- Email: [email protected]
Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States
Accepted Manuscript Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States Chen Chen, MSPH, Christian Stock, PhD, Michael Hoffmeister, PhD, Hermann Brenner, MD, MPH PII:
S0016-5107(17)31807-2
DOI:
10.1016/j.gie.2017.04.005
Reference:
YMGE 10528
To appear in:
Gastrointestinal Endoscopy
Received Date: 13 January 2017 Accepted Date: 4 April 2017
Please cite this article as: Chen C, Stock C, Hoffmeister M, Brenner H, Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States, Gastrointestinal Endoscopy (2017), doi: 10.1016/j.gie.2017.04.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States Running title: Impact of colonoscopy use on CRC mortality in the general population
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Authors: Chen Chen, MSPH,1 Christian Stock, PhD,1, 2 Michael Hoffmeister, PhD,1 Hermann Brenner, MD, MPH1, 3, 4
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
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(DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer
Feld 130.3, D-69120 Heidelberg, Germany 3
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National
Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg,
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Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im
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Neuenheimer Feld 280, D-69120 Heidelberg, Germany
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Corresponding author:
Hermann Brenner, MD, MPH Division of Clinical Epidemiology and Aging Research German Cancer Research Center Im Neuenheimer Feld 581 D-69120 Heidelberg Phone +49-6221-421300 Fax
+49-6221-421302
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Grant support: CC was supported by the Helmholtz International Graduate School for
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Cancer Research at the German Cancer Research Center (DKFZ).
Author contributions: Conception and design: HB; analysis and interpretation of the data: CC, CS, HB; drafting of the article: CC; critical revision of the article for important
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intellectual content: CC, CS, MH, HB; final approval of the article: CC, CS, MH, HB.
ACCEPTED MANUSCRIPT Abstract
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Background and Aims: Colonoscopy has been demonstrated to be effective in reducing
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colorectal cancer (CRC) incidence and mortality, and has been widely used for primary CRC
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screening in Germany and the United States. We performed a population-based analysis to
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evaluate and compare the public health impact of recent colonoscopy use on CRC deaths
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among adults aged 55 to 79 years in Germany and the United States from 2008 to 2011.
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Methods: The epidemiologic metrics of attributable fraction and prevented fraction as well
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as the impact numbers were calculated using colonoscopy utilization data from nationally
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representative health surveys, relative risk estimates from medical literature, and CRC death
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registry data.
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Results: Overall, 36.6% (95% credible interval [CrI], 27.3%-45.5%) of CRC deaths in
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Germany were estimated to be attributable to nonuse of colonoscopy, compared with the U.S.
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estimates of 38.2% (95% CrI, 28.6%-47.1%) and 33.6% (95% CrI, 24.8%-42.2%) for years
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2008 to 2009 and 2010 to 2011, respectively. The proportion of CRC deaths theoretically
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prevented by colonoscopy use within 10 years was 30.7% (95% CrI, 24.8%-35.7%) in
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Germany, whereas in the United States this proportion ranged from 29.0% (95% CrI, 23.4%-
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33.6%) for 2008 to 2009 to 33.9% (95% CrI, 27.4%-39.2%) for 2010 to 2011.
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Conclusions: Recent colonoscopy use is likely to have prevented a considerable fraction of
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CRC mortality in both countries, and more deaths could be avoided by increasing
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colonoscopy utilization in the target population. Attributable and prevented fraction can
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provide valuable information on the public health impact of colonoscopy use and guide the
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policy making.
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ACCEPTED MANUSCRIPT Background
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and a
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significant cause of cancer morbidity and mortality in North America and Europe.1 Because
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of the slow progression from adenomas to invasive cancers, substantial proportions of CRC
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cases and deaths could be prevented by screening.2 Through detection and removal of
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precancerous lesions and early cancers, lower gastrointestinal endoscopy can effectively
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reduce the incidence of advanced disease and thus lead to a decrease in CRC mortality.3-11
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Lower gastrointestinal endoscopy, especially colonoscopy, is recommended by several
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guidelines to be used as a screening tool for persons aged 50 and older at average risk for
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CRC,12-14 and has become one of the principal screening tests in countries like the US and
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Germany.15, 16
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The continuous and widespread use of colonoscopy screening is believed to be a major
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contributory factor in the decreasing CRC incidence and mortality observed in the United
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States during the past decade.17, 18 Using the epidemiologic metrics of prevented fraction (PF)
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and attributable fraction (AF), Stock et al19 estimated that approximately 7300 to 11,700 CRC
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deaths in the United States in 2005 were prevented by colonoscopy use, accounting for 13%
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to 19% of total CRC deaths among persons aged over 50 years, and about twice as many
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deaths could be avoided if nonuse of colonoscopy were to be eliminated. In another study,
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Meester et al20 used both the standard epidemiological method and a microsimulation model
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to estimate the AF, and reported about 46% to 63% of CRC deaths in the United States in
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2010 were attributable to not having any of the screening tests.
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In Germany, colonoscopy has become more commonly accepted and frequently used by the
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general population over the past decade. In 2008 to 2011, more than half of the screening-
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Although modeling studies have previously evaluated the expected effects of screening
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colonoscopy on future CRC incidence,21, 22 the actual public health benefits of colonoscopy
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on deaths from CRC in the general German population have not been explored and remain
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largely unclear. In this study, we aimed to estimate the CRC mortality prevented by use of
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colonoscopy and the further potential of colonoscopy use in reducing CRC mortality in
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Germany, and to compare these results with the estimates of the United States over the same
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time period.
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Methods
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Data sources
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The epidemiologic metrics of AF and PF were estimated to reflect the impact of colonoscopy
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use within the past 10 years on CRC deaths in the general population. Data from several
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sources were combined for the calculation of AF and PF estimates for Germany and the
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United States.
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Colonoscopy effectiveness estimates were derived from the medical literature. Studies
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assessing the effects of colonoscopy versus no colonoscopy on CRC mortality in the general
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average-risk population were searched at PubMed and Web of Science from inception to June,
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2016 and combined using meta-analysis to obtain a pooled estimate that also includes the
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most recent evidence (that is not yet covered in published meta-analyses).
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Data on colonoscopy use in the general population were derived from nationally
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representative health surveys. The German Health Interview and Examination Survey for
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Adults (DEGS) is a periodically repeated nationwide health survey of non-institutionalized
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CRC screening adherence were available from the first wave of DEGS (2008-2011).
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Respondents aged 55 to 79 years were asked if they had ever undergone colonoscopy and the
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time since the last examination. This age range was selected because screening colonoscopy
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is offered from age 55 on only in Germany. Indication for colonoscopy use was not
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ascertained. The proportion of people who have undergone colonoscopy within the past 10
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years as well as the age- and sex-specific prevalence estimates, which were weighted to be
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representative of the resident population of Germany as of 31 December 2010, were directly
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extracted from the study report.16
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Endoscopy use data in the United States were drawn from the National Health Interview
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Survey (NHIS), a household, multistage probability sample survey conducted annually since
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1957.24, 25 The NHIS is one of the principle sources of information on the health of the
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civilian, non-institutionalized U.S. population. To enable comparisons of estimates from the 2
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countries, data among adults aged 55 to 79 years from 2008 and 2010, when CRC screening
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test utilization was ascertained, were used as estimates for 2008 to 2009 and 2010 to 2011,
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respectively. In the 2008 NHIS, respondents aged 40 and older were asked if they have ever
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had sigmoidoscopy, colonoscopy or proctoscopy. If utilization was reported, respondents
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were then asked to specify the type of the most recent examination they had (sigmoidoscopy,
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colonoscopy or proctoscopy) as well as the time and reason for this most recent exam. In the
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2010 NHIS, respondents aged 40 and older were asked separate questions on colonoscopy,
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sigmoidoscopy, CT colonography and fecal occult blood test (FOBT). A brief description of
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each test was provided. Regarding colonoscopy use, participants were asked if they have ever
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had colonoscopy and the time and reason for the most recent examination.
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International Classification of Diseases-10 Version), were extracted from the German Centre
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for Cancer Registry Data (ZfKD)26 and the United States Cancer Statistics (USCS) report,27
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for the time period 2008 to 2011. The cancer mortality data on the ZfKD platform are
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provided by the Federal Statistical Office Germany, which collects data on all deaths in
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Germany. The USCS is a Web-based report that includes the official federal statistics on
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cancer mortality provided by the National Vital Statistics System, with 100% of the U.S.
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population covered.27
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Statistical analysis
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The colonoscopy effectiveness parameter was obtained by combining the effect estimates of
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observational studies that evaluated the impact of colonoscopy on CRC mortality. Studies
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that specifically and exclusively addressed screening colonoscopy were excluded. Risk ratios
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and hazard ratios from cohort studies as well as odds ratios from case-control studies that
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were used to measure effects were all referred to as relative risk. The pooled effect size and
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95% confidence intervals (CIs) were calculated using a random-effects model.28
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Prevalence of colonoscopy use in the United States was calculated from NHIS 2008 and 2010
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data. All colonoscopies were included in the analysis regardless of indication. Respondents
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with a history of CRC or missing information on CRC history were excluded to enable an
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analysis in the average-risk population. To obtain nationally representative estimates, sample
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weights were applied to reflect the selection probabilities as well as adjustments for non-
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response and post-stratification.29, 30 Variance estimates were computed by Taylor series
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linearization method to adjust for complex sample design.29, 30
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on CRC mortality. The metric of AF was first introduced in a study on the association of
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smoking and lung cancer, and has gradually become widely used for measuring the impact of
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an exposure on an outcome at the population level.31 AF is often interpreted as the proportion
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of those with the outcome that might be attributable to the exposure, or the maximum
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proportion of those with the outcome that might be reduced if the exposure is eliminated.32, 33
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In our study, the AF for colonoscopy use refers to the proportion of CRC mortality that is
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likely to be attributable to not having had a colonoscopy within 10 years, and also means the
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maximum proportional reduction in CRC mortality if nonuse of colonoscopy were to be
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eliminated.19 PF is an alternative public health impact measure that is more commonly used
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in the cases of protective exposure or intervention. It represents the proportion of those
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avoiding the outcome because of the protective exposure.34 In our analysis, the PF for
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colonoscopy use is defined as the proportion of hypothetical CRC deaths that have been
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prevented by recent colonoscopy use.19 Absolute numbers of CRC deaths attributable to
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nonuse and prevented by use of colonoscopy were derived by multiplying the estimated AFs
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and PFs with the observed number of CRC deaths and estimated hypothetical CRC deaths if
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colonoscopy use were eliminated. (See Appendix for detailed methods.) We used 2 different
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metrics in an effort to reflect both the benefits of colonoscopy use in the past and the
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potential gains of further increasing colonoscopy use in the future. The 95% credible intervals
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(CrIs) of AFs, PFs, and absolute impact numbers account for the uncertainty in both
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prevalence of colonoscopy use and colonoscopy effectiveness, and were calculated by Monte
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Carlo simulation. The probability distribution for included parameters was built based on
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their point estimates and standard errors. Distributions of outcomes were then generated by
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running simulations with 10,000 iterations, from which the quantiles 2.5% and 97.5% were
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extracted to derive 95% CrIs. Monte Carlo errors were smaller than 5% of the standard
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deviation of the outcomes under 10,000 iterations.
