210
`
`COLORECTAL CANCER
`Comparison of a guaiac based and an immunochemical
`faecal occult blood test in screening for colorectal cancer in a
`general average risk population
`L Guittet, V Bouvier, N Mariotte, J P Vallee, D Arse`ne, S Boutreux, J Tichet, G Launoy
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Gut 2007;56:210–214. doi: 10.1136/gut.2006.101428
`
`Background: The guaiac faecal occult blood test (G-FOBT) is recommended as a screening test for colorectal
`cancer but its low sensitivity has prevented its use throughout the world.
`Methods: We compared the performances of the reference G-FOBT (non-rehydrated Hemoccult II test) and
`the immunochemical faecal occult blood test (I-FOBT) using different positivity cut-off values in an average risk
`population sample of 10 673 patients who completed the two tests. Patients with at least one test positive were
`asked to undergo colonoscopy.
`Results: Using the usual cut-off point of 20 ng/ml haemoglobin, the gain in sensitivity associated with the use
`of I-FOBT (50% increase for cancer and 256% increase for high risk adenoma) was balanced by a decrease
`in specificity. The number of extra false positive results associated with the detection of one extra advanced
`neoplasia (cancer or high risk adenoma) was 2.17 (95% confidence interval 1.65–2.85). With a threshold of
`50 ng/ml, I-FOBT detected more than twice as many advanced neoplasias as the G-FOBT (ratio of
`sensitivity = 2.33) without any loss in specificity (ratio of false positive rate = 0.99). With a threshold of 75 ng/
`ml, associated with a similar positivity rate to G-FOBT (2.4%), the use of I-FOBT allowed a gain in sensitivity of
`90% and a decrease in the false positive rate of 33% for advanced neoplasia.
`Conclusions: Evidence in favour of the substitution of G-FOBT by I-FOBT is increasing, the gain being more
`important for high risk adenomas than for cancers. The automated reading technology allows choice of the
`positivity rate associated with an ideal balance between sensitivity and specificity.
`
`See end of article for
`authors’ affiliations
`. . . . . . . . . . . . . . . . . . . . . . . .
`
`Correspondence to:
`Guy Launoy, Cancers and
`Populations, ERI 3 INSERM,
`UFR Medecine , CHU-
`14000, Caen, France; guy.
`launoy@unicaen.fr
`
`Revised 5 July 2006
`Accepted 18 July 2006
`Published Online First
`4 August 2006
`. . . . . . . . . . . . . . . . . . . . . . . .
`
`C olorectal cancer is a major public health issue in all
`
`industrialised countries. As a consequence of the char-
`acteristics of
`this cancer (major effect on prognosis
`depending on stage at diagnosis, long preclinical phase with
`frequent precancerous lesions), screening is of considerable
`value. Colonoscopy is the most accurate test for detecting early
`cancers and for the detection and removal of high risk
`adenomas. However, because of
`its potential harm,
`the
`availability of qualified endoscopists as well as costs aspects,
`strategies, including the use of the faecal occult blood test
`(FOBT), have been proposed for large scale population screen-
`ing programmes in several areas throughout the world. The
`efficacy of strategies based on biennial FOBT has been
`established in three randomised and one non-randomised
`controlled trial using Hemoccult, a guaiac-faecal occult blood
`test (G-FOBT).1–4 Such results have been available for many
`years but several test limitations have, to a great extent,
`prevented its use throughout the world, the major weakness
`being its
`low sensitivity. The higher
`sensitivity of
`the
`immunochemical faecal occult blood test (I-FOBT), using a
`specific human haemoglobin, has been established in numer-
`ous recently reviewed studies.5–7 However,
`to represent a
`valuable alternative screening test in large scale populations,
`I-FOBT needs
`to demonstrate other qualities,
`including
`reproducibility and high specificity. Several recent studies have
`emphasised the value of an automated reading process as it
`ensures reproducibility and provides a quantitative outcome,
`making it possible to identify the cut-off corresponding to the
`optimal balance between sensitivity and specificity.8–10
`The aim of this study was to compare the performances of the
`reference G-FOBT (non-rehydrated Hemoccult II test) and I-
`FOBT in a general average risk population, with automated
`reading process (Magstream 1000; Fujirebio, Tokyo, Japan),
`
`enabling a comparison between different positivity cut-off
`points for I-FOBT.
