%PDF-1.3 1 0 obj << /Type /Catalog /Outlines 2 0 R /Pages 3 0 R >> endobj 2 0 obj << /Type /Outlines /Count 0 >> endobj 3 0 obj << /Type /Pages /Kids [6 0 R 86 0 R 197 0 R 253 0 R 316 0 R 402 0 R 476 0 R ] /Count 7 /Resources << /ProcSet 4 0 R /Font << /F1 8 0 R /F2 9 0 R /F3 10 0 R /F4 11 0 R /F5 88 0 R /F6 255 0 R >> /XObject << /I1 12 0 R /I2 13 0 R /I3 215 0 R /I4 216 0 R /I5 233 0 R /I6 234 0 R /I7 251 0 R /I8 252 0 R >> >> /MediaBox [0.000 0.000 612.000 792.000] >> endobj 4 0 obj [/PDF /Text /ImageC ] endobj 5 0 obj << /Creator (DOMPDF) /CreationDate (D:20180721032756+00'00') /ModDate (D:20180721032756+00'00') /Title (Fecal DNA testing for Colorectal Cancer Screening: the ColoSure test PLOS Currents Evidence on Genomic Tests) >> endobj 6 0 obj << /Type /Page /Parent 3 0 R /Annots [ 14 0 R 16 0 R 18 0 R 20 0 R 22 0 R 24 0 R 26 0 R 28 0 R 30 0 R 32 0 R 34 0 R 36 0 R 38 0 R 40 0 R 42 0 R 44 0 R 46 0 R 48 0 R 50 0 R 52 0 R 54 0 R 56 0 R 58 0 R 60 0 R 62 0 R 64 0 R 66 0 R 68 0 R 70 0 R 72 0 R 74 0 R 76 0 R 78 0 R 80 0 R 82 0 R 84 0 R ] /Contents 7 0 R >> endobj 7 0 obj << /Length 23309 >> stream q 375.000 0 0 39.000 222.000 738.000 cm /I2 Do Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Fecal DNA testing for Colorectal Cancer Screening: the )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(ColoSure test)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(March 22, 2011)] TJ ET BT 82.431 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 87.306 675.088 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET 0.271 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Rene M. Ned)] TJ ET 0.271 0.267 0.267 rg BT 99.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 105.371 663.247 Td /F1 9.8 Tf [(Stephanie Melillo)] TJ ET 0.271 0.267 0.267 rg BT 179.608 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 185.029 663.247 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Ned RM, Melillo S, Marrone M. Fecal DNA testing for Colorectal Cancer Screening: the ColoSure test. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Evidence on Genomic Tests. 2011 Mar 22 . Edition 1. doi: 10.1371/currents.RRN1220.)] TJ ET q 15.000 25.125 577.500 611.932 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Screening has been shown to be effective in reducing colorectal cancer incidence and mortality. Colonoscopy, sigmoidoscopy, )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(and fecal occult blood tests are all recommended screening tests that have widespread availability. Nevertheless, many people )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(do not receive the evidence-based recommended screening for colorectal cancer. Additional stool-based methods have been )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(developed that offer more options for colorectal cancer screening, including a variety of fecal DNA tests. The only fecal DNA )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(test that is currently available commercially in the United States is ColoSure\(TM\), which is marketed as a non-invasive test that )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(detects an epigenetic marker \(methylated vimentin\) associated with colorectal cancer and pre-cancerous adenomas. We )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(examined the published literature on the analytic validity, clinical validity, and clinical utility of ColoSure and we briefly )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(summarized the current colorectal cancer screening guidelines regarding fecal DNA testing. We also addressed the public )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(health implications of the test and contextual issues surrounding the integration of fecal DNA testing into current colorectal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(cancer screening strategies. The primary goal was to provide a basic overview of ColoSure and identify gaps in knowledge and )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(evidence that affect the recommendation and adoption of the test in colorectal cancer screening strategies.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Application: Screening)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 365.720 Td /F4 9.8 Tf [(Colorectal Cancer \(CRC\) screening)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Screening by colonoscopy, sigmoidoscopy and fecal occult blood testing has been shown to prevent colorectal cancer \(CRC\) )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(and to reduce mortality through the detection and removal of pre-cancerous lesions and through the detection of CRC in its )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(early stages )] TJ ET 0.267 0.267 0.267 rg BT 81.523 322.506 Td /F1 9.8 Tf [([1] [2])] TJ ET 0.271 0.267 0.267 rg BT 105.917 322.506 Td /F1 9.8 Tf [(. Indeed, CRC incidence and mortality have been decreasing since 1985 )] TJ ET 0.267 0.267 0.267 rg BT 421.320 322.506 Td /F1 9.8 Tf [([2] [3])] TJ ET 0.271 0.267 0.267 rg BT 445.715 322.506 Td /F1 9.8 Tf [(. Research suggests that CRC )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(screening may be responsible for approximately half of the declines )] TJ ET 0.267 0.267 0.267 rg BT 319.959 310.601 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 330.801 310.601 Td /F1 9.8 Tf [(. However, uptake of CRC screening recommendations )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(in the U.S. is not optimal. In 2008, only about 62% of men and women aged 50-75 years reported getting the most commonly )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(recommended CRC screening tests, a percentage that varied from 49-75% among states )] TJ ET 0.267 0.267 0.267 rg BT 413.705 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 424.547 286.791 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Several tests are available to identify colorectal cancer and pre-cancerous polyps in asymptomatic individuals. Colonoscopy )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(visually inspects the interior walls of the entire rectum and colon. Performance characteristics \(such as sensitivity and )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(specificity\) of new tests are commonly evaluated in comparison with colonoscopy )] TJ ET 0.267 0.267 0.267 rg BT 378.459 243.577 Td /F1 9.8 Tf [([1] [5])] TJ ET 0.271 0.267 0.267 rg BT 402.853 243.577 Td /F1 9.8 Tf [(. Flexible sigmoidoscopy involves a )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(more limited visual inspection of the distal colon and rectum. Fecal occult blood tests \(FOBTs\), which include conventional )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(guaiac FOBT, high-sensitivity guaiac FOBT, and fecal immunochemical tests \(FITs\), chemically detect small amounts of fecal )] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(blood \(which can originate from pre-cancerous and cancerous colorectal lesions\). CT colonography \(i.e., virtual colonoscopy\) )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(and double-contrast barium enema \(DCBE\) are additional tests, offering enhanced x-ray images of the interior rectum and colon )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(to aid in detecting abnormalities.)] TJ ET BT 26.250 164.649 Td /F1 9.8 Tf [(Fecal \(stool\) DNA tests have been under continuous development over the past several years. These tests are designed to )] TJ ET BT 26.250 152.744 Td /F1 9.8 Tf [(detect in stool samples any number of DNA markers shown to be associated with CRC. ColoSure is the latest example of a )] TJ ET BT 26.250 140.839 Td /F1 9.8 Tf [(clinically available stool DNA test.)] TJ ET BT 26.250 121.434 Td /F4 9.8 Tf [(Clinical Scenario)] TJ ET BT 26.250 102.030 Td /F1 9.8 Tf [(The clinical scenario for fecal DNA testing in general is most often presented as colorectal cancer screening in average-risk )] TJ ET BT 26.250 90.125 Td /F1 9.8 Tf [(individuals.)] TJ ET BT 26.250 70.720 Td /F1 9.8 Tf [(A technical brochure for ColoSure )] TJ ET 0.267 0.267 0.267 rg BT 175.269 70.720 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 186.111 70.720 Td /F1 9.8 Tf [( states that:)] TJ ET BT 26.250 51.315 Td /F1 9.8 Tf [(ColoSure is not intended to replace a colonoscopy in those patients who are willing and able to undergo the procedure. )] TJ ET BT 26.250 39.411 Td /F1 9.8 Tf [(Additionally, while it may be used adjunctively or in patients noncompliant with screening recommendations, it is not a screening )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Fecal DNA testing for Colorectal Cancer Screening: the )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(ColoSure test)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(March 22, 2011)] TJ ET BT 82.431 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 87.306 675.088 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET 0.271 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Rene M. Ned)] TJ ET 0.271 0.267 0.267 rg BT 99.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 105.371 663.247 Td /F1 9.8 Tf [(Stephanie Melillo)] TJ ET 0.271 0.267 0.267 rg BT 179.608 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 185.029 663.247 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Ned RM, Melillo S, Marrone M. Fecal DNA testing for Colorectal Cancer Screening: the ColoSure test. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Evidence on Genomic Tests. 2011 Mar 22 . Edition 1. doi: 10.1371/currents.RRN1220.)] TJ ET q 15.000 25.125 577.500 611.932 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Screening has been shown to be effective in reducing colorectal cancer incidence and mortality. Colonoscopy, sigmoidoscopy, )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(and fecal occult blood tests are all recommended screening tests that have widespread availability. Nevertheless, many people )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(do not receive the evidence-based recommended screening for colorectal cancer. Additional stool-based methods have been )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(developed that offer more options for colorectal cancer screening, including a variety of fecal DNA tests. The only fecal DNA )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(test that is currently available commercially in the United States is ColoSure\(TM\), which is marketed as a non-invasive test that )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(detects an epigenetic marker \(methylated vimentin\) associated with colorectal cancer and pre-cancerous adenomas. We )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(examined the published literature on the analytic validity, clinical validity, and clinical utility of ColoSure and we briefly )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(summarized the current colorectal cancer screening guidelines regarding fecal DNA testing. We also addressed the public )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(health implications of the test and contextual issues surrounding the integration of fecal DNA testing into current colorectal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(cancer screening strategies. The primary goal was to provide a basic overview of ColoSure and identify gaps in knowledge and )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(evidence that affect the recommendation and adoption of the test in colorectal cancer screening strategies.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Application: Screening)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 365.720 Td /F4 9.8 Tf [(Colorectal Cancer \(CRC\) screening)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Screening by colonoscopy, sigmoidoscopy and fecal occult blood testing has been shown to prevent colorectal cancer \(CRC\) )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(and to reduce mortality through the detection and removal of pre-cancerous lesions and through the detection of CRC in its )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(early stages )] TJ ET 0.267 0.267 0.267 rg BT 81.523 322.506 Td /F1 9.8 Tf [([1] [2])] TJ ET 0.271 0.267 0.267 rg BT 105.917 322.506 Td /F1 9.8 Tf [(. Indeed, CRC incidence and mortality have been decreasing since 1985 )] TJ ET 0.267 0.267 0.267 rg BT 421.320 322.506 Td /F1 9.8 Tf [([2] [3])] TJ ET 0.271 0.267 0.267 rg BT 445.715 322.506 Td /F1 9.8 Tf [(. Research suggests that CRC )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(screening may be responsible for approximately half of the declines )] TJ ET 0.267 0.267 0.267 rg BT 319.959 310.601 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 330.801 310.601 Td /F1 9.8 Tf [(. However, uptake of CRC screening recommendations )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(in the U.S. is not optimal. In 2008, only about 62% of men and women aged 50-75 years reported getting the most commonly )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(recommended CRC screening tests, a percentage that varied from 49-75% among states )] TJ ET 0.267 0.267 0.267 rg BT 413.705 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 424.547 286.791 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Several tests are available to identify colorectal cancer and pre-cancerous polyps in asymptomatic individuals. Colonoscopy )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(visually inspects the interior walls of the entire rectum and colon. Performance characteristics \(such as sensitivity and )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(specificity\) of new tests are commonly evaluated in comparison with colonoscopy )] TJ ET 0.267 0.267 0.267 rg BT 378.459 243.577 Td /F1 9.8 Tf [([1] [5])] TJ ET 0.271 0.267 0.267 rg BT 402.853 243.577 Td /F1 9.8 Tf [(. Flexible sigmoidoscopy involves a )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(more limited visual inspection of the distal colon and rectum. Fecal occult blood tests \(FOBTs\), which include conventional )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(guaiac FOBT, high-sensitivity guaiac FOBT, and fecal immunochemical tests \(FITs\), chemically detect small amounts of fecal )] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(blood \(which can originate from pre-cancerous and cancerous colorectal lesions\). CT colonography \(i.e., virtual colonoscopy\) )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(and double-contrast barium enema \(DCBE\) are additional tests, offering enhanced x-ray images of the interior rectum and colon )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(to aid in detecting abnormalities.)] TJ ET BT 26.250 164.649 Td /F1 9.8 Tf [(Fecal \(stool\) DNA tests have been under continuous development over the past several years. These tests are designed to )] TJ ET BT 26.250 152.744 Td /F1 9.8 Tf [(detect in stool samples any number of DNA markers shown to be associated with CRC. ColoSure is the latest example of a )] TJ ET BT 26.250 140.839 Td /F1 9.8 Tf [(clinically available stool DNA test.)] TJ ET BT 26.250 121.434 Td /F4 9.8 Tf [(Clinical Scenario)] TJ ET BT 26.250 102.030 Td /F1 9.8 Tf [(The clinical scenario for fecal DNA testing in general is most often presented as colorectal cancer screening in average-risk )] TJ ET BT 26.250 90.125 Td /F1 9.8 Tf [(individuals.)] TJ ET BT 26.250 70.720 Td /F1 9.8 Tf [(A technical brochure for ColoSure )] TJ ET 0.267 0.267 0.267 rg BT 175.269 70.720 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 186.111 70.720 Td /F1 9.8 Tf [( states that:)] TJ ET BT 26.250 51.315 Td /F1 9.8 Tf [(ColoSure is not intended to replace a colonoscopy in those patients who are willing and able to undergo the procedure. )] TJ ET BT 26.250 39.411 Td /F1 9.8 Tf [(Additionally, while it may be used adjunctively or in patients noncompliant with screening recommendations, it is not a screening )] TJ ET Q q 15.000 684.354 577.500 53.646 re W n 0.267 0.267 0.267 rg BT 15.000 718.042 Td /F2 21.0 Tf [(Fecal DNA testing for Colorectal Cancer Screening: the )] TJ ET BT 15.000 693.094 Td /F2 21.0 Tf [(ColoSure test)] TJ ET Q 0.271 0.267 0.267 rg BT 15.000 675.088 Td /F3 9.8 Tf [(March 22, 2011)] TJ ET BT 82.431 675.088 Td /F3 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg BT 87.306 675.088 Td /F3 9.8 Tf [(Evidence on Genomic Tests)] TJ ET 0.271 0.267 0.267 rg BT 26.250 663.247 Td /F1 9.8 Tf [(, )] TJ ET BT 31.671 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 37.092 663.247 Td /F1 9.8 Tf [(Rene M. Ned)] TJ ET 0.271 0.267 0.267 rg BT 99.950 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 105.371 663.247 Td /F1 9.8 Tf [(Stephanie Melillo)] TJ ET 0.271 0.267 0.267 rg BT 179.608 663.247 Td /F1 9.8 Tf [(, )] TJ ET 0.267 0.267 0.267 rg BT 185.029 663.247 Td /F1 9.8 Tf [(Michael Marrone)] TJ ET 0.271 0.267 0.267 rg BT 26.250 651.342 Td /F1 9.8 Tf [(Ned RM, Melillo S, Marrone M. Fecal DNA testing for Colorectal Cancer Screening: the ColoSure test. PLOS Currents )] TJ ET BT 26.250 639.438 Td /F1 9.8 Tf [(Evidence on Genomic Tests. 2011 Mar 22 . Edition 1. doi: 10.1371/currents.RRN1220.)] TJ ET q 15.000 25.125 577.500 611.932 re W n 0.271 0.267 0.267 rg BT 26.250 610.335 Td /F4 12.0 Tf [(Abstract)] TJ ET BT 26.250 590.381 Td /F1 9.8 Tf [(Colorectal cancer is the third most common cancer and the second leading cause of cancer-related deaths in the United States. )] TJ ET BT 26.250 578.476 Td /F1 9.8 Tf [(Screening has been shown to be effective in reducing colorectal cancer incidence and mortality. Colonoscopy, sigmoidoscopy, )] TJ ET BT 26.250 566.571 Td /F1 9.8 Tf [(and fecal occult blood tests are all recommended screening tests that have widespread availability. Nevertheless, many people )] TJ ET BT 26.250 554.667 Td /F1 9.8 Tf [(do not receive the evidence-based recommended screening for colorectal cancer. Additional stool-based methods have been )] TJ ET BT 26.250 542.762 Td /F1 9.8 Tf [(developed that offer more options for colorectal cancer screening, including a variety of fecal DNA tests. The only fecal DNA )] TJ ET BT 26.250 530.857 Td /F1 9.8 Tf [(test that is currently available commercially in the United States is ColoSure\(TM\), which is marketed as a non-invasive test that )] TJ ET BT 26.250 518.952 Td /F1 9.8 Tf [(detects an epigenetic marker \(methylated vimentin\) associated with colorectal cancer and pre-cancerous adenomas. We )] TJ ET BT 26.250 507.048 Td /F1 9.8 Tf [(examined the published literature on the analytic validity, clinical validity, and clinical utility of ColoSure and we briefly )] TJ ET BT 26.250 495.143 Td /F1 9.8 Tf [(summarized the current colorectal cancer screening guidelines regarding fecal DNA testing. We also addressed the public )] TJ ET BT 26.250 483.238 Td /F1 9.8 Tf [(health implications of the test and contextual issues surrounding the integration of fecal DNA testing into current colorectal )] TJ ET BT 26.250 471.333 Td /F1 9.8 Tf [(cancer screening strategies. The primary goal was to provide a basic overview of ColoSure and identify gaps in knowledge and )] TJ ET BT 26.250 459.429 Td /F1 9.8 Tf [(evidence that affect the recommendation and adoption of the test in colorectal cancer screening strategies.)] TJ ET BT 26.250 422.826 Td /F4 12.0 Tf [(Application: Screening)] TJ ET BT 26.250 385.674 Td /F4 12.0 Tf [(Background)] TJ ET BT 26.250 365.720 Td /F4 9.8 Tf [(Colorectal Cancer \(CRC\) screening)] TJ ET BT 26.250 346.315 Td /F1 9.8 Tf [(Screening by colonoscopy, sigmoidoscopy and fecal occult blood testing has been shown to prevent colorectal cancer \(CRC\) )] TJ ET BT 26.250 334.410 Td /F1 9.8 Tf [(and to reduce mortality through the detection and removal of pre-cancerous lesions and through the detection of CRC in its )] TJ ET BT 26.250 322.506 Td /F1 9.8 Tf [(early stages )] TJ ET 0.267 0.267 0.267 rg BT 81.523 322.506 Td /F1 9.8 Tf [([1] [2])] TJ ET 0.271 0.267 0.267 rg BT 105.917 322.506 Td /F1 9.8 Tf [(. Indeed, CRC incidence and mortality have been decreasing since 1985 )] TJ ET 0.267 0.267 0.267 rg BT 421.320 322.506 Td /F1 9.8 Tf [([2] [3])] TJ ET 0.271 0.267 0.267 rg BT 445.715 322.506 Td /F1 9.8 Tf [(. Research suggests that CRC )] TJ ET BT 26.250 310.601 Td /F1 9.8 Tf [(screening may be responsible for approximately half of the declines )] TJ ET 0.267 0.267 0.267 rg BT 319.959 310.601 Td /F1 9.8 Tf [([2])] TJ ET 0.271 0.267 0.267 rg BT 330.801 310.601 Td /F1 9.8 Tf [(. However, uptake of CRC screening recommendations )] TJ ET BT 26.250 298.696 Td /F1 9.8 Tf [(in the U.S. is not optimal. In 2008, only about 62% of men and women aged 50-75 years reported getting the most commonly )] TJ ET BT 26.250 286.791 Td /F1 9.8 Tf [(recommended CRC screening tests, a percentage that varied from 49-75% among states )] TJ ET 0.267 0.267 0.267 rg BT 413.705 286.791 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 424.547 286.791 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 267.387 Td /F1 9.8 Tf [(Several tests are available to identify colorectal cancer and pre-cancerous polyps in asymptomatic individuals. Colonoscopy )] TJ ET BT 26.250 255.482 Td /F1 9.8 Tf [(visually inspects the interior walls of the entire rectum and colon. Performance characteristics \(such as sensitivity and )] TJ ET BT 26.250 243.577 Td /F1 9.8 Tf [(specificity\) of new tests are commonly evaluated in comparison with colonoscopy )] TJ ET 0.267 0.267 0.267 rg BT 378.459 243.577 Td /F1 9.8 Tf [([1] [5])] TJ ET 0.271 0.267 0.267 rg BT 402.853 243.577 Td /F1 9.8 Tf [(. Flexible sigmoidoscopy involves a )] TJ ET BT 26.250 231.672 Td /F1 9.8 Tf [(more limited visual inspection of the distal colon and rectum. Fecal occult blood tests \(FOBTs\), which include conventional )] TJ ET BT 26.250 219.768 Td /F1 9.8 Tf [(guaiac FOBT, high-sensitivity guaiac FOBT, and fecal immunochemical tests \(FITs\), chemically detect small amounts of fecal )] TJ ET BT 26.250 207.863 Td /F1 9.8 Tf [(blood \(which can originate from pre-cancerous and cancerous colorectal lesions\). CT colonography \(i.e., virtual colonoscopy\) )] TJ ET BT 26.250 195.958 Td /F1 9.8 Tf [(and double-contrast barium enema \(DCBE\) are additional tests, offering enhanced x-ray images of the interior rectum and colon )] TJ ET BT 26.250 184.053 Td /F1 9.8 Tf [(to aid in detecting abnormalities.)] TJ ET BT 26.250 164.649 Td /F1 9.8 Tf [(Fecal \(stool\) DNA tests have been under continuous development over the past several years. These tests are designed to )] TJ ET BT 26.250 152.744 Td /F1 9.8 Tf [(detect in stool samples any number of DNA markers shown to be associated with CRC. 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Colorectal cancer cells, which are shed into the feces, are known to have several )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(genetic alterations which offer an array of molecular targets for DNA-based stool testing for both pre-cancerous and cancerous )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(lesions )] TJ ET 0.267 0.267 0.267 rg BT 59.303 625.929 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 83.697 625.929 Td /F1 9.8 Tf [(. Consequently, fecal DNA has been explored for its potential as a non-invasive CRC screening methodology.)] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(ColoSure is a single-marker test that detects methylation of the vimentin gene. Increased DNA methylation in the promoter )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(region of genes is an epigenetic change that is common in human cancers, including colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 470.080 594.619 Td /F1 9.8 Tf [([9] [10])] TJ ET 0.271 0.267 0.267 rg BT 499.895 594.619 Td /F1 9.8 Tf [(. 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It is thought that the natural history of CRC development takes between 10 and 20 years, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(offering an excellent opportunity for early intervention )] TJ ET 0.267 0.267 0.267 rg BT 258.193 374.143 Td /F1 9.8 Tf [([1] [21])] TJ ET 0.271 0.267 0.267 rg BT 288.008 374.143 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 354.738 Td /F1 9.8 Tf [(Three types of tests \(colonoscopy, flexible sigmoidoscopy, and fecal occult blood tests\) are currently recommended as evidence-)] TJ ET BT 26.250 342.834 Td /F1 9.8 Tf [(based CRC screening options by the U.S. Preventive Services Task Force )] TJ ET 0.267 0.267 0.267 rg BT 349.745 342.834 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 360.587 342.834 Td /F1 9.8 Tf [(. However, only a modest percentage of adults )] TJ ET BT 26.250 330.929 Td /F1 9.8 Tf [(meet the recommended CRC screening guidelines )] TJ ET 0.267 0.267 0.267 rg BT 247.331 330.929 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 258.173 330.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 311.524 Td /F1 9.8 Tf [(Stool-based DNA tests are suggested by some experts as another option for CRC screening. However, these tests are under )] TJ ET BT 26.250 299.619 Td /F1 9.8 Tf [(rapid development and research to establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) )] TJ ET BT 26.250 287.715 Td /F1 9.8 Tf [(population is needed before any fecal DNA test can be integrated into current CRC screening strategies. We now examine )] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(these factors for the ColoSure test based on the current literature.)] TJ ET BT 26.250 256.405 Td /F4 9.8 Tf [(Published Reviews, Recommendations and Guidelines \(see Table 1 below\))] TJ ET BT 26.250 237.000 Td /F5 9.8 Tf [(Important Note: The following groups considered fecal DNA testing in general, but largely based their )] TJ ET BT 26.250 225.096 Td /F5 9.8 Tf [(recommendations and guidelines on published research relevant to stool DNA tests that are no longer commercially )] TJ ET BT 26.250 213.191 Td /F5 9.8 Tf [(available.)] TJ ET BT 26.250 193.786 Td /F4 9.8 Tf [(Systematic evidence reviews)] TJ ET BT 26.250 174.381 Td /F1 9.8 Tf [(The Agency for Healthcare Research and Quality \(AHRQ\) commissioned an evidence report/technology assessment on )] TJ ET BT 26.250 162.477 Td /F1 9.8 Tf [(enhancing the use and quality of CRC screening )] TJ ET 0.267 0.267 0.267 rg BT 238.147 162.477 Td /F1 9.8 Tf [([22] [23])] TJ ET 0.271 0.267 0.267 rg BT 273.383 162.477 Td /F1 9.8 Tf [(. They found no reliable data among the included studies concerning )] TJ ET BT 26.250 150.572 Td /F1 9.8 Tf [(the trends in use or quality \(evidence of misuse, overuse, or underuse\) of fecal DNA testing.)] TJ ET BT 26.250 131.167 Td /F1 9.8 Tf [(A systematic evidence review was performed that guided the current recommendations on CRC screening by the U.S. )] TJ ET BT 26.250 119.262 Td /F1 9.8 Tf [(Preventive Services Task Force \(USPSTF\) )] TJ ET 0.267 0.267 0.267 rg BT 214.250 119.262 Td /F1 9.8 Tf [([5] [24])] TJ ET 0.271 0.267 0.267 rg BT 244.065 119.262 Td /F1 9.8 Tf [( \(see subsection below\).)] TJ ET BT 26.250 99.858 Td /F4 9.8 Tf [(Recommendations by independent group)] TJ ET BT 26.250 80.453 Td /F1 9.8 Tf [(Fecal DNA testing was considered by the USPSTF in its most recent recommendation statement on CRC screening \(see )] TJ ET BT 549.688 80.453 Td /F4 9.8 Tf [(Table )] TJ ET BT 26.250 68.548 Td /F4 9.8 Tf [(1)] TJ ET BT 31.671 68.548 Td /F1 9.8 Tf [( below\). The USPSTF found insufficient evidence to evaluate the benefits and harms of this kind of testing as a screening )] TJ ET BT 26.250 56.643 Td /F1 9.8 Tf [(modality for CRC \(I statement\) )] TJ ET 0.267 0.267 0.267 rg BT 160.615 56.643 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 171.457 56.643 Td /F1 9.8 Tf [(.)] TJ ET Q q 15.000 27.358 577.500 749.642 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(tool for individuals at increased risk for developing disease.)] TJ ET BT 26.250 748.071 Td /F4 9.8 Tf [(Test Description)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(ColoSure \(Laboratory Corporation of America, https://www.labcorp.com \) is currently the only commercially or clinically )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(available fecal DNA test marketed for CRC screening in the U.S. The at-home test requires that patients collect and mail one )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(whole stool sample. The test was developed by the Laboratory Corporation of America \(LabCorp\), which required licensing )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(intellectual property from Exact Sciences Corporation \( www.exactsciences.com \). As a laboratory-developed \(home-brewed\) )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(test, ColoSure is not subject to regulation by the U.S. Food and Drug Administration \(FDA\) and has not obtained FDA clearance )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(or approval.