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Sex- and age-specific estimates were calculated for each of the parameters and outcomes
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except colonoscopy effectiveness. Stata 13.1 (StataCorp, College Station, Tex, USA) and
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SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) were used to perform meta-analyses
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and the estimation of colonoscopy use prevalence, respectively. R version 3.2.5 (R
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Foundation for Statistical Computing, Vienna, Austria) was used for Monte Carlo
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simulation.35
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Results
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Estimates of parameters
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Estimates of the effects of colonoscopy use on CRC mortality are summarized in Table 1. Of
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the included 8 observational studies that evaluated the relative risk, 4 were cohort studies36-39
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and 4 case-control studies.40-43 All studies were carried out in North America. Except in one
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study in which persons who had colonoscopy use were compared with the general
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population,36 all other studies conducted the comparison between those with colonoscopy use
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and without. The 8 studies comprised colonoscopy use and CRC deaths data collected
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between 1981 and 2010, and covered colonoscopy performed up to 10 or more years before
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CRC diagnosis or death. All studies were at least matched by or adjusted for age and sex.
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Despite the heterogeneity in populations, settings, and study design, colonoscopy use for any
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indication was consistently associated with a reduction in CRC mortality in all studies, with a
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pooled estimate of 56% risk reduction (RR 0.44; 95% CI, 0.35-0.55).
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Prevalence of colonoscopy use in Germany and the United States are shown in Table 2.
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During 2008 to 2011, 54.8% (95% CI, 52.5%-57.0%) of German adults aged 55 to 79 years 7
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age groups 60 to 69 (58.4%) and 70 to 79 (56.6%) than in age group 55 to 59 (46.1%). Data
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from the NHIS yielded comparable estimates. In 2008, 55.8% (95% CI, 54.2%-57.4%) of the
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U.S. population aged 55 to 79 had undergone a colorectal endoscopy (colonoscopy,
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sigmoidoscopy, or proctoscopy) in the past 10 years (data not shown), from which over 90%
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identified colonoscopy as the most recent endoscopy (51.7% [95% CI, 50.1%-53.2%] of the
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overall 55-79 population). In 2010, 60.4% (95% CI, 59.0%-61.8%) of respondents indicated
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that they have had this procedure in the preceding 10 years. For both calendar years, the
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estimated proportion was found to be increasing with age.
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During 2008 to 2011, a total of 109,479 and 57,591 persons aged 55 to 79 years died of CRC
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in the United States and Germany, respectively (Supplementary Table 1). Figure 1 displays
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the trend in CRC deaths with age. For both countries the death count and mortality rate
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increased with age. This increase in mortality with age was much larger in Germany than in
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the United States. When examining the trends in CRC deaths during the 4 years, a decreasing
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trend for the mortality rate was observed for both countries.
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Estimates of AFs and PFs
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Overall from 2008 to 2011, 21,086 (95% CrI, 15,720-26,215) CRC deaths in Germany were
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estimated to be attributable to nonuse of colonoscopy within the previous 10 years,
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accounting for 36.6% (95% CrI, 27.3%-45.5%) of total CRC deaths among people aged 55-
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79 years (Table 3). The AFs in the United States were 38.2% (95% CrI, 28.6%-47.1%) and
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33.6% (95% CrI, 24.8%-42.2%) for years 2008 to 2009 and 2010 to 2011, respectively,
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which implies that a maximum of 20,947 (95% CrI, 15,724-25,864) and 18,344 (95% CrI,
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13,525-23,052) estimated deaths would have been avoided if all adults 55 to 79 years of age
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had had a colonoscopy within 10 years. In both countries, more CRC deaths among men were
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attributable to nonuse of colonoscopy than among women. In Germany, the vast majority of
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attributable deaths occurred in age group 70 to 79 years, whereas such estimates were more
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equally distributed across age groups in the United States.
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Over the same period of time, 25,564 (95% CrI, 18,983-32,002) CRC deaths in Germany
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were theoretically prevented by recent use of colonoscopy, accounting for 30.7% (95% CrI,
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24.8%-35.7%) of the estimated hypothetical CRC deaths of the population in the absence of
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colonoscopy (Table 4). The percentage of CRC deaths theoretically prevented by
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colonoscopy use in the United States for years 2008 to 09 and 2010 to 11 were 29.0% (95%
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CrI, 23.4%-33.6%) and 33.9% (95% CrI, 27.4%-39.2%), respectively. These translated into
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22,422 (95% CrI, 16,786-27,794) and 27,980 (95% CrI, 20,595-35,235) prevented deaths. In
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stratified analyses, although no systematic differences emerged between male and female in
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PFs, substantially more deaths could be prevented by the use of colonoscopy among men
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than among women, and the largest number of deaths was prevented in age group 70 to 79 in
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both countries.
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Discussion
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In this study, we evaluated the public health impact of colonoscopy use on CRC deaths in
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Germany and the United States. Our results indicate that in Germany from 2008 to 2011
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approximately 25,600 deaths among adults aged 55 to 79 years were prevented by
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colonoscopy use within the past 10 years, and about 37% of the actual 57,591 CRC deaths at
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best could have been avoided if 100% colonoscopy utilization were achieved. Comparable
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with the estimates of Germany, colonoscopy is likely to have saved around 50,400 persons
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aged 55 to 79 from CRC death in the United States over the same time period, and about
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39,300 out of 109,479 actual CRC deaths (36%) at the most could have been prevented by
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100% use of colonoscopy within 10 years.
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The observed trend in AF and PF estimates with age primarily reflects the differences in
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colonoscopy use. Persons aged 55 to 59 years, as the group with the lowest prevalence of
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recent colonoscopy use, had the highest AFs and the lowest PFs, though absolute numbers of
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attributable and prevented deaths were largest in age group 70 to 79 as a result of the
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substantially higher CRC mortality rate in this age group. Compared with the United States,
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Germany had a particularly high proportion of attributable CRC deaths in age group 70 to 79.
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This can be explained by a much larger increase of CRC mortality with age and much smaller
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reduction in population size from age 55 to 79 in Germany,26, 27 which might serve as
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evidence for including the elderly aged 75 to 79 years as screening target in this country.
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Because of the similar proportions of persons who have undergone colonoscopy within 10
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years, sex differences in AF and PF estimates were small. However, with males having a
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higher CRC mortality rate in both countries, especially Germany, where the CRC mortality
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estimates of men are about 70% to 80% higher than those of women in the target age group
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for CRC screening,26 more men can be prevented from dying from CRC by recent use of
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colonoscopy. Estimates of 2008 and 2010 from the United States confirmed the expectation
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of Stock et al. that with increasing use of colonoscopy and decreasing CRC mortality rate in
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recent years, AFs would decrease and PFs would increase over time.19
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Colonoscopy is recommended as one of the primary screening tools to persons at average risk
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for CRC in both Germany and the United States.13, 44 CRC screening by FOBT, followed by
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colonoscopy in case of a positive FOBT result, has been offered in Germany since 1977.
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Since 2002, colonoscopy has been recommended for primary CRC screening to persons over
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contributed to the increase in colonoscopy use prevalence in Germany over the past decade,
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which has gradually risen to the level of the United States and is much higher than in other
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European countries.15, 16, 45, 46 With the increased use of colonoscopy, over 30% of CRC
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deaths in Germany were avoided from 2008 to 2011, similar to the estimate of the United
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States. Our findings thereby underline the large potential for reducing the mortality from
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CRC through colonoscopy, even though even larger reductions would be possible by higher
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utilization of the screening offers.
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The accuracy of AF and PF estimates is dependent on how well the colonoscopy
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effectiveness parameter we used represents the true association between the test and CRC
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mortality in the target population. There have been many recent cohort and case-control
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studies investigating the effect of colonoscopy on CRC incidence and mortality in multiple
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populations.47, 48 Our summary estimate of colonoscopy effectiveness is in line with estimates
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derived in 2 other previously reported meta-analyses that summarized the effect of
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colonoscopy for any indication (relative risk, 0.40; 95% CI, 0.32-0.49, and 0.43 95% CI,
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0.33-0.58, respectively),47, 48 but had not yet included the most recently published studies
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addressing this research question.39, 43
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Although the metrics of AF and PF have been widely used to quantify the impact of an
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exposure on an outcome in epidemiological studies, there have been relatively few attempts
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to estimate the public health impact of colonoscopy as a protective factor on CRC.19, 20 Our
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results are generally consistent with the findings of these analyses that nonuse of colonoscopy
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or other screening tests contributed to a considerable fraction of CRC deaths in the United
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States, though there are some variations that generate from the different colonoscopy
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Stock et al,19 colonoscopy effectiveness from 2 case-control studies, one optimistic and one
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conservative estimate were used for analysis, which led to 2 estimates for AF and PF each for
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2005: 28% and 44%, and 13% and 19%, respectively.19 Meester et al20 evaluated the impact
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of all CRC screening tests on CRC deaths in the United States in 2010, and obtained an AF of
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46% when a relative risk of 0.32 from one specific prospective cohort study was applied.
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It is worth noting that use of colonoscopy is not a preventive measure by itself, but that its
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preventive effect comes through removal of precancerous lesions or treatment of CRC at an
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early stage when these lesions are detected at colonoscopy. In the majority of colonoscopies,
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no such lesions are detected, and those colonoscopies do not have any preventive effect.
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Calculation of AFs and PFs for use of colonoscopy is nevertheless meaningful in countries,
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such as Germany and the United States where colonoscopy is offered and widely used for
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primary CRC screening and to a large extent reflects screening coverage. In countries where
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CRC screening is primarily based on noninvasive methods, such as fecal immunochemical
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test for hemoglobin (FIT), such as the Netherlands,49 and colonoscopy is primarily used to
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follow-up positive results of such noninvasive tests, comparable levels of prevention should
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be achievable with much lower rates of use of colonoscopy, as the proportion of
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colonoscopies that yield a preventive effect, ie, those with relevant findings, should be much
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larger under such circumstances.
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Some limitations should also be noted in considering the findings of our study. First, only 2
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of the studies evaluating colonoscopy effects included procedures performed in the past
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decade,36, 43 whereas others considered colonoscopy completed many years ago, with the
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furthest dating back to 1980s.40 This might underestimate the strength of the association
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the advances in technology. Second, an overall relative risk instead of age- and sex-specific
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estimates was used in stratified analyses due to lack of reporting of subgroup data and
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different categorization of ages. This is not expected to bias our estimates greatly, especially
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sex-specific estimates, because colonoscopy is found to provide a similar magnitude of
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protection towards men and women.48 Third, questions regarding CRC screening tests
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utilization in the NHIS across different survey years were not phrased in a standardized way,
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which makes it hard to conduct direct comparisons over time. In 2008, respondents were
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asked to report the type of the most recent colorectal endoscopy from colonoscopy,
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sigmoidoscopy, or proctoscopy, which might underestimate the proportion of colonoscopy
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use within 10 years; however, as the vast majority identified colonoscopy as the most recent
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test, the impact should not be major. Another limitation relates to the self-reporting nature of
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colonoscopy use data for both countries, which might result in an overestimation of
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utilization; however, high sensitivity and specificity between self-reports and medical record
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data were found.50
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In summary, colonoscopy use within 10 years prevented a considerable fraction of CRC
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mortality in Germany and the United States during 2008 to 2011, and there is a large
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potential for further reducing the mortality by increasing colonoscopy utilization, either as
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primary screening examination or to follow-up positive results of promising noninvasive
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screening tests, such as FITs, in the target population. Our findings confirm the values of AF
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and PF metrics in evaluating the public health impacts of colonoscopy in screening settings,
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which can serve as evidence in the development and prioritization of intervention programs
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and strategies regarding endoscopic CRC screening. Although how to set up an attainable and
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realistic goal requires more exploration, our results underline the need to further encourage
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CRC screening in the general population.