`
`MATERIAL AND METHODS
`Study population
`Since June 2004, a screening programme has been implemen-
`ted using a conventional G-FOBT,
`the Hemoccult
`II,
`for
`individuals aged 50–74 years
`in the geographic area of
`Calvados (Normandy, France). The beginning of the pro-
`gramme was staggered among six separate zones within the
`area. Attendees were offered the possibility of joining a study
`comparing I-FOBT (Immudia/RPHA; Fujirebio, Tokyo, Japan)
`with the conventional G-FOBT. This preliminary analysis
`focused on all tests performed from 1 June 2004 to 30 June
`2005. During this period, among 11 333 people who were
`offered the test, 529 declined and participated only in the
`screening programme with the G-FOBT and 10 804 participated
`in the study by undertaking the two tests.
`
`Study design
`The targeted population was contacted by post to explain the
`aim of the study, and invited to contact their practitioner to
`undergo both tests. Practitioners were supplied with study kits
`and invited to administer tests to patients aged 50–74 years at
`the end of their regular consultation. Study kits contained a
`short description of the study, instructions for the collection of
`faeces and mailing of samples to the laboratory, a consent form,
`two sample tubes for collection of faeces (Immudia/RPHA), a
`
`Abbreviations: G-FOBT, guaiac faecal occult blood test; I-FOBT,
`immunochemical faecal occult blood test; RFP, ratio of false positive rate;
`RSN, ratio of sensitivity
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`Screening for colorectal cancer in an average risk population
`
`211
`
`test kit card (Hemoccult II) and a prestamped envelope for
`mailing of samples.
`The screening procedure was considered positive when at
`least one of the tests was positive. The patient and practitioner
`were informed of
`the overall screening procedure result,
`blinded to each individual test result. In the case of a positive
`result, the patient was invited to consult his/her practitioner.
`The primary care provider was responsible for referring patients
`with positive test results for further evaluation.
`The study was approved by the local ethics committee
`(Comite´ Consultatif de Protection des Personnes dans la
`Recherche Biome´dicale) and all participants gave written
`informed consent.
`
`Faecal occult blood test
`Patients were asked to obtain two faecal samples at home on
`two different days for the I-FOBT and two faecal samples each
`from three consecutive stools for the conventional G-FOBT. The
`same stools could be used for both tests. No specific dietary
`restriction was stipulated. Samples for the Hemoccult II test
`were spread directly onto filter paper containing guaiac gum
`through oval spaces on the test kit card. Samples for the
`Immudia/RPHA test were obtained using a brush contained
`within the collection tube. Samples of both tests were sent to
`the central analysis centre (Institut inter-Re´gional pour la
`Sante´, Tours, France).
`All
`immunochemical tests were processed at the central
`laboratory using the Magstream 1000 automated device
`(Fujirebio). Faecal occult blood was detected using immuno-
`logical
`indirect agglutination. Magnetic gelatin particles
`attached to antihuman haemoglobin placed in a magnetic field
`were used to quantify the level of haemoglobin using an optical
`reader. When a plate with 80 samples was tilted 60˚ from the
`horizontal position, free magnetic particles could slide down
`the slope of the well, thus forming a measurable line. The
`higher the presence of human haemoglobin, the more the
`
`particles are prevented from sliding down the well, and
`therefore the shorter the line is. Thus haemoglobin level was
`expressed as a quantitative outcome. According to the
`manufacturer’s instructions, the test was considered positive
`when at least one of the two samples contained at least 20 ng/
`ml haemoglobin (0.1–0.2 mg haemoglobin/g stool).
`All guaiac tests were processed at the central laboratory.
`Reading was not automated but was performed by trained staff
`and under strict quality control (double reading, control of
`frequency of positive tests, reproducibility). Readers of the
`guaiac test were blinded to the patient’s history and to the
`result of the immunochemical test. Hemoccult II tests with at
`least one positive oval were considered positive.
`According to the recommendations of the manufacturers of
`Hemoccult, the delay from first faeces deposit to processing
`must not exceed 14 days. Where there was a delay of more than
`14 days (0.11%), the test was returned to the patient with a
`new test requested.
`
`Colonoscopy
`Colonoscopies were performed in 20 centres (public hospitals or
`private clinics). Data on colonoscopies were recorded on a
`specific form with information on the quality of the investiga-
`tion (quality of preparation, completeness of colonoscopy) and
`results (number, size and localisation of adenomas and
`colorectal cancers, and whether a biopsy was performed).