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(What is the theory behind stool DNA testing? Colorectal cancer cells, which are shed into the feces, are known to have several )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(genetic alterations which offer an array of molecular targets for DNA-based stool testing for both pre-cancerous and cancerous )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(lesions )] TJ ET 0.267 0.267 0.267 rg BT 59.303 625.929 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 83.697 625.929 Td /F1 9.8 Tf [(. Consequently, fecal DNA has been explored for its potential as a non-invasive CRC screening methodology.)] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(ColoSure is a single-marker test that detects methylation of the vimentin gene. Increased DNA methylation in the promoter )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(region of genes is an epigenetic change that is common in human cancers, including colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 470.080 594.619 Td /F1 9.8 Tf [([9] [10])] TJ ET 0.271 0.267 0.267 rg BT 499.895 594.619 Td /F1 9.8 Tf [(. Vimentin is a )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(protein characteristically expressed in cells of mesenchymal origin, such as fibroblasts, macrophages, smooth muscle cells, and )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(endothelial cells. Studies have demonstrated that the vimentin gene is not \(or rarely\) methylated in normal colonic epithelial )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(cells, but is methylated in colorectal cancer and adenomas )] TJ ET 0.267 0.267 0.267 rg BT 281.486 558.905 Td /F1 9.8 Tf [([11] [12] [13])] TJ ET 0.271 0.267 0.267 rg BT 335.695 558.905 Td /F1 9.8 Tf [(. Aberrant methylation of vimentin has been detected in )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(53-83% of colorectal cancer tissue, 50-84% of adenoma samples, and 0-11% of normal colon tissue samples )] TJ ET 0.267 0.267 0.267 rg BT 499.330 547.000 Td /F1 9.8 Tf [([11] [12] [13] [14] )] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [([15])] TJ ET 0.271 0.267 0.267 rg BT 42.513 535.095 Td /F1 9.8 Tf [(, though one preliminary study detected methylated vimentin in 29% of normal colon tissue )] TJ ET 0.267 0.267 0.267 rg BT 435.399 535.095 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 451.662 535.095 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(ColoSure requires a prescription for testing. It is currently available from two sources: LabCorp )] TJ ET 0.267 0.267 0.267 rg BT 435.896 515.691 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 452.159 515.691 Td /F1 9.8 Tf [( and from DNA Directs )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(Genomic Medicine Institutes \(which only offers referrals to physicians who can prescribe the test\) )] TJ ET 0.267 0.267 0.267 rg BT 447.274 503.786 Td /F1 9.8 Tf [([18] [19])] TJ ET 0.271 0.267 0.267 rg BT 482.511 503.786 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 484.381 Td /F4 9.8 Tf [(Public Health Importance)] TJ ET BT 26.250 464.976 Td /F1 9.8 Tf [(Colorectal cancer \(CRC\) is currently the third leading cancer diagnosed in the United States, where the lifetime risk is )] TJ ET BT 26.250 453.072 Td /F1 9.8 Tf [(approximately 5% in the general population )] TJ ET 0.267 0.267 0.267 rg BT 215.927 453.072 Td /F1 9.8 Tf [([3] [7])] TJ ET 0.271 0.267 0.267 rg BT 240.321 453.072 Td /F1 9.8 Tf [(. According to the U.S. Cancer Statistics, ~143,000 cases of CRC occurred in )] TJ ET BT 26.250 441.167 Td /F1 9.8 Tf [(the U.S. in 2007 )] TJ ET 0.267 0.267 0.267 rg BT 98.878 441.167 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 115.141 441.167 Td /F1 9.8 Tf [(. CRC is also the second leading cause of cancer-related deaths in the United States, with approximately )] TJ ET BT 26.250 429.262 Td /F1 9.8 Tf [(53,000 deaths occurring in 2007 )] TJ ET 0.267 0.267 0.267 rg BT 168.249 429.262 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 184.512 429.262 Td /F1 9.8 Tf [(. Approximately half of colorectal cancers are diagnosed at a late stage, when survival is )] TJ ET BT 26.250 417.357 Td /F1 9.8 Tf [(poorer )] TJ ET 0.267 0.267 0.267 rg BT 57.138 417.357 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 67.980 417.357 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 397.953 Td /F1 9.8 Tf [(The most effective way of reducing the risk of developing CRC and of reducing CRC mortality is early detection and removal of )] TJ ET BT 26.250 386.048 Td /F1 9.8 Tf [(pre-cancerous or cancerous lesions. It is thought that the natural history of CRC development takes between 10 and 20 years, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(offering an excellent opportunity for early intervention )] TJ ET 0.267 0.267 0.267 rg BT 258.193 374.143 Td /F1 9.8 Tf [([1] [21])] TJ ET 0.271 0.267 0.267 rg BT 288.008 374.143 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 354.738 Td /F1 9.8 Tf [(Three types of tests \(colonoscopy, flexible sigmoidoscopy, and fecal occult blood tests\) are currently recommended as evidence-)] TJ ET BT 26.250 342.834 Td /F1 9.8 Tf [(based CRC screening options by the U.S. Preventive Services Task Force )] TJ ET 0.267 0.267 0.267 rg BT 349.745 342.834 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 360.587 342.834 Td /F1 9.8 Tf [(. However, only a modest percentage of adults )] TJ ET BT 26.250 330.929 Td /F1 9.8 Tf [(meet the recommended CRC screening guidelines )] TJ ET 0.267 0.267 0.267 rg BT 247.331 330.929 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 258.173 330.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 311.524 Td /F1 9.8 Tf [(Stool-based DNA tests are suggested by some experts as another option for CRC screening. However, these tests are under )] TJ ET BT 26.250 299.619 Td /F1 9.8 Tf [(rapid development and research to establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) )] TJ ET BT 26.250 287.715 Td /F1 9.8 Tf [(population is needed before any fecal DNA test can be integrated into current CRC screening strategies. We now examine )] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(these factors for the ColoSure test based on the current literature.)] TJ ET BT 26.250 256.405 Td /F4 9.8 Tf [(Published Reviews, Recommendations and Guidelines \(see Table 1 below\))] TJ ET BT 26.250 237.000 Td /F5 9.8 Tf [(Important Note: The following groups considered fecal DNA testing in general, but largely based their )] TJ ET BT 26.250 225.096 Td /F5 9.8 Tf [(recommendations and guidelines on published research relevant to stool DNA tests that are no longer commercially )] TJ ET BT 26.250 213.191 Td /F5 9.8 Tf [(available.)] TJ ET BT 26.250 193.786 Td /F4 9.8 Tf [(Systematic evidence reviews)] TJ ET BT 26.250 174.381 Td /F1 9.8 Tf [(The Agency for Healthcare Research and Quality \(AHRQ\) commissioned an evidence report/technology assessment on )] TJ ET BT 26.250 162.477 Td /F1 9.8 Tf [(enhancing the use and quality of CRC screening )] TJ ET 0.267 0.267 0.267 rg BT 238.147 162.477 Td /F1 9.8 Tf [([22] [23])] TJ ET 0.271 0.267 0.267 rg BT 273.383 162.477 Td /F1 9.8 Tf [(. They found no reliable data among the included studies concerning )] TJ ET BT 26.250 150.572 Td /F1 9.8 Tf [(the trends in use or quality \(evidence of misuse, overuse, or underuse\) of fecal DNA testing.)] TJ ET BT 26.250 131.167 Td /F1 9.8 Tf [(A systematic evidence review was performed that guided the current recommendations on CRC screening by the U.S. )] TJ ET BT 26.250 119.262 Td /F1 9.8 Tf [(Preventive Services Task Force \(USPSTF\) )] TJ ET 0.267 0.267 0.267 rg BT 214.250 119.262 Td /F1 9.8 Tf [([5] [24])] TJ ET 0.271 0.267 0.267 rg BT 244.065 119.262 Td /F1 9.8 Tf [( \(see subsection below\).)] TJ ET BT 26.250 99.858 Td /F4 9.8 Tf [(Recommendations by independent group)] TJ ET BT 26.250 80.453 Td /F1 9.8 Tf [(Fecal DNA testing was considered by the USPSTF in its most recent recommendation statement on CRC screening \(see )] TJ ET BT 549.688 80.453 Td /F4 9.8 Tf [(Table )] TJ ET BT 26.250 68.548 Td /F4 9.8 Tf [(1)] TJ ET BT 31.671 68.548 Td /F1 9.8 Tf [( below\). The USPSTF found insufficient evidence to evaluate the benefits and harms of this kind of testing as a screening )] TJ ET BT 26.250 56.643 Td /F1 9.8 Tf [(modality for CRC \(I statement\) )] TJ ET 0.267 0.267 0.267 rg BT 160.615 56.643 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 171.457 56.643 Td /F1 9.8 Tf [(.)] TJ ET Q q 15.000 27.358 577.500 749.642 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F1 9.8 Tf [(tool for individuals at increased risk for developing disease.)] TJ ET BT 26.250 748.071 Td /F4 9.8 Tf [(Test Description)] TJ ET BT 26.250 728.667 Td /F1 9.8 Tf [(ColoSure \(Laboratory Corporation of America, https://www.labcorp.com \) is currently the only commercially or clinically )] TJ ET BT 26.250 716.762 Td /F1 9.8 Tf [(available fecal DNA test marketed for CRC screening in the U.S. The at-home test requires that patients collect and mail one )] TJ ET BT 26.250 704.857 Td /F1 9.8 Tf [(whole stool sample. The test was developed by the Laboratory Corporation of America \(LabCorp\), which required licensing )] TJ ET BT 26.250 692.952 Td /F1 9.8 Tf [(intellectual property from Exact Sciences Corporation \( www.exactsciences.com \). As a laboratory-developed \(home-brewed\) )] TJ ET BT 26.250 681.048 Td /F1 9.8 Tf [(test, ColoSure is not subject to regulation by the U.S. Food and Drug Administration \(FDA\) and has not obtained FDA clearance )] TJ ET BT 26.250 669.143 Td /F1 9.8 Tf [(or approval.)] TJ ET BT 26.250 649.738 Td /F1 9.8 Tf [(What is the theory behind stool DNA testing? Colorectal cancer cells, which are shed into the feces, are known to have several )] TJ ET BT 26.250 637.833 Td /F1 9.8 Tf [(genetic alterations which offer an array of molecular targets for DNA-based stool testing for both pre-cancerous and cancerous )] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(lesions )] TJ ET 0.267 0.267 0.267 rg BT 59.303 625.929 Td /F1 9.8 Tf [([7] [8])] TJ ET 0.271 0.267 0.267 rg BT 83.697 625.929 Td /F1 9.8 Tf [(. Consequently, fecal DNA has been explored for its potential as a non-invasive CRC screening methodology.)] TJ ET BT 26.250 606.524 Td /F1 9.8 Tf [(ColoSure is a single-marker test that detects methylation of the vimentin gene. Increased DNA methylation in the promoter )] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(region of genes is an epigenetic change that is common in human cancers, including colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 470.080 594.619 Td /F1 9.8 Tf [([9] [10])] TJ ET 0.271 0.267 0.267 rg BT 499.895 594.619 Td /F1 9.8 Tf [(. Vimentin is a )] TJ ET BT 26.250 582.714 Td /F1 9.8 Tf [(protein characteristically expressed in cells of mesenchymal origin, such as fibroblasts, macrophages, smooth muscle cells, and )] TJ ET BT 26.250 570.810 Td /F1 9.8 Tf [(endothelial cells. Studies have demonstrated that the vimentin gene is not \(or rarely\) methylated in normal colonic epithelial )] TJ ET BT 26.250 558.905 Td /F1 9.8 Tf [(cells, but is methylated in colorectal cancer and adenomas )] TJ ET 0.267 0.267 0.267 rg BT 281.486 558.905 Td /F1 9.8 Tf [([11] [12] [13])] TJ ET 0.271 0.267 0.267 rg BT 335.695 558.905 Td /F1 9.8 Tf [(. Aberrant methylation of vimentin has been detected in )] TJ ET BT 26.250 547.000 Td /F1 9.8 Tf [(53-83% of colorectal cancer tissue, 50-84% of adenoma samples, and 0-11% of normal colon tissue samples )] TJ ET 0.267 0.267 0.267 rg BT 499.330 547.000 Td /F1 9.8 Tf [([11] [12] [13] [14] )] TJ ET BT 26.250 535.095 Td /F1 9.8 Tf [([15])] TJ ET 0.271 0.267 0.267 rg BT 42.513 535.095 Td /F1 9.8 Tf [(, though one preliminary study detected methylated vimentin in 29% of normal colon tissue )] TJ ET 0.267 0.267 0.267 rg BT 435.399 535.095 Td /F1 9.8 Tf [([16])] TJ ET 0.271 0.267 0.267 rg BT 451.662 535.095 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 515.691 Td /F1 9.8 Tf [(ColoSure requires a prescription for testing. It is currently available from two sources: LabCorp )] TJ ET 0.267 0.267 0.267 rg BT 435.896 515.691 Td /F1 9.8 Tf [([17])] TJ ET 0.271 0.267 0.267 rg BT 452.159 515.691 Td /F1 9.8 Tf [( and from DNA Directs )] TJ ET BT 26.250 503.786 Td /F1 9.8 Tf [(Genomic Medicine Institutes \(which only offers referrals to physicians who can prescribe the test\) )] TJ ET 0.267 0.267 0.267 rg BT 447.274 503.786 Td /F1 9.8 Tf [([18] [19])] TJ ET 0.271 0.267 0.267 rg BT 482.511 503.786 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 484.381 Td /F4 9.8 Tf [(Public Health Importance)] TJ ET BT 26.250 464.976 Td /F1 9.8 Tf [(Colorectal cancer \(CRC\) is currently the third leading cancer diagnosed in the United States, where the lifetime risk is )] TJ ET BT 26.250 453.072 Td /F1 9.8 Tf [(approximately 5% in the general population )] TJ ET 0.267 0.267 0.267 rg BT 215.927 453.072 Td /F1 9.8 Tf [([3] [7])] TJ ET 0.271 0.267 0.267 rg BT 240.321 453.072 Td /F1 9.8 Tf [(. According to the U.S. Cancer Statistics, ~143,000 cases of CRC occurred in )] TJ ET BT 26.250 441.167 Td /F1 9.8 Tf [(the U.S. in 2007 )] TJ ET 0.267 0.267 0.267 rg BT 98.878 441.167 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 115.141 441.167 Td /F1 9.8 Tf [(. CRC is also the second leading cause of cancer-related deaths in the United States, with approximately )] TJ ET BT 26.250 429.262 Td /F1 9.8 Tf [(53,000 deaths occurring in 2007 )] TJ ET 0.267 0.267 0.267 rg BT 168.249 429.262 Td /F1 9.8 Tf [([20])] TJ ET 0.271 0.267 0.267 rg BT 184.512 429.262 Td /F1 9.8 Tf [(. Approximately half of colorectal cancers are diagnosed at a late stage, when survival is )] TJ ET BT 26.250 417.357 Td /F1 9.8 Tf [(poorer )] TJ ET 0.267 0.267 0.267 rg BT 57.138 417.357 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 67.980 417.357 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 397.953 Td /F1 9.8 Tf [(The most effective way of reducing the risk of developing CRC and of reducing CRC mortality is early detection and removal of )] TJ ET BT 26.250 386.048 Td /F1 9.8 Tf [(pre-cancerous or cancerous lesions. It is thought that the natural history of CRC development takes between 10 and 20 years, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(offering an excellent opportunity for early intervention )] TJ ET 0.267 0.267 0.267 rg BT 258.193 374.143 Td /F1 9.8 Tf [([1] [21])] TJ ET 0.271 0.267 0.267 rg BT 288.008 374.143 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 354.738 Td /F1 9.8 Tf [(Three types of tests \(colonoscopy, flexible sigmoidoscopy, and fecal occult blood tests\) are currently recommended as evidence-)] TJ ET BT 26.250 342.834 Td /F1 9.8 Tf [(based CRC screening options by the U.S. Preventive Services Task Force )] TJ ET 0.267 0.267 0.267 rg BT 349.745 342.834 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 360.587 342.834 Td /F1 9.8 Tf [(. However, only a modest percentage of adults )] TJ ET BT 26.250 330.929 Td /F1 9.8 Tf [(meet the recommended CRC screening guidelines )] TJ ET 0.267 0.267 0.267 rg BT 247.331 330.929 Td /F1 9.8 Tf [([4])] TJ ET 0.271 0.267 0.267 rg BT 258.173 330.929 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 311.524 Td /F1 9.8 Tf [(Stool-based DNA tests are suggested by some experts as another option for CRC screening. However, these tests are under )] TJ ET BT 26.250 299.619 Td /F1 9.8 Tf [(rapid development and research to establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) )] TJ ET BT 26.250 287.715 Td /F1 9.8 Tf [(population is needed before any fecal DNA test can be integrated into current CRC screening strategies. We now examine )] TJ ET BT 26.250 275.810 Td /F1 9.8 Tf [(these factors for the ColoSure test based on the current literature.)] TJ ET BT 26.250 256.405 Td /F4 9.8 Tf [(Published Reviews, Recommendations and Guidelines \(see Table 1 below\))] TJ ET BT 26.250 237.000 Td /F5 9.8 Tf [(Important Note: The following groups considered fecal DNA testing in general, but largely based their )] TJ ET BT 26.250 225.096 Td /F5 9.8 Tf [(recommendations and guidelines on published research relevant to stool DNA tests that are no longer commercially )] TJ ET BT 26.250 213.191 Td /F5 9.8 Tf [(available.)] TJ ET BT 26.250 193.786 Td /F4 9.8 Tf [(Systematic evidence reviews)] TJ ET BT 26.250 174.381 Td /F1 9.8 Tf [(The Agency for Healthcare Research and Quality \(AHRQ\) commissioned an evidence report/technology assessment on )] TJ ET BT 26.250 162.477 Td /F1 9.8 Tf [(enhancing the use and quality of CRC screening )] TJ ET 0.267 0.267 0.267 rg BT 238.147 162.477 Td /F1 9.8 Tf [([22] [23])] TJ ET 0.271 0.267 0.267 rg BT 273.383 162.477 Td /F1 9.8 Tf [(. They found no reliable data among the included studies concerning )] TJ ET BT 26.250 150.572 Td /F1 9.8 Tf [(the trends in use or quality \(evidence of misuse, overuse, or underuse\) of fecal DNA testing.)] TJ ET BT 26.250 131.167 Td /F1 9.8 Tf [(A systematic evidence review was performed that guided the current recommendations on CRC screening by the U.S. )] TJ ET BT 26.250 119.262 Td /F1 9.8 Tf [(Preventive Services Task Force \(USPSTF\) )] TJ ET 0.267 0.267 0.267 rg BT 214.250 119.262 Td /F1 9.8 Tf [([5] [24])] TJ ET 0.271 0.267 0.267 rg BT 244.065 119.262 Td /F1 9.8 Tf [( \(see subsection below\).)] TJ ET BT 26.250 99.858 Td /F4 9.8 Tf [(Recommendations by independent group)] TJ ET BT 26.250 80.453 Td /F1 9.8 Tf [(Fecal DNA testing was considered by the USPSTF in its most recent recommendation statement on CRC screening \(see )] TJ ET BT 549.688 80.453 Td /F4 9.8 Tf [(Table )] TJ ET BT 26.250 68.548 Td /F4 9.8 Tf [(1)] TJ ET BT 31.671 68.548 Td /F1 9.8 Tf [( below\). 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Stool DNA testing in general was recommended for )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(those aged 50 years or older, but the testing interval could not be determined. In 2009, the American College of )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Gastroenterology \(ACG\) published CRC screening guidelines, in which a weak recommendation \(Grade 2B\) was made for stool )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(DNA testing every 3 years for persons 50 years of age or older )] TJ ET 0.267 0.267 0.267 rg BT 299.367 700.452 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 315.630 700.452 Td /F1 9.8 Tf [(. The American Academy of Family Physicians \(AAFP\) )] TJ ET 0.267 0.267 0.267 rg BT 554.027 700.452 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 26.250 688.548 Td /F1 9.8 Tf [(published recommendations in 2010, which deferred to the analysis and findings of the USPSTF. 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Stool DNA testing in general was recommended for )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(those aged 50 years or older, but the testing interval could not be determined. In 2009, the American College of )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Gastroenterology \(ACG\) published CRC screening guidelines, in which a weak recommendation \(Grade 2B\) was made for stool )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(DNA testing every 3 years for persons 50 years of age or older )] TJ ET 0.267 0.267 0.267 rg BT 299.367 700.452 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 315.630 700.452 Td /F1 9.8 Tf [(. The American Academy of Family Physicians \(AAFP\) )] TJ ET 0.267 0.267 0.267 rg BT 554.027 700.452 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 26.250 688.548 Td /F1 9.8 Tf [(published recommendations in 2010, which deferred to the analysis and findings of the USPSTF. 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Routine Colorectal Cancer Screening Guidelines and Recommendations for average-risk adults.)] TJ ET q 426.000 0 0 421.500 26.250 143.833 cm /I6 Do Q BT 26.250 126.810 Td /F1 9.8 Tf [(CTC = CT colonoscopy; DCBE = double-contrast barium enema; FIT = fecal immunochemical test; FOBT = fecal occult blood )] TJ ET BT 26.250 114.905 Td /F1 9.8 Tf [(test; FSIG = flexible sigmoidoscopy; sDNA = stool DNA.)] TJ ET BT 26.250 95.500 Td /F1 9.8 Tf [(NM = not mentioned; NR = Not Recommended. )] TJ ET BT 234.334 99.388 Td /F1 8.7 Tf [(1)] TJ ET BT 239.153 95.500 Td /F1 9.8 Tf [( In combination with high-sensitivity FOBT every 3 years.)] TJ ET BT 26.250 76.095 Td /F4 9.8 Tf [(Evidence Overview)] TJ ET Q q 15.000 34.905 577.500 742.095 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F4 9.8 Tf [(Guidelines by professional)] TJ ET BT 150.875 767.476 Td /F4 9.8 Tf [(groups \(in order by year of publication\))] TJ ET BT 26.250 748.071 Td /F1 9.8 Tf [(A Joint Guideline was published in 2008 by the American Cancer Society, the U.S. Multi-Society Task Force on Colorectal )] TJ ET BT 26.250 736.167 Td /F1 9.8 Tf [(Cancer, and the American College of Radiology \(ACS-USMSTF-ACR\) )] TJ ET 0.267 0.267 0.267 rg BT 331.288 736.167 Td /F1 9.8 Tf [([25])] TJ ET 0.271 0.267 0.267 rg BT 347.551 736.167 Td /F1 9.8 Tf [( . Stool DNA testing in general was recommended for )] TJ ET BT 26.250 724.262 Td /F1 9.8 Tf [(those aged 50 years or older, but the testing interval could not be determined. In 2009, the American College of )] TJ ET BT 26.250 712.357 Td /F1 9.8 Tf [(Gastroenterology \(ACG\) published CRC screening guidelines, in which a weak recommendation \(Grade 2B\) was made for stool )] TJ ET BT 26.250 700.452 Td /F1 9.8 Tf [(DNA testing every 3 years for persons 50 years of age or older )] TJ ET 0.267 0.267 0.267 rg BT 299.367 700.452 Td /F1 9.8 Tf [([26])] TJ ET 0.271 0.267 0.267 rg BT 315.630 700.452 Td /F1 9.8 Tf [(. The American Academy of Family Physicians \(AAFP\) )] TJ ET 0.267 0.267 0.267 rg BT 554.027 700.452 Td /F1 9.8 Tf [([27])] TJ ET 0.271 0.267 0.267 rg BT 26.250 688.548 Td /F1 9.8 Tf [(published recommendations in 2010, which deferred to the analysis and findings of the USPSTF. Also in 2010, the guidelines of )] TJ ET BT 26.250 676.643 Td /F1 9.8 Tf [(the National Comprehensive Cancer Network \(NCCN\) )] TJ ET 0.267 0.267 0.267 rg BT 261.927 676.643 Td /F1 9.8 Tf [([28])] TJ ET 0.271 0.267 0.267 rg BT 278.190 676.643 Td /F1 9.8 Tf [( stated that: 1\) stool DNA testing is not currently considered a first-)] TJ ET BT 26.250 664.738 Td /F1 9.8 Tf [(line screening test except in specific circumstances; and, that 2\) the testing interval is uncertain.)] TJ ET BT 26.250 645.333 Td /F4 9.8 Tf [(Health Plan/Payer policies)] TJ ET BT 26.250 625.929 Td /F1 9.8 Tf [(CRC screening guidelines have been issued by Kaiser Permanente )] TJ ET 0.267 0.267 0.267 rg BT 319.959 625.929 Td /F1 9.8 Tf [([29])] TJ ET 0.271 0.267 0.267 rg BT 336.222 625.929 Td /F1 9.8 Tf [(, Aetna, Inc. )] TJ ET 0.267 0.267 0.267 rg BT 390.968 625.929 Td /F1 9.8 Tf [([30])] TJ ET 0.271 0.267 0.267 rg BT 407.231 625.929 Td /F1 9.8 Tf [(, and United Healthcare Group )] TJ ET 0.267 0.267 0.267 rg BT 542.171 625.929 Td /F1 9.8 Tf [([31])] TJ ET BT 558.434 625.929 Td /F1 9.8 Tf [([32])] TJ ET 0.271 0.267 0.267 rg BT 574.697 625.929 Td /F1 9.8 Tf [(, )] TJ ET BT 26.250 614.024 Td /F1 9.8 Tf [(all of which describe fecal DNA screening as experimental and not recommended for use.)] TJ ET BT 26.250 594.619 Td /F1 9.8 Tf [(A summary of all mentioned recommendations and guidelines appear in Table 1 below.)] TJ ET BT 26.250 575.214 Td /F4 9.8 Tf [(Table 1. Routine Colorectal Cancer Screening Guidelines and Recommendations for average-risk adults.)] TJ ET q 426.000 0 0 421.500 26.250 143.833 cm /I8 Do Q BT 26.250 126.810 Td /F1 9.8 Tf [(CTC = CT colonoscopy; DCBE = double-contrast barium enema; FIT = fecal immunochemical test; FOBT = fecal occult blood )] TJ ET BT 26.250 114.905 Td /F1 9.8 Tf [(test; FSIG = flexible sigmoidoscopy; sDNA = stool DNA.)] TJ ET BT 26.250 95.500 Td /F1 9.8 Tf [(NM = not mentioned; NR = Not Recommended. )] TJ ET BT 234.334 99.388 Td /F1 8.7 Tf [(1)] TJ ET BT 239.153 95.500 Td /F1 9.8 Tf [( In combination with high-sensitivity FOBT every 3 years.)] TJ ET BT 26.250 76.095 Td /F4 9.8 Tf [(Evidence Overview)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(3)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET 0.39 w 1 J 1 j Q endstream endobj 199 0 obj << /Type /Annot /Subtype /Link /A 200 0 R /Border [0 0 0] /H /I /Rect [ 331.2885 735.2648 347.5515 745.1854 ] >> endobj 200 0 obj << /Type /Action >> endobj 201 0 obj << /Type /Annot /Subtype /Link /A 202 0 R /Border [0 0 0] /H /I /Rect [ 299.3670 699.5506 315.6300 709.4712 ] >> endobj 202 0 obj << /Type /Action >> endobj 203 0 obj << /Type /Annot /Subtype /Link /A 204 0 R /Border [0 0 0] /H /I /Rect [ 554.0272 699.5506 570.2903 709.4712 ] >> endobj 204 0 obj << /Type /Action >> endobj 205 0 obj << /Type /Annot /Subtype /Link /A 206 0 R /Border [0 0 0] /H /I /Rect [ 261.9270 675.7411 278.1900 685.6617 ] >> endobj 206 0 obj << /Type /Action >> endobj 207 0 obj << /Type /Annot /Subtype /Link /A 208 0 R /Border [0 0 0] /H /I /Rect [ 319.9590 625.0268 336.2220 634.9474 ] >> endobj 208 0 obj << /Type /Action >> endobj 209 0 obj << /Type /Annot /Subtype /Link /A 210 0 R /Border [0 0 0] /H /I /Rect [ 390.9683 625.0268 407.2312 634.9474 ] >> endobj 210 0 obj << /Type /Action >> endobj 211 0 obj << /Type /Annot /Subtype /Link /A 212 0 R /Border [0 0 0] /H /I /Rect [ 542.1712 625.0268 558.4343 634.9474 ] >> endobj 212 0 obj << /Type /Action >> endobj 213 0 obj << /Type /Annot /Subtype /Link /A 214 0 R /Border [0 0 0] /H /I /Rect [ 558.4343 625.0268 574.6973 634.9474 ] >> endobj 214 0 obj << /Type /Action >> endobj 215 0 obj << /Type /XObject /Subtype /Image /Width 568 /Height 562 /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 1 /Columns 568 /BitsPerComponent 8>> /ColorSpace /DeviceGray /BitsPerComponent 8 /Length 1364>> stream x1 0 =C GA08$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCb8$!1qHCbdz endstream endobj 216 0 obj << /Type /XObject /Subtype /Image /Width 568 /Height 562 /SMask 215 0 R /Filter /FlateDecode /DecodeParms << /Predictor 15 /Colors 3 /Columns 568 /BitsPerComponent 8>> /ColorSpace /DeviceRGB /BitsPerComponent 8 /Length 136995>> stream xu\U?