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References
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1.
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Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide:
325
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer
326
2015;136:E359-86.
327
2.
Knudsen AB, Zauber AG, Rutter CM, et al. Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies: Modeling Study for the US
329
Preventive Services Task Force. JAMA 2016;315:2595-609. 3.
M AN U
330
SC
328
Atkin W, Wooldrage K, Parkin DM, et al. Long term effects of once-only flexible
331
sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy
332
Screening randomised controlled trial. Lancet 2017, DOI:10.1016/s0140-
333
6736(17)30396-3. 4.
Lin JS, Piper MA, Perdue LA, et al. Screening for Colorectal Cancer: A Systematic
TE D
334
Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 135.
336
AHRQ Publication No. 14-05203-EF-1. Rockville, MD: Agency for Healthcare
337
Research and Quality, 2016. 5.
colorectal cancer incidence and mortality: a randomized clinical trial. JAMA
339
2014;312:606-15.
340 341
Holme O, Loberg M, Kalager M, et al. Effect of flexible sigmoidoscopy screening on
AC C
338
EP
335
6.
Brenner H, Stock C, Hoffmeister M. Effect of screening sigmoidoscopy and screening
342
colonoscopy on colorectal cancer incidence and mortality: systematic review and
343
meta-analysis of randomised controlled trials and observational studies. BMJ
344
2014;348:g2467.
14
ACCEPTED MANUSCRIPT 345
7.
with screening flexible sigmoidoscopy. N Engl J Med 2012;366:2345-57.
346 347
Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer incidence and mortality
8.
Manser CN, Bachmann LM, Brunner J, et al. Colonoscopy screening markedly reduces the occurrence of colon carcinomas and carcinoma-related death: a closed
349
cohort study. Gastrointest Endosc 2012;76:110-7.
350
9.
RI PT
348
Elmunzer BJ, Hayward RA, Schoenfeld PS, et al. Effect of flexible sigmoidoscopybased screening on incidence and mortality of colorectal cancer: a systematic review
352
and meta-analysis of randomized controlled trials. PLoS Med 2012;9:e1001352. 10.
following a colonoscopy. Dig Liver Dis 2011;43:899-904.
354 355
Strock P, Mossong J, Scheiden R, et al. Colorectal cancer incidence is low in patients
11.
M AN U
353
SC
351
Segnan N, Armaroli P, Bonelli L, et al. Once-only sigmoidoscopy in colorectal cancer
356
screening: follow-up findings of the Italian Randomized Controlled Trial--SCORE. J
357
Natl Cancer Inst 2011;103:1310-22. 12.
Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Colorectal Cancer:
TE D
358 359
US Preventive Services Task Force Recommendation Statement. JAMA
360
2016;315:2564-75.
the American College of Physicians. Ann Intern Med 2015;162:718-25.
362 363
14.
Burt RW, Cannon JA, David DS, et al. Colorectal cancer screening. J Natl Compr Canc Netw 2013;11:1538-75.
364 365
Wilt TJ, Harris RP, Qaseem A. Screening for cancer: advice for high-value care from
EP
13.
AC C
361
15.
Shapiro JA, Klabunde CN, Thompson TD, et al. Patterns of colorectal cancer test use,
366
including CT colonography, in the 2010 National Health Interview Survey. Cancer
367
Epidemiol Biomarkers Prev 2012;21:895-904.
15
ACCEPTED MANUSCRIPT 368
16.
Starker A, Sass AC. Participation in cancer screening in Germany. Results of the
369
German Health Interview and Examination Survey for Adults (DEGS1).
370
Bundesgesundheitsblatt-Gesundheitsforschung-Gesundheitsschutz 2013;56:858-867.
2014;64:104-17.
372 373
18.
Zauber AG. The impact of screening on colorectal cancer mortality and incidence: has it really made a difference? Dig Dis Sci 2015;60:681-91.
374 375
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin
19.
RI PT
17.
Stock C, Knudsen AB, Lansdorp-Vogelaar I, et al. Colorectal cancer mortality
SC
371
prevented by use and attributable to nonuse of colonoscopy. Gastrointest Endosc
377
2011;73:435-443 e5.
378
20.
M AN U
376
Meester RG, Doubeni CA, Lansdorp-Vogelaar I, et al. Colorectal cancer deaths
379
attributable to nonuse of screening in the United States. Ann Epidemiol 2015;25:208-
380
213 e1. 21.
Brenner H, Altenhofen L, Stock C, et al. Expected long-term impact of the German
TE D
381 382
screening colonoscopy programme on colorectal cancer prevention: analyses based on
383
4,407,971 screening colonoscopies. Eur J Cancer 2015;51:1346-53.
endoscopy on colorectal cancer incidence: a modelling study. Oncotarget 2016, DOI:
385
10.18632/oncotarget.10178.
386 387
23.
first data collection wave. BMC Public Health 2012;12:730.
389
391
Scheidt-Nave C, Kamtsiuris P, Gosswald A, et al. German health interview and examination survey for adults (DEGS) - design, objectives and implementation of the
388
390
Brenner H, Kretschmann J, Stock C, et al. Expected long-term impact of screening
EP
22.
AC C
384
24.
National Center for Health Statistics. Data File Documentation, National Health Interview Survey, 2010 (machine readable data file and documentation). National
16
ACCEPTED MANUSCRIPT 392
Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville,
393
Maryland. 2011.
394
25.
National Center for Health Statistics. Data File Documentation, National Health Interview Survey, 2008 (machine readable data file and documentation). National
396
Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville,
397
Maryland. 2009.
398
26.
RI PT
395
The German Centre for Cancer Registry Data (ZfKD). Available at:
www.krebsdaten.de/Krebs/EN/Database/databasequery_step1_node. Accessed July
400
19, 2016. 27.
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2013
M AN U
401
SC
399
402
Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and
403
Human Services, Centers for Disease Control and Prevention and National Cancer
404
Institute; 2016. Available at: www.cdc.gov/uscs. Accessed July 19, 2016. 28.
1986;7:177-88.
406 407
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
29.
TE D
405
National Center for Health Statistics, Centers for Disease Control and Prevention. 2008 National Health Interview Survey (NHIS) Public Use Data Release: NHIS
409
Survey Description. Available at: ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/Dataset_Documentation/NHIS/2008/srv
410
ydesc.pdf. Accessed May 27, 2016.
411 412
AC C
EP
408
30.
National Center for Health Statistics, Centers for Disease Control and Prevention.
413
2010 National Health Interview Survey (NHIS) Public Use Data Release: NHIS
414
Survey Description. Available at:
415
ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/Dataset_Documentation/NHIS/2010/srv
416
ydesc.pdf. Accessed May 27, 2016.
17
ACCEPTED MANUSCRIPT 31.
Epidemiol 2015;25:147-54.
418
32.
prevented fractions, and causation probabilities. Ann Epidemiol 2015;25:155-61.
420 421
33.
34.
Benichou J. A review of adjusted estimators of attributable risk. Stat Methods Med Res 2001;10:195-216.
424 425
Levine B. What does the population attributable fraction mean. Prev Chronic Dis 2007;4:A14.
422 423
Greenland S. Concepts and pitfalls in measuring and interpreting attributable fractions,
RI PT
419
Poole C. A history of the population attributable fraction and related measures. Ann
35.
SC
417
R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2016. URL https://www.R-
427
project.org/. 36.
after colonoscopy varies by site of the cancer. Gastroenterology 2010;139:1128-37.
429 430
Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer mortality
37.
Jacob BJ, Moineddin R, Sutradhar R, et al. Effect of colonoscopy on colorectal cancer
TE D
428
M AN U
426
431
incidence and mortality: an instrumental variable analysis. Gastrointest Endosc
432
2012;76:355-64 e1.
screening effectiveness: an example of colonoscopy. J Med Screen 2013;20:198-207.
434 435
39.
wide cohort of screening age. Gastrointest Endosc 2016, DOI:
437
10.1016/j.gie.2015.12.035.
438
440
Stock D, Paszat LF, Rabeneck L. Colorectal cancer mortality reduction is associated with having at least 1 colonoscopy within the previous 10 years among a population-
436
439
Eldridge RC, Doubeni CA, Fletcher RH, et al. Uncontrolled confounding in studies of
EP
38.
AC C
433
40.
Muller AD, Sonnenberg A. Protection by endoscopy against death from colorectal cancer. A case-control study among veterans. Arch Intern Med 1995;155:1741-8.
18
ACCEPTED MANUSCRIPT 441
41.
from colorectal cancer. Ann Intern Med 2009;150:1-8.
442 443
Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death
42.
Baxter NN, Warren JL, Barrett MJ, et al. Association between colonoscopy and colorectal cancer mortality in a US cohort according to site of cancer and
445
colonoscopist specialty. J Clin Oncol 2012;30:2664-9.
446
43.
RI PT
444
Samadder NJ, Curtin K, Pappas L, et al. Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol
448
2016;14:279-286.e2.
449
44.
SC
447
German Guideline Program in Oncology (German Cancer Society, German Cancer Aid, AWMF): Evidenced-based Guideline for Colorectal Cancer, long version 1.0,
451
AWMF registration number: 021-007OL,
452
http://leitlinienprogrammonkologie.de/Leitlinien.7.0.html. Accessed August 28, 2016.
453
45.
M AN U
450
Spaeth A, Zwahlen M. Use of lower gastrointestinal endoscopy and fecal occult blood test in the 2007 Swiss Health Interview Survey respondents aged 50 years and older.
455
Endoscopy 2013;45:560-6.
456
46.
TE D
454
Benning TM, Dellaert BGC, Severens JL, et al. The Effect of Presenting Information about Invasive Follow-Up Testing on Individuals' Noninvasive Colorectal Cancer
458
Screening Participation Decision: Results from a Discrete Choice Experiment. Value Health 2014;17:578-587.
459 460
47.
Elmunzer BJ, Singal AG, Sussman JB, et al. Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.
461
Gastrointest Endosc 2015;81:700-709 e3.
462 463
AC C
EP
457
48.
Pan J, Xin L, Ma YF, et al. Colonoscopy Reduces Colorectal Cancer Incidence and
464
Mortality in Patients With Non-Malignant Findings: A Meta-Analysis. Am J
465
Gastroenterol 2016;111:355-65.
19
ACCEPTED MANUSCRIPT 49.
overview of existing programmes. Gut 2015;64:1637-49.
