Quantitation of Hemoglobin Improves Fecal Immunochemical Tests for Noninvasive Screening

Abstract

There are many test options available for screening for colorectal cancer (CRC). These include endoscopy, imaging techniques, fecal tests, and emerging blood tests. Screening guidelines differ markedly between and even within countries but, recently, studies have shown that participant preferences should be considered when making CRC screening recommendations.1Inadomi J.M. Vijan S. Janz N.K. et al.Adherence to colorectal cancer screening: a randomized trial of competing strategies.Arch Intern Med. 2012; 172: 572-582Google Scholar Greater emphasis now is being directed to ensuring that offering a choice of test takes account of the preferences of the individual or the groups making the decisions.2Church T.R. Screening for colorectal cancer–which strategy is the best?.J Natl Cancer Inst. 2011; 103: 1282-1283Crossref PubMed Scopus (12) Google Scholar This has led to a growing realization that noninvasive tests have considerable advantages.3Flitcroft K.L. Irwig L.M. Carter S.M. et al.Colorectal cancer screening: why immunochemical fecal occult blood tests may be the best option.BMC Gastroenterol. 2012; 12: 183Crossref PubMed Scopus (13) Google Scholar Of these, fecal immunochemical tests (FITs) for hemoglobin (Hb) have so many advantages compared with traditional guaiac-based fecal occult blood tests and other published fecal biomarkers to date such as DNA, RNA, and proteins, that they generally are recognized to be the best currently available.4Imperiale T.F. Noninvasive screening tests for colorectal cancer.Dig Dis. 2012; 30: 16-26Crossref PubMed Scopus (39) Google Scholar FITs fulfill the criteria suggested as desirable because they can detect both advanced adenomas and early cancers, have high specificity to keep the costs of screening low and minimize risks to healthy people and are user-friendly, affordable, and widely available.4Imperiale T.F. Noninvasive screening tests for colorectal cancer.Dig Dis. 2012; 30: 16-26Crossref PubMed Scopus (39) Google ScholarFITs are available in 2 formats: qualitative tests that simply provide a dichotomous positive or negative result, and quantitative tests that provide high-quality measurement of the fecal Hb concentration. In this issue of Clinical Gastroenterology and Hepatology, Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar report on the association between early stage colorectal neoplasia and false-negative FIT results. By using a qualitative FIT, those with nonadvanced adenoma, advanced adenoma, and cancer were identified with sensitivities of 10.6%, 28.0%, and 78.6%, respectively, with proximal advanced adenomas and nonpolypoid lesions being detected with lower sensitivities than distal advanced adenomas. The FIT used resulted in a high false-negative rate in the detection of adenomas smaller than 15 mm and nonpolypoid adenomas, and also detection of what were described as “carcinoma in situ”5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and T1 cancer as compared with T2 to T4 cancers. These data could impact the design of FIT-based screening programs, but a number of pertinent questions arise.First, are these results applicable to other qualitative FITs? It is vital for users to recognize that all FITs are not the same and that, using the same specimens, different FITs yield markedly different positivity rates, sensitivities, and specificities.6Brenner H. Haug U. Hundt S. Inter-test agreement and quantitative cross-validation of immunochromatographical fecal occult blood tests.Int J Cancer. 2010; 127: 1643-1649Crossref PubMed Scopus (44) Google Scholar Thus, the exact results obtained by Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar may not be applicable directly to other FITs. Moreover, we have shown that the earlier-described clinical characteristics are not related directly to the stated cut-off Hb concentrations when these are expressed in units of ng Hb/mL buffer.7Fraser C.G. Allison J.E. Halloran S.P. et al.A proposal to standardize reporting units for fecal immunochemical tests for hemoglobin.J Natl Cancer Inst. 2012; 104: 810-814Crossref PubMed Scopus (130) Google Scholar The FIT used had a cut-off Hb concentration of 50 ng Hb/mL buffer. The guideline from the Expert Working Group on Fecal Immunochemical Tests for Hemoglobin, Colorectal Cancer Screening Committee, World Endoscopy Organization, urges all involved with FITs to report cut-off concentrations in μg Hb/g feces (for the FIT used by Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar: 10 μg Hb/g feces), because this will facilitate a more objective