`Histological results were also requested. Patients were excluded
`from the analysis if the endoscopic examination was incom-
`plete (caecum not visualised) and no double-contrast barium
`enema confirmed the absence of polypoid lesions. However, if a
`colonoscopic examination was incomplete because of obstruct-
`ing tumours, the results were included in the analysis. If a
`patient had more than one polyp,
`the most advanced
`pathological lesion or the largest lesion was included in the
`analysis.
`
`Figure 1 Study design.
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`212
`
`Guittet, Bouvier, Mariotte, et al
`
`Table 1 Characteristics of the study population
`
`Number of patients (%)
`
`Patients with two
`analysable tests
`(n = 10 673)
`
`Analysed patients (negative
`tests or analysable
`colonoscopy)
`(n = 10 431)
`
`4553 (42.7)
`6120 (57.3)
`
`62.1 (6.9)
`2020 (18.9)
`2584 (24.2)
`2052 (19.2)
`2190 (20.5)
`1827 (17.1)
`
`886 (8.3)
`260 (2.4)
`733 (6.9)
`9787 (91.7)
`
`4427 (42.4)
`6004 (57.6)
`
`62.1 (6.9)
`1991 (19.1)
`2532 (24.3)
`2001 (19.2)
`2134 (20.5)
`1773 (17.0)
`
`644 (6.2)
`191 (1.8)
`530 (5.1)
`9787 (93.8)
`
`Sex (n (%))
`Male
`Female
`Age
`Mean (SD) (y)
`50–54 (n (%))
`55–59 (n (%))
`60–64 (n (%))
`65–69 (n (%))
`70–74 (n (%))
`FOBT (n (%))
`G-FOBT and/or I-FOBT positive
`G-FOBT positive
`I-FOBT positive
`I-FOBT and G-FOBT negative
`
`G-FOBT, guaiac faecal occult blood test.
`The immunochemical faecal occult blood test (I-FOBT) was used at the usual cut-off value.
`
`Pathological findings (histology)
`Histological characteristics of
`the polyps included normal
`mucosa, hyperplasic polyps and adenoma (tubular, tubulovil-
`lous, or villous). Hyperplasic polyps were not included as
`neoplasias. Advanced colonic neoplasia was defined as adeno-
`mas measuring 10 mm or more, adenomas with high grade
`dysplasia or invasive cancer. Intramucosal carcinoma and
`carcinoma in situ were classified as adenoma with high grade
`dysplasia. The criterion for diagnosing cancer was an invasion
`of malignant cells beyond the muscularis mucosa.
`
`Statistical analysis
`The population of eligible patients comprised all patients who
`had given written consent, from 1 June 2004 to 30 June 2005
`(n = 10 804). Patients in whom one or both tests was not
`performed or who had inconclusive results (n = 131) were
`excluded from the study, as were those with a positive
`screening
`test
`but no
`satisfactory
`colonoscopy
`result
`(n = 242). Figure 1 shows a summary of the study.
`As the confirmatory procedure (colonoscopy) was restricted
`to subjects classified as positive on at least one of the tests, the
`sensitivity and specificity of each test could not be directly
`estimated. We therefore compared the accuracy of both tests by
`calculating the ratio of sensitivities (RSN) and the ratio of false
`positive rates (RFP), as originally suggested by Schatzkin et al.11
`Briefly, if the number of true positive patients for the I-FOBT is
`denoted by m’1, and the number of true positive patients for the
`G-FOBT by n’1, RSN is calculated as
`RSNI-FOBT/G-FOBT = m’1/n’1.
`
`If the number of false positive patients for the I-FOBT is
`denoted by m’’1 and the number of false positive patients for
`the G-FOBT by n’’1, RFP is calculated as
`RFPI-FOBT/G-FOBT = m’’1/n’’1.
`Confidence intervals (95%) were calculated according to the
`formulas proposed by Cheng and Macaluso.12 The number of
`extra false positives associated with the detection of one extra
`true positive, if the I-FOBT was used instead of the G-FOBT,
`denoted FP:TP, was calculated as the ratio between the
`difference in the number of false positive patients with I-
`FOBT versus G-FOBT and the difference in the number of true
`positive patients with I-FOBT versus G-FOBT.13
`Comparison of the two tests (G-FOBT and I-FOBT) was
`conducted using different cut-off points for I-FOBT: the usual
`cut-off point (20 ng/ml) and two alternative cut-off points (50
`and 75 ng/ml).