467 468
Schreuders EH, Ruco A, Rabeneck L, et al. Colorectal cancer screening: a global
50.
Dodou D, de Winter JC. Agreement between self-reported and registered colorectal cancer screening: a meta-analysis. Eur J Cancer Care (Engl) 2015;24:286-98.
469
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Figure legends
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Figure 1. CRC death counts and mortality rates in Germany and the United States, 2008 to
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2011
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Death count is the total CRC death count during 2008 to 2011.
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CRC = colorectal cancer
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Data source:
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1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999 to 2013
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Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human
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Services, Centers for Disease Control and Prevention and National Cancer Institute; 2016.
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Available at: www.cdc.gov/uscs.
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2. The German Centre for Cancer Registry Data (ZfKD). Available at:
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www.krebsdaten.de/Krebs/EN/Database/databasequery_step1_node.
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Table 1. Effects of colonoscopy use on colorectal cancer mortality from observational studies Country Study design Years US Case-control 1981-1992
No. Cases: 4358; controls: 16,531
Colonoscopy time frame* Up to 10 years before diagnosis
Covariates adjusted/matched Matched by age, sex, race; adjusted for other colorectal procedures, procedures other than colorectal, length of coverage by the Department of Veterans Affairs, arthritis-related diseases
Relative risk (95% CI) 0.45 (0.30-0.66)
Baxter, 2009 41
Canada
Case-control
1992-2003
Cases: 10,292; controls: 51,460
6 months-10 years before diagnosis
Matched by age, sex, geographic location, socioeconomic status; adjusted for comorbid conditions
0.63 (0.57-0.69)
Singh, 2010 36
Canada
Cohort†
1987-2008
54,803
6 months before diagnosis21 years before CRC deaths
Age, sex, calendar year
0.71 (0.61-0.82)
Baxter, 2012 42
US
Case-control
1991-2007
Cases: 9458; controls: 27,641
6 months-12 years before diagnosis
Matched by sex, year of birth, race, SEER registry; adjusted for socioeconomic status, comorbidities, urban/rural status
0.40 (0.37-0.43)
Jacob, 2012 37
Canada
Retrospective 1996-2005 cohort
1,089,998
3 years before diagnosis-10 years before CRC deaths
Primary care physician (age, sex, country of medical training) and patient characteristics (age, sex, income, comorbidity)
0.19 (0.07-0.47)
Eldridge, 2013 38
US
Cohort
1996-2008
68,531
Before diagnosis-16 years before CRC deaths
Age, sex, education, race, diabetes, family history of CRC, hormone replacement therapy use, healthy lifestyle score
0.41 (0.30-0.55)
Samadder, 2016 43
US
Case-control
1996-2010
Cases: 5128; controls: 20,512
6 months-10 years before diagnosis
Matched by age, sex; adjusted for family history of CRC, church affiliation status
0.33 (0.28-0.39)
Stock, 2016 39
Canada
Cohort
1992-2009
1,509,423
6 months before diagnosis10 years before CRC deaths
Age, sex, socioeconomic status, comorbidity
0.36 (0.33-0.38)
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Pooled estimate from random effects model
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First author, year Muller, 1995 40
0.44 (0.35-0.55)
* Colonoscopy time frame for colorectal cancer cases † Comparison with the general population 21
ACCEPTED MANUSCRIPT Table 2. Prevalence of colonoscopy use within 10 years in Germany and the United States* Germany
United States 2008-09 6022
2010-11 7366
Overall†
54.8 (52.5-57.0)
51.7 (50.1-53.2)
60.4 (59.0-61.8)
Sex Male Female
54.1 (50.8-57.3) 55.4 (52.6-58.2)
52.0 (49.7-54.3) 51.4 (49.4-53.4)
60.8 (58.7-63.0) 60.0 (58.3-61.8)
Age (years) 55-59 60-69 70-79
46.1 (41.4-50.8) 58.4 (55.0-61.7) 56.6 (52.9-60.2)
47.6 (44.9-50.4) 52.6 (50.3-54.9) 54.9 (52.2-57.6)
55.5 (52.8-58.2) 61.7 (59.9-63.6) 63.6 (61.2-65.9)
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Sample size
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2008-11 1889
* Prevalence estimates were based on DEGS1 for Germany and NHIS 2008 and 2010 for the US [% (95% CI)]
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† Overall prevalence of colonoscopy use among persons aged 55 to 79 years
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Table 3. Estimated fractions and numbers of CRC deaths attributable to nonuse of colonoscopy in Germany and United States
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United States 2008-09 AF, % (95% CI) No. of deaths (95% CI)† 38.2 (28.6-47.1) 20,947 (15,724-25,864)
37.0 (27.5-46.0) 36.3 (27.0-45.2)
13,069 (9728-16,259) 8074 (6003-10,062)
38.0 (28.5-47.0) 38.3 (28.8-47.3)
Age 55-59 60-69 70-79
40.8 (30.8-50.1) 34.7 (25.6-43.6) 35.7 (26.4-44.7)
2040 (1538-2504) 6475 (4770-8133) 12,107 (8948-15,158)
40.1 (30.3-49.2) 37.7 (28.3-47.0) 36.6 (27.2-45.5)
3227 (2439-3959) 7889 (5909-9766) 9479 (7058-11,798)
2010-11 No. of deaths (95% CI)† AF, % (95% CI) 33.6 (24.8-42.2) 18,344 (13,525-23,052)
33.4 (24.6-42.0) 33.8 (24.9-42.5)
10,435 (7676-13,143) 7891 (5818-9912)
36.3 (27.0-45.2) 32.9 (24.1-41.4) 31.7 (23.2-40.3)
3007 (2236-3747) 7083 (5203-8933) 7856 (5733-9968)
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AF = attributable fraction; CRC = colorectal cancer.
11,907 (8928-14,723) 9029 (6780-11,145)
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Sex Male Female
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Overall*
Germany 2008-11 AF, % (95% CI) No. of deaths (95% CI)† 36.6 (27.3-45.5) 21,086 (15,720-26,215)
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* Overall estimates for persons aged 55 to 79 years. † Sex- and age-specific estimates do not necessarily sum up to the overall estimate.
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Table 4. Estimated fractions and numbers of CRC deaths prevented by colonoscopy use in Germany and United States
2008-09 No. of deaths (95% CI)† PF, % (95% CI) 29.0 (23.4-33.6) 22,422 (16,786-27,794)
Sex Male Female
30.4 (24.4-35.5) 31.1 (25.0-36.2)
15,404 (11,392-19,453) 10,029 (7421-12,633)
29.2 (23.5-33.9) 28.8 (23.3-33.5)
Age 55-59 60-69 70-79
25.9 (20.4-30.8) 32.8 (26.3-38.3) 31.8 (25.5-37.2)
1745 (1283-2228) 9089 (6664-11,570) 15,789 (11,597-20,094)
26.7 (21.5-31.2) 29.5 (23.8-34.3) 30.8 (24.8-35.9)
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12,899 (9627-16,083) 9549 (7143-11,862)
2931 (2197-3649) 8755 (6527-10,925) 11,539 (8551-14,510)
2010-11 No. of deaths (95% CI)† PF, % (95% CI) 33.9 (27.4-39.2) 27,980 (20,595-35,235)
34.1 (27.5-39.6) 33.7 (27.2-39.0)
16,185 (11,878-20,482) 11,836 (8709-14,917)
31.1 (25.1-36.3) 34.6 (28.0-40.1) 35.7 (28.8-41.4)
3750 (2776-4720) 11,411 (8362-14,441) 13,726 (10,003-17,489)
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United States
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Overall*
Germany 2008-11 PF, % (95% CI) No. of deaths (95% CI)† 30.7 (24.8-35.7) 25,564 (18,983-32,002)
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* Overall estimates for persons aged 55 to 79 years. † Sex- and age-specific estimates do not necessarily sum up to the overall estimate.
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Supplementary Table 1. Colorectal cancer death counts ages 55-79 years in Germany and the United States, 2008-2011* Germany 2009 2010 14,319 14,194
2011 14,101
2008 27,675
9157 5820
8774 5545
8683 5511
8736 5365
15,726 11,949
Age 55-59 60-64 65-69 70-74 75-79
1269 1754 3291 4194 4469
1256 1711 3148 4083 4121
1211 1688 2740 4362 4193
1265 1805 2517 4167 4347
4003 4927 5514 6170 7061
15,593 11,617
15,652 11,522
15,615 11,805
4042 5063 5410 6036 6659
4047 5230 5498 5865 6534
4248 5456 5371 5960 6385
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Deaths from cancers of colon and rectum (C18-20 by International Classification of Diseases-10 Version)
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*
2011 27,420
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Sex Male Female
United States 2009 2010 27,210 27,174
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Total
2008 14,977
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ACCEPTED MANUSCRIPT Appendix. Statistical analysis of AF and PF We applied the method described in detail in the study of Stock et al. to calculate the estimates of AF, PF and the corresponding death numbers, Naf and Npf.19 Naf and Npf were
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derived by multiplying the estimated AF and PF with the observed number of CRC deaths and estimated hypothetical CRC deaths in the absence of colonoscopy, respectively. Briefly, the following formulas were used:
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AF = P0(RR0/1-1)/[ P0(RR0/1-1)+1]
Naf = AF×N Npf = PF×N/[P1(RR1/0-1)+1]
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PF = P1(1-RR1/0)
(1) (2) (3) (4)
AF: attributable fraction PF: prevented fraction
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Symbols and acronyms were defined as follows:
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P0: prevalence of nonuse of colonoscopy (unexposed) P1: prevalence of colonoscopy use (exposed); P1=1-P0
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RR1/0: relative risk of deaths from CRC in people with use of colonoscopy (exposed) versus people without (unexposed) RR0/1: inverse of the relative risk for exposure to colonoscopy use; RR0/1=1/ RR1/0 Naf: Number of CRC deaths attributable to nonuse of colonoscopy Npf: Number of CRC deaths prevented by use of colonoscopy N: actual CRC death number of the year
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ACCEPTED MANUSCRIPT Acronyms List AF, attributable fraction; CI, confidence interval; CRC, colorectal cancer; CrI, credible interval; DEGS, German Health Interview and Examination Survey for Adults; FIT, fecal
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immunochemical test for hemoglobin; FOBT, fecal occult blood test; NHIS, National Health Interview Survey; PF, prevented fraction; USCS, United States Cancer Statistics; ZfKD,
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German Centre for Cancer Registry Data
S0016-5107(17)31807-2
DOI:
10.1016/j.gie.2017.04.005
Reference:
YMGE 10528
To appear in:
Gastrointestinal Endoscopy
Received Date: 13 January 2017 Accepted Date: 4 April 2017
Please cite this article as: Chen C, Stock C, Hoffmeister M, Brenner H, Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States, Gastrointestinal Endoscopy (2017), doi: 10.1016/j.gie.2017.04.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Public health impact of colonoscopy use on colorectal cancer mortality in Germany and the United States Running title: Impact of colonoscopy use on CRC mortality in the general population
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Authors: Chen Chen, MSPH,1 Christian Stock, PhD,1, 2 Michael Hoffmeister, PhD,1 Hermann Brenner, MD, MPH1, 3, 4
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center
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1
2
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(DKFZ), Im Neuenheimer Feld 581, D-69120 Heidelberg, Germany
Institute of Medical Biometry and Informatics, University of Heidelberg, Im Neuenheimer
Feld 130.3, D-69120 Heidelberg, Germany 3
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National
Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg,
4
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Germany
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im
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Neuenheimer Feld 280, D-69120 Heidelberg, Germany
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Corresponding author:
Hermann Brenner, MD, MPH Division of Clinical Epidemiology and Aging Research German Cancer Research Center Im Neuenheimer Feld 581 D-69120 Heidelberg Phone +49-6221-421300 Fax
+49-6221-421302
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Grant support: CC was supported by the Helmholtz International Graduate School for
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Cancer Research at the German Cancer Research Center (DKFZ).