ۗNF@)):g̙ 6clgw* tw罗'S~< L& .'0 I* i R04JaT* jIoO 'p8ZDYY1AZDT655~hAPYYه rRUSScbb_AC !S𖿙{z>2 QZiTe[߷^V:蠃:t TOxZߦr2q;v  6pHܳ ]xG- ."?80?wr(PP?Оbdyc{tl#@ýz:}L@n>ӯH? aw0°EPRo~$񑙱CAjKMvת$?C$WWW5rC!PmcWХm#JKKU*i?tuWKN [}!)C|yAPi>CU#r6w]rΛE#*++_O?=uDEדSyy. 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TWM&I"y8b)quko~%J`-VRtZ,e2KpנN"Zۣ磹,O$U`eYF#mAzU֭R#s!X*]T͎J^4 GpQUPkk hXdw~Wl1\4qDQAO;5ìJ?+dgℍiS--0g1F|z|cl~O?pKG 9k[ iV0 9Ǜ9Gcz0s3f̘1o̘1cYQ1cƌ72*n^ՆƖ٠+g۷OޓXZt>aBF۷ẁk?m:{+&kG{wgveH6f^hoFy79>L1+*3 Iu;ۅ%73aWCU:`;:vz>@u3vcoJMyr肟9{i?&CF8}C~=FꩃYxەL-[OipYQixIg3'߹0&ʮP+&ڠ(ʺ_A=>n)).z%T&`W+": '|'e| ( tj̻Y^=B_{}@YY{ I]VjhI1_u%+ s zBhK ggOOٹdiފ+" 2))ڻiF-0T*ݻAն~n&;4/Y[N3X2B?{UuzZP*OI X@cZ>a-+cܕ8~<4ãUܐ>;y>]ZzZG`_㍇:GNQ+0g SEso8YN' }+yFeQSvljʻ*k)#u/hRN߬lt-Fz'2vX9;y 8Reےb|>:YfX&z SKFN_[KE r^q|A3Pfgψ4ċI{7ЧͰ `T3hٹ+e5kW-yr%kx,lHf,iOEO5 MFsȡ9,8c>}}:>aw_*$gǢUo U<~_@.m9mDm7{])mCbvJ< ER*ڄ;dLo$ޯeV7XV{n ::z;5f$poji깘yּFeu@iZ;£*Cot7ܲV_;vௗ˃tA8xR/M=.(/wWWێYQyX69ԀPױ-QZ1[@^S#C:ٽ+Ʒj;9ĿMiD-F<+\GqEC3/y=6^z5:95=Ċo(̼mi3f̘1c1̊ʌ3f̼јMf*Яg+19mF8K}w9htes3tE!FD LN-(HpahG%Q>/'ou{ϙ-Xq^`3o~yFe=\ /-vnTcu0].bl-t%XP77ܓ5DB߽?:9oj5IQ4e ߬ ཤ+:uo޼cIbQi`2w_l;,cp_ӋZ5|fV_R5t^#Pw%7}QM܁ umT ,$1]&'Nu,v} Gu3b5'f#W@H/43Ϩ4,{nHIֵh~:ӊZo̭nSV[_H * rl"ZiMf_WUzH+;9cK Dlb\Sv!z!MlHMjvL$fpvڸai mQ'{ kWa+? mqvf_o6 1,R޺6oORbgHqv Ò 5|I0ⰵ @ ;a'.b0fEeaJM[tT48A12#>wdS|\rxpqiH]ͣީ}Eps,$Uq9zC7; l%wN}o~{ @*ª_TYצeGȶrR~n5h*Zzb F5GW p+YlY&P$0!mVШ;J[}Ȉ UuG iڗQ.cƦx}aYQiP`۹ٗN;>ɥỀ5)@dG=; noq%BͧSW̝l |0 1  ;ta@gTl= "F-kÉ͕l3ؔ~~aZM OPjEVa3pw}h;*@aA[ pr(dv8Z mcl8t ge\>nr]Elz *pdVB@ڍ{H\skf Ё4ªjhbt$VNʤzK үt ^E&5v~1GPL7|Xtћ <5(* +>÷/G %M2q8K0[y ^kkd`xu>2 n`Ypr_%u$&Gԩ;kvi1UL r#`>q8}F7\lmPJBl%4gjn2+My 4ou$glFG?q;#S`]&tϪULzRc`߮۴%8uC=&Y2 ULRNږ ﮕ|,Q`x.pУ[0YY^0%z)fEeAq}CTNz >)ޮ\Ov!6\ o܀V-pf6";\dwm#FК|yl%@C1 %3ғdQt֓@0j䮯Pk[LAv흃mp@&a H$2AU*:L ] /N tGaإIz=]dp&;*OT Zm92.`A *X]:0  ]H5Uys*0 9G>j[rscd .VQ? zwqN>ga>^1T{[:|gTf^;H~=ԍ_2ƀҤ'yD:קHLg ѽ#i[.Wq5Ĺv34KRwELx+aؿm㵻VPu?ɡSYoʆu7 ~[LC$c|a ԚtZD,F% 1F8JqZ-pxyb Ҡ3ZJFӔDJ$bľ5a,tZ bhS)J++@( hD/S0`J%otU6FQEbkRQꌯH~5cNb4:e)@j0 C;%a؛>7^HW&`8XRD ÿuﱝEb~a@psq>oƌ3f^?b'\}A$x endstream endobj 253 0 obj << /Type /Page /Parent 3 0 R /Annots [ 256 0 R 258 0 R 260 0 R 262 0 R 264 0 R 266 0 R 268 0 R 270 0 R 272 0 R 274 0 R 276 0 R 278 0 R 280 0 R 282 0 R 284 0 R 286 0 R 288 0 R 290 0 R 292 0 R 294 0 R 296 0 R 298 0 R 300 0 R 302 0 R 304 0 R 306 0 R 308 0 R 310 0 R 312 0 R 314 0 R ] /Contents 254 0 R >> endobj 254 0 obj << /Length 61084 >> stream 0.271 0.267 0.267 rg q 15.000 66.045 577.500 710.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F5 9.8 Tf [(We performed literature searches \(through PubMed and Ovid MEDLINE\) that included search terms such as )] TJ ET BT 26.250 755.571 Td /F5 9.8 Tf [(vimentin, fecal DNA, and colorectal cancer.)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(Analytic Validity)] TJ ET BT 101.569 736.167 Td /F4 9.8 Tf [(: )] TJ ET BT 107.526 736.167 Td /F1 9.8 Tf [( Test accuracy and reliability in measuring methylated vimentin \(analytic sensitivity and specificity\).)] TJ ET 0.271 0.267 0.267 RG 40.337 719.730 m 40.337 720.176 40.154 720.620 39.838 720.936 c 39.522 721.252 39.078 721.436 38.631 721.436 c 38.185 721.436 37.741 721.252 37.425 720.936 c 37.109 720.620 36.925 720.176 36.925 719.730 c 36.925 719.283 37.109 718.839 37.425 718.523 c 37.741 718.207 38.185 718.023 38.631 718.023 c 39.078 718.023 39.522 718.207 39.838 718.523 c 40.154 718.839 40.337 719.283 40.337 719.730 c f BT 45.750 716.762 Td /F1 9.8 Tf [(We found no published data on the analytic sensitivity or specificity of the ColoSure test for methylated vimentin.)] TJ ET 40.337 704.075 m 40.337 704.521 40.154 704.965 39.838 705.281 c 39.522 705.597 39.078 705.781 38.631 705.781 c 38.185 705.781 37.741 705.597 37.425 705.281 c 37.109 704.965 36.925 704.521 36.925 704.075 c 36.925 703.628 37.109 703.184 37.425 702.868 c 37.741 702.552 38.185 702.369 38.631 702.369 c 39.078 702.369 39.522 702.552 39.838 702.868 c 40.154 703.184 40.337 703.628 40.337 704.075 c f BT 45.750 701.107 Td /F1 9.8 Tf [(The amount \(total and relative\) of methylated vimentin in stool samples can vary widely in patients with adenoma or )] TJ ET BT 45.750 689.202 Td /F1 9.8 Tf [(colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 122.151 689.202 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 138.414 689.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 676.515 m 40.337 676.962 40.154 677.406 39.838 677.722 c 39.522 678.038 39.078 678.221 38.631 678.221 c 38.185 678.221 37.741 678.038 37.425 677.722 c 37.109 677.406 36.925 676.962 36.925 676.515 c 36.925 676.069 37.109 675.625 37.425 675.309 c 37.741 674.993 38.185 674.809 38.631 674.809 c 39.078 674.809 39.522 674.993 39.838 675.309 c 40.154 675.625 40.337 676.069 40.337 676.515 c f BT 45.750 673.548 Td /F1 9.8 Tf [(The methylation-specific PCR \(MSP\) assay used in the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 347.561 673.548 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 358.403 673.548 Td /F1 9.8 Tf [( may not have adequate sensitivity for detecting )] TJ ET BT 45.750 661.643 Td /F1 9.8 Tf [(methylated vimentin. Researchers have shown an inability to detect methylated vimentin using MSP in CRC patient stool )] TJ ET BT 45.750 649.738 Td /F1 9.8 Tf [(samples \(n = 8\) that contained low concentrations of human DNA. However, these researchers demonstrated that methyl-)] TJ ET BT 45.750 637.833 Td /F1 9.8 Tf [(binding domain protein enrichment prior to MSP increased assay sensitivity )] TJ ET 0.267 0.267 0.267 rg BT 373.038 637.833 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 389.301 637.833 Td /F1 9.8 Tf [(. In addition, a new technology methyl-)] TJ ET BT 45.750 625.929 Td /F1 9.8 Tf [(BEAMing has been developed that enhances the overall technical sensitivity for detecting methylated vimentin by at least )] TJ ET BT 45.750 614.024 Td /F1 9.8 Tf [(62-fold relative to MSP )] TJ ET 0.267 0.267 0.267 rg BT 147.082 614.024 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 163.345 614.024 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 590.869 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 590.869 Td /F1 9.8 Tf [( the analytic validity of the ColoSure test could not be determined from the identified research.)] TJ ET BT 26.250 571.464 Td /F5 9.8 Tf [(Clinical Validity)] TJ ET BT 98.322 571.464 Td /F4 9.8 Tf [(: )] TJ ET BT 104.279 571.464 Td /F1 9.8 Tf [( Test accuracy and reliability in detecting colorectal cancer or adenomas \(clinical sensitivity and specificity; )] TJ ET BT 26.250 559.560 Td /F1 9.8 Tf [(predictive value\).)] TJ ET 40.337 543.122 m 40.337 543.569 40.154 544.013 39.838 544.329 c 39.522 544.645 39.078 544.829 38.631 544.829 c 38.185 544.829 37.741 544.645 37.425 544.329 c 37.109 544.013 36.925 543.569 36.925 543.122 c 36.925 542.676 37.109 542.232 37.425 541.916 c 37.741 541.600 38.185 541.416 38.631 541.416 c 39.078 541.416 39.522 541.600 39.838 541.916 c 40.154 542.232 40.337 542.676 40.337 543.122 c f BT 45.750 540.155 Td /F1 9.8 Tf [(In general, one potential advantage of DNA-based stool tests over FOBTs is the continuous exfoliation of colorectal cells )] TJ ET BT 45.750 528.250 Td /F1 9.8 Tf [(into the feces \(as opposed to occult bleeding, which is intermittent\). This finding possibly increases the sensitivity of stool )] TJ ET BT 45.750 516.345 Td /F1 9.8 Tf [(DNA tests )] TJ ET 0.267 0.267 0.267 rg BT 92.345 516.345 Td /F1 9.8 Tf [([8][35])] TJ ET 0.271 0.267 0.267 rg BT 119.450 516.345 Td /F1 9.8 Tf [(.)] TJ ET 40.337 503.658 m 40.337 504.105 40.154 504.549 39.838 504.865 c 39.522 505.181 39.078 505.365 38.631 505.365 c 38.185 505.365 37.741 505.181 37.425 504.865 c 37.109 504.549 36.925 504.105 36.925 503.658 c 36.925 503.212 37.109 502.768 37.425 502.452 c 37.741 502.136 38.185 501.952 38.631 501.952 c 39.078 501.952 39.522 502.136 39.838 502.452 c 40.154 502.768 40.337 503.212 40.337 503.658 c f BT 45.750 500.691 Td /F1 9.8 Tf [(Six studies relevant to the clinical validity of the ColoSure test were identified )] TJ ET 0.267 0.267 0.267 rg BT 379.015 500.691 Td /F1 9.8 Tf [([11][14][33][36][37][38])] TJ ET 0.271 0.267 0.267 rg BT 476.593 500.691 Td /F1 9.8 Tf [(. These studies are )] TJ ET BT 45.750 488.786 Td /F1 9.8 Tf [(summarized below in Table 2, in which research findings on methylated vimentin as a stand-alone marker are highlighted.)] TJ ET 40.337 476.099 m 40.337 476.545 40.154 476.989 39.838 477.305 c 39.522 477.621 39.078 477.805 38.631 477.805 c 38.185 477.805 37.741 477.621 37.425 477.305 c 37.109 476.989 36.925 476.545 36.925 476.099 c 36.925 475.652 37.109 475.208 37.425 474.892 c 37.741 474.576 38.185 474.393 38.631 474.393 c 39.078 474.393 39.522 474.576 39.838 474.892 c 40.154 475.208 40.337 475.652 40.337 476.099 c f BT 45.750 473.131 Td /F1 9.8 Tf [(All 6 studies were case-control in design, having selected patients known to have CRC confirmed by colonoscopy )] TJ ET BT 45.750 461.226 Td /F1 9.8 Tf [(compared with controls who were negative for CRC after colonoscopy. None of these analyses were conducted )] TJ ET BT 45.750 449.322 Td /F1 9.8 Tf [(prospectively or in a general screening population \(ages 50-75 yrs, average CRC risk\). It is, therefore, important to interpret )] TJ ET BT 45.750 437.417 Td /F1 9.8 Tf [(these observational data with caution, as some methodologists report that case-control studies tend to overestimate )] TJ ET BT 45.750 425.512 Td /F1 9.8 Tf [(screening or diagnostic accuracy due to design-related bias )] TJ ET 0.267 0.267 0.267 rg BT 305.324 425.512 Td /F1 9.8 Tf [([39][40][41])] TJ ET 0.271 0.267 0.267 rg BT 354.113 425.512 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 402.357 Td /F4 9.8 Tf [(Table 2. Summary of the published case-control studies relevant to ColoSure that reported measures of clinical )] TJ ET BT 26.250 390.453 Td /F4 9.8 Tf [(validity using fecal DNA testing in selected populations)] TJ ET 1.000 1.000 1.000 rg 26.250 66.045 555.000 314.526 re f 0.267 0.267 0.267 rg 26.625 379.447 94.133 0.750 re f 26.625 363.566 0.750 16.631 re f 120.008 379.447 219.805 0.750 re f 120.008 363.566 0.750 16.631 re f 339.063 379.447 68.853 0.750 re f 407.916 379.447 81.738 0.750 re f 339.063 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 369.592 Td /F4 9.8 Tf [(Sensitivity)] TJ ET 0.267 0.267 0.267 rg 488.904 379.447 90.188 0.750 re f 488.904 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 369.592 Td /F4 9.8 Tf [(Specificity)] TJ ET 0.267 0.267 0.267 rg 26.625 363.566 94.133 0.750 re f 26.625 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 353.711 Td /F4 9.8 Tf [(Study)] TJ ET 0.267 0.267 0.267 rg 120.008 363.566 219.805 0.750 re f 120.008 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 353.711 Td /F4 9.8 Tf [(Marker\(s\))] TJ ET 0.267 0.267 0.267 rg 339.063 363.566 69.228 0.750 re f 339.063 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 353.711 Td /F4 9.8 Tf [(CRC)] TJ ET 0.267 0.267 0.267 rg 407.541 363.566 82.113 0.750 re f 407.541 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 351.350 Td /F4 9.8 Tf [(Adenoma)] TJ ET BT 457.212 351.350 Td /F4 8.7 Tf [(1)] TJ ET 0.267 0.267 0.267 rg 488.904 363.566 90.188 0.750 re f 488.904 344.734 0.750 19.582 re f 26.625 344.734 93.758 0.750 re f 120.383 344.734 219.055 0.750 re f 339.438 344.734 68.478 0.750 re f 407.916 344.734 81.363 0.750 re f 489.279 344.734 89.813 0.750 re f 26.625 343.984 0.750 1.500 re f 26.625 343.984 94.133 0.750 re f 26.625 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 334.129 Td /F4 9.8 Tf [(Chen 2005)] TJ ET 0.267 0.267 0.267 rg BT 80.644 334.129 Td /F4 9.8 Tf [([11])] TJ ET 0.573 0.816 0.314 rg 120.383 328.477 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 343.984 219.805 0.750 re f 120.008 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 334.129 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 334.129 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 328.477 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 343.984 69.228 0.750 re f 339.063 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 334.129 Td /F1 9.8 Tf [(46% \(43/94\))] TJ ET 0.573 0.816 0.314 rg 407.916 328.477 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 343.984 82.113 0.750 re f 407.541 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 334.129 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 328.477 89.438 15.881 re f 0.267 0.267 0.267 rg 488.904 343.984 90.188 0.750 re f 488.904 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 334.129 Td /F1 9.8 Tf [(90% \(178/198\))] TJ ET 0.267 0.267 0.267 rg 26.625 328.102 94.133 0.750 re f 26.625 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 318.247 Td /F4 9.8 Tf [(Itzkowitz 2007)] TJ ET 0.267 0.267 0.267 rg BT 31.875 310.616 Td /F4 9.8 Tf [([38])] TJ ET 0.573 0.816 0.314 rg 120.383 302.014 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 328.102 219.805 0.750 re f 120.008 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 318.247 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 318.247 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 302.014 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 328.102 69.228 0.750 re f 339.063 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 318.247 Td /F1 9.8 Tf [(73% \(29/40\) )] TJ ET BT 344.313 310.821 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 302.014 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 328.102 82.113 0.750 re f 407.541 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 318.247 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 302.014 89.438 26.463 re f 0.267 0.267 0.267 rg 488.904 328.102 90.188 0.750 re f 488.904 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 315.887 Td /F1 9.8 Tf [(87% \(106/122\) )] TJ ET BT 560.815 318.452 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 301.639 94.133 0.750 re f 26.625 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 291.784 Td /F1 9.8 Tf [(\(Phase 1a\))] TJ ET 0.267 0.267 0.267 rg 120.008 301.639 219.805 0.750 re f 120.008 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 291.784 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 301.639 69.228 0.750 re f 339.063 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 291.784 Td /F1 9.8 Tf [(65% \(26/40\) )] TJ ET BT 344.313 284.357 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 301.639 82.113 0.750 re f 407.541 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 291.784 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 301.639 89.813 0.750 re f 578.718 301.639 2.157 0.750 re f 488.904 275.176 0.750 27.213 re f 580.125 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 289.423 Td /F1 9.8 Tf [(93% \(113/122\) )] TJ ET BT 560.815 291.989 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 275.176 94.133 0.750 re f 26.625 248.713 0.750 27.213 re f 120.008 275.176 219.805 0.750 re f 120.008 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 265.321 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 265.321 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 265.321 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 275.176 69.228 0.750 re f 339.063 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 265.321 Td /F1 9.8 Tf [(88% \(35/40\) )] TJ ET BT 344.313 257.894 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 275.176 82.113 0.750 re f 407.541 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 265.321 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 275.176 89.813 0.750 re f 578.718 275.176 2.157 0.750 re f 488.904 248.713 0.750 27.213 re f 580.125 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 262.960 Td /F1 9.8 Tf [(82% \(100/122\) )] TJ ET BT 560.815 265.525 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 248.713 94.133 0.750 re f 26.625 225.200 0.750 24.263 re f 0.271 0.267 0.267 rg BT 31.875 238.858 Td /F4 9.8 Tf [(Itzkowitz 2008)] TJ ET 0.267 0.267 0.267 rg BT 31.875 231.226 Td /F4 9.8 Tf [([37])] TJ ET 120.008 248.713 219.805 0.750 re f 120.008 225.200 0.750 24.263 re f 339.063 248.713 69.228 0.750 re f 339.063 225.200 0.750 24.263 re f 407.541 248.713 82.113 0.750 re f 407.541 225.200 0.750 24.263 re f 488.904 248.713 90.188 0.750 re f 488.904 225.200 0.750 24.263 re f 26.625 225.200 94.133 0.750 re f 26.625 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 215.345 Td /F1 9.8 Tf [(\(Phase 1b\))] TJ ET 0.573 0.816 0.314 rg 120.383 199.112 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 225.200 219.805 0.750 re f 120.008 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 215.345 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 215.345 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 199.112 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 225.200 69.228 0.750 re f 339.063 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 215.345 Td /F1 9.8 Tf [(81% \(34/42\) )] TJ ET BT 344.313 207.918 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 199.112 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 225.200 82.113 0.750 re f 407.541 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 215.345 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 199.112 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 225.200 89.813 0.750 re f 578.718 225.200 2.157 0.750 re f 488.904 198.737 0.750 27.213 re f 580.125 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 212.984 Td /F1 9.8 Tf [(82% \(198/241\) )] TJ ET BT 560.815 215.550 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 198.737 94.133 0.750 re f 26.625 172.274 0.750 27.213 re f 120.008 198.737 219.805 0.750 re f 120.008 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 188.882 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 198.737 69.228 0.750 re f 339.063 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 188.882 Td /F1 9.8 Tf [(60% \(25/42\) )] TJ ET BT 344.313 181.455 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 198.737 82.113 0.750 re f 407.541 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 188.882 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 198.737 89.813 0.750 re f 578.718 198.737 2.157 0.750 re f 488.904 172.274 0.750 27.213 re f 580.125 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 186.521 Td /F1 9.8 Tf [(85% \(205/241\) )] TJ ET BT 560.815 189.086 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 172.274 94.133 0.750 re f 26.625 145.810 0.750 27.213 re f 120.008 172.274 219.805 0.750 re f 120.008 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 162.419 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 162.419 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 162.419 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 172.274 69.228 0.750 re f 339.063 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 162.419 Td /F1 9.8 Tf [(86% \(36/42\) )] TJ ET BT 344.313 154.992 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 172.274 82.113 0.750 re f 407.541 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 162.419 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 172.274 89.813 0.750 re f 578.718 172.274 2.157 0.750 re f 488.904 145.810 0.750 27.213 re f 580.125 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 160.058 Td /F1 9.8 Tf [(73% \(176/241\) )] TJ ET BT 560.815 162.623 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 145.810 94.133 0.750 re f 26.625 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 135.955 Td /F1 9.8 Tf [(\(Combined Data\))] TJ ET 0.573 0.816 0.314 rg 120.383 119.722 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 145.810 219.805 0.750 re f 120.008 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 135.955 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 135.955 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 119.722 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 145.810 69.228 0.750 re f 339.063 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 135.955 Td /F1 9.8 Tf [(77% \(63/82\) )] TJ ET BT 344.313 128.529 Td /F1 8.7 Tf [(2,3)] TJ ET 0.573 0.816 0.314 rg 407.916 119.722 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 145.810 82.113 0.750 re f 407.541 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 135.955 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 119.722 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 145.810 89.813 0.750 re f 578.718 145.810 2.157 0.750 re f 488.904 119.347 0.750 27.213 re f 580.125 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 133.595 Td /F1 9.8 Tf [(83% \( 301/363\) )] TJ ET BT 563.525 136.160 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 119.347 94.133 0.750 re f 26.625 92.884 0.750 27.213 re f 120.008 119.347 219.805 0.750 re f 120.008 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 109.492 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 119.347 69.228 0.750 re f 339.063 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 109.492 Td /F1 9.8 Tf [(48% \(39/82\) )] TJ ET BT 344.313 102.065 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 119.347 82.113 0.750 re f 407.541 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 109.492 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 119.347 89.813 0.750 re f 578.718 119.347 2.157 0.750 re f 488.904 92.884 0.750 27.213 re f 580.125 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 107.131 Td /F1 9.8 Tf [(96% \(348/363\) )] TJ ET BT 560.815 109.697 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 92.884 94.133 0.750 re f 26.625 66.420 94.133 0.750 re f 26.625 66.420 0.750 27.213 re f 120.008 92.884 219.805 0.750 re f 120.008 66.420 219.805 0.750 re f 120.008 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 83.029 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 83.029 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 83.029 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 92.884 69.228 0.750 re f 339.063 66.420 69.228 0.750 re f 339.063 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 83.029 Td /F1 9.8 Tf [(83% \(68/82\) )] TJ ET BT 344.313 75.602 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 92.884 82.113 0.750 re f 407.541 66.420 82.113 0.750 re f 407.541 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 83.029 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 92.884 89.813 0.750 re f 488.904 66.420 89.813 0.750 re f 578.718 92.884 2.157 0.750 re f 578.718 66.420 2.157 0.750 re f 488.904 66.420 0.750 27.213 re f 580.125 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 80.668 Td /F1 9.8 Tf [(82% \(298/363\) )] TJ ET BT 560.815 83.233 Td /F1 8.7 Tf [(2,3)] TJ ET Q q 15.000 66.045 577.500 710.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F5 9.8 Tf [(We performed literature searches \(through PubMed and Ovid MEDLINE\) that included search terms such as )] TJ ET BT 26.250 755.571 Td /F5 9.8 Tf [(vimentin, fecal DNA, and colorectal cancer.)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(Analytic Validity)] TJ ET BT 101.569 736.167 Td /F4 9.8 Tf [(: )] TJ ET BT 107.526 736.167 Td /F1 9.8 Tf [( Test accuracy and reliability in measuring methylated vimentin \(analytic sensitivity and specificity\).)] TJ ET 0.271 0.267 0.267 RG 40.337 719.730 m 40.337 720.176 40.154 720.620 39.838 720.936 c 39.522 721.252 39.078 721.436 38.631 721.436 c 38.185 721.436 37.741 721.252 37.425 720.936 c 37.109 720.620 36.925 720.176 36.925 719.730 c 36.925 719.283 37.109 718.839 37.425 718.523 c 37.741 718.207 38.185 718.023 38.631 718.023 c 39.078 718.023 39.522 718.207 39.838 718.523 c 40.154 718.839 40.337 719.283 40.337 719.730 c f BT 45.750 716.762 Td /F1 9.8 Tf [(We found no published data on the analytic sensitivity or specificity of the ColoSure test for methylated vimentin.)] TJ ET 40.337 704.075 m 40.337 704.521 40.154 704.965 39.838 705.281 c 39.522 705.597 39.078 705.781 38.631 705.781 c 38.185 705.781 37.741 705.597 37.425 705.281 c 37.109 704.965 36.925 704.521 36.925 704.075 c 36.925 703.628 37.109 703.184 37.425 702.868 c 37.741 702.552 38.185 702.369 38.631 702.369 c 39.078 702.369 39.522 702.552 39.838 702.868 c 40.154 703.184 40.337 703.628 40.337 704.075 c f BT 45.750 701.107 Td /F1 9.8 Tf [(The amount \(total and relative\) of methylated vimentin in stool samples can vary widely in patients with adenoma or )] TJ ET BT 45.750 689.202 Td /F1 9.8 Tf [(colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 122.151 689.202 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 138.414 689.