`Statistical analysis was performed using SAS software
`version 9.1.
`
`RESULTS
`Patients
`Table 1 shows the characteristics of the study population. Of the
`10 673 patients who completed the G-FOBT and I-FOBT, 886
`had at least one positive test. Using the usual cut-off point, the
`positivity rate of the I-FOBT was markedly higher than that of
`the Hemoccult test (6.9% v 2.4%). A total of 711 (80.2%)
`patients with at
`least one positive FOBT test underwent
`colonoscopy. Among them, 46 had an incomplete colonoscopy
`and 21 lacked sufficient information on the polypoid lesion
`
`Table 2 Colonoscopy findings according to the test results
`
`Positive
`G-FOBT
`
`Hb level (I-FOBT) (ng/ml)
`
`20–50
`
`50–75
`
`.75
`
`Positive G-FOBT
`or I-FOBT
`
`No neoplasia
`Adenoma ,10 mm
`Advanced neoplasia
`Adenoma >10 mm or high grade
`dysplasia ,10 mm
`Invasive cancer
`
`108
`30
`53
`39
`
`14
`
`167
`67
`50
`48
`
`2
`
`28
`15
`20
`17
`
`3
`
`72
`21
`90
`74
`
`16
`
`350
`124
`170
`149
`
`21
`
`Hb, haemoglobin; G-FOBT, guaiac faecal occult blood test; I-FOBT, immunochemical faecal occult blood test.
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`
`213
`
`Table 3 Comparison of the relative performance of I-FOBT versus G-FOBT, according to the positivity level of I-FOBT
`
`Positivity
`threshold
`(I-FOBT
`ng/ml)
`
`Positivity
`rate (%)*
`
`I-FOBT
`
`20 ng/ml
`
`6.9
`
`50 ng/ml
`
`3.3
`
`75 ng/ml
`
`2.4
`
`G-FOBT
`
`2.4
`
`Adenoma
`>10 mm or
`high grade
`dysplasia
`(RSNÀ)
`
`3.56
`[2.66–4.77]
`2.08
`[1.63–2.64]
`1.70
`[1.33–2.16]
`
`Colorectal cancer
`
`Advanced neoplasia (colorectal cancer or
`adenoma>10 mm or high grade dysplasia)
`
`PPV
`
`RSNÀ
`
`RFP`
`
`FP:TP1
`
`PPV
`
`RSNÀ
`
`RFP`
`
`FP:TP1
`
`4.0
`
`7.7
`
`8.7
`
`7.3
`
`1.50
`[1.11–2.03]
`1.36
`[0.99–1.87]
`1.14
`[0.83–1.58]
`
`2.88
`[2.46–3.36]
`1.28
`[1.08–1.53]
`0.94
`[0.78–1.14]
`
`47.43
`[22.32–100.80]
`10.00
`[2.86–34.97]
`–
`
`3.02
`[2.38–3.84]
`2.33
`[1.73–3.14]
`1.90
`[1.41–2.56]
`
`2.68
`[2.24–3.22]
`0.99
`[0.79-1.23]
`0.67
`[0.53–0.86]
`
`2.17
`[1.65–2.85]
`–
`
`–
`
`30.2
`
`44.7
`
`49.2
`
`27.7
`
`G-FOBT, guaiac faecal occult blood test; I-FOBT, immunochemical faecal occult blood test; PPV, predictive positive value; RFP, ratio of false positive rate; RSN, ratio of sensitivity.
`Values for RSN, RFP and FP:TP are mean [95% confidence interval].
`*Patients with both analysable tests, independent of whether or not a colonoscopy was performed or not (n = 887).
`ÀRSN.1, sensitivity of I-FOBT is greater than that of G-FOBT.
``RFP.1, false positive rate of I-FOBT is greater than that of G-FOBT, the specificity of I-FOBT is therefore inferior to G-FOBT.
`1FP:TP, number of extra false positives associated with the detection of one extra true disease case using I-FOBT instead of G-FOBT.
`
`detected. Colonoscopy was performed within two months after
`the test reading for half of the patients and within 8 months for
`98% of patients. The frequency of patients undergoing endo-
`scopic examination did not differ regardless of whether one or
`both screening tests were positive (G-FOBT and I-FOBT
`positives, 80.4%; G-FOBT positive only, 81.7%; I-FOBT positive
`only, 79.9%, p = 0.88).