Author contributions: Conception and design: HB; analysis and interpretation of the data: CC, CS, HB; drafting of the article: CC; critical revision of the article for important
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intellectual content: CC, CS, MH, HB; final approval of the article: CC, CS, MH, HB.
ACCEPTED MANUSCRIPT Abstract
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Background and Aims: Colonoscopy has been demonstrated to be effective in reducing
3
colorectal cancer (CRC) incidence and mortality, and has been widely used for primary CRC
4
screening in Germany and the United States. We performed a population-based analysis to
5
evaluate and compare the public health impact of recent colonoscopy use on CRC deaths
6
among adults aged 55 to 79 years in Germany and the United States from 2008 to 2011.
7
Methods: The epidemiologic metrics of attributable fraction and prevented fraction as well
8
as the impact numbers were calculated using colonoscopy utilization data from nationally
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representative health surveys, relative risk estimates from medical literature, and CRC death
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registry data.
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Results: Overall, 36.6% (95% credible interval [CrI], 27.3%-45.5%) of CRC deaths in
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Germany were estimated to be attributable to nonuse of colonoscopy, compared with the U.S.
13
estimates of 38.2% (95% CrI, 28.6%-47.1%) and 33.6% (95% CrI, 24.8%-42.2%) for years
14
2008 to 2009 and 2010 to 2011, respectively. The proportion of CRC deaths theoretically
15
prevented by colonoscopy use within 10 years was 30.7% (95% CrI, 24.8%-35.7%) in
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Germany, whereas in the United States this proportion ranged from 29.0% (95% CrI, 23.4%-
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33.6%) for 2008 to 2009 to 33.9% (95% CrI, 27.4%-39.2%) for 2010 to 2011.
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Conclusions: Recent colonoscopy use is likely to have prevented a considerable fraction of
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CRC mortality in both countries, and more deaths could be avoided by increasing
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colonoscopy utilization in the target population. Attributable and prevented fraction can
21
provide valuable information on the public health impact of colonoscopy use and guide the
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policy making.
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ACCEPTED MANUSCRIPT Background
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Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, and a
25
significant cause of cancer morbidity and mortality in North America and Europe.1 Because
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of the slow progression from adenomas to invasive cancers, substantial proportions of CRC
27
cases and deaths could be prevented by screening.2 Through detection and removal of
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precancerous lesions and early cancers, lower gastrointestinal endoscopy can effectively
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reduce the incidence of advanced disease and thus lead to a decrease in CRC mortality.3-11
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Lower gastrointestinal endoscopy, especially colonoscopy, is recommended by several
31
guidelines to be used as a screening tool for persons aged 50 and older at average risk for
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CRC,12-14 and has become one of the principal screening tests in countries like the US and
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Germany.15, 16
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The continuous and widespread use of colonoscopy screening is believed to be a major
36
contributory factor in the decreasing CRC incidence and mortality observed in the United
37
States during the past decade.17, 18 Using the epidemiologic metrics of prevented fraction (PF)
38
and attributable fraction (AF), Stock et al19 estimated that approximately 7300 to 11,700 CRC
39
deaths in the United States in 2005 were prevented by colonoscopy use, accounting for 13%
40
to 19% of total CRC deaths among persons aged over 50 years, and about twice as many
41
deaths could be avoided if nonuse of colonoscopy were to be eliminated. In another study,
42
Meester et al20 used both the standard epidemiological method and a microsimulation model
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to estimate the AF, and reported about 46% to 63% of CRC deaths in the United States in
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2010 were attributable to not having any of the screening tests.
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In Germany, colonoscopy has become more commonly accepted and frequently used by the
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general population over the past decade. In 2008 to 2011, more than half of the screening-
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Although modeling studies have previously evaluated the expected effects of screening
50
colonoscopy on future CRC incidence,21, 22 the actual public health benefits of colonoscopy
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on deaths from CRC in the general German population have not been explored and remain
52
largely unclear. In this study, we aimed to estimate the CRC mortality prevented by use of
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colonoscopy and the further potential of colonoscopy use in reducing CRC mortality in
54
Germany, and to compare these results with the estimates of the United States over the same
55
time period.
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Methods
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Data sources
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The epidemiologic metrics of AF and PF were estimated to reflect the impact of colonoscopy
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use within the past 10 years on CRC deaths in the general population. Data from several
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sources were combined for the calculation of AF and PF estimates for Germany and the
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United States.
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Colonoscopy effectiveness estimates were derived from the medical literature. Studies
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assessing the effects of colonoscopy versus no colonoscopy on CRC mortality in the general
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average-risk population were searched at PubMed and Web of Science from inception to June,
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2016 and combined using meta-analysis to obtain a pooled estimate that also includes the
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most recent evidence (that is not yet covered in published meta-analyses).
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69 70
Data on colonoscopy use in the general population were derived from nationally
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representative health surveys. The German Health Interview and Examination Survey for
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Adults (DEGS) is a periodically repeated nationwide health survey of non-institutionalized
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ACCEPTED MANUSCRIPT German population aged between 18 to 79 years.23 The most recent estimates of endoscopic
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CRC screening adherence were available from the first wave of DEGS (2008-2011).
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Respondents aged 55 to 79 years were asked if they had ever undergone colonoscopy and the
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time since the last examination. This age range was selected because screening colonoscopy
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is offered from age 55 on only in Germany. Indication for colonoscopy use was not
78
ascertained. The proportion of people who have undergone colonoscopy within the past 10
79
years as well as the age- and sex-specific prevalence estimates, which were weighted to be
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representative of the resident population of Germany as of 31 December 2010, were directly
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extracted from the study report.16
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Endoscopy use data in the United States were drawn from the National Health Interview
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Survey (NHIS), a household, multistage probability sample survey conducted annually since
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1957.24, 25 The NHIS is one of the principle sources of information on the health of the
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civilian, non-institutionalized U.S. population. To enable comparisons of estimates from the 2
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countries, data among adults aged 55 to 79 years from 2008 and 2010, when CRC screening
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test utilization was ascertained, were used as estimates for 2008 to 2009 and 2010 to 2011,
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respectively. In the 2008 NHIS, respondents aged 40 and older were asked if they have ever
90
had sigmoidoscopy, colonoscopy or proctoscopy. If utilization was reported, respondents
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were then asked to specify the type of the most recent examination they had (sigmoidoscopy,
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colonoscopy or proctoscopy) as well as the time and reason for this most recent exam. In the
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2010 NHIS, respondents aged 40 and older were asked separate questions on colonoscopy,
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sigmoidoscopy, CT colonography and fecal occult blood test (FOBT). A brief description of
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each test was provided. Regarding colonoscopy use, participants were asked if they have ever
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had colonoscopy and the time and reason for the most recent examination.
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International Classification of Diseases-10 Version), were extracted from the German Centre
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for Cancer Registry Data (ZfKD)26 and the United States Cancer Statistics (USCS) report,27
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for the time period 2008 to 2011. The cancer mortality data on the ZfKD platform are
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provided by the Federal Statistical Office Germany, which collects data on all deaths in
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Germany. The USCS is a Web-based report that includes the official federal statistics on
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cancer mortality provided by the National Vital Statistics System, with 100% of the U.S.
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population covered.27
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Statistical analysis
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The colonoscopy effectiveness parameter was obtained by combining the effect estimates of
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observational studies that evaluated the impact of colonoscopy on CRC mortality. Studies
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that specifically and exclusively addressed screening colonoscopy were excluded. Risk ratios
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and hazard ratios from cohort studies as well as odds ratios from case-control studies that
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were used to measure effects were all referred to as relative risk. The pooled effect size and
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95% confidence intervals (CIs) were calculated using a random-effects model.28
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Prevalence of colonoscopy use in the United States was calculated from NHIS 2008 and 2010
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data. All colonoscopies were included in the analysis regardless of indication. Respondents
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with a history of CRC or missing information on CRC history were excluded to enable an
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analysis in the average-risk population. To obtain nationally representative estimates, sample
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weights were applied to reflect the selection probabilities as well as adjustments for non-
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response and post-stratification.29, 30 Variance estimates were computed by Taylor series
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linearization method to adjust for complex sample design.29, 30
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ACCEPTED MANUSCRIPT We used 2 measures of attribution and prevention to quantify the impact of colonoscopy use
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on CRC mortality. The metric of AF was first introduced in a study on the association of
125
smoking and lung cancer, and has gradually become widely used for measuring the impact of
126
an exposure on an outcome at the population level.31 AF is often interpreted as the proportion
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of those with the outcome that might be attributable to the exposure, or the maximum
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proportion of those with the outcome that might be reduced if the exposure is eliminated.32, 33
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In our study, the AF for colonoscopy use refers to the proportion of CRC mortality that is
130
likely to be attributable to not having had a colonoscopy within 10 years, and also means the
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maximum proportional reduction in CRC mortality if nonuse of colonoscopy were to be
132
eliminated.19 PF is an alternative public health impact measure that is more commonly used
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in the cases of protective exposure or intervention. It represents the proportion of those
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avoiding the outcome because of the protective exposure.34 In our analysis, the PF for
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colonoscopy use is defined as the proportion of hypothetical CRC deaths that have been
136
prevented by recent colonoscopy use.19 Absolute numbers of CRC deaths attributable to
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nonuse and prevented by use of colonoscopy were derived by multiplying the estimated AFs
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and PFs with the observed number of CRC deaths and estimated hypothetical CRC deaths if
139
colonoscopy use were eliminated. (See Appendix for detailed methods.) We used 2 different
140
metrics in an effort to reflect both the benefits of colonoscopy use in the past and the
141
potential gains of further increasing colonoscopy use in the future. The 95% credible intervals
142
(CrIs) of AFs, PFs, and absolute impact numbers account for the uncertainty in both
143
prevalence of colonoscopy use and colonoscopy effectiveness, and were calculated by Monte
144
Carlo simulation. The probability distribution for included parameters was built based on
145
their point estimates and standard errors. Distributions of outcomes were then generated by
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running simulations with 10,000 iterations, from which the quantiles 2.5% and 97.5% were
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extracted to derive 95% CrIs. Monte Carlo errors were smaller than 5% of the standard
148
deviation of the outcomes under 10,000 iterations.