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 676.515 m 40.337 676.962 40.154 677.406 39.838 677.722 c 39.522 678.038 39.078 678.221 38.631 678.221 c 38.185 678.221 37.741 678.038 37.425 677.722 c 37.109 677.406 36.925 676.962 36.925 676.515 c 36.925 676.069 37.109 675.625 37.425 675.309 c 37.741 674.993 38.185 674.809 38.631 674.809 c 39.078 674.809 39.522 674.993 39.838 675.309 c 40.154 675.625 40.337 676.069 40.337 676.515 c f BT 45.750 673.548 Td /F1 9.8 Tf [(The methylation-specific PCR \(MSP\) assay used in the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 347.561 673.548 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 358.403 673.548 Td /F1 9.8 Tf [( may not have adequate sensitivity for detecting )] TJ ET BT 45.750 661.643 Td /F1 9.8 Tf [(methylated vimentin. Researchers have shown an inability to detect methylated vimentin using MSP in CRC patient stool )] TJ ET BT 45.750 649.738 Td /F1 9.8 Tf [(samples \(n = 8\) that contained low concentrations of human DNA. However, these researchers demonstrated that methyl-)] TJ ET BT 45.750 637.833 Td /F1 9.8 Tf [(binding domain protein enrichment prior to MSP increased assay sensitivity )] TJ ET 0.267 0.267 0.267 rg BT 373.038 637.833 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 389.301 637.833 Td /F1 9.8 Tf [(. In addition, a new technology methyl-)] TJ ET BT 45.750 625.929 Td /F1 9.8 Tf [(BEAMing has been developed that enhances the overall technical sensitivity for detecting methylated vimentin by at least )] TJ ET BT 45.750 614.024 Td /F1 9.8 Tf [(62-fold relative to MSP )] TJ ET 0.267 0.267 0.267 rg BT 147.082 614.024 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 163.345 614.024 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 590.869 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 590.869 Td /F1 9.8 Tf [( the analytic validity of the ColoSure test could not be determined from the identified research.)] TJ ET BT 26.250 571.464 Td /F5 9.8 Tf [(Clinical Validity)] TJ ET BT 98.322 571.464 Td /F4 9.8 Tf [(: )] TJ ET BT 104.279 571.464 Td /F1 9.8 Tf [( Test accuracy and reliability in detecting colorectal cancer or adenomas \(clinical sensitivity and specificity; )] TJ ET BT 26.250 559.560 Td /F1 9.8 Tf [(predictive value\).)] TJ ET 40.337 543.122 m 40.337 543.569 40.154 544.013 39.838 544.329 c 39.522 544.645 39.078 544.829 38.631 544.829 c 38.185 544.829 37.741 544.645 37.425 544.329 c 37.109 544.013 36.925 543.569 36.925 543.122 c 36.925 542.676 37.109 542.232 37.425 541.916 c 37.741 541.600 38.185 541.416 38.631 541.416 c 39.078 541.416 39.522 541.600 39.838 541.916 c 40.154 542.232 40.337 542.676 40.337 543.122 c f BT 45.750 540.155 Td /F1 9.8 Tf [(In general, one potential advantage of DNA-based stool tests over FOBTs is the continuous exfoliation of colorectal cells )] TJ ET BT 45.750 528.250 Td /F1 9.8 Tf [(into the feces \(as opposed to occult bleeding, which is intermittent\). This finding possibly increases the sensitivity of stool )] TJ ET BT 45.750 516.345 Td /F1 9.8 Tf [(DNA tests )] TJ ET 0.267 0.267 0.267 rg BT 92.345 516.345 Td /F1 9.8 Tf [([8][35])] TJ ET 0.271 0.267 0.267 rg BT 119.450 516.345 Td /F1 9.8 Tf [(.)] TJ ET 40.337 503.658 m 40.337 504.105 40.154 504.549 39.838 504.865 c 39.522 505.181 39.078 505.365 38.631 505.365 c 38.185 505.365 37.741 505.181 37.425 504.865 c 37.109 504.549 36.925 504.105 36.925 503.658 c 36.925 503.212 37.109 502.768 37.425 502.452 c 37.741 502.136 38.185 501.952 38.631 501.952 c 39.078 501.952 39.522 502.136 39.838 502.452 c 40.154 502.768 40.337 503.212 40.337 503.658 c f BT 45.750 500.691 Td /F1 9.8 Tf [(Six studies relevant to the clinical validity of the ColoSure test were identified )] TJ ET 0.267 0.267 0.267 rg BT 379.015 500.691 Td /F1 9.8 Tf [([11][14][33][36][37][38])] TJ ET 0.271 0.267 0.267 rg BT 476.593 500.691 Td /F1 9.8 Tf [(. These studies are )] TJ ET BT 45.750 488.786 Td /F1 9.8 Tf [(summarized below in Table 2, in which research findings on methylated vimentin as a stand-alone marker are highlighted.)] TJ ET 40.337 476.099 m 40.337 476.545 40.154 476.989 39.838 477.305 c 39.522 477.621 39.078 477.805 38.631 477.805 c 38.185 477.805 37.741 477.621 37.425 477.305 c 37.109 476.989 36.925 476.545 36.925 476.099 c 36.925 475.652 37.109 475.208 37.425 474.892 c 37.741 474.576 38.185 474.393 38.631 474.393 c 39.078 474.393 39.522 474.576 39.838 474.892 c 40.154 475.208 40.337 475.652 40.337 476.099 c f BT 45.750 473.131 Td /F1 9.8 Tf [(All 6 studies were case-control in design, having selected patients known to have CRC confirmed by colonoscopy )] TJ ET BT 45.750 461.226 Td /F1 9.8 Tf [(compared with controls who were negative for CRC after colonoscopy. None of these analyses were conducted )] TJ ET BT 45.750 449.322 Td /F1 9.8 Tf [(prospectively or in a general screening population \(ages 50-75 yrs, average CRC risk\). It is, therefore, important to interpret )] TJ ET BT 45.750 437.417 Td /F1 9.8 Tf [(these observational data with caution, as some methodologists report that case-control studies tend to overestimate )] TJ ET BT 45.750 425.512 Td /F1 9.8 Tf [(screening or diagnostic accuracy due to design-related bias )] TJ ET 0.267 0.267 0.267 rg BT 305.324 425.512 Td /F1 9.8 Tf [([39][40][41])] TJ ET 0.271 0.267 0.267 rg BT 354.113 425.512 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 402.357 Td /F4 9.8 Tf [(Table 2. Summary of the published case-control studies relevant to ColoSure that reported measures of clinical )] TJ ET BT 26.250 390.453 Td /F4 9.8 Tf [(validity using fecal DNA testing in selected populations)] TJ ET 1.000 1.000 1.000 rg 26.250 66.045 555.000 314.526 re f 0.267 0.267 0.267 rg 26.625 379.447 94.133 0.750 re f 26.625 363.566 0.750 16.631 re f 120.008 379.447 219.805 0.750 re f 120.008 363.566 0.750 16.631 re f 339.063 379.447 68.853 0.750 re f 407.916 379.447 81.738 0.750 re f 339.063 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 369.592 Td /F4 9.8 Tf [(Sensitivity)] TJ ET 0.267 0.267 0.267 rg 488.904 379.447 90.188 0.750 re f 488.904 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 369.592 Td /F4 9.8 Tf [(Specificity)] TJ ET 0.267 0.267 0.267 rg 26.625 363.566 94.133 0.750 re f 26.625 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 353.711 Td /F4 9.8 Tf [(Study)] TJ ET 0.267 0.267 0.267 rg 120.008 363.566 219.805 0.750 re f 120.008 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 353.711 Td /F4 9.8 Tf [(Marker\(s\))] TJ ET 0.267 0.267 0.267 rg 339.063 363.566 69.228 0.750 re f 339.063 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 353.711 Td /F4 9.8 Tf [(CRC)] TJ ET 0.267 0.267 0.267 rg 407.541 363.566 82.113 0.750 re f 407.541 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 351.350 Td /F4 9.8 Tf [(Adenoma)] TJ ET BT 457.212 351.350 Td /F4 8.7 Tf [(1)] TJ ET 0.267 0.267 0.267 rg 488.904 363.566 90.188 0.750 re f 488.904 344.734 0.750 19.582 re f 26.625 344.734 93.758 0.750 re f 120.383 344.734 219.055 0.750 re f 339.438 344.734 68.478 0.750 re f 407.916 344.734 81.363 0.750 re f 489.279 344.734 89.813 0.750 re f 26.625 343.984 0.750 1.500 re f 26.625 343.984 94.133 0.750 re f 26.625 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 334.129 Td /F4 9.8 Tf [(Chen 2005)] TJ ET 0.267 0.267 0.267 rg BT 80.644 334.129 Td /F4 9.8 Tf [([11])] TJ ET 0.573 0.816 0.314 rg 120.383 328.477 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 343.984 219.805 0.750 re f 120.008 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 334.129 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 334.129 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 328.477 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 343.984 69.228 0.750 re f 339.063 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 334.129 Td /F1 9.8 Tf [(46% \(43/94\))] TJ ET 0.573 0.816 0.314 rg 407.916 328.477 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 343.984 82.113 0.750 re f 407.541 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 334.129 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 328.477 89.438 15.881 re f 0.267 0.267 0.267 rg 488.904 343.984 90.188 0.750 re f 488.904 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 334.129 Td /F1 9.8 Tf [(90% \(178/198\))] TJ ET 0.267 0.267 0.267 rg 26.625 328.102 94.133 0.750 re f 26.625 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 318.247 Td /F4 9.8 Tf [(Itzkowitz 2007)] TJ ET 0.267 0.267 0.267 rg BT 31.875 310.616 Td /F4 9.8 Tf [([38])] TJ ET 0.573 0.816 0.314 rg 120.383 302.014 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 328.102 219.805 0.750 re f 120.008 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 318.247 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 318.247 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 302.014 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 328.102 69.228 0.750 re f 339.063 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 318.247 Td /F1 9.8 Tf [(73% \(29/40\) )] TJ ET BT 344.313 310.821 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 302.014 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 328.102 82.113 0.750 re f 407.541 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 318.247 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 302.014 89.438 26.463 re f 0.267 0.267 0.267 rg 488.904 328.102 90.188 0.750 re f 488.904 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 315.887 Td /F1 9.8 Tf [(87% \(106/122\) )] TJ ET BT 560.815 318.452 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 301.639 94.133 0.750 re f 26.625 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 291.784 Td /F1 9.8 Tf [(\(Phase 1a\))] TJ ET 0.267 0.267 0.267 rg 120.008 301.639 219.805 0.750 re f 120.008 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 291.784 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 301.639 69.228 0.750 re f 339.063 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 291.784 Td /F1 9.8 Tf [(65% \(26/40\) )] TJ ET BT 344.313 284.357 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 301.639 82.113 0.750 re f 407.541 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 291.784 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 301.639 89.813 0.750 re f 578.718 301.639 2.157 0.750 re f 488.904 275.176 0.750 27.213 re f 580.125 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 289.423 Td /F1 9.8 Tf [(93% \(113/122\) )] TJ ET BT 560.815 291.989 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 275.176 94.133 0.750 re f 26.625 248.713 0.750 27.213 re f 120.008 275.176 219.805 0.750 re f 120.008 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 265.321 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 265.321 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 265.321 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 275.176 69.228 0.750 re f 339.063 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 265.321 Td /F1 9.8 Tf [(88% \(35/40\) )] TJ ET BT 344.313 257.894 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 275.176 82.113 0.750 re f 407.541 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 265.321 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 275.176 89.813 0.750 re f 578.718 275.176 2.157 0.750 re f 488.904 248.713 0.750 27.213 re f 580.125 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 262.960 Td /F1 9.8 Tf [(82% \(100/122\) )] TJ ET BT 560.815 265.525 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 248.713 94.133 0.750 re f 26.625 225.200 0.750 24.263 re f 0.271 0.267 0.267 rg BT 31.875 238.858 Td /F4 9.8 Tf [(Itzkowitz 2008)] TJ ET 0.267 0.267 0.267 rg BT 31.875 231.226 Td /F4 9.8 Tf [([37])] TJ ET 120.008 248.713 219.805 0.750 re f 120.008 225.200 0.750 24.263 re f 339.063 248.713 69.228 0.750 re f 339.063 225.200 0.750 24.263 re f 407.541 248.713 82.113 0.750 re f 407.541 225.200 0.750 24.263 re f 488.904 248.713 90.188 0.750 re f 488.904 225.200 0.750 24.263 re f 26.625 225.200 94.133 0.750 re f 26.625 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 215.345 Td /F1 9.8 Tf [(\(Phase 1b\))] TJ ET 0.573 0.816 0.314 rg 120.383 199.112 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 225.200 219.805 0.750 re f 120.008 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 215.345 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 215.345 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 199.112 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 225.200 69.228 0.750 re f 339.063 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 215.345 Td /F1 9.8 Tf [(81% \(34/42\) )] TJ ET BT 344.313 207.918 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 199.112 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 225.200 82.113 0.750 re f 407.541 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 215.345 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 199.112 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 225.200 89.813 0.750 re f 578.718 225.200 2.157 0.750 re f 488.904 198.737 0.750 27.213 re f 580.125 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 212.984 Td /F1 9.8 Tf [(82% \(198/241\) )] TJ ET BT 560.815 215.550 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 198.737 94.133 0.750 re f 26.625 172.274 0.750 27.213 re f 120.008 198.737 219.805 0.750 re f 120.008 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 188.882 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 198.737 69.228 0.750 re f 339.063 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 188.882 Td /F1 9.8 Tf [(60% \(25/42\) )] TJ ET BT 344.313 181.455 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 198.737 82.113 0.750 re f 407.541 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 188.882 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 198.737 89.813 0.750 re f 578.718 198.737 2.157 0.750 re f 488.904 172.274 0.750 27.213 re f 580.125 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 186.521 Td /F1 9.8 Tf [(85% \(205/241\) )] TJ ET BT 560.815 189.086 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 172.274 94.133 0.750 re f 26.625 145.810 0.750 27.213 re f 120.008 172.274 219.805 0.750 re f 120.008 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 162.419 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 162.419 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 162.419 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 172.274 69.228 0.750 re f 339.063 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 162.419 Td /F1 9.8 Tf [(86% \(36/42\) )] TJ ET BT 344.313 154.992 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 172.274 82.113 0.750 re f 407.541 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 162.419 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 172.274 89.813 0.750 re f 578.718 172.274 2.157 0.750 re f 488.904 145.810 0.750 27.213 re f 580.125 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 160.058 Td /F1 9.8 Tf [(73% \(176/241\) )] TJ ET BT 560.815 162.623 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 145.810 94.133 0.750 re f 26.625 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 135.955 Td /F1 9.8 Tf [(\(Combined Data\))] TJ ET 0.573 0.816 0.314 rg 120.383 119.722 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 145.810 219.805 0.750 re f 120.008 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 135.955 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 135.955 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 119.722 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 145.810 69.228 0.750 re f 339.063 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 135.955 Td /F1 9.8 Tf [(77% \(63/82\) )] TJ ET BT 344.313 128.529 Td /F1 8.7 Tf [(2,3)] TJ ET 0.573 0.816 0.314 rg 407.916 119.722 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 145.810 82.113 0.750 re f 407.541 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 135.955 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 119.722 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 145.810 89.813 0.750 re f 578.718 145.810 2.157 0.750 re f 488.904 119.347 0.750 27.213 re f 580.125 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 133.595 Td /F1 9.8 Tf [(83% \( 301/363\) )] TJ ET BT 563.525 136.160 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 119.347 94.133 0.750 re f 26.625 92.884 0.750 27.213 re f 120.008 119.347 219.805 0.750 re f 120.008 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 109.492 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 119.347 69.228 0.750 re f 339.063 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 109.492 Td /F1 9.8 Tf [(48% \(39/82\) )] TJ ET BT 344.313 102.065 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 119.347 82.113 0.750 re f 407.541 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 109.492 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 119.347 89.813 0.750 re f 578.718 119.347 2.157 0.750 re f 488.904 92.884 0.750 27.213 re f 580.125 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 107.131 Td /F1 9.8 Tf [(96% \(348/363\) )] TJ ET BT 560.815 109.697 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 92.884 94.133 0.750 re f 26.625 66.420 94.133 0.750 re f 26.625 66.420 0.750 27.213 re f 120.008 92.884 219.805 0.750 re f 120.008 66.420 219.805 0.750 re f 120.008 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 83.029 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 83.029 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 83.029 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 92.884 69.228 0.750 re f 339.063 66.420 69.228 0.750 re f 339.063 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 83.029 Td /F1 9.8 Tf [(83% \(68/82\) )] TJ ET BT 344.313 75.602 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 92.884 82.113 0.750 re f 407.541 66.420 82.113 0.750 re f 407.541 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 83.029 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 92.884 89.813 0.750 re f 488.904 66.420 89.813 0.750 re f 578.718 92.884 2.157 0.750 re f 578.718 66.420 2.157 0.750 re f 488.904 66.420 0.750 27.213 re f 580.125 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 80.668 Td /F1 9.8 Tf [(82% \(298/363\) )] TJ ET BT 560.815 83.233 Td /F1 8.7 Tf [(2,3)] TJ ET Q q 15.000 66.045 577.500 710.955 re W n 0.271 0.267 0.267 rg BT 26.250 767.476 Td /F5 9.8 Tf [(We performed literature searches \(through PubMed and Ovid MEDLINE\) that included search terms such as )] TJ ET BT 26.250 755.571 Td /F5 9.8 Tf [(vimentin, fecal DNA, and colorectal cancer.)] TJ ET BT 26.250 736.167 Td /F5 9.8 Tf [(Analytic Validity)] TJ ET BT 101.569 736.167 Td /F4 9.8 Tf [(: )] TJ ET BT 107.526 736.167 Td /F1 9.8 Tf [( Test accuracy and reliability in measuring methylated vimentin \(analytic sensitivity and specificity\).)] TJ ET 0.271 0.267 0.267 RG 40.337 719.730 m 40.337 720.176 40.154 720.620 39.838 720.936 c 39.522 721.252 39.078 721.436 38.631 721.436 c 38.185 721.436 37.741 721.252 37.425 720.936 c 37.109 720.620 36.925 720.176 36.925 719.730 c 36.925 719.283 37.109 718.839 37.425 718.523 c 37.741 718.207 38.185 718.023 38.631 718.023 c 39.078 718.023 39.522 718.207 39.838 718.523 c 40.154 718.839 40.337 719.283 40.337 719.730 c f BT 45.750 716.762 Td /F1 9.8 Tf [(We found no published data on the analytic sensitivity or specificity of the ColoSure test for methylated vimentin.)] TJ ET 40.337 704.075 m 40.337 704.521 40.154 704.965 39.838 705.281 c 39.522 705.597 39.078 705.781 38.631 705.781 c 38.185 705.781 37.741 705.597 37.425 705.281 c 37.109 704.965 36.925 704.521 36.925 704.075 c 36.925 703.628 37.109 703.184 37.425 702.868 c 37.741 702.552 38.185 702.369 38.631 702.369 c 39.078 702.369 39.522 702.552 39.838 702.868 c 40.154 703.184 40.337 703.628 40.337 704.075 c f BT 45.750 701.107 Td /F1 9.8 Tf [(The amount \(total and relative\) of methylated vimentin in stool samples can vary widely in patients with adenoma or )] TJ ET BT 45.750 689.202 Td /F1 9.8 Tf [(colorectal cancer )] TJ ET 0.267 0.267 0.267 rg BT 122.151 689.202 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 138.414 689.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 676.515 m 40.337 676.962 40.154 677.406 39.838 677.722 c 39.522 678.038 39.078 678.221 38.631 678.221 c 38.185 678.221 37.741 678.038 37.425 677.722 c 37.109 677.406 36.925 676.962 36.925 676.515 c 36.925 676.069 37.109 675.625 37.425 675.309 c 37.741 674.993 38.185 674.809 38.631 674.809 c 39.078 674.809 39.522 674.993 39.838 675.309 c 40.154 675.625 40.337 676.069 40.337 676.515 c f BT 45.750 673.548 Td /F1 9.8 Tf [(The methylation-specific PCR \(MSP\) assay used in the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 347.561 673.548 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 358.403 673.548 Td /F1 9.8 Tf [( may not have adequate sensitivity for detecting )] TJ ET BT 45.750 661.643 Td /F1 9.8 Tf [(methylated vimentin. Researchers have shown an inability to detect methylated vimentin using MSP in CRC patient stool )] TJ ET BT 45.750 649.738 Td /F1 9.8 Tf [(samples \(n = 8\) that contained low concentrations of human DNA. However, these researchers demonstrated that methyl-)] TJ ET BT 45.750 637.833 Td /F1 9.8 Tf [(binding domain protein enrichment prior to MSP increased assay sensitivity )] TJ ET 0.267 0.267 0.267 rg BT 373.038 637.833 Td /F1 9.8 Tf [([34])] TJ ET 0.271 0.267 0.267 rg BT 389.301 637.833 Td /F1 9.8 Tf [(. In addition, a new technology methyl-)] TJ ET BT 45.750 625.929 Td /F1 9.8 Tf [(BEAMing has been developed that enhances the overall technical sensitivity for detecting methylated vimentin by at least )] TJ ET BT 45.750 614.024 Td /F1 9.8 Tf [(62-fold relative to MSP )] TJ ET 0.267 0.267 0.267 rg BT 147.082 614.024 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 163.345 614.024 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 590.869 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 590.869 Td /F1 9.8 Tf [( the analytic validity of the ColoSure test could not be determined from the identified research.)] TJ ET BT 26.250 571.464 Td /F5 9.8 Tf [(Clinical Validity)] TJ ET BT 98.322 571.464 Td /F4 9.8 Tf [(: )] TJ ET BT 104.279 571.464 Td /F1 9.8 Tf [( Test accuracy and reliability in detecting colorectal cancer or adenomas \(clinical sensitivity and specificity; )] TJ ET BT 26.250 559.560 Td /F1 9.8 Tf [(predictive value\).)] TJ ET 40.337 543.122 m 40.337 543.569 40.154 544.013 39.838 544.329 c 39.522 544.645 39.078 544.829 38.631 544.829 c 38.185 544.829 37.741 544.645 37.425 544.329 c 37.109 544.013 36.925 543.569 36.925 543.122 c 36.925 542.676 37.109 542.232 37.425 541.916 c 37.741 541.600 38.185 541.416 38.631 541.416 c 39.078 541.416 39.522 541.600 39.838 541.916 c 40.154 542.232 40.337 542.676 40.337 543.122 c f BT 45.750 540.155 Td /F1 9.8 Tf [(In general, one potential advantage of DNA-based stool tests over FOBTs is the continuous exfoliation of colorectal cells )] TJ ET BT 45.750 528.250 Td /F1 9.8 Tf [(into the feces \(as opposed to occult bleeding, which is intermittent\). This finding possibly increases the sensitivity of stool )] TJ ET BT 45.750 516.345 Td /F1 9.8 Tf [(DNA tests )] TJ ET 0.267 0.267 0.267 rg BT 92.345 516.345 Td /F1 9.8 Tf [([8][35])] TJ ET 0.271 0.267 0.267 rg BT 119.450 516.345 Td /F1 9.8 Tf [(.)] TJ ET 40.337 503.658 m 40.337 504.105 40.154 504.549 39.838 504.865 c 39.522 505.181 39.078 505.365 38.631 505.365 c 38.185 505.365 37.741 505.181 37.425 504.865 c 37.109 504.549 36.925 504.105 36.925 503.658 c 36.925 503.212 37.109 502.768 37.425 502.452 c 37.741 502.136 38.185 501.952 38.631 501.952 c 39.078 501.952 39.522 502.136 39.838 502.452 c 40.154 502.768 40.337 503.212 40.337 503.658 c f BT 45.750 500.691 Td /F1 9.8 Tf [(Six studies relevant to the clinical validity of the ColoSure test were identified )] TJ ET 0.267 0.267 0.267 rg BT 379.015 500.691 Td /F1 9.8 Tf [([11][14][33][36][37][38])] TJ ET 0.271 0.267 0.267 rg BT 476.593 500.691 Td /F1 9.8 Tf [(. These studies are )] TJ ET BT 45.750 488.786 Td /F1 9.8 Tf [(summarized below in Table 2, in which research findings on methylated vimentin as a stand-alone marker are highlighted.)] TJ ET 40.337 476.099 m 40.337 476.545 40.154 476.989 39.838 477.305 c 39.522 477.621 39.078 477.805 38.631 477.805 c 38.185 477.805 37.741 477.621 37.425 477.305 c 37.109 476.989 36.925 476.545 36.925 476.099 c 36.925 475.652 37.109 475.208 37.425 474.892 c 37.741 474.576 38.185 474.393 38.631 474.393 c 39.078 474.393 39.522 474.576 39.838 474.892 c 40.154 475.208 40.337 475.652 40.337 476.099 c f BT 45.750 473.131 Td /F1 9.8 Tf [(All 6 studies were case-control in design, having selected patients known to have CRC confirmed by colonoscopy )] TJ ET BT 45.750 461.226 Td /F1 9.8 Tf [(compared with controls who were negative for CRC after colonoscopy. None of these analyses were conducted )] TJ ET BT 45.750 449.322 Td /F1 9.8 Tf [(prospectively or in a general screening population \(ages 50-75 yrs, average CRC risk\). It is, therefore, important to interpret )] TJ ET BT 45.750 437.417 Td /F1 9.8 Tf [(these observational data with caution, as some methodologists report that case-control studies tend to overestimate )] TJ ET BT 45.750 425.512 Td /F1 9.8 Tf [(screening or diagnostic accuracy due to design-related bias )] TJ ET 0.267 0.267 0.267 rg BT 305.324 425.512 Td /F1 9.8 Tf [([39][40][41])] TJ ET 0.271 0.267 0.267 rg BT 354.113 425.512 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 402.357 Td /F4 9.8 Tf [(Table 2. Summary of the published case-control studies relevant to ColoSure that reported measures of clinical )] TJ ET BT 26.250 390.453 Td /F4 9.8 Tf [(validity using fecal DNA testing in selected populations)] TJ ET 1.000 1.000 1.000 rg 26.250 66.045 555.000 314.526 re f 0.267 0.267 0.267 rg 26.625 379.447 94.133 0.750 re f 26.625 363.566 0.750 16.631 re f 120.008 379.447 219.805 0.750 re f 120.008 363.566 0.750 16.631 re f 339.063 379.447 68.853 0.750 re f 407.916 379.447 81.738 0.750 re f 339.063 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 369.592 Td /F4 9.8 Tf [(Sensitivity)] TJ ET 0.267 0.267 0.267 rg 488.904 379.447 90.188 0.750 re f 488.904 363.566 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 369.592 Td /F4 9.8 Tf [(Specificity)] TJ ET 0.267 0.267 0.267 rg 26.625 363.566 94.133 0.750 re f 26.625 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 353.711 Td /F4 9.8 Tf [(Study)] TJ ET 0.267 0.267 0.267 rg 120.008 363.566 219.805 0.750 re f 120.008 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 353.711 Td /F4 9.8 Tf [(Marker\(s\))] TJ ET 0.267 0.267 0.267 rg 339.063 363.566 69.228 0.750 re f 339.063 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 353.711 Td /F4 9.8 Tf [(CRC)] TJ ET 0.267 0.267 0.267 rg 407.541 363.566 82.113 0.750 re f 407.541 344.734 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 351.350 Td /F4 9.8 Tf [(Adenoma)] TJ ET BT 457.212 351.350 Td /F4 8.7 Tf [(1)] TJ ET 0.267 0.267 0.267 rg 488.904 363.566 90.188 0.750 re f 488.904 344.734 0.750 19.582 re f 26.625 344.734 93.758 0.750 re f 120.383 344.734 219.055 0.750 re f 339.438 344.734 68.478 0.750 re f 407.916 344.734 81.363 0.750 re f 489.279 344.734 89.813 0.750 re f 26.625 343.984 0.750 1.500 re f 26.625 343.984 94.133 0.750 re f 26.625 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 334.129 Td /F4 9.8 Tf [(Chen 2005)] TJ ET 0.267 0.267 0.267 rg BT 80.644 334.129 Td /F4 9.8 Tf [([11])] TJ ET 0.573 0.816 0.314 rg 120.383 328.477 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 343.984 219.805 0.750 re f 120.008 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 334.129 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 334.129 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 328.477 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 343.984 69.228 0.750 re f 339.063 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 334.129 Td /F1 9.8 Tf [(46% \(43/94\))] TJ ET 0.573 0.816 0.314 rg 407.916 328.477 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 343.984 82.113 0.750 re f 407.541 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 334.129 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 328.477 89.438 15.881 re f 0.267 0.267 0.267 rg 488.904 343.984 90.188 0.750 re f 488.904 328.102 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 334.129 Td /F1 9.8 Tf [(90% \(178/198\))] TJ ET 0.267 0.267 0.267 rg 26.625 328.102 94.133 0.750 re f 26.625 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 318.247 Td /F4 9.8 Tf [(Itzkowitz 2007)] TJ ET 0.267 0.267 0.267 rg BT 31.875 310.616 Td /F4 9.8 Tf [([38])] TJ ET 0.573 0.816 0.314 rg 120.383 302.014 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 328.102 219.805 0.750 re f 120.008 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 318.247 