`
`Colonoscopic findings
`A total of 21 (3.3%) colorectal cancers and 149 (23.1%) patients
`with high risk adenomas (size >10 mm or high grade
`dysplasia) were detected in 644 colonoscopies. Table 2 shows
`the results of colonoscopy according to the FOBT results and
`amount of haemoglobin detected by the I-FOBT. One perfora-
`tion was recorded after colonoscopy (0.2%).
`
`Performance comparison between G-FOBT and I-FOBT
`at the usual positive threshold of 20 ng/ml (table 3)
`Using the usual cut-off point, the sensitivity of I-FOBT was
`higher than that of G-FOBT for cancer (RSN = 1.50) and for
`high risk adenoma (RSN = 3.56). The predictive positive value
`of I-FOBT was lower than that of G-FOBT for cancer (4.0% v
`7.3%) and similar for high risk adenomas (22% v 27%). As the
`positivity rate was more than twofold higher for I-FOBT than
`for G-FOBT, the RFP was unfavourable to I-FOBT. Using this
`usual cut-off point, the gain in sensitivity associated with the
`use of I-FOBT (50% increase for cancer and 256% increase for
`high risk adenoma) was balanced by a decrease in specificity.
`The number of extra false positives associated with the
`detection of one extra invasive colorectal cancer was 47.43
`(95% confidence interval 22.32–100.80). For the detection of
`one extra advanced neoplasia (cancer or high risk adenoma)
`the corresponding value was 2.17 (1.65–2.85).
`
`Analysis of the relative performance of I-FOBT
`compared with G-FOBT at two alternative thresholds
`(table 3)
`The use of two alternative thresholds (50 and 75 ng/ml) for the
`I-FOBT test provided a lower gain in sensitivity but allowed a
`decrease in the positivity rate as well as an increase in the
`predictive positive value for both cancer and high risk
`adenomas. FP:TP for advanced neoplasia was not calculated
`for these two alternative cut-off points as both RSN and RFP
`were in favour of I-FOBT. With a threshold of 50 ng/ml, I-FOBT
`detected more than twice as many advanced neoplasias as G-
`FOBT
`(RSN = 2.33), without
`any
`loss
`in
`specificity
`(RFP = 0.99). With a threshold of 75 ng/ml, sensitivity and
`specificity were higher with the I-FOBT than with the G-FOBT
`for both invasive colorectal cancer and advanced neoplasia.
`
`Using this cut-off point associated with a similar positivity rate
`to G-FOBT (2.4%), the use of I-FOBT allowed a gain in
`sensitivity of 90% and a decrease in false positive rate of 33% for
`advanced neoplasia.
`
`DISCUSSION
`In patients who performed the two tests, the I-FOBT had a
`higher sensitivity for both cancer and high risk adenomas
`irrespective of the cut-off value used for I-FOBT. With the usual
`cut-off point (20 ng haemoglobin/ml), this gain in sensitivity
`was associated with a decrease in specificity, 2.17 extra false
`positives being associated with the detection of one extra
`advanced neoplasia (cancer or high risk adenoma). Using a
`higher cut-off point, our results suggest that the I-FOBT rather
`than the G-FOBT offers a gain in both sensitivity and
`specificity. When I-FOBT was used at a cut-off value associated
`with a positivity rate similar to G-FOBT, it offered a gain in
`sensitivity of 90% and a decrease in false positive rate of 33% for
`advanced neoplasia.
`The study had several drawbacks. To estimate screening test
`performances for cancers and high risk adenomas, the ideal is
`to obtain the disease status for all individuals, independent of
`the screening test results. With the exception of the recent
`study by Morikawa et al,9 large scale asymptomatic populations
`have not undergone screening, and available direct estimation
`of
`I-FOBT performance originates mainly from high risk
`individuals referred for colonoscopy.10 14 Hence the results
`may not be directly applicable to the general average risk
`population. Studies conducted in large samples of the general
`population, with follow-up for individuals with negative tests,
`provided complete and reliable information on cancer but not
`on high risk adenomas.15–17 Our study was conducted in an
`average risk population but our analysis was conducted before
`the collection of cancers by local registries, and does not
`therefore provide an estimation of the sensitivity and specificity
`of each test. However, it does enable direct comparison of the
`sensitivity and specificity of the two tests by calculating proper
`ratios (RSN and RFP), as suggested by Schatzkin et al and
`Cheng et al,11 12 18 and thus quantification of the potential gain
`obtained by the substitution of G-FOBT by I-FOBT. This
`method allowed the calculation of the 95% confidence interval
`for each ratio; the 95% confidence interval for RSN for detection
`of invasive colorectal cancer was probably underestimated in
`our study because of the small number of cases.