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Sex- and age-specific estimates were calculated for each of the parameters and outcomes
151
except colonoscopy effectiveness. Stata 13.1 (StataCorp, College Station, Tex, USA) and
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SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) were used to perform meta-analyses
153
and the estimation of colonoscopy use prevalence, respectively. R version 3.2.5 (R
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Foundation for Statistical Computing, Vienna, Austria) was used for Monte Carlo
155
simulation.35
156
Results
157
Estimates of parameters
158
Estimates of the effects of colonoscopy use on CRC mortality are summarized in Table 1. Of
159
the included 8 observational studies that evaluated the relative risk, 4 were cohort studies36-39
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and 4 case-control studies.40-43 All studies were carried out in North America. Except in one
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study in which persons who had colonoscopy use were compared with the general
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population,36 all other studies conducted the comparison between those with colonoscopy use
163
and without. The 8 studies comprised colonoscopy use and CRC deaths data collected
164
between 1981 and 2010, and covered colonoscopy performed up to 10 or more years before
165
CRC diagnosis or death. All studies were at least matched by or adjusted for age and sex.
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Despite the heterogeneity in populations, settings, and study design, colonoscopy use for any
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indication was consistently associated with a reduction in CRC mortality in all studies, with a
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pooled estimate of 56% risk reduction (RR 0.44; 95% CI, 0.35-0.55).
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Prevalence of colonoscopy use in Germany and the United States are shown in Table 2.
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During 2008 to 2011, 54.8% (95% CI, 52.5%-57.0%) of German adults aged 55 to 79 years 7
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173
age groups 60 to 69 (58.4%) and 70 to 79 (56.6%) than in age group 55 to 59 (46.1%). Data
174
from the NHIS yielded comparable estimates. In 2008, 55.8% (95% CI, 54.2%-57.4%) of the
175
U.S. population aged 55 to 79 had undergone a colorectal endoscopy (colonoscopy,
176
sigmoidoscopy, or proctoscopy) in the past 10 years (data not shown), from which over 90%
177
identified colonoscopy as the most recent endoscopy (51.7% [95% CI, 50.1%-53.2%] of the
178
overall 55-79 population). In 2010, 60.4% (95% CI, 59.0%-61.8%) of respondents indicated
179
that they have had this procedure in the preceding 10 years. For both calendar years, the
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estimated proportion was found to be increasing with age.
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During 2008 to 2011, a total of 109,479 and 57,591 persons aged 55 to 79 years died of CRC
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in the United States and Germany, respectively (Supplementary Table 1). Figure 1 displays
184
the trend in CRC deaths with age. For both countries the death count and mortality rate
185
increased with age. This increase in mortality with age was much larger in Germany than in
186
the United States. When examining the trends in CRC deaths during the 4 years, a decreasing
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trend for the mortality rate was observed for both countries.
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Estimates of AFs and PFs
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Overall from 2008 to 2011, 21,086 (95% CrI, 15,720-26,215) CRC deaths in Germany were
191
estimated to be attributable to nonuse of colonoscopy within the previous 10 years,
192
accounting for 36.6% (95% CrI, 27.3%-45.5%) of total CRC deaths among people aged 55-
193
79 years (Table 3). The AFs in the United States were 38.2% (95% CrI, 28.6%-47.1%) and
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33.6% (95% CrI, 24.8%-42.2%) for years 2008 to 2009 and 2010 to 2011, respectively,
195
which implies that a maximum of 20,947 (95% CrI, 15,724-25,864) and 18,344 (95% CrI,
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13,525-23,052) estimated deaths would have been avoided if all adults 55 to 79 years of age
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had had a colonoscopy within 10 years. In both countries, more CRC deaths among men were
198
attributable to nonuse of colonoscopy than among women. In Germany, the vast majority of
199
attributable deaths occurred in age group 70 to 79 years, whereas such estimates were more
200
equally distributed across age groups in the United States.
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Over the same period of time, 25,564 (95% CrI, 18,983-32,002) CRC deaths in Germany
203
were theoretically prevented by recent use of colonoscopy, accounting for 30.7% (95% CrI,
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24.8%-35.7%) of the estimated hypothetical CRC deaths of the population in the absence of
205
colonoscopy (Table 4). The percentage of CRC deaths theoretically prevented by
206
colonoscopy use in the United States for years 2008 to 09 and 2010 to 11 were 29.0% (95%
207
CrI, 23.4%-33.6%) and 33.9% (95% CrI, 27.4%-39.2%), respectively. These translated into
208
22,422 (95% CrI, 16,786-27,794) and 27,980 (95% CrI, 20,595-35,235) prevented deaths. In
209
stratified analyses, although no systematic differences emerged between male and female in
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PFs, substantially more deaths could be prevented by the use of colonoscopy among men
211
than among women, and the largest number of deaths was prevented in age group 70 to 79 in
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both countries.
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Discussion
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In this study, we evaluated the public health impact of colonoscopy use on CRC deaths in
216
Germany and the United States. Our results indicate that in Germany from 2008 to 2011
217
approximately 25,600 deaths among adults aged 55 to 79 years were prevented by
218
colonoscopy use within the past 10 years, and about 37% of the actual 57,591 CRC deaths at
219
best could have been avoided if 100% colonoscopy utilization were achieved. Comparable
220
with the estimates of Germany, colonoscopy is likely to have saved around 50,400 persons
221
aged 55 to 79 from CRC death in the United States over the same time period, and about
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39,300 out of 109,479 actual CRC deaths (36%) at the most could have been prevented by
223
100% use of colonoscopy within 10 years.
224
The observed trend in AF and PF estimates with age primarily reflects the differences in
226
colonoscopy use. Persons aged 55 to 59 years, as the group with the lowest prevalence of
227
recent colonoscopy use, had the highest AFs and the lowest PFs, though absolute numbers of
228
attributable and prevented deaths were largest in age group 70 to 79 as a result of the
229
substantially higher CRC mortality rate in this age group. Compared with the United States,
230
Germany had a particularly high proportion of attributable CRC deaths in age group 70 to 79.
231
This can be explained by a much larger increase of CRC mortality with age and much smaller
232
reduction in population size from age 55 to 79 in Germany,26, 27 which might serve as
233
evidence for including the elderly aged 75 to 79 years as screening target in this country.
234
Because of the similar proportions of persons who have undergone colonoscopy within 10
235
years, sex differences in AF and PF estimates were small. However, with males having a
236
higher CRC mortality rate in both countries, especially Germany, where the CRC mortality
237
estimates of men are about 70% to 80% higher than those of women in the target age group
238
for CRC screening,26 more men can be prevented from dying from CRC by recent use of
239
colonoscopy. Estimates of 2008 and 2010 from the United States confirmed the expectation
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of Stock et al. that with increasing use of colonoscopy and decreasing CRC mortality rate in
241
recent years, AFs would decrease and PFs would increase over time.19
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Colonoscopy is recommended as one of the primary screening tools to persons at average risk
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for CRC in both Germany and the United States.13, 44 CRC screening by FOBT, followed by
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colonoscopy in case of a positive FOBT result, has been offered in Germany since 1977.
246
Since 2002, colonoscopy has been recommended for primary CRC screening to persons over
10
ACCEPTED MANUSCRIPT 55 years. This change, along with increased use of colonoscopy for diagnostic purposes, has
248
contributed to the increase in colonoscopy use prevalence in Germany over the past decade,
249
which has gradually risen to the level of the United States and is much higher than in other
250
European countries.15, 16, 45, 46 With the increased use of colonoscopy, over 30% of CRC
251
deaths in Germany were avoided from 2008 to 2011, similar to the estimate of the United
252
States. Our findings thereby underline the large potential for reducing the mortality from
253
CRC through colonoscopy, even though even larger reductions would be possible by higher
254
utilization of the screening offers.
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255
The accuracy of AF and PF estimates is dependent on how well the colonoscopy
257
effectiveness parameter we used represents the true association between the test and CRC
258
mortality in the target population. There have been many recent cohort and case-control
259
studies investigating the effect of colonoscopy on CRC incidence and mortality in multiple
260
populations.47, 48 Our summary estimate of colonoscopy effectiveness is in line with estimates
261
derived in 2 other previously reported meta-analyses that summarized the effect of
262
colonoscopy for any indication (relative risk, 0.40; 95% CI, 0.32-0.49, and 0.43 95% CI,
263
0.33-0.58, respectively),47, 48 but had not yet included the most recently published studies
264
addressing this research question.39, 43
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Although the metrics of AF and PF have been widely used to quantify the impact of an
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exposure on an outcome in epidemiological studies, there have been relatively few attempts
268
to estimate the public health impact of colonoscopy as a protective factor on CRC.19, 20 Our
269
results are generally consistent with the findings of these analyses that nonuse of colonoscopy
270
or other screening tests contributed to a considerable fraction of CRC deaths in the United
271
States, though there are some variations that generate from the different colonoscopy
11
ACCEPTED MANUSCRIPT effectiveness parameter used, screening tests considered and years explored. In the study of
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Stock et al,19 colonoscopy effectiveness from 2 case-control studies, one optimistic and one
274
conservative estimate were used for analysis, which led to 2 estimates for AF and PF each for
275
2005: 28% and 44%, and 13% and 19%, respectively.19 Meester et al20 evaluated the impact
276
of all CRC screening tests on CRC deaths in the United States in 2010, and obtained an AF of
277
46% when a relative risk of 0.32 from one specific prospective cohort study was applied.
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It is worth noting that use of colonoscopy is not a preventive measure by itself, but that its
280
preventive effect comes through removal of precancerous lesions or treatment of CRC at an
281
early stage when these lesions are detected at colonoscopy. In the majority of colonoscopies,
282
no such lesions are detected, and those colonoscopies do not have any preventive effect.
283
Calculation of AFs and PFs for use of colonoscopy is nevertheless meaningful in countries,
284
such as Germany and the United States where colonoscopy is offered and widely used for
285
primary CRC screening and to a large extent reflects screening coverage. In countries where
286
CRC screening is primarily based on noninvasive methods, such as fecal immunochemical
287
test for hemoglobin (FIT), such as the Netherlands,49 and colonoscopy is primarily used to
288
follow-up positive results of such noninvasive tests, comparable levels of prevention should
289
be achievable with much lower rates of use of colonoscopy, as the proportion of
290
colonoscopies that yield a preventive effect, ie, those with relevant findings, should be much
291
larger under such circumstances.