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 318.247 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 302.014 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 328.102 69.228 0.750 re f 339.063 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 318.247 Td /F1 9.8 Tf [(73% \(29/40\) )] TJ ET BT 344.313 310.821 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 302.014 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 328.102 82.113 0.750 re f 407.541 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 318.247 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 302.014 89.438 26.463 re f 0.267 0.267 0.267 rg 488.904 328.102 90.188 0.750 re f 488.904 301.639 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 315.887 Td /F1 9.8 Tf [(87% \(106/122\) )] TJ ET BT 560.815 318.452 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 301.639 94.133 0.750 re f 26.625 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 291.784 Td /F1 9.8 Tf [(\(Phase 1a\))] TJ ET 0.267 0.267 0.267 rg 120.008 301.639 219.805 0.750 re f 120.008 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 291.784 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 301.639 69.228 0.750 re f 339.063 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 291.784 Td /F1 9.8 Tf [(65% \(26/40\) )] TJ ET BT 344.313 284.357 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 301.639 82.113 0.750 re f 407.541 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 291.784 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 301.639 89.813 0.750 re f 578.718 301.639 2.157 0.750 re f 488.904 275.176 0.750 27.213 re f 580.125 275.176 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 289.423 Td /F1 9.8 Tf [(93% \(113/122\) )] TJ ET BT 560.815 291.989 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 275.176 94.133 0.750 re f 26.625 248.713 0.750 27.213 re f 120.008 275.176 219.805 0.750 re f 120.008 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 265.321 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 265.321 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 265.321 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 275.176 69.228 0.750 re f 339.063 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 265.321 Td /F1 9.8 Tf [(88% \(35/40\) )] TJ ET BT 344.313 257.894 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 275.176 82.113 0.750 re f 407.541 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 265.321 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 275.176 89.813 0.750 re f 578.718 275.176 2.157 0.750 re f 488.904 248.713 0.750 27.213 re f 580.125 248.713 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 262.960 Td /F1 9.8 Tf [(82% \(100/122\) )] TJ ET BT 560.815 265.525 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 248.713 94.133 0.750 re f 26.625 225.200 0.750 24.263 re f 0.271 0.267 0.267 rg BT 31.875 238.858 Td /F4 9.8 Tf [(Itzkowitz 2008)] TJ ET 0.267 0.267 0.267 rg BT 31.875 231.226 Td /F4 9.8 Tf [([37])] TJ ET 120.008 248.713 219.805 0.750 re f 120.008 225.200 0.750 24.263 re f 339.063 248.713 69.228 0.750 re f 339.063 225.200 0.750 24.263 re f 407.541 248.713 82.113 0.750 re f 407.541 225.200 0.750 24.263 re f 488.904 248.713 90.188 0.750 re f 488.904 225.200 0.750 24.263 re f 26.625 225.200 94.133 0.750 re f 26.625 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 215.345 Td /F1 9.8 Tf [(\(Phase 1b\))] TJ ET 0.573 0.816 0.314 rg 120.383 199.112 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 225.200 219.805 0.750 re f 120.008 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 215.345 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 215.345 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 199.112 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 225.200 69.228 0.750 re f 339.063 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 215.345 Td /F1 9.8 Tf [(81% \(34/42\) )] TJ ET BT 344.313 207.918 Td /F1 8.7 Tf [(2)] TJ ET 0.573 0.816 0.314 rg 407.916 199.112 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 225.200 82.113 0.750 re f 407.541 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 215.345 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 199.112 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 225.200 89.813 0.750 re f 578.718 225.200 2.157 0.750 re f 488.904 198.737 0.750 27.213 re f 580.125 198.737 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 212.984 Td /F1 9.8 Tf [(82% \(198/241\) )] TJ ET BT 560.815 215.550 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 198.737 94.133 0.750 re f 26.625 172.274 0.750 27.213 re f 120.008 198.737 219.805 0.750 re f 120.008 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 188.882 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 198.737 69.228 0.750 re f 339.063 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 188.882 Td /F1 9.8 Tf [(60% \(25/42\) )] TJ ET BT 344.313 181.455 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 198.737 82.113 0.750 re f 407.541 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 188.882 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 198.737 89.813 0.750 re f 578.718 198.737 2.157 0.750 re f 488.904 172.274 0.750 27.213 re f 580.125 172.274 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 186.521 Td /F1 9.8 Tf [(85% \(205/241\) )] TJ ET BT 560.815 189.086 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 172.274 94.133 0.750 re f 26.625 145.810 0.750 27.213 re f 120.008 172.274 219.805 0.750 re f 120.008 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 162.419 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 162.419 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 162.419 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 172.274 69.228 0.750 re f 339.063 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 162.419 Td /F1 9.8 Tf [(86% \(36/42\) )] TJ ET BT 344.313 154.992 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 172.274 82.113 0.750 re f 407.541 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 162.419 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 172.274 89.813 0.750 re f 578.718 172.274 2.157 0.750 re f 488.904 145.810 0.750 27.213 re f 580.125 145.810 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 160.058 Td /F1 9.8 Tf [(73% \(176/241\) )] TJ ET BT 560.815 162.623 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 26.625 145.810 94.133 0.750 re f 26.625 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 31.875 135.955 Td /F1 9.8 Tf [(\(Combined Data\))] TJ ET 0.573 0.816 0.314 rg 120.383 119.722 219.055 26.463 re f 0.267 0.267 0.267 rg 120.008 145.810 219.805 0.750 re f 120.008 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 135.955 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 135.955 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 119.722 68.478 26.463 re f 0.267 0.267 0.267 rg 339.063 145.810 69.228 0.750 re f 339.063 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 135.955 Td /F1 9.8 Tf [(77% \(63/82\) )] TJ ET BT 344.313 128.529 Td /F1 8.7 Tf [(2,3)] TJ ET 0.573 0.816 0.314 rg 407.916 119.722 81.363 26.463 re f 0.267 0.267 0.267 rg 407.541 145.810 82.113 0.750 re f 407.541 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 135.955 Td /F1 9.8 Tf [()] TJ ET 0.573 0.816 0.314 rg 489.279 119.722 91.221 26.463 re f 0.267 0.267 0.267 rg 488.904 145.810 89.813 0.750 re f 578.718 145.810 2.157 0.750 re f 488.904 119.347 0.750 27.213 re f 580.125 119.347 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 133.595 Td /F1 9.8 Tf [(83% \( 301/363\) )] TJ ET BT 563.525 136.160 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 119.347 94.133 0.750 re f 26.625 92.884 0.750 27.213 re f 120.008 119.347 219.805 0.750 re f 120.008 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 109.492 Td /F1 9.8 Tf [(DY)] TJ ET 0.267 0.267 0.267 rg 339.063 119.347 69.228 0.750 re f 339.063 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 109.492 Td /F1 9.8 Tf [(48% \(39/82\) )] TJ ET BT 344.313 102.065 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 119.347 82.113 0.750 re f 407.541 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 109.492 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 119.347 89.813 0.750 re f 578.718 119.347 2.157 0.750 re f 488.904 92.884 0.750 27.213 re f 580.125 92.884 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 107.131 Td /F1 9.8 Tf [(96% \(348/363\) )] TJ ET BT 560.815 109.697 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 26.625 92.884 94.133 0.750 re f 26.625 66.420 94.133 0.750 re f 26.625 66.420 0.750 27.213 re f 120.008 92.884 219.805 0.750 re f 120.008 66.420 219.805 0.750 re f 120.008 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 125.258 83.029 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 83.029 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 211.955 83.029 Td /F1 9.8 Tf [( or DY)] TJ ET 0.267 0.267 0.267 rg 339.063 92.884 69.228 0.750 re f 339.063 66.420 69.228 0.750 re f 339.063 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 344.313 83.029 Td /F1 9.8 Tf [(83% \(68/82\) )] TJ ET BT 344.313 75.602 Td /F1 8.7 Tf [(2,3)] TJ ET 0.267 0.267 0.267 rg 407.541 92.884 82.113 0.750 re f 407.541 66.420 82.113 0.750 re f 407.541 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 412.791 83.029 Td /F1 9.8 Tf [()] TJ ET 0.267 0.267 0.267 rg 488.904 92.884 89.813 0.750 re f 488.904 66.420 89.813 0.750 re f 578.718 92.884 2.157 0.750 re f 578.718 66.420 2.157 0.750 re f 488.904 66.420 0.750 27.213 re f 580.125 66.420 0.750 27.213 re f 0.271 0.267 0.267 rg BT 494.154 80.668 Td /F1 9.8 Tf [(82% \(298/363\) )] TJ ET BT 560.815 83.233 Td /F1 8.7 Tf [(2,3)] 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0.267 rg BT 31.875 766.770 Td /F4 9.8 Tf [(Ahlquist 2008)] TJ ET 0.267 0.267 0.267 rg BT 95.269 766.770 Td /F4 9.8 Tf [([14])] TJ ET 120.008 776.625 219.805 0.750 re f 120.008 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 125.258 766.770 Td /F1 9.8 Tf [(Test SDT-2 \(point mutations on )] TJ ET BT 263.435 766.770 Td /F6 9.8 Tf [(K-ras)] TJ ET BT 286.728 766.770 Td /F1 9.8 Tf [( , scanned )] TJ ET BT 125.258 759.139 Td /F1 9.8 Tf [(mutator cluster region of )] TJ ET BT 233.093 759.139 Td /F6 9.8 Tf [(APC)] TJ ET BT 253.139 759.139 Td /F1 9.8 Tf [( , methylated )] TJ ET BT 125.258 751.508 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 161.557 751.508 Td /F1 9.8 Tf [( \))] TJ ET 0.267 0.267 0.267 rg 339.063 776.625 69.228 0.750 re f 339.063 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 344.313 764.409 Td /F1 9.8 Tf [(58% \(7/12\) )] TJ ET BT 394.711 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 776.625 82.113 0.750 re f 407.541 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 412.791 764.409 Td /F1 9.8 Tf [(46% \(47/103\) )] TJ ET BT 474.031 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 488.904 776.625 89.813 0.750 re f 578.718 776.625 2.157 0.750 re f 488.904 745.369 0.750 32.006 re f 580.125 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 494.154 766.770 Td /F1 9.8 Tf [(Not calculated)] TJ ET 0.267 0.267 0.267 rg 26.625 745.369 94.133 0.750 re f 26.625 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 735.514 Td /F4 9.8 Tf [(Baek 2009)] TJ ET 0.267 0.267 0.267 rg BT 79.572 735.514 Td /F4 9.8 Tf [([36])] TJ ET 120.008 745.369 219.805 0.750 re f 120.008 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 735.514 Td /F6 9.8 Tf [(mMLH1)] TJ ET 0.267 0.267 0.267 rg 339.063 745.369 69.228 0.750 re f 339.063 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 735.514 Td /F1 9.8 Tf [(30% \(18/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 745.369 82.113 0.750 re f 407.541 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 735.514 Td /F1 9.8 Tf [(12% \(6/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 745.369 89.813 0.750 re f 578.718 745.369 2.157 0.750 re f 488.904 726.537 0.750 19.582 re f 580.125 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 733.153 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 735.718 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 726.537 94.133 0.750 re f 26.625 707.705 0.750 19.582 re f 0.573 0.816 0.314 rg 120.383 708.080 219.055 18.832 re f 0.267 0.267 0.267 rg 120.008 726.537 219.805 0.750 re f 120.008 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 716.682 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 716.682 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 708.080 68.478 18.832 re f 0.267 0.267 0.267 rg 339.063 726.537 69.228 0.750 re f 339.063 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 716.682 Td /F1 9.8 Tf [(38% \(23/60\))] TJ ET 0.573 0.816 0.314 rg 407.916 708.080 81.363 18.832 re f 0.267 0.267 0.267 rg 407.541 726.537 82.113 0.750 re f 407.541 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 716.682 Td /F1 9.8 Tf [(15% \(8/52\))] TJ ET 0.573 0.816 0.314 rg 489.279 708.080 91.221 18.832 re f 0.267 0.267 0.267 rg 488.904 726.537 89.813 0.750 re f 578.718 726.537 2.157 0.750 re f 488.904 707.705 0.750 19.582 re f 580.125 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 714.321 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 716.886 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 707.705 94.133 0.750 re f 26.625 691.823 0.750 16.631 re f 120.008 707.705 219.805 0.750 re f 120.008 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 697.850 Td /F1 9.8 Tf [(MGMT)] TJ ET 0.267 0.267 0.267 rg 339.063 707.705 69.228 0.750 re f 339.063 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 697.850 Td /F1 9.8 Tf [(52% \(31/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 707.705 82.113 0.750 re f 407.541 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 697.850 Td /F1 9.8 Tf [(37% \(19/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 707.705 89.813 0.750 re f 578.718 707.705 2.157 0.750 re f 488.904 691.823 0.750 16.631 re f 580.125 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 697.850 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 691.823 94.133 0.750 re f 26.625 675.942 0.750 16.631 re f 120.008 691.823 219.805 0.750 re f 120.008 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 681.968 Td /F1 9.8 Tf [(All three markers \(combined\))] TJ ET 0.267 0.267 0.267 rg 339.063 691.823 69.228 0.750 re f 339.063 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 681.968 Td /F1 9.8 Tf [(75% \(45/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 691.823 82.113 0.750 re f 407.541 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 681.968 Td /F1 9.8 Tf [(60% \(31/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 691.823 89.813 0.750 re f 578.718 691.823 2.157 0.750 re f 488.904 675.942 0.750 16.631 re f 580.125 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 681.968 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 675.942 94.133 0.750 re f 26.625 660.061 94.133 0.750 re f 26.625 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 666.087 Td /F4 9.8 Tf [(Li 2009)] TJ ET 0.267 0.267 0.267 rg BT 64.937 666.087 Td /F4 9.8 Tf [([33])] TJ ET 0.573 0.816 0.314 rg 120.383 660.436 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 675.942 219.805 0.750 re f 120.008 660.061 219.805 0.750 re f 120.008 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 666.087 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 666.087 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 660.436 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 675.942 69.228 0.750 re f 339.063 660.061 69.228 0.750 re f 339.063 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 666.087 Td /F1 9.8 Tf [(41% \(9/22\))] TJ ET 0.573 0.816 0.314 rg 407.916 660.436 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 675.942 82.113 0.750 re f 407.541 660.061 82.113 0.750 re f 407.541 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 666.087 Td /F1 9.8 Tf [(45% \(9/20\))] TJ ET 0.573 0.816 0.314 rg 489.279 660.436 91.221 15.881 re f 0.267 0.267 0.267 rg 488.904 675.942 89.813 0.750 re f 488.904 660.061 89.813 0.750 re f 578.718 675.942 2.157 0.750 re f 578.718 660.061 2.157 0.750 re f 488.904 660.061 0.750 16.631 re f 580.125 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 666.087 Td /F1 9.8 Tf [(95% \(36/38\))] TJ ET BT 26.250 612.662 Td /F1 9.8 Tf [(DY = refers to a specific test for DNA integrity.)] TJ ET BT 26.250 593.257 Td /F1 9.8 Tf [( Not measured.)] TJ ET BT 26.250 577.741 Td /F1 8.7 Tf [(1)] TJ ET BT 31.069 573.853 Td /F1 9.8 Tf [( Refers to adenomas ? 1 cm.)] TJ ET BT 26.250 558.336 Td /F1 8.7 Tf [(2)] TJ ET BT 31.069 554.448 Td /F1 9.8 Tf [( We calculated the numerator using data presented in the article.)] TJ ET BT 26.250 538.931 Td /F1 8.7 Tf [(3)] TJ ET BT 31.069 535.043 Td /F1 9.8 Tf [( In the study, sensitivity and specificity were calculated using optimal cutpoints based on the combined dataset \(Phases 1a + )] TJ ET BT 26.250 523.138 Td /F1 9.8 Tf [(1b\).)] TJ ET BT 26.250 507.622 Td /F1 8.7 Tf [(4)] TJ ET BT 31.069 503.734 Td /F1 9.8 Tf [( We calculated specificity using data presented in the article.)] TJ ET 0.271 0.267 0.267 RG 40.337 487.296 m 40.337 487.743 40.154 488.187 39.838 488.503 c 39.522 488.819 39.078 489.003 38.631 489.003 c 38.185 489.003 37.741 488.819 37.425 488.503 c 37.109 488.187 36.925 487.743 36.925 487.296 c 36.925 486.850 37.109 486.406 37.425 486.090 c 37.741 485.774 38.185 485.590 38.631 485.590 c 39.078 485.590 39.522 485.774 39.838 486.090 c 40.154 486.406 40.337 486.850 40.337 487.296 c f BT 45.750 484.329 Td /F1 9.8 Tf [(Due to the processes for sample collection, sample preparation, and laboratory analysis, the most relevant findings on )] TJ ET BT 45.750 472.424 Td /F1 9.8 Tf [(ColoSure appear to be contained in the two Itzkowitz, )] TJ ET BT 278.785 472.424 Td /F6 9.8 Tf [(et al. )] TJ ET BT 302.633 472.424 Td /F1 9.8 Tf [(reports )] TJ ET 0.267 0.267 0.267 rg BT 335.686 472.424 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 368.212 472.424 Td /F1 9.8 Tf [(. In these studies, a second assay \(for DNA )] TJ ET BT 45.750 460.519 Td /F1 9.8 Tf [(integrity\) was also examined alone and in combination with methylated vimentin. The combined findings from both phases )] TJ ET BT 45.750 448.615 Td /F1 9.8 Tf [(of the study )] TJ ET 0.267 0.267 0.267 rg BT 98.868 448.615 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 115.131 448.615 Td /F1 9.8 Tf [( suggest a sensitivity for CRC of 77% and a specificity of 83% for methylated vimentin. However, )] TJ ET BT 45.750 436.710 Td /F1 9.8 Tf [(informational materials for ColoSure also reference internal LabCorp data, which, combined with the Itzkowitz, )] TJ ET BT 522.057 436.710 Td /F6 9.8 Tf [(et al.)] TJ ET BT 45.750 424.805 Td /F1 9.8 Tf [(studies, suggest that ColoSure has 72-77% sensitivity and 83-94% specificity for CRC )] TJ ET 0.267 0.267 0.267 rg BT 419.107 424.805 Td /F1 9.8 Tf [([6][17])] TJ ET 0.271 0.267 0.267 rg BT 446.212 424.805 Td /F1 9.8 Tf [(.)] TJ ET 40.337 412.118 m 40.337 412.565 40.154 413.009 39.838 413.325 c 39.522 413.640 39.078 413.824 38.631 413.824 c 38.185 413.824 37.741 413.640 37.425 413.325 c 37.109 413.009 36.925 412.565 36.925 412.118 c 36.925 411.671 37.109 411.227 37.425 410.911 c 37.741 410.596 38.185 410.412 38.631 410.412 c 39.078 410.412 39.522 410.596 39.838 410.911 c 40.154 411.227 40.337 411.671 40.337 412.118 c f BT 45.750 409.150 Td /F1 9.8 Tf [(Itzkowitz, )] TJ ET BT 88.553 409.150 Td /F6 9.8 Tf [(et al.)] TJ ET BT 109.691 409.150 Td /F1 9.8 Tf [( did not specifically enroll patients with adenomas in their study populations )] TJ ET 0.267 0.267 0.267 rg BT 436.462 409.150 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 468.988 409.150 Td /F1 9.8 Tf [(, so the clinical validity of )] TJ ET BT 45.750 397.246 Td /F1 9.8 Tf [(ColoSure for pre-cancerous lesions is unclear.)] TJ ET 40.337 384.559 m 40.337 385.005 40.154 385.449 39.838 385.765 c 39.522 386.081 39.078 386.265 38.631 386.265 c 38.185 386.265 37.741 386.081 37.425 385.765 c 37.109 385.449 36.925 385.005 36.925 384.559 c 36.925 384.112 37.109 383.668 37.425 383.352 c 37.741 383.036 38.185 382.852 38.631 382.852 c 39.078 382.852 39.522 383.036 39.838 383.352 c 40.154 383.668 40.337 384.112 40.337 384.559 c f BT 45.750 381.591 Td /F1 9.8 Tf [(Using a more advanced technical method for detecting methylated vimentin, Li, )] TJ ET BT 389.320 381.591 Td /F6 9.8 Tf [(et al.)] TJ ET BT 410.458 381.591 Td /F1 9.8 Tf [( reported sensitivities of 45% and 41% )] TJ ET BT 45.750 369.686 Td /F1 9.8 Tf [(for detecting adenomas and colorectal cancer, respectively, with ~95% specificity )] TJ ET 0.267 0.267 0.267 rg BT 398.252 369.686 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 414.514 369.686 Td /F1 9.8 Tf [(. This research demonstrates that )] TJ ET BT 45.750 357.781 Td /F1 9.8 Tf [(more sensitive methods of methylated vimentin detection \(such as that in )] TJ ET 0.267 0.267 0.267 rg BT 362.762 357.781 Td /F1 9.8 Tf [([33][34])] TJ ET 0.271 0.267 0.267 rg BT 395.288 357.781 Td /F1 9.8 Tf [(\) would likely affect the clinical validity of )] TJ ET BT 45.750 345.877 Td /F1 9.8 Tf [(ColoSure. Of note, Exact Sciences is in the process of developing more sensitive methods to detect methylated vimentin )] TJ ET 0.267 0.267 0.267 rg BT 45.750 333.972 Td /F1 9.8 Tf [([42])] TJ ET 0.271 0.267 0.267 rg BT 62.013 333.972 Td /F1 9.8 Tf [(.)] TJ ET 40.337 321.285 m 40.337 321.731 40.154 322.175 39.838 322.491 c 39.522 322.807 39.078 322.991 38.631 322.991 c 38.185 322.991 37.741 322.807 37.425 322.491 c 37.109 322.175 36.925 321.731 36.925 321.285 c 36.925 320.838 37.109 320.394 37.425 320.078 c 37.741 319.762 38.185 319.579 38.631 319.579 c 39.078 319.579 39.522 319.762 39.838 320.078 c 40.154 320.394 40.337 320.838 40.337 321.285 c f BT 45.750 318.317 Td /F1 9.8 Tf [(It is unclear how fecal DNA screening using methylated vimentin compares to other established CRC screening tests. A pre-)] TJ ET BT 45.750 306.412 Td /F1 9.8 Tf [(commercial version of the first-generation PreGen-Plus fecal DNA test was directly compared to a guaiac FOBT in a large )] TJ ET BT 45.750 294.508 Td /F1 9.8 Tf [(multi-center study of asymptomatic persons )] TJ ET 0.267 0.267 0.267 rg BT 236.480 294.508 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 252.743 294.508 Td /F1 9.8 Tf [(, but no research has been published directly comparing ColoSure to other )] TJ ET BT 45.750 282.603 Td /F1 9.8 Tf [(CRC screening methods. The SDT-2 test \(which contains methylated vimentin\) has been compared to two guaiac tests )] TJ ET 0.267 0.267 0.267 rg BT 561.077 282.603 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 577.340 282.603 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 259.448 Td /F1 9.8 Tf [(Summary)] TJ ET BT 67.960 259.448 Td /F1 9.8 Tf [(: the clinical validity of methylated vimentin as a biomarker for CRC screening remains to be determined in a general )] TJ ET BT 26.250 247.543 Td /F1 9.8 Tf [(\(average-risk\) screening population. This is re-iterated in the LabCorp technical review for the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 493.343 247.543 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 504.185 247.543 Td /F1 9.8 Tf [(, which states )] TJ ET BT 26.250 235.639 Td /F1 9.8 Tf [(that: The detection rates for general population screening have not been determined.)] TJ ET BT 26.250 216.234 Td /F5 9.8 Tf [(Clinical Utility)] TJ ET BT 90.727 216.234 Td /F4 9.8 Tf [( : )] TJ ET BT 99.394 216.234 Td /F1 9.8 Tf [( Net benefit of test in improving health outcomes)] TJ ET 40.337 199.797 m 40.337 200.243 40.154 200.687 39.838 201.003 c 39.522 201.319 39.078 201.503 38.631 201.503 c 38.185 201.503 37.741 201.319 37.425 201.003 c 37.109 200.687 36.925 200.243 36.925 199.797 c 36.925 199.350 37.109 198.906 37.425 198.590 c 37.741 198.274 38.185 198.091 38.631 198.091 c 39.078 198.091 39.522 198.274 39.838 198.590 c 40.154 198.906 40.337 199.350 40.337 199.797 c f BT 45.750 196.829 Td /F1 9.8 Tf [(The clinical utility of ColoSure for CRC screening has not been established through randomized controlled trials of CRC )] TJ ET BT 45.750 184.924 Td /F1 9.8 Tf [(incidence or mortality outcomes. One ongoing prospective cohort study [NCT01270360] is examining the performance )] TJ ET BT 45.750 173.020 Td /F1 9.8 Tf [(characteristics of both blood and/or stool based molecular DNA markers in identifying CRC in patients with positive FOBT, )] TJ ET BT 45.750 161.115 Td /F1 9.8 Tf [(though it is unclear exactly which DNA markers are being tested. The study also aims to determine the cost-effectiveness )] TJ ET BT 45.750 149.210 Td /F1 9.8 Tf [(of adding fecal DNA testing to the screening algorithm for patients with positive FOBT prior to colonoscopy.)] TJ ET 40.337 136.523 m 40.337 136.970 40.154 137.414 39.838 137.730 c 39.522 138.045 39.078 138.229 38.631 138.229 c 38.185 138.229 37.741 138.045 37.425 137.730 c 37.109 137.414 36.925 136.970 36.925 136.523 c 36.925 136.076 37.109 135.632 37.425 135.316 c 37.741 135.001 38.185 134.817 38.631 134.817 c 39.078 134.817 39.522 135.001 39.838 135.316 c 40.154 135.632 40.337 136.076 40.337 136.523 c f BT 45.750 133.555 Td /F1 9.8 Tf [(ColoSure specifically has not been recommended by independent groups or professional organizations )] TJ ET 0.267 0.267 0.267 rg BT 492.290 133.555 Td /F1 9.8 Tf [([1][25][26][27][28])] TJ ET 0.271 0.267 0.267 rg BT 45.750 121.651 Td /F1 9.8 Tf [(to replace colonoscopy in any patient, regardless of whether they are willing and able to undergo the procedure and )] TJ ET BT 45.750 109.746 Td /F1 9.8 Tf [(regardless of CRC risk level.)] TJ ET 40.337 97.059 m 40.337 97.505 40.154 97.949 39.838 98.265 c 39.522 98.581 39.078 98.765 38.631 98.765 c 38.185 98.765 37.741 98.581 37.425 98.265 c 37.109 97.949 36.925 97.505 36.925 97.059 c 36.925 96.612 37.109 96.168 37.425 95.852 c 37.741 95.536 38.185 95.353 38.631 95.353 c 39.078 95.353 39.522 95.536 39.838 95.852 c 40.154 96.168 40.337 96.612 40.337 97.059 c f BT 45.750 94.091 Td /F1 9.8 Tf [(From the patients perspective, stool DNA testing in general may have some advantages over colonoscopy for CRC )] TJ ET BT 45.750 82.186 Td /F1 9.8 Tf [(screening since it: is non-invasive; does not require a formal health care visit; does not require dietary or medication )] TJ ET BT 45.750 70.282 Td /F1 9.8 Tf [(restrictions, bowel preparation, or sedation; and does not require hours of time for testing and recovery, thus alleviating the )] TJ ET BT 45.750 58.377 Td /F1 9.8 Tf [(need to take leave from normal activities \(such as a job\).)] TJ ET 40.337 45.690 m 40.337 46.136 40.154 46.580 39.838 46.896 c 39.522 47.212 39.078 47.396 38.631 47.396 c 38.185 47.396 37.741 47.212 37.425 46.896 c 37.109 46.580 36.925 46.136 36.925 45.690 c 36.925 45.243 37.109 44.799 37.425 44.483 c 37.741 44.167 38.185 43.983 38.631 43.983 c 39.078 43.983 39.522 44.167 39.838 44.483 c 40.154 44.799 40.337 45.243 40.337 45.690 c f BT 45.750 42.722 Td /F1 9.8 Tf [(From the patients perspective, DNA-based stool tests may offer some advantages over