`A significant proportion (20%) of individuals with a positive
`screening test did not undergo colonoscopy. This proportion
`was no higher than those usually observed in mass screening
`campaigns in France. However, it produced potential bias as the
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`Guittet, Bouvier, Mariotte, et al
`
`risk of cancer has been suggested in a previous French study17
`to be higher for people refusing a colonoscopy after a positive
`test. In our case, as the proportion of people not having
`colonoscopy after a positive test did not differ with regard to
`whether one or both screening tests were positive, it did not
`produce bias in the comparison between the tests.
`Despite extensive studies,
`including several randomised
`studies, there is still no consensus on the best strategy for
`colorectal cancer screening for average risk populations, and
`guidelines vary from one country to another and from one
`society to another. Nevertheless, FOBT is included in all recent
`guidelines and reviews.19 20 Limitations of the guaiac tests, in
`particular their low sensitivity, encourage researchers to search
`extensively for alternative FOBT techniques. An increasing
`number of recent papers highlighted their interest in the use of
`immunochemical tests. Our study is in agreement with these
`studies, conducted in general or high risk populations,
`emphasising the high sensitivity of I-FOBT for cancer and
`adenomas,9 10 21 22 and its superiority over G-FOBT.14–16 23 The
`development of automated systems has increased the reliability
`and decreased the cost of test processing and reading. The
`technology evaluated in our study, Magstream 1000/Hem SP
`(Fujirebio), has previously been studied in individuals referred
`for colonoscopy,10 and in two population based studies.9 24 The
`recent study by Morikawa et al comparing this I-FOBT
`technology with colonoscopy in 21 805 Japanese asymptomatic
`individuals provided reliable and promising results.9 However,
`using the usual
`threshold of 20 ng haemoglobin/ml, and
`although the study population was younger than those usually
`screened (mean age 48.2 years), the proportion of patients with
`a positive test was relatively high (5.6%). Such a high positivity
`rate, which would be even higher in older populations, could be
`inappropriate in biennial strategies. As suggested in previous
`studies,17 25 by increasing the positivity threshold of quantitative
`I-FOBT, an appropriate positivity rate can be obtained while
`maintaining a substantial gain in sensitivity. The ideal balance
`between sensitivity and specificity/positivity rate depends on
`health care organisation and cost, and is likely to vary between
`countries. Our study, conducted in a 50–74 year average risk
`population, showed that with a positivity rate of 2.4%, identical
`to the Hemoccult test, I-FOBT increased the number of true
`positives (cancers and high risk adenomas) by nearly 2 (1.9)
`and decreased the number of false positive results by 1.5.
`Evidence in favour of the use of the I-FOBT over the G-FOBT
`is increasing. I-FOBT tests have no dietary or medication
`restrictions. These tests have superior sensitivity and specificity,
`the gain being more important for high risk adenomas than for
`cancers. They also have a higher compliance rate23 26 27 and the
`automated reading technology allows the choice of the ideal
`positivity rate. As suggested in recent reviews,5 7 it is time to
`give colorectal cancer screening a new future by using I-FOBT
`instead of G-FOBT.
`
`ACKNOWLEDGEMENTS
`The authors thank all of the general practitioners, gastroenterologists
`and pathologists of Calvados who participated in the study.
`
`. . . . . . . . . . . . . . . . . . . . . . .
`Authors’ affiliations
`L Guittet, V Bouvier, D Arse`ne, S Boutreux, G Launoy, Cancers and
`Populations, ERI 3 INSERM UFR Me´decine CHU Caen, France
`V Bouvier, J P Vallee, Association Mathilde, Caen, France
`N Mariotte, J Tichet, Institut inter-Re´gional pour la Sante´ (IRSA), Tours,
`France
`
`Conflict of interest: None.
`
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`Geneoscopy Exhibit 1021, Page 5
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