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Some limitations should also be noted in considering the findings of our study. First, only 2
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of the studies evaluating colonoscopy effects included procedures performed in the past
295
decade,36, 43 whereas others considered colonoscopy completed many years ago, with the
296
furthest dating back to 1980s.40 This might underestimate the strength of the association
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ACCEPTED MANUSCRIPT between colonoscopy and CRC death, as better test performance is expected nowadays with
298
the advances in technology. Second, an overall relative risk instead of age- and sex-specific
299
estimates was used in stratified analyses due to lack of reporting of subgroup data and
300
different categorization of ages. This is not expected to bias our estimates greatly, especially
301
sex-specific estimates, because colonoscopy is found to provide a similar magnitude of
302
protection towards men and women.48 Third, questions regarding CRC screening tests
303
utilization in the NHIS across different survey years were not phrased in a standardized way,
304
which makes it hard to conduct direct comparisons over time. In 2008, respondents were
305
asked to report the type of the most recent colorectal endoscopy from colonoscopy,
306
sigmoidoscopy, or proctoscopy, which might underestimate the proportion of colonoscopy
307
use within 10 years; however, as the vast majority identified colonoscopy as the most recent
308
test, the impact should not be major. Another limitation relates to the self-reporting nature of
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colonoscopy use data for both countries, which might result in an overestimation of
310
utilization; however, high sensitivity and specificity between self-reports and medical record
311
data were found.50
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In summary, colonoscopy use within 10 years prevented a considerable fraction of CRC
314
mortality in Germany and the United States during 2008 to 2011, and there is a large
315
potential for further reducing the mortality by increasing colonoscopy utilization, either as
316
primary screening examination or to follow-up positive results of promising noninvasive
317
screening tests, such as FITs, in the target population. Our findings confirm the values of AF
318
and PF metrics in evaluating the public health impacts of colonoscopy in screening settings,
319
which can serve as evidence in the development and prioritization of intervention programs
320
and strategies regarding endoscopic CRC screening. Although how to set up an attainable and
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realistic goal requires more exploration, our results underline the need to further encourage
322
CRC screening in the general population.
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References
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1.
RI PT
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide:
325
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer
326
2015;136:E359-86.
327
2.
Knudsen AB, Zauber AG, Rutter CM, et al. Estimation of Benefits, Burden, and Harms of Colorectal Cancer Screening Strategies: Modeling Study for the US
329
Preventive Services Task Force. JAMA 2016;315:2595-609. 3.
M AN U
330
SC
328
Atkin W, Wooldrage K, Parkin DM, et al. Long term effects of once-only flexible
331
sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy
332
Screening randomised controlled trial. Lancet 2017, DOI:10.1016/s0140-
333
6736(17)30396-3. 4.
Lin JS, Piper MA, Perdue LA, et al. Screening for Colorectal Cancer: A Systematic
TE D
334
Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 135.
336
AHRQ Publication No. 14-05203-EF-1. Rockville, MD: Agency for Healthcare
337
Research and Quality, 2016. 5.
colorectal cancer incidence and mortality: a randomized clinical trial. JAMA
339
2014;312:606-15.
340 341
Holme O, Loberg M, Kalager M, et al. Effect of flexible sigmoidoscopy screening on
AC C
338
EP
335
6.
Brenner H, Stock C, Hoffmeister M. Effect of screening sigmoidoscopy and screening
342
colonoscopy on colorectal cancer incidence and mortality: systematic review and
343
meta-analysis of randomised controlled trials and observational studies. BMJ
344
2014;348:g2467.
14
ACCEPTED MANUSCRIPT 345
7.
with screening flexible sigmoidoscopy. N Engl J Med 2012;366:2345-57.
346 347
Schoen RE, Pinsky PF, Weissfeld JL, et al. Colorectal-cancer incidence and mortality
8.
Manser CN, Bachmann LM, Brunner J, et al. Colonoscopy screening markedly reduces the occurrence of colon carcinomas and carcinoma-related death: a closed
349
cohort study. Gastrointest Endosc 2012;76:110-7.
350
9.
RI PT
348
Elmunzer BJ, Hayward RA, Schoenfeld PS, et al. Effect of flexible sigmoidoscopybased screening on incidence and mortality of colorectal cancer: a systematic review
352
and meta-analysis of randomized controlled trials. PLoS Med 2012;9:e1001352. 10.
following a colonoscopy. Dig Liver Dis 2011;43:899-904.
354 355
Strock P, Mossong J, Scheiden R, et al. Colorectal cancer incidence is low in patients
11.
M AN U
353
SC
351
Segnan N, Armaroli P, Bonelli L, et al. Once-only sigmoidoscopy in colorectal cancer
356
screening: follow-up findings of the Italian Randomized Controlled Trial--SCORE. J
357
Natl Cancer Inst 2011;103:1310-22. 12.
Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for Colorectal Cancer:
TE D
358 359
US Preventive Services Task Force Recommendation Statement. JAMA
360
2016;315:2564-75.
the American College of Physicians. Ann Intern Med 2015;162:718-25.
362 363
14.
Burt RW, Cannon JA, David DS, et al. Colorectal cancer screening. J Natl Compr Canc Netw 2013;11:1538-75.
364 365
Wilt TJ, Harris RP, Qaseem A. Screening for cancer: advice for high-value care from
EP
13.
AC C
361
15.
Shapiro JA, Klabunde CN, Thompson TD, et al. Patterns of colorectal cancer test use,
366
including CT colonography, in the 2010 National Health Interview Survey. Cancer
367
Epidemiol Biomarkers Prev 2012;21:895-904.
15
ACCEPTED MANUSCRIPT 368
16.
Starker A, Sass AC. Participation in cancer screening in Germany. Results of the
369
German Health Interview and Examination Survey for Adults (DEGS1).
370
Bundesgesundheitsblatt-Gesundheitsforschung-Gesundheitsschutz 2013;56:858-867.
2014;64:104-17.
372 373
18.
Zauber AG. The impact of screening on colorectal cancer mortality and incidence: has it really made a difference? Dig Dis Sci 2015;60:681-91.
374 375
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin
19.
RI PT
17.
Stock C, Knudsen AB, Lansdorp-Vogelaar I, et al. Colorectal cancer mortality
SC
371
prevented by use and attributable to nonuse of colonoscopy. Gastrointest Endosc
377
2011;73:435-443 e5.
378
20.
M AN U
376
Meester RG, Doubeni CA, Lansdorp-Vogelaar I, et al. Colorectal cancer deaths
379
attributable to nonuse of screening in the United States. Ann Epidemiol 2015;25:208-
380
213 e1. 21.
Brenner H, Altenhofen L, Stock C, et al. Expected long-term impact of the German
TE D
381 382
screening colonoscopy programme on colorectal cancer prevention: analyses based on
383
4,407,971 screening colonoscopies. Eur J Cancer 2015;51:1346-53.
endoscopy on colorectal cancer incidence: a modelling study. Oncotarget 2016, DOI:
385
10.18632/oncotarget.10178.
386 387
23.
first data collection wave. BMC Public Health 2012;12:730.
389
391
Scheidt-Nave C, Kamtsiuris P, Gosswald A, et al. German health interview and examination survey for adults (DEGS) - design, objectives and implementation of the
388
390
Brenner H, Kretschmann J, Stock C, et al. Expected long-term impact of screening
EP
22.
AC C
384
24.
National Center for Health Statistics. Data File Documentation, National Health Interview Survey, 2010 (machine readable data file and documentation). National
16
ACCEPTED MANUSCRIPT 392
Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville,
393
Maryland. 2011.
394
25.
National Center for Health Statistics. Data File Documentation, National Health Interview Survey, 2008 (machine readable data file and documentation). National
396
Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville,
397
Maryland. 2009.
398
26.
RI PT
395
The German Centre for Cancer Registry Data (ZfKD). Available at:
www.krebsdaten.de/Krebs/EN/Database/databasequery_step1_node. Accessed July
400
19, 2016. 27.
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2013
M AN U
401
SC
399
402
Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and
403
Human Services, Centers for Disease Control and Prevention and National Cancer
404
Institute; 2016. Available at: www.cdc.gov/uscs. Accessed July 19, 2016. 28.
1986;7:177-88.
406 407
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
29.
TE D
405
National Center for Health Statistics, Centers for Disease Control and Prevention. 2008 National Health Interview Survey (NHIS) Public Use Data Release: NHIS
409
Survey Description. Available at: ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/Dataset_Documentation/NHIS/2008/srv
410
ydesc.pdf. Accessed May 27, 2016.
411 412
AC C
EP
408
30.
National Center for Health Statistics, Centers for Disease Control and Prevention.
413
2010 National Health Interview Survey (NHIS) Public Use Data Release: NHIS
414
Survey Description. Available at:
415
ftp://ftp.cdc.gov/pub/Health_Statistics/NCHS/Dataset_Documentation/NHIS/2010/srv
416
ydesc.pdf. Accessed May 27, 2016.
17
ACCEPTED MANUSCRIPT 31.
Epidemiol 2015;25:147-54.
418
32.
prevented fractions, and causation probabilities. Ann Epidemiol 2015;25:155-61.
420 421
33.
34.
Benichou J. A review of adjusted estimators of attributable risk. Stat Methods Med Res 2001;10:195-216.
424 425
Levine B. What does the population attributable fraction mean. Prev Chronic Dis 2007;4:A14.
422 423
Greenland S. Concepts and pitfalls in measuring and interpreting attributable fractions,
RI PT
419
Poole C. A history of the population attributable fraction and related measures. Ann
35.
SC
417
R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2016. URL https://www.R-
427
project.org/. 36.
after colonoscopy varies by site of the cancer. Gastroenterology 2010;139:1128-37.
429 430
Singh H, Nugent Z, Demers AA, et al. The reduction in colorectal cancer mortality
37.
Jacob BJ, Moineddin R, Sutradhar R, et al. Effect of colonoscopy on colorectal cancer
TE D
428
M AN U
426
431
incidence and mortality: an instrumental variable analysis. Gastrointest Endosc
432
2012;76:355-64 e1.
screening effectiveness: an example of colonoscopy. J Med Screen 2013;20:198-207.
434 435
39.
wide cohort of screening age. Gastrointest Endosc 2016, DOI:
437
10.1016/j.gie.2015.12.035.
438
440
Stock D, Paszat LF, Rabeneck L. Colorectal cancer mortality reduction is associated with having at least 1 colonoscopy within the previous 10 years among a population-
436
439
Eldridge RC, Doubeni CA, Fletcher RH, et al. Uncontrolled confounding in studies of
EP
38.
AC C
433
40.
Muller AD, Sonnenberg A. Protection by endoscopy against death from colorectal cancer. A case-control study among veterans. Arch Intern Med 1995;155:1741-8.
18
ACCEPTED MANUSCRIPT 441
41.
from colorectal cancer. Ann Intern Med 2009;150:1-8.
442 443
Baxter NN, Goldwasser MA, Paszat LF, et al. Association of colonoscopy and death
42.
Baxter NN, Warren JL, Barrett MJ, et al. Association between colonoscopy and colorectal cancer mortality in a US cohort according to site of cancer and
445
colonoscopist specialty. J Clin Oncol 2012;30:2664-9.
446
43.
RI PT
444
Samadder NJ, Curtin K, Pappas L, et al. Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol
448
2016;14:279-286.e2.
449
44.
SC
447
German Guideline Program in Oncology (German Cancer Society, German Cancer Aid, AWMF): Evidenced-based Guideline for Colorectal Cancer, long version 1.0,
451
AWMF registration number: 021-007OL,
452
http://leitlinienprogrammonkologie.de/Leitlinien.7.0.html. Accessed August 28, 2016.
453
45.
M AN U
450
Spaeth A, Zwahlen M. Use of lower gastrointestinal endoscopy and fecal occult blood test in the 2007 Swiss Health Interview Survey respondents aged 50 years and older.
455
Endoscopy 2013;45:560-6.
456
46.
