubation, and adenoma detec-
tion rate may be variable. The real-life performance of
each program is influenced by the quality of the colonos-
copy. Studies that report the clinical results of various
392 GASTROINTESTINAL ENDOSCOPY Volume 94, No. 2 : 2021
Lieberman
screening tests should include information about how
the investigators assessed colonoscopy quality.
IMPACT OF CRC RISK ON MODEL
Another issue for decision modelers is how screening
results identify high- or low-risk individuals and how the re-
sults might influence the subsequent use of screening
tests. It is easy to model a patient who has a positive nonin-
vasive screening test result, receives colonoscopy, is found
to have an advanced adenoma, and enters colonoscopy
surveillance because of a higher risk of CRC. What about
a patient who undergoes a colonoscopy for a positive
noninvasive test result, but the result of colonoscopy is
negative? Should this patient receive further colonoscopy
or be re-entered into noninvasive screening at 10 years?
We know that the pretest probability of CRC is low in
this individual, relative to first-time screening. What about
a patient found to have a low-risk adenoma at colonoscopy
after a positive noninvasive screening test result? According
to current literature,4 this patient has a low risk of CRC
during long-term follow-up. Should this patient now have
colonoscopy surveillance, or be followed up with noninva-
sive testing? This is tricky for modelers because we do not
have good clinical answers to these questions. In some mi-
crosimulation models, patients who cross over to colonos-
copy for a positive noninvasive test result remain in
colonoscopy for the duration of the time horizon. Test per-
formance after a negative colonoscopy result is different
than for first-time screening because the rates of CRC
and advanced adenoma will be much lower (pretest prob-
ability) than for first-time screening. This pretest probabil-
ity affects cost-effectiveness in models.
MODEL INPUTS
Finally, decision modeling is only as good as the quality
of the inputs about test performance and should be itera-
tive, and modified as new data appears. In this particular
model, inputs for initial adherence for 3 programs (mt-
sDNA, Epi proColon, and PolypDx) are not based on any
utilization data for CRC screening. These “real-life” adher-
ence data are derived from other stool, blood, and urine
tests, and they may not be accurate for CRC screening.
Only 1 program (FIT) has adherence data for first-time
testing, and the results are highly variable. The authors
model a 49% adherence rate, but recent studies have
shown that an organized program can achieve far higher
adherence.5 Given that decision models can evaluate a
range of assumptions (sensitivity testing), they are quite
useful for determining the threshold levels of adherence
needed to attain desired outcomes.
In summary, this microsimulation model highlights an
important feature of CRC screeningdnamely, that adher-
ence matters. This commentary demonstrates that
modeling CRC screening is complicated and that adherence
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Lieberman
is a many-leveled beast. As models mature they should up-
date their inputs as more clinical data emerge. They should
also try to account for the complexity of the various layers of
screening, intermittent adherence, patient shifting from
one test to another, and the nuances of program quality.
DISCLOSURE
The author disclosed no financial relationships.
David Lieberman, MD
Division of Gastroenterology and Hepatology
Oregon Health and Science University
Portland, Oregon, USA
Abbreviations: CRC, colorectal cancer; FIT, fecal immunochemical test.
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Editorial
REFERENCES
1. Deibel A, Deng L, Cheng C-Y, et al. Evaluating key characteristics of ideal
colorectal cancer screening modalities: the microsimulation approach.
Gastrointest Endosc 2021;94:379-90.
2. Singal AG, Gupta S, Skinner CS, et al. Effect of colonoscopy outreach vs
fecal immunochemical test outreach on colorectal cancer screening
completion. JAMA 2017;318:806-15.
3. Jensen CD, Corley DA, Quinn VP, et al. Fecal immunochemical test pro-
gram performance over 4 rounds of annual screening: a retrospective
cohort study. Ann Intern Med 2016;164:456-63.
4. Gupta S, Lieberman D, Anderson JC, et al. Recommendations for follow-
up after colonoscopy and polypectomy: a consensus update by the US
Multi-Society Task Force on Colorectal Cancer Screening. Gastroenter-
ology 2020;158:1131-53.
5. Levin TR, Corley DA, Jensen CD, et al. Effects of organized colorectal
cancer screening on cancer incidence and mortality in a large
community-based population. Gastroenterology 2018;155:1383-91.
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