FOBT, which requires multiple )] TJ ET Q q 15.000 28.436 577.500 748.564 re W n 1.000 1.000 1.000 rg 26.250 659.686 555.000 117.314 re f 0.267 0.267 0.267 rg 26.625 776.625 94.133 0.750 re f 26.625 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 31.875 766.770 Td /F4 9.8 Tf [(Ahlquist 2008)] TJ ET 0.267 0.267 0.267 rg BT 95.269 766.770 Td /F4 9.8 Tf [([14])] TJ ET 120.008 776.625 219.805 0.750 re f 120.008 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 125.258 766.770 Td /F1 9.8 Tf [(Test SDT-2 \(point mutations on )] TJ ET BT 263.435 766.770 Td /F6 9.8 Tf [(K-ras)] TJ ET BT 286.728 766.770 Td /F1 9.8 Tf [( , scanned )] TJ ET BT 125.258 759.139 Td /F1 9.8 Tf [(mutator cluster region of )] TJ ET BT 233.093 759.139 Td /F6 9.8 Tf [(APC)] TJ ET BT 253.139 759.139 Td /F1 9.8 Tf [( , methylated )] TJ ET BT 125.258 751.508 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 161.557 751.508 Td /F1 9.8 Tf [( \))] TJ ET 0.267 0.267 0.267 rg 339.063 776.625 69.228 0.750 re f 339.063 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 344.313 764.409 Td /F1 9.8 Tf [(58% \(7/12\) )] TJ ET BT 394.711 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 776.625 82.113 0.750 re f 407.541 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 412.791 764.409 Td /F1 9.8 Tf [(46% \(47/103\) )] TJ ET BT 474.031 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 488.904 776.625 89.813 0.750 re f 578.718 776.625 2.157 0.750 re f 488.904 745.369 0.750 32.006 re f 580.125 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 494.154 766.770 Td /F1 9.8 Tf [(Not calculated)] TJ ET 0.267 0.267 0.267 rg 26.625 745.369 94.133 0.750 re f 26.625 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 735.514 Td /F4 9.8 Tf [(Baek 2009)] TJ ET 0.267 0.267 0.267 rg BT 79.572 735.514 Td /F4 9.8 Tf [([36])] TJ ET 120.008 745.369 219.805 0.750 re f 120.008 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 735.514 Td /F6 9.8 Tf [(mMLH1)] TJ ET 0.267 0.267 0.267 rg 339.063 745.369 69.228 0.750 re f 339.063 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 735.514 Td /F1 9.8 Tf [(30% \(18/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 745.369 82.113 0.750 re f 407.541 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 735.514 Td /F1 9.8 Tf [(12% \(6/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 745.369 89.813 0.750 re f 578.718 745.369 2.157 0.750 re f 488.904 726.537 0.750 19.582 re f 580.125 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 733.153 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 735.718 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 726.537 94.133 0.750 re f 26.625 707.705 0.750 19.582 re f 0.573 0.816 0.314 rg 120.383 708.080 219.055 18.832 re f 0.267 0.267 0.267 rg 120.008 726.537 219.805 0.750 re f 120.008 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 716.682 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 716.682 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 708.080 68.478 18.832 re f 0.267 0.267 0.267 rg 339.063 726.537 69.228 0.750 re f 339.063 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 716.682 Td /F1 9.8 Tf [(38% \(23/60\))] TJ ET 0.573 0.816 0.314 rg 407.916 708.080 81.363 18.832 re f 0.267 0.267 0.267 rg 407.541 726.537 82.113 0.750 re f 407.541 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 716.682 Td /F1 9.8 Tf [(15% \(8/52\))] TJ ET 0.573 0.816 0.314 rg 489.279 708.080 91.221 18.832 re f 0.267 0.267 0.267 rg 488.904 726.537 89.813 0.750 re f 578.718 726.537 2.157 0.750 re f 488.904 707.705 0.750 19.582 re f 580.125 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 714.321 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 716.886 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 707.705 94.133 0.750 re f 26.625 691.823 0.750 16.631 re f 120.008 707.705 219.805 0.750 re f 120.008 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 697.850 Td /F1 9.8 Tf [(MGMT)] TJ ET 0.267 0.267 0.267 rg 339.063 707.705 69.228 0.750 re f 339.063 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 697.850 Td /F1 9.8 Tf [(52% \(31/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 707.705 82.113 0.750 re f 407.541 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 697.850 Td /F1 9.8 Tf [(37% \(19/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 707.705 89.813 0.750 re f 578.718 707.705 2.157 0.750 re f 488.904 691.823 0.750 16.631 re f 580.125 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 697.850 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 691.823 94.133 0.750 re f 26.625 675.942 0.750 16.631 re f 120.008 691.823 219.805 0.750 re f 120.008 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 681.968 Td /F1 9.8 Tf [(All three markers \(combined\))] TJ ET 0.267 0.267 0.267 rg 339.063 691.823 69.228 0.750 re f 339.063 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 681.968 Td /F1 9.8 Tf [(75% \(45/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 691.823 82.113 0.750 re f 407.541 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 681.968 Td /F1 9.8 Tf [(60% \(31/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 691.823 89.813 0.750 re f 578.718 691.823 2.157 0.750 re f 488.904 675.942 0.750 16.631 re f 580.125 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 681.968 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 675.942 94.133 0.750 re f 26.625 660.061 94.133 0.750 re f 26.625 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 666.087 Td /F4 9.8 Tf [(Li 2009)] TJ ET 0.267 0.267 0.267 rg BT 64.937 666.087 Td /F4 9.8 Tf [([33])] TJ ET 0.573 0.816 0.314 rg 120.383 660.436 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 675.942 219.805 0.750 re f 120.008 660.061 219.805 0.750 re f 120.008 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 666.087 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 666.087 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 660.436 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 675.942 69.228 0.750 re f 339.063 660.061 69.228 0.750 re f 339.063 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 666.087 Td /F1 9.8 Tf [(41% \(9/22\))] TJ ET 0.573 0.816 0.314 rg 407.916 660.436 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 675.942 82.113 0.750 re f 407.541 660.061 82.113 0.750 re f 407.541 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 666.087 Td /F1 9.8 Tf [(45% \(9/20\))] TJ ET 0.573 0.816 0.314 rg 489.279 660.436 91.221 15.881 re f 0.267 0.267 0.267 rg 488.904 675.942 89.813 0.750 re f 488.904 660.061 89.813 0.750 re f 578.718 675.942 2.157 0.750 re f 578.718 660.061 2.157 0.750 re f 488.904 660.061 0.750 16.631 re f 580.125 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 666.087 Td /F1 9.8 Tf [(95% \(36/38\))] TJ ET BT 26.250 612.662 Td /F1 9.8 Tf [(DY = refers to a specific test for DNA integrity.)] TJ ET BT 26.250 593.257 Td /F1 9.8 Tf [( Not measured.)] TJ ET BT 26.250 577.741 Td /F1 8.7 Tf [(1)] TJ ET BT 31.069 573.853 Td /F1 9.8 Tf [( Refers to adenomas ? 1 cm.)] TJ ET BT 26.250 558.336 Td /F1 8.7 Tf [(2)] TJ ET BT 31.069 554.448 Td /F1 9.8 Tf [( We calculated the numerator using data presented in the article.)] TJ ET BT 26.250 538.931 Td /F1 8.7 Tf [(3)] TJ ET BT 31.069 535.043 Td /F1 9.8 Tf [( In the study, sensitivity and specificity were calculated using optimal cutpoints based on the combined dataset \(Phases 1a + )] TJ ET BT 26.250 523.138 Td /F1 9.8 Tf [(1b\).)] TJ ET BT 26.250 507.622 Td /F1 8.7 Tf [(4)] TJ ET BT 31.069 503.734 Td /F1 9.8 Tf [( We calculated specificity using data presented in the article.)] TJ ET 0.271 0.267 0.267 RG 40.337 487.296 m 40.337 487.743 40.154 488.187 39.838 488.503 c 39.522 488.819 39.078 489.003 38.631 489.003 c 38.185 489.003 37.741 488.819 37.425 488.503 c 37.109 488.187 36.925 487.743 36.925 487.296 c 36.925 486.850 37.109 486.406 37.425 486.090 c 37.741 485.774 38.185 485.590 38.631 485.590 c 39.078 485.590 39.522 485.774 39.838 486.090 c 40.154 486.406 40.337 486.850 40.337 487.296 c f BT 45.750 484.329 Td /F1 9.8 Tf [(Due to the processes for sample collection, sample preparation, and laboratory analysis, the most relevant findings on )] TJ ET BT 45.750 472.424 Td /F1 9.8 Tf [(ColoSure appear to be contained in the two Itzkowitz, )] TJ ET BT 278.785 472.424 Td /F6 9.8 Tf [(et al. )] TJ ET BT 302.633 472.424 Td /F1 9.8 Tf [(reports )] TJ ET 0.267 0.267 0.267 rg BT 335.686 472.424 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 368.212 472.424 Td /F1 9.8 Tf [(. In these studies, a second assay \(for DNA )] TJ ET BT 45.750 460.519 Td /F1 9.8 Tf [(integrity\) was also examined alone and in combination with methylated vimentin. The combined findings from both phases )] TJ ET BT 45.750 448.615 Td /F1 9.8 Tf [(of the study )] TJ ET 0.267 0.267 0.267 rg BT 98.868 448.615 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 115.131 448.615 Td /F1 9.8 Tf [( suggest a sensitivity for CRC of 77% and a specificity of 83% for methylated vimentin. However, )] TJ ET BT 45.750 436.710 Td /F1 9.8 Tf [(informational materials for ColoSure also reference internal LabCorp data, which, combined with the Itzkowitz, )] TJ ET BT 522.057 436.710 Td /F6 9.8 Tf [(et al.)] TJ ET BT 45.750 424.805 Td /F1 9.8 Tf [(studies, suggest that ColoSure has 72-77% sensitivity and 83-94% specificity for CRC )] TJ ET 0.267 0.267 0.267 rg BT 419.107 424.805 Td /F1 9.8 Tf [([6][17])] TJ ET 0.271 0.267 0.267 rg BT 446.212 424.805 Td /F1 9.8 Tf [(.)] TJ ET 40.337 412.118 m 40.337 412.565 40.154 413.009 39.838 413.325 c 39.522 413.640 39.078 413.824 38.631 413.824 c 38.185 413.824 37.741 413.640 37.425 413.325 c 37.109 413.009 36.925 412.565 36.925 412.118 c 36.925 411.671 37.109 411.227 37.425 410.911 c 37.741 410.596 38.185 410.412 38.631 410.412 c 39.078 410.412 39.522 410.596 39.838 410.911 c 40.154 411.227 40.337 411.671 40.337 412.118 c f BT 45.750 409.150 Td /F1 9.8 Tf [(Itzkowitz, )] TJ ET BT 88.553 409.150 Td /F6 9.8 Tf [(et al.)] TJ ET BT 109.691 409.150 Td /F1 9.8 Tf [( did not specifically enroll patients with adenomas in their study populations )] TJ ET 0.267 0.267 0.267 rg BT 436.462 409.150 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 468.988 409.150 Td /F1 9.8 Tf [(, so the clinical validity of )] TJ ET BT 45.750 397.246 Td /F1 9.8 Tf [(ColoSure for pre-cancerous lesions is unclear.)] TJ ET 40.337 384.559 m 40.337 385.005 40.154 385.449 39.838 385.765 c 39.522 386.081 39.078 386.265 38.631 386.265 c 38.185 386.265 37.741 386.081 37.425 385.765 c 37.109 385.449 36.925 385.005 36.925 384.559 c 36.925 384.112 37.109 383.668 37.425 383.352 c 37.741 383.036 38.185 382.852 38.631 382.852 c 39.078 382.852 39.522 383.036 39.838 383.352 c 40.154 383.668 40.337 384.112 40.337 384.559 c f BT 45.750 381.591 Td /F1 9.8 Tf [(Using a more advanced technical method for detecting methylated vimentin, Li, )] TJ ET BT 389.320 381.591 Td /F6 9.8 Tf [(et al.)] TJ ET BT 410.458 381.591 Td /F1 9.8 Tf [( reported sensitivities of 45% and 41% )] TJ ET BT 45.750 369.686 Td /F1 9.8 Tf [(for detecting adenomas and colorectal cancer, respectively, with ~95% specificity )] TJ ET 0.267 0.267 0.267 rg BT 398.252 369.686 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 414.514 369.686 Td /F1 9.8 Tf [(. This research demonstrates that )] TJ ET BT 45.750 357.781 Td /F1 9.8 Tf [(more sensitive methods of methylated vimentin detection \(such as that in )] TJ ET 0.267 0.267 0.267 rg BT 362.762 357.781 Td /F1 9.8 Tf [([33][34])] TJ ET 0.271 0.267 0.267 rg BT 395.288 357.781 Td /F1 9.8 Tf [(\) would likely affect the clinical validity of )] TJ ET BT 45.750 345.877 Td /F1 9.8 Tf [(ColoSure. Of note, Exact Sciences is in the process of developing more sensitive methods to detect methylated vimentin )] TJ ET 0.267 0.267 0.267 rg BT 45.750 333.972 Td /F1 9.8 Tf [([42])] TJ ET 0.271 0.267 0.267 rg BT 62.013 333.972 Td /F1 9.8 Tf [(.)] TJ ET 40.337 321.285 m 40.337 321.731 40.154 322.175 39.838 322.491 c 39.522 322.807 39.078 322.991 38.631 322.991 c 38.185 322.991 37.741 322.807 37.425 322.491 c 37.109 322.175 36.925 321.731 36.925 321.285 c 36.925 320.838 37.109 320.394 37.425 320.078 c 37.741 319.762 38.185 319.579 38.631 319.579 c 39.078 319.579 39.522 319.762 39.838 320.078 c 40.154 320.394 40.337 320.838 40.337 321.285 c f BT 45.750 318.317 Td /F1 9.8 Tf [(It is unclear how fecal DNA screening using methylated vimentin compares to other established CRC screening tests. A pre-)] TJ ET BT 45.750 306.412 Td /F1 9.8 Tf [(commercial version of the first-generation PreGen-Plus fecal DNA test was directly compared to a guaiac FOBT in a large )] TJ ET BT 45.750 294.508 Td /F1 9.8 Tf [(multi-center study of asymptomatic persons )] TJ ET 0.267 0.267 0.267 rg BT 236.480 294.508 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 252.743 294.508 Td /F1 9.8 Tf [(, but no research has been published directly comparing ColoSure to other )] TJ ET BT 45.750 282.603 Td /F1 9.8 Tf [(CRC screening methods. The SDT-2 test \(which contains methylated vimentin\) has been compared to two guaiac tests )] TJ ET 0.267 0.267 0.267 rg BT 561.077 282.603 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 577.340 282.603 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 259.448 Td /F1 9.8 Tf [(Summary)] TJ ET BT 67.960 259.448 Td /F1 9.8 Tf [(: the clinical validity of methylated vimentin as a biomarker for CRC screening remains to be determined in a general )] TJ ET BT 26.250 247.543 Td /F1 9.8 Tf [(\(average-risk\) screening population. This is re-iterated in the LabCorp technical review for the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 493.343 247.543 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 504.185 247.543 Td /F1 9.8 Tf [(, which states )] TJ ET BT 26.250 235.639 Td /F1 9.8 Tf [(that: The detection rates for general population screening have not been determined.)] TJ ET BT 26.250 216.234 Td /F5 9.8 Tf [(Clinical Utility)] TJ ET BT 90.727 216.234 Td /F4 9.8 Tf [( : )] TJ ET BT 99.394 216.234 Td /F1 9.8 Tf [( Net benefit of test in improving health outcomes)] TJ ET 40.337 199.797 m 40.337 200.243 40.154 200.687 39.838 201.003 c 39.522 201.319 39.078 201.503 38.631 201.503 c 38.185 201.503 37.741 201.319 37.425 201.003 c 37.109 200.687 36.925 200.243 36.925 199.797 c 36.925 199.350 37.109 198.906 37.425 198.590 c 37.741 198.274 38.185 198.091 38.631 198.091 c 39.078 198.091 39.522 198.274 39.838 198.590 c 40.154 198.906 40.337 199.350 40.337 199.797 c f BT 45.750 196.829 Td /F1 9.8 Tf [(The clinical utility of ColoSure for CRC screening has not been established through randomized controlled trials of CRC )] TJ ET BT 45.750 184.924 Td /F1 9.8 Tf [(incidence or mortality outcomes. One ongoing prospective cohort study [NCT01270360] is examining the performance )] TJ ET BT 45.750 173.020 Td /F1 9.8 Tf [(characteristics of both blood and/or stool based molecular DNA markers in identifying CRC in patients with positive FOBT, )] TJ ET BT 45.750 161.115 Td /F1 9.8 Tf [(though it is unclear exactly which DNA markers are being tested. The study also aims to determine the cost-effectiveness )] TJ ET BT 45.750 149.210 Td /F1 9.8 Tf [(of adding fecal DNA testing to the screening algorithm for patients with positive FOBT prior to colonoscopy.)] TJ ET 40.337 136.523 m 40.337 136.970 40.154 137.414 39.838 137.730 c 39.522 138.045 39.078 138.229 38.631 138.229 c 38.185 138.229 37.741 138.045 37.425 137.730 c 37.109 137.414 36.925 136.970 36.925 136.523 c 36.925 136.076 37.109 135.632 37.425 135.316 c 37.741 135.001 38.185 134.817 38.631 134.817 c 39.078 134.817 39.522 135.001 39.838 135.316 c 40.154 135.632 40.337 136.076 40.337 136.523 c f BT 45.750 133.555 Td /F1 9.8 Tf [(ColoSure specifically has not been recommended by independent groups or professional organizations )] TJ ET 0.267 0.267 0.267 rg BT 492.290 133.555 Td /F1 9.8 Tf [([1][25][26][27][28])] TJ ET 0.271 0.267 0.267 rg BT 45.750 121.651 Td /F1 9.8 Tf [(to replace colonoscopy in any patient, regardless of whether they are willing and able to undergo the procedure and )] TJ ET BT 45.750 109.746 Td /F1 9.8 Tf [(regardless of CRC risk level.)] TJ ET 40.337 97.059 m 40.337 97.505 40.154 97.949 39.838 98.265 c 39.522 98.581 39.078 98.765 38.631 98.765 c 38.185 98.765 37.741 98.581 37.425 98.265 c 37.109 97.949 36.925 97.505 36.925 97.059 c 36.925 96.612 37.109 96.168 37.425 95.852 c 37.741 95.536 38.185 95.353 38.631 95.353 c 39.078 95.353 39.522 95.536 39.838 95.852 c 40.154 96.168 40.337 96.612 40.337 97.059 c f BT 45.750 94.091 Td /F1 9.8 Tf [(From the patients perspective, stool DNA testing in general may have some advantages over colonoscopy for CRC )] TJ ET BT 45.750 82.186 Td /F1 9.8 Tf [(screening since it: is non-invasive; does not require a formal health care visit; does not require dietary or medication )] TJ ET BT 45.750 70.282 Td /F1 9.8 Tf [(restrictions, bowel preparation, or sedation; and does not require hours of time for testing and recovery, thus alleviating the )] TJ ET BT 45.750 58.377 Td /F1 9.8 Tf [(need to take leave from normal activities \(such as a job\).)] TJ ET 40.337 45.690 m 40.337 46.136 40.154 46.580 39.838 46.896 c 39.522 47.212 39.078 47.396 38.631 47.396 c 38.185 47.396 37.741 47.212 37.425 46.896 c 37.109 46.580 36.925 46.136 36.925 45.690 c 36.925 45.243 37.109 44.799 37.425 44.483 c 37.741 44.167 38.185 43.983 38.631 43.983 c 39.078 43.983 39.522 44.167 39.838 44.483 c 40.154 44.799 40.337 45.243 40.337 45.690 c f BT 45.750 42.722 Td /F1 9.8 Tf [(From the patients perspective, DNA-based stool tests may offer some advantages over FOBT, which requires multiple )] TJ ET Q q 15.000 28.436 577.500 748.564 re W n 1.000 1.000 1.000 rg 26.250 659.686 555.000 117.314 re f 0.267 0.267 0.267 rg 26.625 776.625 94.133 0.750 re f 26.625 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 31.875 766.770 Td /F4 9.8 Tf [(Ahlquist 2008)] TJ ET 0.267 0.267 0.267 rg BT 95.269 766.770 Td /F4 9.8 Tf [([14])] TJ ET 120.008 776.625 219.805 0.750 re f 120.008 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 125.258 766.770 Td /F1 9.8 Tf [(Test SDT-2 \(point mutations on )] TJ ET BT 263.435 766.770 Td /F6 9.8 Tf [(K-ras)] TJ ET BT 286.728 766.770 Td /F1 9.8 Tf [( , scanned )] TJ ET BT 125.258 759.139 Td /F1 9.8 Tf [(mutator cluster region of )] TJ ET BT 233.093 759.139 Td /F6 9.8 Tf [(APC)] TJ ET BT 253.139 759.139 Td /F1 9.8 Tf [( , methylated )] TJ ET BT 125.258 751.508 Td /F6 9.8 Tf [(vimentin)] TJ ET BT 161.557 751.508 Td /F1 9.8 Tf [( \))] TJ ET 0.267 0.267 0.267 rg 339.063 776.625 69.228 0.750 re f 339.063 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 344.313 764.409 Td /F1 9.8 Tf [(58% \(7/12\) )] TJ ET BT 394.711 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 407.541 776.625 82.113 0.750 re f 407.541 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 412.791 764.409 Td /F1 9.8 Tf [(46% \(47/103\) )] TJ ET BT 474.031 766.975 Td /F1 8.7 Tf [(2)] TJ ET 0.267 0.267 0.267 rg 488.904 776.625 89.813 0.750 re f 578.718 776.625 2.157 0.750 re f 488.904 745.369 0.750 32.006 re f 580.125 745.369 0.750 32.006 re f 0.271 0.267 0.267 rg BT 494.154 766.770 Td /F1 9.8 Tf [(Not calculated)] TJ ET 0.267 0.267 0.267 rg 26.625 745.369 94.133 0.750 re f 26.625 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 31.875 735.514 Td /F4 9.8 Tf [(Baek 2009)] TJ ET 0.267 0.267 0.267 rg BT 79.572 735.514 Td /F4 9.8 Tf [([36])] TJ ET 120.008 745.369 219.805 0.750 re f 120.008 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 735.514 Td /F6 9.8 Tf [(mMLH1)] TJ ET 0.267 0.267 0.267 rg 339.063 745.369 69.228 0.750 re f 339.063 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 735.514 Td /F1 9.8 Tf [(30% \(18/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 745.369 82.113 0.750 re f 407.541 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 735.514 Td /F1 9.8 Tf [(12% \(6/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 745.369 89.813 0.750 re f 578.718 745.369 2.157 0.750 re f 488.904 726.537 0.750 19.582 re f 580.125 726.537 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 733.153 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 735.718 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 726.537 94.133 0.750 re f 26.625 707.705 0.750 19.582 re f 0.573 0.816 0.314 rg 120.383 708.080 219.055 18.832 re f 0.267 0.267 0.267 rg 120.008 726.537 219.805 0.750 re f 120.008 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 125.258 716.682 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 716.682 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 708.080 68.478 18.832 re f 0.267 0.267 0.267 rg 339.063 726.537 69.228 0.750 re f 339.063 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 344.313 716.682 Td /F1 9.8 Tf [(38% \(23/60\))] TJ ET 0.573 0.816 0.314 rg 407.916 708.080 81.363 18.832 re f 0.267 0.267 0.267 rg 407.541 726.537 82.113 0.750 re f 407.541 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 412.791 716.682 Td /F1 9.8 Tf [(15% \(8/52\))] TJ ET 0.573 0.816 0.314 rg 489.279 708.080 91.221 18.832 re f 0.267 0.267 0.267 rg 488.904 726.537 89.813 0.750 re f 578.718 726.537 2.157 0.750 re f 488.904 707.705 0.750 19.582 re f 580.125 707.705 0.750 19.582 re f 0.271 0.267 0.267 rg BT 494.154 714.321 Td /F1 9.8 Tf [(100% \(37/37\) )] TJ ET BT 555.394 716.886 Td /F1 8.7 Tf [(4)] TJ ET 0.267 0.267 0.267 rg 26.625 707.705 94.133 0.750 re f 26.625 691.823 0.750 16.631 re f 120.008 707.705 219.805 0.750 re f 120.008 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 697.850 Td /F1 9.8 Tf [(MGMT)] TJ ET 0.267 0.267 0.267 rg 339.063 707.705 69.228 0.750 re f 339.063 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 697.850 Td /F1 9.8 Tf [(52% \(31/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 707.705 82.113 0.750 re f 407.541 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 697.850 Td /F1 9.8 Tf [(37% \(19/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 707.705 89.813 0.750 re f 578.718 707.705 2.157 0.750 re f 488.904 691.823 0.750 16.631 re f 580.125 691.823 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 697.850 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 691.823 94.133 0.750 re f 26.625 675.942 0.750 16.631 re f 120.008 691.823 219.805 0.750 re f 120.008 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 681.968 Td /F1 9.8 Tf [(All three markers \(combined\))] TJ ET 0.267 0.267 0.267 rg 339.063 691.823 69.228 0.750 re f 339.063 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 681.968 Td /F1 9.8 Tf [(75% \(45/60\))] TJ ET 0.267 0.267 0.267 rg 407.541 691.823 82.113 0.750 re f 407.541 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 681.968 Td /F1 9.8 Tf [(60% \(31/52\))] TJ ET 0.267 0.267 0.267 rg 488.904 691.823 89.813 0.750 re f 578.718 691.823 2.157 0.750 re f 488.904 675.942 0.750 16.631 re f 580.125 675.942 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 681.968 Td /F1 9.8 Tf [(86% \(32/37\))] TJ ET 0.267 0.267 0.267 rg 26.625 675.942 94.133 0.750 re f 26.625 660.061 94.133 0.750 re f 26.625 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 31.875 666.087 Td /F4 9.8 Tf [(Li 2009)] TJ ET 0.267 0.267 0.267 rg BT 64.937 666.087 Td /F4 9.8 Tf [([33])] TJ ET 0.573 0.816 0.314 rg 120.383 660.436 219.055 15.881 re f 0.267 0.267 0.267 rg 120.008 675.942 219.805 0.750 re f 120.008 660.061 219.805 0.750 re f 120.008 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 125.258 666.087 Td /F1 9.8 Tf [(Methylated )] TJ ET BT 175.656 666.087 Td /F6 9.8 Tf [(vimentin)] TJ ET 0.573 0.816 0.314 rg 339.438 660.436 68.478 15.881 re f 0.267 0.267 0.267 rg 339.063 675.942 69.228 0.750 re f 339.063 660.061 69.228 0.750 re f 339.063 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 344.313 666.087 Td /F1 9.8 Tf [(41% \(9/22\))] TJ ET 0.573 0.816 0.314 rg 407.916 660.436 81.363 15.881 re f 0.267 0.267 0.267 rg 407.541 675.942 82.113 0.750 re f 407.541 660.061 82.113 0.750 re f 407.541 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 412.791 666.087 Td /F1 9.8 Tf [(45% \(9/20\))] TJ ET 0.573 0.816 0.314 rg 489.279 660.436 91.221 15.881 re f 0.267 0.267 0.267 rg 488.904 675.942 89.813 0.750 re f 488.904 660.061 89.813 0.750 re f 578.718 675.942 2.157 0.750 re f 578.718 660.061 2.157 0.750 re f 488.904 660.061 0.750 16.631 re f 580.125 660.061 0.750 16.631 re f 0.271 0.267 0.267 rg BT 494.154 666.087 Td /F1 9.8 Tf [(95% \(36/38\))] TJ ET BT 26.250 612.662 Td /F1 9.8 Tf [(DY = refers to a specific test for DNA integrity.)] TJ ET BT 26.250 593.257 Td /F1 9.8 Tf [( Not measured.)] TJ ET BT 26.250 577.741 Td /F1 8.7 Tf [(1)] TJ ET BT 31.069 573.853 Td /F1 9.8 Tf [( Refers to adenomas ? 