TE D
454
Benning TM, Dellaert BGC, Severens JL, et al. The Effect of Presenting Information about Invasive Follow-Up Testing on Individuals' Noninvasive Colorectal Cancer
458
Screening Participation Decision: Results from a Discrete Choice Experiment. Value Health 2014;17:578-587.
459 460
47.
Elmunzer BJ, Singal AG, Sussman JB, et al. Comparing the effectiveness of competing tests for reducing colorectal cancer mortality: a network meta-analysis.
461
Gastrointest Endosc 2015;81:700-709 e3.
462 463
AC C
EP
457
48.
Pan J, Xin L, Ma YF, et al. Colonoscopy Reduces Colorectal Cancer Incidence and
464
Mortality in Patients With Non-Malignant Findings: A Meta-Analysis. Am J
465
Gastroenterol 2016;111:355-65.
19
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overview of existing programmes. Gut 2015;64:1637-49.
467 468
Schreuders EH, Ruco A, Rabeneck L, et al. Colorectal cancer screening: a global
50.
Dodou D, de Winter JC. Agreement between self-reported and registered colorectal cancer screening: a meta-analysis. Eur J Cancer Care (Engl) 2015;24:286-98.
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Figure legends
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Figure 1. CRC death counts and mortality rates in Germany and the United States, 2008 to
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2011
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Death count is the total CRC death count during 2008 to 2011.
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CRC = colorectal cancer
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Data source:
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1. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999 to 2013
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Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human
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Services, Centers for Disease Control and Prevention and National Cancer Institute; 2016.
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Available at: www.cdc.gov/uscs.
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2. The German Centre for Cancer Registry Data (ZfKD). Available at:
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www.krebsdaten.de/Krebs/EN/Database/databasequery_step1_node.
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Table 1. Effects of colonoscopy use on colorectal cancer mortality from observational studies Country Study design Years US Case-control 1981-1992
No. Cases: 4358; controls: 16,531
Colonoscopy time frame* Up to 10 years before diagnosis
Covariates adjusted/matched Matched by age, sex, race; adjusted for other colorectal procedures, procedures other than colorectal, length of coverage by the Department of Veterans Affairs, arthritis-related diseases
Relative risk (95% CI) 0.45 (0.30-0.66)
Baxter, 2009 41
Canada
Case-control
1992-2003
Cases: 10,292; controls: 51,460
6 months-10 years before diagnosis
Matched by age, sex, geographic location, socioeconomic status; adjusted for comorbid conditions
0.63 (0.57-0.69)
Singh, 2010 36
Canada
Cohort†
1987-2008
54,803
6 months before diagnosis21 years before CRC deaths
Age, sex, calendar year
0.71 (0.61-0.82)
Baxter, 2012 42
US
Case-control
1991-2007
Cases: 9458; controls: 27,641
6 months-12 years before diagnosis
Matched by sex, year of birth, race, SEER registry; adjusted for socioeconomic status, comorbidities, urban/rural status
0.40 (0.37-0.43)
Jacob, 2012 37
Canada
Retrospective 1996-2005 cohort
1,089,998
3 years before diagnosis-10 years before CRC deaths
Primary care physician (age, sex, country of medical training) and patient characteristics (age, sex, income, comorbidity)
0.19 (0.07-0.47)
Eldridge, 2013 38
US
Cohort
1996-2008
68,531
Before diagnosis-16 years before CRC deaths
Age, sex, education, race, diabetes, family history of CRC, hormone replacement therapy use, healthy lifestyle score
0.41 (0.30-0.55)
Samadder, 2016 43
US
Case-control
1996-2010
Cases: 5128; controls: 20,512
6 months-10 years before diagnosis
Matched by age, sex; adjusted for family history of CRC, church affiliation status
0.33 (0.28-0.39)
Stock, 2016 39
Canada
Cohort
1992-2009
1,509,423
6 months before diagnosis10 years before CRC deaths
Age, sex, socioeconomic status, comorbidity
0.36 (0.33-0.38)
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Pooled estimate from random effects model
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First author, year Muller, 1995 40
0.44 (0.35-0.55)
* Colonoscopy time frame for colorectal cancer cases † Comparison with the general population 21
ACCEPTED MANUSCRIPT Table 2. Prevalence of colonoscopy use within 10 years in Germany and the United States* Germany
United States 2008-09 6022
2010-11 7366
Overall†
54.8 (52.5-57.0)
51.7 (50.1-53.2)
60.4 (59.0-61.8)
Sex Male Female
54.1 (50.8-57.3) 55.4 (52.6-58.2)
52.0 (49.7-54.3) 51.4 (49.4-53.4)
60.8 (58.7-63.0) 60.0 (58.3-61.8)
Age (years) 55-59 60-69 70-79
46.1 (41.4-50.8) 58.4 (55.0-61.7) 56.6 (52.9-60.2)
47.6 (44.9-50.4) 52.6 (50.3-54.9) 54.9 (52.2-57.6)
55.5 (52.8-58.2) 61.7 (59.9-63.6) 63.6 (61.2-65.9)
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Sample size
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2008-11 1889
* Prevalence estimates were based on DEGS1 for Germany and NHIS 2008 and 2010 for the US [% (95% CI)]
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† Overall prevalence of colonoscopy use among persons aged 55 to 79 years
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Table 3. Estimated fractions and numbers of CRC deaths attributable to nonuse of colonoscopy in Germany and United States
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United States 2008-09 AF, % (95% CI) No. of deaths (95% CI)† 38.2 (28.6-47.1) 20,947 (15,724-25,864)
37.0 (27.5-46.0) 36.3 (27.0-45.2)
13,069 (9728-16,259) 8074 (6003-10,062)
38.0 (28.5-47.0) 38.3 (28.8-47.3)
Age 55-59 60-69 70-79
40.8 (30.8-50.1) 34.7 (25.6-43.6) 35.7 (26.4-44.7)
2040 (1538-2504) 6475 (4770-8133) 12,107 (8948-15,158)
40.1 (30.3-49.2) 37.7 (28.3-47.0) 36.6 (27.2-45.5)
3227 (2439-3959) 7889 (5909-9766) 9479 (7058-11,798)
2010-11 No. of deaths (95% CI)† AF, % (95% CI) 33.6 (24.8-42.2) 18,344 (13,525-23,052)
33.4 (24.6-42.0) 33.8 (24.9-42.5)
10,435 (7676-13,143) 7891 (5818-9912)
36.3 (27.0-45.2) 32.9 (24.1-41.4) 31.7 (23.2-40.3)
3007 (2236-3747) 7083 (5203-8933) 7856 (5733-9968)
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AF = attributable fraction; CRC = colorectal cancer.
11,907 (8928-14,723) 9029 (6780-11,145)
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Sex Male Female
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Overall*
Germany 2008-11 AF, % (95% CI) No. of deaths (95% CI)† 36.6 (27.3-45.5) 21,086 (15,720-26,215)
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* Overall estimates for persons aged 55 to 79 years. † Sex- and age-specific estimates do not necessarily sum up to the overall estimate.
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Table 4. Estimated fractions and numbers of CRC deaths prevented by colonoscopy use in Germany and United States
2008-09 No. of deaths (95% CI)† PF, % (95% CI) 29.0 (23.4-33.6) 22,422 (16,786-27,794)
Sex Male Female
30.4 (24.4-35.5) 31.1 (25.0-36.2)
15,404 (11,392-19,453) 10,029 (7421-12,633)
29.2 (23.5-33.9) 28.8 (23.3-33.5)
Age 55-59 60-69 70-79
25.9 (20.4-30.8) 32.8 (26.3-38.3) 31.8 (25.5-37.2)
1745 (1283-2228) 9089 (6664-11,570) 15,789 (11,597-20,094)
26.7 (21.5-31.2) 29.5 (23.8-34.3) 30.8 (24.8-35.9)
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12,899 (9627-16,083) 9549 (7143-11,862)
2931 (2197-3649) 8755 (6527-10,925) 11,539 (8551-14,510)
2010-11 No. of deaths (95% CI)† PF, % (95% CI) 33.9 (27.4-39.2) 27,980 (20,595-35,235)
34.1 (27.5-39.6) 33.7 (27.2-39.0)
16,185 (11,878-20,482) 11,836 (8709-14,917)
31.1 (25.1-36.3) 34.6 (28.0-40.1) 35.7 (28.8-41.4)
3750 (2776-4720) 11,411 (8362-14,441) 13,726 (10,003-17,489)
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United States
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Overall*
Germany 2008-11 PF, % (95% CI) No. of deaths (95% CI)† 30.7 (24.8-35.7) 25,564 (18,983-32,002)
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Supplementary Table 1. Colorectal cancer death counts ages 55-79 years in Germany and the United States, 2008-2011* Germany 2009 2010 14,319 14,194
2011 14,101
2008 27,675
9157 5820
8774 5545
8683 5511
8736 5365
15,726 11,949
Age 55-59 60-64 65-69 70-74 75-79
1269 1754 3291 4194 4469
1256 1711 3148 4083 4121
1211 1688 2740 4362 4193
1265 1805 2517 4167 4347
4003 4927 5514 6170 7061
15,593 11,617
15,652 11,522
15,615 11,805
4042 5063 5410 6036 6659
4047 5230 5498 5865 6534
4248 5456 5371 5960 6385
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Deaths from cancers of colon and rectum (C18-20 by International Classification of Diseases-10 Version)
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*
2011 27,420
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Sex Male Female
United States 2009 2010 27,210 27,174
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Total
2008 14,977
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ACCEPTED MANUSCRIPT Appendix. Statistical analysis of AF and PF We applied the method described in detail in the study of Stock et al. to calculate the estimates of AF, PF and the corresponding death numbers, Naf and Npf.19 Naf and Npf were
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derived by multiplying the estimated AF and PF with the observed number of CRC deaths and estimated hypothetical CRC deaths in the absence of colonoscopy, respectively. Briefly, the following formulas were used:
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AF = P0(RR0/1-1)/[ P0(RR0/1-1)+1]
Naf = AF×N Npf = PF×N/[P1(RR1/0-1)+1]
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PF = P1(1-RR1/0)
(1) (2) (3) (4)
AF: attributable fraction PF: prevented fraction
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Symbols and acronyms were defined as follows:
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P0: prevalence of nonuse of colonoscopy (unexposed) P1: prevalence of colonoscopy use (exposed); P1=1-P0
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RR1/0: relative risk of deaths from CRC in people with use of colonoscopy (exposed) versus people without (unexposed) RR0/1: inverse of the relative risk for exposure to colonoscopy use; RR0/1=1/ RR1/0 Naf: Number of CRC deaths attributable to nonuse of colonoscopy Npf: Number of CRC deaths prevented by use of colonoscopy N: actual CRC death number of the year
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ACCEPTED MANUSCRIPT Acronyms List AF, attributable fraction; CI, confidence interval; CRC, colorectal cancer; CrI, credible interval; DEGS, German Health Interview and Examination Survey for Adults; FIT, fecal
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immunochemical test for hemoglobin; FOBT, fecal occult blood test; NHIS, National Health Interview Survey; PF, prevented fraction; USCS, United States Cancer Statistics; ZfKD,
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German Centre for Cancer Registry Data