comparison of clinical outcome data across different FITs.7Fraser C.G. Allison J.E. Halloran S.P. et al.A proposal to standardize reporting units for fecal immunochemical tests for hemoglobin.J Natl Cancer Inst. 2012; 104: 810-814Crossref PubMed Scopus (130) Google ScholarSecond, is it surprising that the FITs resulted in a high rate of false-negative results for small or nonpolypoid adenomas? We think that the reported results for early stage cancers should not include neoplasms labeled carcinoma in situ, a term no longer used in clinical pathology. They should be labeled stage 1(T1) cancers, provided that they show signs of invasion: if not, then they represent high-grade dysplasia. However, irrespective of terminology, it was shown that these had more false-negative FIT results compared with more advanced cancers. Even with the now near-obsolete guaiac-based fecal occult blood tests, significant evidence was gathered over many years that positivity was greater the more advanced the colorectal neoplasia. Quantitative FITs have allowed this to be explored in more detail, including by Levi et al,8Levi Z. Rozen P. Hazazi R. et al.A quantitative immunochemical fecal occult blood test for colorectal neoplasia.Ann Intern Med. 2007; 146: 244-255Crossref PubMed Scopus (280) Google Scholar who showed that adenoma size was related to mean fecal Hb concentration, and Ciatto et al,9Ciatto S. Martinelli F. Castiglione G. et al.Association of FOBT-assessed faecal Hb content with colonic lesions detected in the Florence screening programme.Br J Cancer. 2007; 96: 218-221Crossref PubMed Scopus (76) Google Scholar who showed that 191 colorectal cancers and 890 adenomas were detected at colonoscopy in 2597 FIT-positive individuals, and, among adenomas, higher fecal Hb concentration was associated significantly with size, presence of severe dysplasia, and presence of a villous component.9Ciatto S. Martinelli F. Castiglione G. et al.Association of FOBT-assessed faecal Hb content with colonic lesions detected in the Florence screening programme.Br J Cancer. 2007; 96: 218-221Crossref PubMed Scopus (76) Google Scholar Further studies have shown that fecal Hb concentration increases in individuals with no colonic neoplasia as disease becomes more severe through clinically less important lesions through nonadvanced and small adenomas through larger and more advanced adenomas to cancer, although there is considerable overlap between these groups.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar Indeed, screening using FITs would be successful only if a relationship existed between fecal Hb concentration and disease.The work of Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar provides additional support for this relationship by showing that small and early lesions have negative FIT results, equivalent to low fecal Hb concentrations. A number of studies have investigated the effect of fecal Hb cut-off concentration on the performance characteristics of FITs: these have used quantitative FITs, which usually involve automated immunoturbidimetry.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar As the cut-off Hb concentration is decreased, the positivity rate and sensitivity for neoplasia increase, but at the expense of specificity and positive predictive value. Thus, as pointed out by Chiu et al,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar their documented sensitivity and specificity for adenomas and cancer could be modified by changing the cut-off fecal Hb concentration. Qualitative FITs do not allow this desirable opportunity. In contrast, quantitative FITs have the major advantage, particularly for countries with national programmatic screening approaches, that the organizers of screening programs can select the cut-off Hb concentration that fulfills their preset objectives. Moreover, instead of taking more than one sample or decreasing the interscreening interval as mentioned,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar the cut-off Hb concentration simply could be made lower to achieve the stated desirable outcome of increased sensitivity. Although the assays require automated analytical systems and are more costly overall, quantitative FITs have so many advantages compared with qualitative FITs10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar that they ought to be available everywhere, particularly recommended in all CRC screening guidelines, and approved for use by all relevant regulatory bodies.Third, what would be gained by using different cut-off fecal Hb concentrations for different groups? It has become well recognized that fecal Hb concentration is affected by age, with older people having a higher concentration than younger people, and by sex, with men having a higher concentration than women.