1 cm.)] TJ ET BT 26.250 558.336 Td /F1 8.7 Tf [(2)] TJ ET BT 31.069 554.448 Td /F1 9.8 Tf [( We calculated the numerator using data presented in the article.)] TJ ET BT 26.250 538.931 Td /F1 8.7 Tf [(3)] TJ ET BT 31.069 535.043 Td /F1 9.8 Tf [( In the study, sensitivity and specificity were calculated using optimal cutpoints based on the combined dataset \(Phases 1a + )] TJ ET BT 26.250 523.138 Td /F1 9.8 Tf [(1b\).)] TJ ET BT 26.250 507.622 Td /F1 8.7 Tf [(4)] TJ ET BT 31.069 503.734 Td /F1 9.8 Tf [( We calculated specificity using data presented in the article.)] TJ ET 0.271 0.267 0.267 RG 40.337 487.296 m 40.337 487.743 40.154 488.187 39.838 488.503 c 39.522 488.819 39.078 489.003 38.631 489.003 c 38.185 489.003 37.741 488.819 37.425 488.503 c 37.109 488.187 36.925 487.743 36.925 487.296 c 36.925 486.850 37.109 486.406 37.425 486.090 c 37.741 485.774 38.185 485.590 38.631 485.590 c 39.078 485.590 39.522 485.774 39.838 486.090 c 40.154 486.406 40.337 486.850 40.337 487.296 c f BT 45.750 484.329 Td /F1 9.8 Tf [(Due to the processes for sample collection, sample preparation, and laboratory analysis, the most relevant findings on )] TJ ET BT 45.750 472.424 Td /F1 9.8 Tf [(ColoSure appear to be contained in the two Itzkowitz, )] TJ ET BT 278.785 472.424 Td /F6 9.8 Tf [(et al. )] TJ ET BT 302.633 472.424 Td /F1 9.8 Tf [(reports )] TJ ET 0.267 0.267 0.267 rg BT 335.686 472.424 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 368.212 472.424 Td /F1 9.8 Tf [(. In these studies, a second assay \(for DNA )] TJ ET BT 45.750 460.519 Td /F1 9.8 Tf [(integrity\) was also examined alone and in combination with methylated vimentin. The combined findings from both phases )] TJ ET BT 45.750 448.615 Td /F1 9.8 Tf [(of the study )] TJ ET 0.267 0.267 0.267 rg BT 98.868 448.615 Td /F1 9.8 Tf [([37])] TJ ET 0.271 0.267 0.267 rg BT 115.131 448.615 Td /F1 9.8 Tf [( suggest a sensitivity for CRC of 77% and a specificity of 83% for methylated vimentin. However, )] TJ ET BT 45.750 436.710 Td /F1 9.8 Tf [(informational materials for ColoSure also reference internal LabCorp data, which, combined with the Itzkowitz, )] TJ ET BT 522.057 436.710 Td /F6 9.8 Tf [(et al.)] TJ ET BT 45.750 424.805 Td /F1 9.8 Tf [(studies, suggest that ColoSure has 72-77% sensitivity and 83-94% specificity for CRC )] TJ ET 0.267 0.267 0.267 rg BT 419.107 424.805 Td /F1 9.8 Tf [([6][17])] TJ ET 0.271 0.267 0.267 rg BT 446.212 424.805 Td /F1 9.8 Tf [(.)] TJ ET 40.337 412.118 m 40.337 412.565 40.154 413.009 39.838 413.325 c 39.522 413.640 39.078 413.824 38.631 413.824 c 38.185 413.824 37.741 413.640 37.425 413.325 c 37.109 413.009 36.925 412.565 36.925 412.118 c 36.925 411.671 37.109 411.227 37.425 410.911 c 37.741 410.596 38.185 410.412 38.631 410.412 c 39.078 410.412 39.522 410.596 39.838 410.911 c 40.154 411.227 40.337 411.671 40.337 412.118 c f BT 45.750 409.150 Td /F1 9.8 Tf [(Itzkowitz, )] TJ ET BT 88.553 409.150 Td /F6 9.8 Tf [(et al.)] TJ ET BT 109.691 409.150 Td /F1 9.8 Tf [( did not specifically enroll patients with adenomas in their study populations )] TJ ET 0.267 0.267 0.267 rg BT 436.462 409.150 Td /F1 9.8 Tf [([37][38])] TJ ET 0.271 0.267 0.267 rg BT 468.988 409.150 Td /F1 9.8 Tf [(, so the clinical validity of )] TJ ET BT 45.750 397.246 Td /F1 9.8 Tf [(ColoSure for pre-cancerous lesions is unclear.)] TJ ET 40.337 384.559 m 40.337 385.005 40.154 385.449 39.838 385.765 c 39.522 386.081 39.078 386.265 38.631 386.265 c 38.185 386.265 37.741 386.081 37.425 385.765 c 37.109 385.449 36.925 385.005 36.925 384.559 c 36.925 384.112 37.109 383.668 37.425 383.352 c 37.741 383.036 38.185 382.852 38.631 382.852 c 39.078 382.852 39.522 383.036 39.838 383.352 c 40.154 383.668 40.337 384.112 40.337 384.559 c f BT 45.750 381.591 Td /F1 9.8 Tf [(Using a more advanced technical method for detecting methylated vimentin, Li, )] TJ ET BT 389.320 381.591 Td /F6 9.8 Tf [(et al.)] TJ ET BT 410.458 381.591 Td /F1 9.8 Tf [( reported sensitivities of 45% and 41% )] TJ ET BT 45.750 369.686 Td /F1 9.8 Tf [(for detecting adenomas and colorectal cancer, respectively, with ~95% specificity )] TJ ET 0.267 0.267 0.267 rg BT 398.252 369.686 Td /F1 9.8 Tf [([33])] TJ ET 0.271 0.267 0.267 rg BT 414.514 369.686 Td /F1 9.8 Tf [(. This research demonstrates that )] TJ ET BT 45.750 357.781 Td /F1 9.8 Tf [(more sensitive methods of methylated vimentin detection \(such as that in )] TJ ET 0.267 0.267 0.267 rg BT 362.762 357.781 Td /F1 9.8 Tf [([33][34])] TJ ET 0.271 0.267 0.267 rg BT 395.288 357.781 Td /F1 9.8 Tf [(\) would likely affect the clinical validity of )] TJ ET BT 45.750 345.877 Td /F1 9.8 Tf [(ColoSure. Of note, Exact Sciences is in the process of developing more sensitive methods to detect methylated vimentin )] TJ ET 0.267 0.267 0.267 rg BT 45.750 333.972 Td /F1 9.8 Tf [([42])] TJ ET 0.271 0.267 0.267 rg BT 62.013 333.972 Td /F1 9.8 Tf [(.)] TJ ET 40.337 321.285 m 40.337 321.731 40.154 322.175 39.838 322.491 c 39.522 322.807 39.078 322.991 38.631 322.991 c 38.185 322.991 37.741 322.807 37.425 322.491 c 37.109 322.175 36.925 321.731 36.925 321.285 c 36.925 320.838 37.109 320.394 37.425 320.078 c 37.741 319.762 38.185 319.579 38.631 319.579 c 39.078 319.579 39.522 319.762 39.838 320.078 c 40.154 320.394 40.337 320.838 40.337 321.285 c f BT 45.750 318.317 Td /F1 9.8 Tf [(It is unclear how fecal DNA screening using methylated vimentin compares to other established CRC screening tests. A pre-)] TJ ET BT 45.750 306.412 Td /F1 9.8 Tf [(commercial version of the first-generation PreGen-Plus fecal DNA test was directly compared to a guaiac FOBT in a large )] TJ ET BT 45.750 294.508 Td /F1 9.8 Tf [(multi-center study of asymptomatic persons )] TJ ET 0.267 0.267 0.267 rg BT 236.480 294.508 Td /F1 9.8 Tf [([43])] TJ ET 0.271 0.267 0.267 rg BT 252.743 294.508 Td /F1 9.8 Tf [(, but no research has been published directly comparing ColoSure to other )] TJ ET BT 45.750 282.603 Td /F1 9.8 Tf [(CRC screening methods. The SDT-2 test \(which contains methylated vimentin\) has been compared to two guaiac tests )] TJ ET 0.267 0.267 0.267 rg BT 561.077 282.603 Td /F1 9.8 Tf [([14])] TJ ET 0.271 0.267 0.267 rg BT 577.340 282.603 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 259.448 Td /F1 9.8 Tf [(Summary)] TJ ET BT 67.960 259.448 Td /F1 9.8 Tf [(: the clinical validity of methylated vimentin as a biomarker for CRC screening remains to be determined in a general )] TJ ET BT 26.250 247.543 Td /F1 9.8 Tf [(\(average-risk\) screening population. This is re-iterated in the LabCorp technical review for the ColoSure test )] TJ ET 0.267 0.267 0.267 rg BT 493.343 247.543 Td /F1 9.8 Tf [([6])] TJ ET 0.271 0.267 0.267 rg BT 504.185 247.543 Td /F1 9.8 Tf [(, which states )] TJ ET BT 26.250 235.639 Td /F1 9.8 Tf [(that: The detection rates for general population screening have not been determined.)] TJ ET BT 26.250 216.234 Td /F5 9.8 Tf [(Clinical Utility)] TJ ET BT 90.727 216.234 Td /F4 9.8 Tf [( : )] TJ ET BT 99.394 216.234 Td /F1 9.8 Tf [( Net benefit of test in improving health outcomes)] TJ ET 40.337 199.797 m 40.337 200.243 40.154 200.687 39.838 201.003 c 39.522 201.319 39.078 201.503 38.631 201.503 c 38.185 201.503 37.741 201.319 37.425 201.003 c 37.109 200.687 36.925 200.243 36.925 199.797 c 36.925 199.350 37.109 198.906 37.425 198.590 c 37.741 198.274 38.185 198.091 38.631 198.091 c 39.078 198.091 39.522 198.274 39.838 198.590 c 40.154 198.906 40.337 199.350 40.337 199.797 c f BT 45.750 196.829 Td /F1 9.8 Tf [(The clinical utility of ColoSure for CRC screening has not been established through randomized controlled trials of CRC )] TJ ET BT 45.750 184.924 Td /F1 9.8 Tf [(incidence or mortality outcomes. One ongoing prospective cohort study [NCT01270360] is examining the performance )] TJ ET BT 45.750 173.020 Td /F1 9.8 Tf [(characteristics of both blood and/or stool based molecular DNA markers in identifying CRC in patients with positive FOBT, )] TJ ET BT 45.750 161.115 Td /F1 9.8 Tf [(though it is unclear exactly which DNA markers are being tested. The study also aims to determine the cost-effectiveness )] TJ ET BT 45.750 149.210 Td /F1 9.8 Tf [(of adding fecal DNA testing to the screening algorithm for patients with positive FOBT prior to colonoscopy.)] TJ ET 40.337 136.523 m 40.337 136.970 40.154 137.414 39.838 137.730 c 39.522 138.045 39.078 138.229 38.631 138.229 c 38.185 138.229 37.741 138.045 37.425 137.730 c 37.109 137.414 36.925 136.970 36.925 136.523 c 36.925 136.076 37.109 135.632 37.425 135.316 c 37.741 135.001 38.185 134.817 38.631 134.817 c 39.078 134.817 39.522 135.001 39.838 135.316 c 40.154 135.632 40.337 136.076 40.337 136.523 c f BT 45.750 133.555 Td /F1 9.8 Tf [(ColoSure specifically has not been recommended by independent groups or professional organizations )] TJ ET 0.267 0.267 0.267 rg BT 492.290 133.555 Td /F1 9.8 Tf [([1][25][26][27][28])] TJ ET 0.271 0.267 0.267 rg BT 45.750 121.651 Td /F1 9.8 Tf [(to replace colonoscopy in any patient, regardless of whether they are willing and able to undergo the procedure and )] TJ ET BT 45.750 109.746 Td /F1 9.8 Tf [(regardless of CRC risk level.)] TJ ET 40.337 97.059 m 40.337 97.505 40.154 97.949 39.838 98.265 c 39.522 98.581 39.078 98.765 38.631 98.765 c 38.185 98.765 37.741 98.581 37.425 98.265 c 37.109 97.949 36.925 97.505 36.925 97.059 c 36.925 96.612 37.109 96.168 37.425 95.852 c 37.741 95.536 38.185 95.353 38.631 95.353 c 39.078 95.353 39.522 95.536 39.838 95.852 c 40.154 96.168 40.337 96.612 40.337 97.059 c f BT 45.750 94.091 Td /F1 9.8 Tf [(From the patients perspective, stool DNA testing in general may have some advantages over colonoscopy for CRC )] TJ ET BT 45.750 82.186 Td /F1 9.8 Tf [(screening since it: is non-invasive; does not require a formal health care visit; does not require dietary or medication )] TJ ET BT 45.750 70.282 Td /F1 9.8 Tf [(restrictions, bowel preparation, or sedation; and does not require hours of time for testing and recovery, thus alleviating the )] TJ ET BT 45.750 58.377 Td /F1 9.8 Tf [(need to take leave from normal activities \(such as a job\).)] TJ ET 40.337 45.690 m 40.337 46.136 40.154 46.580 39.838 46.896 c 39.522 47.212 39.078 47.396 38.631 47.396 c 38.185 47.396 37.741 47.212 37.425 46.896 c 37.109 46.580 36.925 46.136 36.925 45.690 c 36.925 45.243 37.109 44.799 37.425 44.483 c 37.741 44.167 38.185 43.983 38.631 43.983 c 39.078 43.983 39.522 44.167 39.838 44.483 c 40.154 44.799 40.337 45.243 40.337 45.690 c f BT 45.750 42.722 Td /F1 9.8 Tf [(From the patients perspective, DNA-based stool tests may offer some advantages over FOBT, which requires multiple )] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(5)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET 0.39 w 1 J 1 j Q endstream endobj 318 0 obj << /Type /Annot /Subtype /Link /A 319 0 R /Border [0 0 0] /H /I /Rect [ 95.2695 765.8681 112.6050 775.7888 ] >> endobj 319 0 obj << /Type /Action >> endobj 320 0 obj << /Type /Annot /Subtype /Link /A 321 0 R /Border [0 0 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39.838 729.773 c 40.154 730.089 40.337 730.533 40.337 730.980 c f BT 45.750 728.012 Td /F1 9.8 Tf [(Some studies have noted high patient satisfaction with fecal DNA testing or a patient preference for stool DNA testing over )] TJ ET BT 45.750 716.107 Td /F1 9.8 Tf [(colonoscopy, though colonoscopy was perceived as the more accurate test )] TJ ET 0.267 0.267 0.267 rg BT 372.531 716.107 Td /F1 9.8 Tf [([38][44][45])] TJ ET 0.271 0.267 0.267 rg BT 421.320 716.107 Td /F1 9.8 Tf [(. However, other populations )] TJ ET BT 45.750 704.202 Td /F1 9.8 Tf [(surveyed had a higher preference for colonoscopy than for fecal DNA testing )] TJ ET 0.267 0.267 0.267 rg BT 379.034 704.202 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 395.297 704.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 691.515 m 40.337 691.962 40.154 692.406 39.838 692.722 c 39.522 693.038 39.078 693.221 38.631 693.221 c 38.185 693.221 37.741 693.038 37.425 692.722 c 37.109 692.406 36.925 691.962 36.925 691.515 c 36.925 691.069 37.109 690.625 37.425 690.309 c 37.741 689.993 38.185 689.809 38.631 689.809 c 39.078 689.809 39.522 689.993 39.838 690.309 c 40.154 690.625 40.337 691.069 40.337 691.515 c f BT 45.750 688.548 Td /F1 9.8 Tf [(There is potential for the improvement in health outcomes if more people are willing to undergo fecal DNA testing )] TJ ET BT 535.083 688.548 Td /F1 9.8 Tf [(compared )] TJ ET BT 45.750 676.643 Td /F1 9.8 Tf [(to a screening colonoscopy or other invasive test methods, thereby increasing the percentage of adults who undergo CRC )] TJ ET BT 45.750 664.738 Td /F1 9.8 Tf [(screening. In addition, the USPSTF notes that the chief benefit of less invasive screening tests \(assuming they have )] TJ ET BT 45.750 652.833 Td /F1 9.8 Tf [(adequate clinical sensitivity and specificity\) is that they may reduce the number of colonoscopies required, since )] TJ ET BT 45.750 640.929 Td /F1 9.8 Tf [(colonoscopies have risks of their own )] TJ ET 0.267 0.267 0.267 rg BT 209.940 640.929 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 220.782 640.929 Td /F1 9.8 Tf [(. However, there are a few issues related to these ideas that need to be )] TJ ET BT 45.750 629.024 Td /F1 9.8 Tf [(addressed: )] TJ ET 0.39 w 1 J 1 j 59.837 616.337 m 59.837 616.783 59.654 617.227 59.338 617.543 c 59.022 617.859 58.578 618.043 58.131 618.043 c 57.685 618.043 57.241 617.859 56.925 617.543 c 56.609 617.227 56.425 616.783 56.425 616.337 c 56.425 615.890 56.609 615.446 56.925 615.130 c 57.241 614.814 57.685 614.630 58.131 614.630 c 58.578 614.630 59.022 614.814 59.338 615.130 c 59.654 615.446 59.837 615.890 59.837 616.337 c s BT 65.250 613.369 Td /F1 9.8 Tf [(There is an uncertain disease detection benefit, unless fecal DNA is at least as sensitive as FOBTs )] TJ ET 0.267 0.267 0.267 rg BT 494.435 613.369 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 537.803 613.369 Td /F1 9.8 Tf [( for pre-)] TJ ET BT 65.250 601.464 Td /F1 9.8 Tf [(cancerous and cancerous lesions;)] TJ ET 0.39 w 1 J 1 j 59.837 588.777 m 59.837 589.224 59.654 589.668 59.338 589.984 c 59.022 590.300 58.578 590.483 58.131 590.483 c 57.685 590.483 57.241 590.300 56.925 589.984 c 56.609 589.668 56.425 589.224 56.425 588.777 c 56.425 588.331 56.609 587.887 56.925 587.571 c 57.241 587.255 57.685 587.071 58.131 587.071 c 58.578 587.071 59.022 587.255 59.338 587.571 c 59.654 587.887 59.837 588.331 59.837 588.777 c s BT 65.250 585.810 Td /F1 9.8 Tf [(Current research suggests that fecal DNA tests have poorer specificity than FOBT \(especially guaiac-based or FIT\) )] TJ ET 0.267 0.267 0.267 rg BT 65.250 573.905 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 108.618 573.905 Td /F1 9.8 Tf [(, which would lead to unnecessary colonoscopies due to a higher number of false positives;)] TJ ET 0.39 w 1 J 1 j 59.837 561.218 m 59.837 561.664 59.654 562.108 59.338 562.424 c 59.022 562.740 58.578 562.924 58.131 562.924 c 57.685 562.924 57.241 562.740 56.925 562.424 c 56.609 562.108 56.425 561.664 56.425 561.218 c 56.425 560.771 56.609 560.327 56.925 560.011 c 57.241 559.695 57.685 559.511 58.131 559.511 c 58.578 559.511 59.022 559.695 59.338 560.011 c 59.654 560.327 59.837 560.771 59.837 561.218 c s BT 65.250 558.250 Td /F1 9.8 Tf [(There is no research available to determine re-screening intervals for stool DNA testing;)] TJ ET 0.39 w 1 J 1 j 59.837 545.563 m 59.837 546.010 59.654 546.454 59.338 546.770 c 59.022 547.085 58.578 547.269 58.131 547.269 c 57.685 547.269 57.241 547.085 56.925 546.770 c 56.609 546.454 56.425 546.010 56.425 545.563 c 56.425 545.116 56.609 544.672 56.925 544.356 c 57.241 544.041 57.685 543.857 58.131 543.857 c 58.578 543.857 59.022 544.041 59.338 544.356 c 59.654 544.672 59.837 545.116 59.837 545.563 c s BT 65.250 542.595 Td /F1 9.8 Tf [(In general, fecal DNA testing may not be cost-effective when compared to other CRC screening tests )] TJ ET 0.267 0.267 0.267 rg BT 503.103 542.595 Td /F1 9.8 Tf [([48])] TJ ET 0.271 0.267 0.267 rg BT 519.366 542.595 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 529.908 m 59.837 530.355 59.654 530.799 59.338 531.115 c 59.022 531.431 58.578 531.614 58.131 531.614 c 57.685 531.614 57.241 531.431 56.925 531.115 c 56.609 530.799 56.425 530.355 56.425 529.908 c 56.425 529.462 56.609 529.018 56.925 528.702 c 57.241 528.386 57.685 528.202 58.131 528.202 c 58.578 528.202 59.022 528.386 59.338 528.702 c 59.654 529.018 59.837 529.462 59.837 529.908 c s BT 65.250 526.941 Td /F1 9.8 Tf [(Patients may not comply with recommendations for frequent \(e.g., annual or biennial\) screening intervals. Indeed, )] TJ ET BT 65.250 515.036 Td /F1 9.8 Tf [(longitudinal data have shown less than 50% adherence with screening frequency recommendations for stool-based )] TJ ET BT 65.250 503.131 Td /F1 9.8 Tf [(tests such as FOBT )] TJ ET 0.267 0.267 0.267 rg BT 153.575 503.131 Td /F1 9.8 Tf [([49])] TJ ET 0.271 0.267 0.267 rg BT 169.838 503.131 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 490.444 m 59.837 490.891 59.654 491.335 59.338 491.651 c 59.022 491.966 58.578 492.150 58.131 492.150 c 57.685 492.150 57.241 491.966 56.925 491.651 c 56.609 491.335 56.425 490.891 56.425 490.444 c 56.425 489.997 56.609 489.553 56.925 489.237 c 57.241 488.922 57.685 488.738 58.131 488.738 c 58.578 488.738 59.022 488.922 59.338 489.237 c 59.654 489.553 59.837 489.997 59.837 490.444 c s BT 65.250 487.476 Td /F1 9.8 Tf [(There may also be poor follow-up \(e.g., colonoscopy\) after a positive result on a fecal DNA test, as has been shown for )] TJ ET BT 65.250 475.572 Td /F1 9.8 Tf [(FOBT )] TJ ET 0.267 0.267 0.267 rg BT 93.964 475.572 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 110.227 475.572 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 448.667 Td /F1 9.8 Tf [( the clinical utility of ColoSure \(or methylated vimentin in general\) in an average-risk screening population could not )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(be determined from the identified research.)] TJ ET BT 26.250 417.357 Td /F4 9.8 Tf [(Final important note:)] TJ ET BT 26.250 397.953 Td /F1 9.8 Tf [(Fecal DNA tests are under rapid development. Exact Sciences Corporation has developed several approaches to fecal DNA )] TJ ET BT 26.250 386.048 Td /F1 9.8 Tf [(testing for colorectal cancer screening over the past few years. Previous tests were replaced sequentially with newer versions, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(which differed in laboratory methodology or tested for a different panel of DNA markers. The current ColoSure test is a )] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(replacement of a version of the PreGen-Plus test \(Laboratory Corporation of America\), which has been discontinued. Exact )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(Sciences recently reported results from a validation study of its newest stool-based DNA test for colorectal cancer screening, )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(named Cologuard. The panel that was presented included methylated vimentin as one of the tested markers )] TJ ET 0.267 0.267 0.267 rg BT 504.770 338.429 Td /F1 9.8 Tf [([42] [50] [51])] TJ ET 0.271 0.267 0.267 rg BT 558.980 338.429 Td /F1 9.8 Tf [(. )] TJ ET BT 26.250 326.524 Td /F1 9.8 Tf [(Exact Science is currently funding a case-only study [ NCT01260168 ] to determine the sensitivity of this new multi-marker DNA )] TJ ET BT 26.250 314.619 Td /F1 9.8 Tf [(panel in CRC cases. The company is planning to pursue FDA approval for Cologuard in 2012 )] TJ ET 0.267 0.267 0.267 rg BT 431.050 314.619 Td /F1 9.8 Tf [([50])] TJ ET 0.271 0.267 0.267 rg BT 447.313 314.619 Td /F1 9.8 Tf [(. These developments likely )] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(mean that ColoSure will be replaced in the future by this, or other, tests.)] TJ ET BT 26.250 283.310 Td /F4 9.8 Tf [(Concluding remarks:)] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(In order to consider integrating fecal DNA testing into current CRC screening strategies, additional research is needed to )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) population. The estimates of DNA )] TJ ET BT 26.250 240.096 Td /F1 9.8 Tf [(marker sensitivity and specificity found from small case-control studies should not be extrapolated to make any estimates of the )] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(performance of methylated vimentin or ColoSure in the general population.)] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(In addition, the ongoing development and refinement of stool DNA tests presents some difficulty for the integration of these tests )] TJ ET BT 26.250 196.881 Td /F1 9.8 Tf [(as a CRC screening approach. Currently, only one fecal DNA test is commercially available in the U.S., a test that will likely be )] TJ ET BT 26.250 184.977 Td /F1 9.8 Tf [(replaced by a newer version for which FDA approval will be sought.)] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Other critical matters must also be addressed, including the determination of cost-effectiveness, optimal testing intervals, and )] TJ ET BT 26.250 153.667 Td /F1 9.8 Tf [(strategies for the follow-up evaluation of patients who test positive on a fecal DNA test. Moreover, the willingness of individuals )] TJ ET BT 26.250 141.762 Td /F1 9.8 Tf [(from the general population to adopt fecal DNA test protocols and future screening recommendations is a vital consideration. All )] TJ ET BT 26.250 129.858 Td /F1 9.8 Tf [(of these factors will be crucial in affecting the impact of fecal DNA testing on the overall CRC screening paradigm and on )] TJ ET BT 26.250 117.953 Td /F1 9.8 Tf [(colorectal cancer incidence and mortality.)] TJ ET BT 26.250 81.350 Td /F4 12.0 Tf [(Links \(not referenced above\))] TJ ET 40.337 64.364 m 40.337 64.810 40.154 65.254 39.838 65.570 c 39.522 65.886 39.078 66.070 38.631 66.070 c 38.185 66.070 37.741 65.886 37.425 65.570 c 37.109 65.254 36.925 64.810 36.925 64.364 c 36.925 63.917 37.109 63.473 37.425 63.157 c 37.741 62.841 38.185 62.658 38.631 62.658 c 39.078 62.658 39.522 62.841 39.838 63.157 c 40.154 63.473 40.337 63.917 40.337 64.364 c f BT 45.750 61.396 Td /F1 9.8 Tf [(Online Mendelian Inheritance in Men \(OMIM\) entry on colorectal cancer: )] TJ ET 0.267 0.267 0.267 rg BT 360.031 61.396 Td /F1 9.8 Tf [(https://www.ncbi.nlm.nih.gov/omim/114500)] TJ ET 0.271 0.267 0.267 rg 40.337 48.709 m 40.337 49.156 40.154 49.600 39.838 49.916 c 39.522 50.231 39.078 50.415 38.631 50.415 c 38.185 50.415 37.741 50.231 37.425 49.916 c 37.109 49.600 36.925 49.156 36.925 48.709 c 36.925 48.262 37.109 47.818 37.425 47.502 c 37.741 47.187 38.185 47.003 38.631 47.003 c 39.078 47.003 39.522 47.187 39.838 47.502 c 40.154 47.818 40.337 48.262 40.337 48.709 c f BT 45.750 45.741 Td /F1 9.8 Tf [(CDC webpage: )] TJ ET 0.267 0.267 0.267 rg BT 114.566 45.741 Td /F1 9.8 Tf [(Colorectal Cancer Screening)] TJ ET Q q 15.000 39.611 577.500 737.389 re W n 0.271 0.267 0.267 rg BT 45.750 767.476 Td /F1 9.8 Tf [(stool smears as well as some pre-test dietary and medication restrictions \(which are necessary for guaiac-based testing\). )] TJ ET BT 45.750 755.571 Td /F1 9.8 Tf [(However, ColoSure does require handling a minimum 36 g sample of stool, which may be less acceptable than handling )] TJ ET BT 45.750 743.667 Td /F1 9.8 Tf [(stool smears.)] TJ ET 0.271 0.267 0.267 RG 40.337 730.980 m 40.337 731.426 40.154 731.870 39.838 732.186 c 39.522 732.502 39.078 732.686 38.631 732.686 c 38.185 732.686 37.741 732.502 37.425 732.186 c 37.109 731.870 36.925 731.426 36.925 730.980 c 36.925 730.533 37.109 730.089 37.425 729.773 c 37.741 729.457 38.185 729.273 38.631 729.273 c 39.078 729.273 39.522 729.457 39.838 729.773 c 40.154 730.089 40.337 730.533 40.337 730.980 c f BT 45.750 728.012 Td /F1 9.8 Tf [(Some studies have noted high patient satisfaction with fecal DNA testing or a patient preference for stool DNA testing over )] TJ ET BT 45.750 716.107 Td /F1 9.8 Tf [(colonoscopy, though colonoscopy was perceived as the more accurate test )] TJ ET 0.267 0.267 0.267 rg BT 372.531 716.107 Td /F1 9.8 Tf [([38][44][45])] TJ ET 0.271 0.267 0.267 rg BT 421.320 716.107 Td /F1 9.8 Tf [(. However, other populations )] TJ ET BT 45.750 704.202 Td /F1 9.8 Tf [(surveyed had a higher preference for colonoscopy than for fecal DNA testing )] TJ ET 0.267 0.267 0.267 rg BT 379.034 704.202 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 395.297 704.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 691.515 m 40.337 691.962 40.154 692.406 39.838 692.722 c 39.522 693.038 39.078 693.221 38.631 693.221 c 38.185 693.221 37.741 693.038 37.425 692.722 c 37.109 692.406 36.925 691.962 36.925 691.515 c 36.925 691.069 37.109 690.625 37.425 690.309 c 37.741 689.993 38.185 689.809 38.631 689.809 c 39.078 689.809 39.522 689.993 39.838 690.309 c 40.154 690.625 40.337 691.069 40.337 691.515 c f BT 45.750 688.548 Td /F1 9.8 Tf [(There is potential for the improvement in health outcomes if more people are willing to undergo fecal DNA testing )] TJ ET BT 535.083 688.548 Td /F1 9.8 Tf [(compared )] TJ ET BT 45.750 676.643 Td /F1 9.8 Tf [(to a screening colonoscopy or other invasive test methods, thereby increasing the percentage of adults who undergo CRC )] TJ ET BT 45.750 664.738 Td /F1 9.8 Tf [(screening. In addition, the USPSTF notes that the chief benefit of less invasive screening tests \(assuming they have )] TJ ET BT 45.750 652.833 Td /F1 9.8 Tf [(adequate clinical sensitivity and specificity\) is that they may reduce the number of colonoscopies required, since )] TJ ET BT 45.750 640.929 Td /F1 9.8 Tf [(colonoscopies have risks of their own )] TJ ET 0.267 0.267 0.267 rg BT 209.940 640.929 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 220.782 640.929 Td /F1 9.8 Tf [(. However, there are a few issues related to these ideas that need to be )] TJ ET BT 45.750 629.024 Td /F1 9.8 Tf [(addressed: )] TJ ET 0.39 w 1 J 1 j 59.837 616.337 m 59.837 616.783 59.654 617.227 59.338 617.543 c 59.022 617.859 58.578 618.043 58.131 618.043 c 57.685 618.043 57.241 617.859 56.925 617.543 c 56.609 617.227 56.425 616.783 56.425 616.337 c 56.425 615.890 56.609 615.446 56.925 615.130 c 57.241 614.814 57.685 614.630 58.131 614.630 c 58.578 614.630 59.022 614.814 59.338 615.130 c 59.654 615.446 59.837 615.890 59.837 616.337 c s BT 65.250 613.369 Td /F1 9.8 Tf [(There is an uncertain disease detection benefit, unless fecal DNA is at least as sensitive as FOBTs )] TJ ET 0.267 0.267 0.267 rg BT 494.435 613.369 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 537.803 613.369 Td /F1 9.8 Tf [( for pre-)] TJ ET BT 65.250 601.464 Td /F1 9.8 Tf [(cancerous and cancerous lesions;)] TJ ET 0.39 w 1 J 1 j 59.837 588.777 m 59.837 589.224 59.654 589.668 59.338 589.984 c 59.022 590.300 58.578 590.483 58.131 590.483 c 57.685 590.483 57.241 590.300 56.925 589.984 c 56.609 589.668 56.425 589.224 56.425 588.777 c 56.425 588.331 56.609 587.887 56.925 587.571 c 57.241 587.255 57.685 587.071 58.131 587.071 c 58.578 587.071 59.022 587.255 59.338 587.571 c 59.654 587.887 59.837 588.331 59.837 588.777 c s BT 65.250 585.810 Td /F1 9.8 Tf [(Current research suggests that fecal DNA tests have poorer specificity than FOBT \(especially guaiac-based or FIT\) )] TJ ET 0.267 0.267 0.267 rg BT 65.250 573.905 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 108.618 573.905 Td /F1 9.8 Tf [(, which would lead to unnecessary colonoscopies due to a higher number of false positives;)] TJ ET 0.39 w 1 J 1 j 59.837 561.218 m 59.837 561.664 59.654 562.108 59.338 562.424 c 59.022 562.740 58.578 562.924 58.131 562.924 c 57.685 562.924 57.241 562.740 56.925 562.424 c 56.609 562.108 56.425 561.664 56.425 561.218 c 56.425 560.771 56.609 560.327 56.925 560.011 c 57.241 559.695 57.685 559.511 58.131 559.511 c 58.578 559.511 59.022 559.695 59.338 560.011 c 59.654 560.327 59.837 560.771 59.837 561.218 c s BT 65.250 558.250 Td /F1 9.8 Tf [(There is no research available to determine re-screening intervals for stool DNA testing;)] TJ ET 0.39 w 1 J 1 j 59.837 545.563 m 59.837 546.010 59.654 546.454 59.338 546.770 c 59.022 547.085 58.578 547.269 58.131 547.269 c 57.685 547.269 57.241 547.085 56.925 546.770 c 56.609 546.454 56.425 546.010 56.425 545.563 c 56.425 545.116 56.609 544.672 56.925 544.356 c 57.241 544.041 57.685 543.857 58.131 543.857 c 58.578 543.857 59.022 544.041 59.338 544.356 c 59.654 544.672 59.837 545.116 59.837 545.563 c s BT 65.250 542.595 Td /F1 9.8 Tf [(In general, fecal DNA testing may not be cost-effective when compared to other CRC screening tests )] TJ ET 0.267 0.267 0.267 rg BT 503.103 542.595 Td /F1 9.8 Tf [([48])] TJ ET 0.271 0.267 0.267 rg BT 519.366 542.595 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 529.908 m 59.837 530.355 59.654 530.799 59.338 531.115 c 59.022 531.431 58.578 531.614 58.131 531.614 c 57.685 531.614 57.241 531.431 56.925 531.115 c 56.609 530.799 56.425 530.355 56.425 529.908 c 56.425 529.462 56.609 529.018 56.925 528.702 c 57.241 528.386 57.685 528.202 58.131 528.202 c 58.578 528.202 59.022 528.386 59.338 528.702 c 59.654 529.018 59.837 529.462 59.837 529.908 c s BT 65.250 526.941 Td /F1 9.8 Tf [(Patients may not comply with recommendations for frequent \(e.g., annual or biennial\) screening intervals. Indeed, )] TJ ET BT 65.250 515.036 Td /F1 9.8 Tf [(longitudinal data have shown less than 50% adherence with screening frequency recommendations for stool-based )] TJ ET BT 65.250 503.131 Td /F1 9.8 Tf [(tests such as FOBT )] TJ ET 0.267 0.267 0.267 rg BT 153.575 503.131 Td /F1 9.8 Tf [([49])] TJ ET 0.271 0.267 0.267 rg BT 169.838 503.131 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 490.444 m 59.837 490.891 59.654 491.335 59.338 491.651 c 59.022 491.966 58.578 492.150 58.131 492.150 c 57.685 492.150 57.241 491.966 56.925 491.651 c 56.609 491.335 56.425 490.891 56.425 490.444 c 56.425 489.997 56.609 489.553 56.925 489.237 c 57.241 488.922 57.685 488.738 58.131 488.738 c 58.578 488.738 59.022 488.922 59.338 489.237 c 59.654 489.553 59.837 489.997 59.837 490.444 c s BT 65.250 487.476 Td /F1 9.8 Tf [(There may also be poor follow-up \(e.g., colonoscopy\) after a positive result on a fecal DNA test, as has been shown for )] TJ ET BT 65.250 475.572 Td /F1 9.8 Tf [(FOBT )] TJ ET 0.267 0.267 0.267 rg BT 93.964 475.572 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 110.227 475.572 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 448.667 Td /F1 9.8 Tf [( the clinical utility of ColoSure \(or methylated vimentin in general\) in an average-risk screening population could not )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(be determined from the identified research.)] TJ ET BT 26.250 417.357 Td /F4 9.8 Tf [(Final important note:)] TJ ET BT 26.250 397.953 Td /F1 9.8 Tf [(Fecal DNA tests are under rapid development. Exact Sciences Corporation has developed several approaches to fecal DNA )] TJ ET BT 26.250 386.048 Td /F1 9.8 Tf [(testing for colorectal cancer screening over the past few years. Previous tests were replaced sequentially with newer versions, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(which differed in laboratory methodology or tested for a different panel of DNA markers. The current ColoSure test is a )] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(replacement of a version of the PreGen-Plus test \(Laboratory Corporation of America\), which has been discontinued. Exact )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(Sciences recently reported results from a validation study of its newest stool-based DNA test for colorectal cancer screening, )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(named Cologuard. The panel that was presented included methylated vimentin as one of the tested markers )] TJ ET 0.267 0.267 0.267 rg BT 504.770 338.429 Td /F1 9.8 Tf [([42] [50] [51])] TJ ET 0.271 0.267 0.267 rg BT 558.980 338.429 Td /F1 9.8 Tf [(. )] TJ ET BT 26.250 326.524 Td /F1 9.8 Tf [(Exact Science is currently funding a case-only study [ NCT01260168 ] to determine the sensitivity of this new multi-marker DNA )] TJ ET BT 26.250 314.619 Td /F1 9.8 Tf [(panel in CRC cases. The company is planning to pursue FDA approval for Cologuard in 2012 )] TJ ET 0.267 0.267 0.267 rg BT 431.050 314.619 Td /F1 9.8 Tf [([50])] TJ ET 0.271 0.267 0.267 rg BT 447.313 314.619 Td /F1 9.8 Tf [(. These developments likely )] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(mean that ColoSure will be replaced in the future by this, or other, tests.)] TJ ET BT 26.250 283.310 Td /F4 9.8 Tf [(Concluding remarks:)] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(In order to consider integrating fecal DNA testing into current CRC screening strategies, additional research is needed to )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) population. The estimates of DNA )] TJ ET BT 26.250 240.096 Td /F1 9.8 Tf [(marker sensitivity and specificity found from small case-control studies should not be extrapolated to make any estimates of the )] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(performance of methylated vimentin or ColoSure in the general population.)] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(In addition, the ongoing development and refinement of stool DNA tests presents some difficulty for the integration of these tests )] TJ ET BT 26.250 196.881 Td /F1 9.8 Tf [(as a CRC screening approach. Currently, only one fecal DNA test is commercially available in the U.S., a test that will likely be )] TJ ET BT 26.250 184.977 Td /F1 9.8 Tf [(replaced by a newer version for which FDA approval will be sought.)] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Other critical matters must also be addressed, including the determination of cost-effectiveness, optimal testing intervals, and )] TJ ET BT 26.250 153.667 Td /F1 9.8 Tf [(strategies for the follow-up evaluation of patients who test positive on a fecal DNA test. Moreover, the willingness of individuals )] TJ ET BT 26.250 141.762 Td /F1 9.8 Tf [(from the general population to adopt fecal DNA test protocols and future screening recommendations is a vital consideration. All )] TJ ET BT 26.250 129.858 Td /F1 9.8 Tf [(of these factors will be crucial in affecting the impact of fecal DNA testing on the overall CRC screening paradigm and on )] TJ ET BT 26.250 117.953 Td /F1 9.8 Tf [(colorectal cancer incidence and mortality.)] TJ ET BT 26.250 81.350 Td /F4 12.0 Tf [(Links \(not referenced above\))] TJ ET 40.337 64.364 m 40.337 64.810 40.154 65.254 39.838 65.570 c 39.522 65.886 39.078 66.070 38.631 66.070 c 38.185 66.070 37.741 65.886 37.425 65.570 c 37.109 65.254 36.925 64.810 36.925 64.364 c 36.925 63.917 37.109 63.473 37.425 63.157 c 37.741 62.841 38.185 62.658 38.631 62.658 c 39.078 62.658 39.522 62.841 39.838 63.157 c 40.154 63.473 40.337 63.917 40.337 64.364 c f BT 45.750 61.396 Td /F1 9.8 Tf [(Online Mendelian Inheritance in Men \(OMIM\) entry on colorectal cancer: )] TJ ET 0.267 0.267 0.267 rg BT 360.031 61.396 Td /F1 9.8 Tf [(https://www.ncbi.nlm.nih.gov/omim/114500)] TJ ET 0.271 0.267 0.267 rg 40.337 48.709 m 40.337 49.156 40.154 49.600 39.838 49.916 c 39.522 50.231 39.078 50.415 38.631 50.415 c 38.185 50.415 37.741 50.231 37.425 49.916 c 37.109 49.600 36.925 49.156 36.925 48.709 c 36.925 48.262 37.109 47.818 37.425 47.502 c 37.741 47.187 38.185 47.003 38.631 47.003 c 39.078 47.003 39.522 47.187 39.838 47.502 c 40.154 47.818 40.337 48.262 40.337 48.709 c f BT 45.750 45.741 Td /F1 9.8 Tf [(CDC webpage: )] TJ ET 0.267 0.267 0.267 rg BT 114.566 45.741 Td /F1 9.8 Tf [(Colorectal Cancer Screening)] TJ ET Q q 15.000 39.611 577.500 737.389 re W n 0.271 0.267 0.267 rg BT 45.750 767.476 Td /F1 9.8 Tf [(stool smears as well as some pre-test dietary and medication restrictions \(which are necessary for guaiac-based testing\). )] TJ ET BT 45.750 755.571 Td /F1 9.8 Tf [(However, ColoSure does require handling a minimum 36 g sample of stool, which may be less acceptable than handling )] TJ ET BT 45.750 743.667 Td /F1 9.8 Tf [(stool smears.)] TJ ET 0.271 0.267 0.267 RG 40.337 730.980 m 40.337 731.426 40.154 731.870 39.838 732.186 c 39.522 732.502 39.078 732.686 38.631 732.686 c 38.185 732.686 37.741 732.502 37.425 732.186 c 37.109 731.870 36.925 731.426 36.925 730.980 c 36.925 730.533 37.109 730.089 37.425 729.773 c 37.741 729.457 38.185 729.273 38.631 729.273 c 39.078 729.273 39.522 729.457 39.838 729.773 c 40.154 730.089 40.337 730.533 40.337 730.980 c f BT 45.750 728.012 Td /F1 9.8 Tf [(Some studies have noted high patient satisfaction with fecal DNA testing or a patient preference for stool DNA testing over )] TJ ET BT 45.750 716.107 Td /F1 9.8 Tf [(colonoscopy, though colonoscopy was perceived as the more accurate test )] TJ ET 0.267 0.267 0.267 rg BT 372.531 716.107 Td /F1 9.8 Tf [([38][44][45])] TJ ET 0.271 0.267 0.267 rg BT 421.320 716.107 Td /F1 9.8 Tf [(. However, other populations )] TJ ET BT 45.750 704.202 Td /F1 9.8 Tf [(surveyed had a higher preference for colonoscopy than for fecal DNA testing )] TJ ET 0.267 0.267 0.267 rg BT 379.034 704.202 Td /F1 9.8 Tf [([46])] TJ ET 0.271 0.267 0.267 rg BT 395.297 704.202 Td /F1 9.8 Tf [(.)] TJ ET 40.337 691.515 m 40.337 691.962 40.154 692.406 39.838 692.722 c 39.522 693.038 39.078 693.221 38.631 693.221 c 38.185 693.221 37.741 693.038 37.425 692.722 c 37.109 692.406 36.925 691.962 36.925 691.515 c 36.925 691.069 37.109 690.625 37.425 690.309 c 37.741 689.993 38.185 689.809 38.631 689.809 c 39.078 689.809 39.522 689.993 39.838 690.309 c 40.154 690.625 40.337 691.069 40.337 691.515 c f BT 45.750 688.548 Td /F1 9.8 Tf [(There is potential for the improvement in health outcomes if more people are willing to undergo fecal DNA testing )] TJ ET BT 535.083 688.548 Td /F1 9.8 Tf [(compared )] TJ ET BT 45.750 676.643 Td /F1 9.8 Tf [(to a screening colonoscopy or other invasive test methods, thereby increasing the percentage of adults who undergo CRC )] TJ ET BT 45.750 664.738 Td /F1 9.8 Tf [(screening. In addition, the USPSTF notes that the chief benefit of less invasive screening tests \(assuming they have )] TJ ET BT 45.750 652.833 Td /F1 9.8 Tf [(adequate clinical sensitivity and specificity\) is that they may reduce the number of colonoscopies required, since )] TJ ET BT 45.750 640.929 Td /F1 9.8 Tf [(colonoscopies have risks of their own )] TJ ET 0.267 0.267 0.267 rg BT 209.940 640.929 Td /F1 9.8 Tf [([1])] TJ ET 0.271 0.267 0.267 rg BT 220.782 640.929 Td /F1 9.8 Tf [(. However, there are a few issues related to these ideas that need to be )] TJ ET BT 45.750 629.024 Td /F1 9.8 Tf [(addressed: )] TJ ET 0.39 w 1 J 1 j 59.837 616.337 m 59.837 616.783 59.654 617.227 59.338 617.543 c 59.022 617.859 58.578 618.043 58.131 618.043 c 57.685 618.043 57.241 617.859 56.925 617.543 c 56.609 617.227 56.425 616.783 56.425 616.337 c 56.425 615.890 56.609 615.446 56.925 615.130 c 57.241 614.814 57.685 614.630 58.131 614.630 c 58.578 614.630 59.022 614.814 59.338 615.130 c 59.654 615.446 59.837 615.890 59.837 616.337 c s BT 65.250 613.369 Td /F1 9.8 Tf [(There is an uncertain disease detection benefit, unless fecal DNA is at least as sensitive as FOBTs )] TJ ET 0.267 0.267 0.267 rg BT 494.435 613.369 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 537.803 613.369 Td /F1 9.8 Tf [( for pre-)] TJ ET BT 65.250 601.464 Td /F1 9.8 Tf [(cancerous and cancerous lesions;)] TJ ET 0.39 w 1 J 1 j 59.837 588.777 m 59.837 589.224 59.654 589.668 59.338 589.984 c 59.022 590.300 58.578 590.483 58.131 590.483 c 57.685 590.483 57.241 590.300 56.925 589.984 c 56.609 589.668 56.425 589.224 56.425 588.777 c 56.425 588.331 56.609 587.887 56.925 587.571 c 57.241 587.255 57.685 587.071 58.131 587.071 c 58.578 587.071 59.022 587.255 59.338 587.571 c 59.654 587.887 59.837 588.331 59.837 588.777 c s BT 65.250 585.810 Td /F1 9.8 Tf [(Current research suggests that fecal DNA tests have poorer specificity than FOBT \(especially guaiac-based or FIT\) )] TJ ET 0.267 0.267 0.267 rg BT 65.250 573.905 Td /F1 9.8 Tf [([5][24][47])] TJ ET 0.271 0.267 0.267 rg BT 108.618 573.905 Td /F1 9.8 Tf [(, which would lead to unnecessary colonoscopies due to a higher number of false positives;)] TJ ET 0.39 w 1 J 1 j 59.837 561.218 m 59.837 561.664 59.654 562.108 59.338 562.424 c 59.022 562.740 58.578 562.924 58.131 562.924 c 57.685 562.924 57.241 562.740 56.925 562.424 c 56.609 562.108 56.425 561.664 56.425 561.218 c 56.425 560.771 56.609 560.327 56.925 560.011 c 57.241 559.695 57.685 559.511 58.131 559.511 c 58.578 559.511 59.022 559.695 59.338 560.011 c 59.654 560.327 59.837 560.771 59.837 561.218 c s BT 65.250 558.250 Td /F1 9.8 Tf [(There is no research available to determine re-screening intervals for stool DNA testing;)] TJ ET 0.39 w 1 J 1 j 59.837 545.563 m 59.837 546.010 59.654 546.454 59.338 546.770 c 59.022 547.085 58.578 547.269 58.131 547.269 c 57.685 547.269 57.241 547.085 56.925 546.770 c 56.609 546.454 56.425 546.010 56.425 545.563 c 56.425 545.116 56.609 544.672 56.925 544.356 c 57.241 544.041 57.685 543.857 58.131 543.857 c 58.578 543.857 59.022 544.041 59.338 544.356 c 59.654 544.672 59.837 545.116 59.837 545.563 c s BT 65.250 542.595 Td /F1 9.8 Tf [(In general, fecal DNA testing may not be cost-effective when compared to other CRC screening tests )] TJ ET 0.267 0.267 0.267 rg BT 503.103 542.595 Td /F1 9.8 Tf [([48])] TJ ET 0.271 0.267 0.267 rg BT 519.366 542.595 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 529.908 m 59.837 530.355 59.654 530.799 59.338 531.115 c 59.022 531.431 58.578 531.614 58.131 531.614 c 57.685 531.614 57.241 531.431 56.925 531.115 c 56.609 530.799 56.425 530.355 56.425 529.908 c 56.425 529.462 56.609 529.018 56.925 528.702 c 57.241 528.386 57.685 528.202 58.131 528.202 c 58.578 528.202 59.022 528.386 59.338 528.702 c 59.654 529.018 59.837 529.462 59.837 529.908 c s BT 65.250 526.941 Td /F1 9.8 Tf [(Patients may not comply with recommendations for frequent \(e.g., annual or biennial\) screening intervals. Indeed, )] TJ ET BT 65.250 515.036 Td /F1 9.8 Tf [(longitudinal data have shown less than 50% adherence with screening frequency recommendations for stool-based )] TJ ET BT 65.250 503.131 Td /F1 9.8 Tf [(tests such as FOBT )] TJ ET 0.267 0.267 0.267 rg BT 153.575 503.131 Td /F1 9.8 Tf [([49])] TJ ET 0.271 0.267 0.267 rg BT 169.838 503.131 Td /F1 9.8 Tf [(;)] TJ ET 0.39 w 1 J 1 j 59.837 490.444 m 59.837 490.891 59.654 491.335 59.338 491.651 c 59.022 491.966 58.578 492.150 58.131 492.150 c 57.685 492.150 57.241 491.966 56.925 491.651 c 56.609 491.335 56.425 490.891 56.425 490.444 c 56.425 489.997 56.609 489.553 56.925 489.237 c 57.241 488.922 57.685 488.738 58.131 488.738 c 58.578 488.738 59.022 488.922 59.338 489.237 c 59.654 489.553 59.837 489.997 59.837 490.444 c s BT 65.250 487.476 Td /F1 9.8 Tf [(There may also be poor follow-up \(e.g., colonoscopy\) after a positive result on a fecal DNA test, as has been shown for )] TJ ET BT 65.250 475.572 Td /F1 9.8 Tf [(FOBT )] TJ ET 0.267 0.267 0.267 rg BT 93.964 475.572 Td /F1 9.8 Tf [([22])] TJ ET 0.271 0.267 0.267 rg BT 110.227 475.572 Td /F1 9.8 Tf [(.)] TJ ET BT 26.250 448.667 Td /F1 9.8 Tf [(Summary:)] TJ ET BT 70.671 448.667 Td /F1 9.8 Tf [( the clinical utility of ColoSure \(or methylated vimentin in general\) in an average-risk screening population could not )] TJ ET BT 26.250 436.762 Td /F1 9.8 Tf [(be determined from the identified research.)] TJ ET BT 26.250 417.357 Td /F4 9.8 Tf [(Final important note:)] TJ ET BT 26.250 397.953 Td /F1 9.8 Tf [(Fecal DNA tests are under rapid development. Exact Sciences Corporation has developed several approaches to fecal DNA )] TJ ET BT 26.250 386.048 Td /F1 9.8 Tf [(testing for colorectal cancer screening over the past few years. Previous tests were replaced sequentially with newer versions, )] TJ ET BT 26.250 374.143 Td /F1 9.8 Tf [(which differed in laboratory methodology or tested for a different panel of DNA markers. The current ColoSure test is a )] TJ ET BT 26.250 362.238 Td /F1 9.8 Tf [(replacement of a version of the PreGen-Plus test \(Laboratory Corporation of America\), which has been discontinued. Exact )] TJ ET BT 26.250 350.334 Td /F1 9.8 Tf [(Sciences recently reported results from a validation study of its newest stool-based DNA test for colorectal cancer screening, )] TJ ET BT 26.250 338.429 Td /F1 9.8 Tf [(named Cologuard. The panel that was presented included methylated vimentin as one of the tested markers )] TJ ET 0.267 0.267 0.267 rg BT 504.770 338.429 Td /F1 9.8 Tf [([42] [50] [51])] TJ ET 0.271 0.267 0.267 rg BT 558.980 338.429 Td /F1 9.8 Tf [(. )] TJ ET BT 26.250 326.524 Td /F1 9.8 Tf [(Exact Science is currently funding a case-only study [ NCT01260168 ] to determine the sensitivity of this new multi-marker DNA )] TJ ET BT 26.250 314.619 Td /F1 9.8 Tf [(panel in CRC cases. The company is planning to pursue FDA approval for Cologuard in 2012 )] TJ ET 0.267 0.267 0.267 rg BT 431.050 314.619 Td /F1 9.8 Tf [([50])] TJ ET 0.271 0.267 0.267 rg BT 447.313 314.619 Td /F1 9.8 Tf [(. These developments likely )] TJ ET BT 26.250 302.715 Td /F1 9.8 Tf [(mean that ColoSure will be replaced in the future by this, or other, tests.)] TJ ET BT 26.250 283.310 Td /F4 9.8 Tf [(Concluding remarks:)] TJ ET BT 26.250 263.905 Td /F1 9.8 Tf [(In order to consider integrating fecal DNA testing into current CRC screening strategies, additional research is needed to )] TJ ET BT 26.250 252.000 Td /F1 9.8 Tf [(establish analytic validity, clinical validity, and clinical utility within the general \(average-risk\) population. The estimates of DNA )] TJ ET BT 26.250 240.096 Td /F1 9.8 Tf [(marker sensitivity and specificity found from small case-control studies should not be extrapolated to make any estimates of the )] TJ ET BT 26.250 228.191 Td /F1 9.8 Tf [(performance of methylated vimentin or ColoSure in the general population.)] TJ ET BT 26.250 208.786 Td /F1 9.8 Tf [(In addition, the ongoing development and refinement of stool DNA tests presents some difficulty for the integration of these tests )] TJ ET BT 26.250 196.881 Td /F1 9.8 Tf [(as a CRC screening approach. Currently, only one fecal DNA test is commercially available in the U.S., a test that will likely be )] TJ ET BT 26.250 184.977 Td /F1 9.8 Tf [(replaced by a newer version for which FDA approval will be sought.)] TJ ET BT 26.250 165.572 Td /F1 9.8 Tf [(Other critical matters must also be addressed, including the determination of cost-effectiveness, optimal testing intervals, and )] TJ ET BT 26.250 153.667 Td /F1 9.8 Tf [(strategies for the follow-up evaluation of patients who test positive on a fecal DNA test. Moreover, the willingness of individuals )] TJ ET BT 26.250 141.762 Td /F1 9.8 Tf [(from the general population to adopt fecal DNA test protocols and future screening recommendations is a vital consideration. All )] TJ ET BT 26.250 129.858 Td /F1 9.8 Tf [(of these factors will be crucial in affecting the impact of fecal DNA testing on the overall CRC screening paradigm and on )] TJ ET BT 26.250 117.953 Td /F1 9.8 Tf [(colorectal cancer incidence and mortality.)] TJ ET BT 26.250 81.350 Td /F4 12.0 Tf [(Links \(not referenced above\))] TJ ET 40.337 64.364 m 40.337 64.810 40.154 65.254 39.838 65.570 c 39.522 65.886 39.078 66.070 38.631 66.070 c 38.185 66.070 37.741 65.886 37.425 65.570 c 37.109 65.254 36.925 64.810 36.925 64.364 c 36.925 63.917 37.109 63.473 37.425 63.157 c 37.741 62.841 38.185 62.658 38.631 62.658 c 39.078 62.658 39.522 62.841 39.838 63.157 c 40.154 63.473 40.337 63.917 40.337 64.364 c f BT 45.750 61.396 Td /F1 9.8 Tf [(Online Mendelian Inheritance in Men \(OMIM\) entry on colorectal cancer: )] TJ ET 0.267 0.267 0.267 rg BT 360.031 61.396 Td /F1 9.8 Tf [(https://www.ncbi.nlm.nih.gov/omim/114500)] TJ ET 0.271 0.267 0.267 rg 40.337 48.709 m 40.337 49.156 40.154 49.600 39.838 49.916 c 39.522 50.231 39.078 50.415 38.631 50.415 c 38.185 50.415 37.741 50.231 37.425 49.916 c 37.109 49.600 36.925 49.156 36.925 48.709 c 36.925 48.262 37.109 47.818 37.425 47.502 c 37.741 47.187 38.185 47.003 38.631 47.003 c 39.078 47.003 39.522 47.187 39.838 47.502 c 40.154 47.818 40.337 48.262 40.337 48.709 c f BT 45.750 45.741 Td /F1 9.8 Tf [(CDC webpage: )] TJ ET 0.267 0.267 0.267 rg BT 114.566 45.741 Td /F1 9.8 Tf [(Colorectal Cancer Screening)] TJ ET Q q 0.000 0.000 0.000 rg BT 291.710 19.825 Td /F1 11.0 Tf [(6)] TJ ET BT 25.000 19.825 Td /F1 11.0 Tf [(PLOS Currents Evidence on Genomic Tests)] TJ ET 0.39 w 1 J 1 j Q endstream endobj 404 0 obj << /Type /Annot /Subtype /Link /A 405 0 R /Border [0 0 0] /H /I /Rect [ 372.5310 715.2053 421.3200 725.1259 ] >> endobj 405 0 obj << /Type /Action >> endobj 406 0 obj << /Type /Annot /Subtype /Link /A 407 0 R /Border [0 0 0] /H /I /Rect [ 379.0342 703.3006 395.2972 713.2212 ] >> endobj 407 0 obj << /Type /Action >> endobj 408 0 obj << 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(https://www.cdc.gov/cancer/colorectal/basic_info/screening/) >> endobj 476 0 obj << /Type /Page /Parent 3 0 R /Annots [ 478 0 R 480 0 R 482 0 R ] /Contents 477 0 R >> endobj 477 0 obj << /Length 8641 >> stream 0.267 0.267 0.267 rg 0.271 0.267 0.267 RG 0.39 w 1 J 1 j q 15.000 386.071 577.500 390.929 re W n 0.271 0.267 0.267 rg 0.271 0.267 0.267 RG 40.337 770.444 m 40.337 770.890 40.154 771.334 39.838 771.650 c 39.522 771.966 39.078 772.150 38.631 772.150 c 38.185 772.150 37.741 771.966 37.425 771.650 c 37.109 771.334 36.925 770.890 36.925 770.444 c 36.925 769.997 37.109 769.553 37.425 769.237 c 37.741 768.921 38.185 768.738 38.631 768.738 c 39.078 768.738 39.522 768.921 39.838 769.237 c 40.154 769.553 40.337 769.997 40.337 770.444 c f BT 45.750 767.476 Td /F1 9.8 Tf [(National Cancer Institute: )] TJ ET 0.267 0.267 0.267 rg BT 157.924 767.476 Td /F1 9.8 Tf [(Colorectal Cancer Screening Fact Sheet)] TJ ET 0.271 0.267 0.267 rg BT 26.250 744.321 Td /F1 9.8 Tf [(Last updated: March 14, 2011)] TJ ET BT 26.250 707.719 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 687.765 Td /F1 9.8 Tf [(The authors would like to thank the following individuals for invaluable input and guidance on the content of this manuscript: )] TJ ET BT 26.250 675.860 Td /F1 9.8 Tf [(Dave Dotson, Ralph Coates and Katie Kolor \(Office of Public Health Genomics, CDC\); Lisa Richardson and Djenaba Joseph )] TJ ET BT 26.250 663.955 Td /F1 9.8 Tf [(\(Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, CDC\); and )] TJ ET BT 26.250 652.050 Td /F1 9.8 Tf [(Evelyn Whitlock, Beth Webber, and their colleagues \(Kaiser Permanente Center for Health Research\).)] TJ ET BT 26.250 615.448 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 595.494 Td /F1 9.8 Tf [(This work was funded by the Office of Public Health Genomics, Centers for Disease Control and Prevention.)] TJ ET BT 26.250 558.891 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 538.937 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 502.334 Td /F4 12.0 Tf [(Disclaimers)] TJ ET BT 26.250 482.380 Td /F1 9.8 Tf [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET BT 26.250 470.475 Td /F1 9.8 Tf [(for Disease Control and Prevention \(CDC\).)] TJ ET BT 26.250 451.071 Td /F1 9.8 Tf [(The information provided in this manuscript does not constitute an endorsement of ColoSure\(TM\) or of any fecal DNA test by )] TJ ET BT 26.250 439.166 Td /F1 9.8 Tf [(the CDC nor the Department of Health and Human Services \(DHHS\) of the U.S. government. No endorsement should be )] TJ ET BT 26.250 427.261 Td /F1 9.8 Tf [(inferred.)] TJ ET BT 26.250 407.856 Td /F1 9.8 Tf [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET BT 26.250 395.952 Td /F1 9.8 Tf [(suggest that you discuss them with your health care provider.)] TJ ET Q q 15.000 386.071 577.500 390.929 re W n 0.271 0.267 0.267 rg 0.271 0.267 0.267 RG 40.337 770.444 m 40.337 770.890 40.154 771.334 39.838 771.650 c 39.522 771.966 39.078 772.150 38.631 772.150 c 38.185 772.150 37.741 771.966 37.425 771.650 c 37.109 771.334 36.925 770.890 36.925 770.444 c 36.925 769.997 37.109 769.553 37.425 769.237 c 37.741 768.921 38.185 768.738 38.631 768.738 c 39.078 768.738 39.522 768.921 39.838 769.237 c 40.154 769.553 40.337 769.997 40.337 770.444 c f BT 45.750 767.476 Td /F1 9.8 Tf [(National Cancer Institute: )] TJ ET 0.267 0.267 0.267 rg BT 157.924 767.476 Td /F1 9.8 Tf [(Colorectal Cancer Screening Fact Sheet)] TJ ET 0.271 0.267 0.267 rg BT 26.250 744.321 Td /F1 9.8 Tf [(Last updated: March 14, 2011)] TJ ET BT 26.250 707.719 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 687.765 Td /F1 9.8 Tf [(The authors would like to thank the following individuals for invaluable input and guidance on the content of this manuscript: )] TJ ET BT 26.250 675.860 Td /F1 9.8 Tf [(Dave Dotson, Ralph Coates and Katie Kolor \(Office of Public Health Genomics, CDC\); Lisa Richardson and Djenaba Joseph )] TJ ET BT 26.250 663.955 Td /F1 9.8 Tf [(\(Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, CDC\); and )] TJ ET BT 26.250 652.050 Td /F1 9.8 Tf [(Evelyn Whitlock, Beth Webber, and their colleagues \(Kaiser Permanente Center for Health Research\).)] TJ ET BT 26.250 615.448 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 595.494 Td /F1 9.8 Tf [(This work was funded by the Office of Public Health Genomics, Centers for Disease Control and Prevention.)] TJ ET BT 26.250 558.891 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 538.937 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 502.334 Td /F4 12.0 Tf [(Disclaimers)] TJ ET BT 26.250 482.380 Td /F1 9.8 Tf [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET BT 26.250 470.475 Td /F1 9.8 Tf [(for Disease Control and Prevention \(CDC\).)] TJ ET BT 26.250 451.071 Td /F1 9.8 Tf [(The information provided in this manuscript does not constitute an endorsement of ColoSure\(TM\) or of any fecal DNA test by )] TJ ET BT 26.250 439.166 Td /F1 9.8 Tf [(the CDC nor the Department of Health and Human Services \(DHHS\) of the U.S. government. No endorsement should be )] TJ ET BT 26.250 427.261 Td /F1 9.8 Tf [(inferred.)] TJ ET BT 26.250 407.856 Td /F1 9.8 Tf [(The CDC does not offer medical advice to individuals. If you have specific concerns about your health or genetic testing, we )] TJ ET BT 26.250 395.952 Td /F1 9.8 Tf [(suggest that you discuss them with your health care provider.)] TJ ET Q q 15.000 386.071 577.500 390.929 re W n 0.271 0.267 0.267 rg 0.271 0.267 0.267 RG 40.337 770.444 m 40.337 770.890 40.154 771.334 39.838 771.650 c 39.522 771.966 39.078 772.150 38.631 772.150 c 38.185 772.150 37.741 771.966 37.425 771.650 c 37.109 771.334 36.925 770.890 36.925 770.444 c 36.925 769.997 37.109 769.553 37.425 769.237 c 37.741 768.921 38.185 768.738 38.631 768.738 c 39.078 768.738 39.522 768.921 39.838 769.237 c 40.154 769.553 40.337 769.997 40.337 770.444 c f BT 45.750 767.476 Td /F1 9.8 Tf [(National Cancer Institute: )] TJ ET 0.267 0.267 0.267 rg BT 157.924 767.476 Td /F1 9.8 Tf [(Colorectal Cancer Screening Fact Sheet)] TJ ET 0.271 0.267 0.267 rg BT 26.250 744.321 Td /F1 9.8 Tf [(Last updated: March 14, 2011)] TJ ET BT 26.250 707.719 Td /F4 12.0 Tf [(Acknowledgments)] TJ ET BT 26.250 687.765 Td /F1 9.8 Tf [(The authors would like to thank the following individuals for invaluable input and guidance on the content of this manuscript: )] TJ ET BT 26.250 675.860 Td /F1 9.8 Tf [(Dave Dotson, Ralph Coates and Katie Kolor \(Office of Public Health Genomics, CDC\); Lisa Richardson and Djenaba Joseph )] TJ ET BT 26.250 663.955 Td /F1 9.8 Tf [(\(Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, CDC\); and )] TJ ET BT 26.250 652.050 Td /F1 9.8 Tf [(Evelyn Whitlock, Beth Webber, and their colleagues \(Kaiser Permanente Center for Health Research\).)] TJ ET BT 26.250 615.448 Td /F4 12.0 Tf [(Funding information)] TJ ET BT 26.250 595.494 Td /F1 9.8 Tf [(This work was funded by the Office of Public Health Genomics, Centers for Disease Control and Prevention.)] TJ ET BT 26.250 558.891 Td /F4 12.0 Tf [(Competing interests)] TJ ET BT 26.250 538.937 Td /F1 9.8 Tf [(The authors have declared that no competing interests exist.)] TJ ET BT 26.250 502.334 Td /F4 12.0 Tf [(Disclaimers)] TJ ET BT 26.250 482.380 Td /F1 9.8 Tf [(The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers )] TJ ET BT 26.250 470.475 Td /F1 9.8 Tf [(for Disease Control and Prevention \(CDC\).)] TJ ET BT 26.250 451.071 Td /F1 9.8 Tf [(The information provided in this manuscript does not constitute an endorsement of ColoSure\(TM\) or of any fecal DNA test by )] TJ ET BT 26.250 439.166 Td /F1 9.8 Tf [(the CDC nor the Department of Health and Human Services \(DHHS\) of the U.S. government. 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