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar Indeed, many10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar have commented that these relationships should affect the design of FIT-based screening programs. Although undoubtedly difficult to institute in practice, it is likely that programs would benefit considerably if different cut-off fecal Hb concentrations were used as criteria for the initiation of further investigation, usually colonoscopy, for different groups. Selecting the appropriate cut-off Hb concentrations for different groups would be based on the FIT performance characteristic that was decided to be the most important by the individual program organizers, such as positivity rate, sensitivity, specificity, or positive predictive value. By using a qualitative FIT, Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar treated their large study population as a single entity. It would be of interest to examine the influence of age and sex on false-negative FIT results with quantitative FITs using different cut-off fecal Hb concentrations.Finally, how correct is the often-quoted take-away message that FITs are not good screening tests because they have high false-negative rates for small and nonpolypoid adenomas and early cancers? This conclusion does not take into consideration that the reported sensitivities5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are examples of test application sensitivity (test once only) and not test programmatic sensitivity (test repeatedly performed in a program of repeated screening episodes over time) as per recommendations for population screening with FITs. As pointed out by Chiu et al,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar good programmatic sensitivity allows for missed advanced adenomas and early cancers to be detected in subsequent screens before they become fatal cancers. It is also important to explain that the term advanced neoplasms, as used in the gastroenterology literature, actually refers most commonly to advanced adenomas and not cancers. Advanced adenomas are benign lesions of a certain size and histology and their natural history is unknown. Only a very few actually become fatal cancers. Labeling these neoplasms as advanced is a form of overdiagnosis for most of them. Overdiagnosis is the detection of lesions that require treatment for which the treatment will confer no benefit to survival in the course of the patient's lifetime.This study5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar is a valuable addition to the literature on FITs for screening. It adds some information on sensitivity of the FITs used for proximal and distal advanced neoplasms as well as for polypoid vs flat neoplasms. It raises important questions that we hope will be answered by investigators using quantitative FITs and standardized reporting of FIT results. We then will be closer to the day when guidelines can make evidence-based recommendations on which FITs are best for any given screening strategy. There are many test options available for screening for colorectal cancer (CRC). These include endoscopy, imaging techniques, fecal tests, and emerging blood tests. Screening guidelines differ markedly between and even within countries but, recently, studies have shown that participant preferences should be considered when making CRC screening recommendations.1Inadomi J.M. Vijan S. Janz N.K. et al.Adherence to colorectal cancer screening: a randomized trial of competing strategies.Arch Intern Med. 2012; 172: 572-582Google Scholar Greater emphasis now is being directed to ensuring that offering a choice of test takes account of the preferences of the individual or the groups making the decisions.2Church T.R. Screening for colorectal cancer–which strategy is the best?.J Natl Cancer Inst. 2011; 103: 1282-1283Crossref PubMed Scopus (12) Google Scholar This has led to a growing realization that noninvasive tests have considerable advantages.3Flitcroft K.L. Irwig L.M. Carter S.M. et al.Colorectal cancer screening: why immunochemical fecal occult blood tests may be the best option.BMC Gastroenterol. 2012; 12: 183Crossref PubMed Scopus (13) Google Scholar Of these, fecal immunochemical tests (FITs) for hemoglobin (Hb) have so many advantages compared with traditional guaiac-based fecal occult blood tests and other published fecal biomarkers to date such as DNA, RNA, and proteins, that they generally are recognized to be the best currently available.4Imperiale T.F. Noninvasive screening tests for colorectal cancer.Dig Dis. 2012; 30: 16-26Crossref PubMed Scopus (39) Google Scholar FITs fulfill the criteria suggested as desirable because they can detect both advanced adenomas and early cancers, have high specificity to keep the costs of screening low and minimize risks to healthy people and are user-friendly, affordable, and widely available.4Imperiale T.F. Noninvasive screening tests for colorectal cancer.Dig Dis. 2012; 30: 16-26Crossref PubMed Scopus (39) Google Scholar FITs are available in 2 formats: qualitative tests that simply provide a dichotomous positive or negative result, and quantitative tests that provide high-quality measurement of the fecal Hb concentration. In this issue of Clinical Gastroenterology and Hepatology, Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar report on the association between early stage colorectal neoplasia and false-negative FIT results. By using a qualitative FIT, those with nonadvanced adenoma, advanced adenoma, and cancer were identified with sensitivities of 10.6%, 28.0%, and 78.6%, respectively, with proximal advanced adenomas and nonpolypoid lesions being detected with lower sensitivities than distal advanced adenomas. The FIT used resulted in a high false-negative rate in the detection of adenomas smaller than 15 mm and nonpolypoid adenomas, and also detection of what were described as “carcinoma in situ”5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and T1 cancer as compared with T2 to T4 cancers. These data could impact the design of FIT-based screening programs, but a number of pertinent questions arise. First, are these results applicable to other qualitative FITs? It is vital for users to recognize that all FITs are not the same and that, using the same specimens, different FITs yield markedly different positivity rates, sensitivities, and specificities.6Brenner H. Haug U. Hundt S. Inter-test agreement and quantitative cross-validation of immunochromatographical fecal occult blood tests.Int J Cancer. 2010; 127: 1643-1649Crossref PubMed Scopus (44) Google Scholar Thus, the exact results obtained by Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar may not be applicable directly to other FITs. Moreover, we have shown that the earlier-described clinical characteristics are not related directly to the stated cut-off Hb concentrations when these are expressed in units of ng Hb/mL buffer.7Fraser C.G. Allison J.E. Halloran S.P. et al.A proposal to standardize reporting units for fecal immunochemical tests for hemoglobin.J Natl Cancer Inst. 2012; 104: 810-814Crossref PubMed Scopus (130) Google Scholar The FIT used had a cut-off Hb concentration of 50 ng Hb/mL buffer. The guideline from the Expert Working Group on Fecal Immunochemical Tests for Hemoglobin, Colorectal Cancer Screening Committee, World Endoscopy Organization, urges all involved with FITs to report cut-off concentrations in μg Hb/g feces (for the FIT used by Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar: 10 μg Hb/g feces), because this will facilitate a more objective comparison of clinical outcome data across different FITs.7Fraser C.G. Allison J.E. Halloran S.P. et al.A proposal to standardize reporting units for fecal immunochemical tests for hemoglobin.J Natl Cancer Inst. 2012; 104: 810-814Crossref PubMed Scopus (130) Google Scholar Second, is it surprising that the FITs resulted in a high rate of false-negative results for small or nonpolypoid adenomas? We think that the reported results for early stage cancers should not include neoplasms labeled carcinoma in situ, a term no longer used in clinical pathology. They should be labeled stage 1(T1) cancers, provided that they show signs of invasion: if not, then they represent high-grade dysplasia. However, irrespective of terminology, it was shown that these had more false-negative FIT results compared with more advanced cancers. Even with the now near-obsolete guaiac-based fecal occult blood tests, significant evidence was gathered over many years that positivity was greater the more advanced the colorectal neoplasia. Quantitative FITs have allowed this to be explored in more detail, including by Levi et al,8Levi Z. Rozen P. Hazazi R. et al.A quantitative immunochemical fecal occult blood test for colorectal neoplasia.Ann Intern Med. 2007; 146: 244-255Crossref PubMed Scopus (280) Google Scholar who showed that adenoma size was related to mean fecal Hb concentration, and Ciatto et al,9Ciatto S. Martinelli F. Castiglione G. et al.Association of FOBT-assessed faecal Hb content with colonic lesions detected in the Florence screening programme.Br J Cancer. 2007; 96: 218-221Crossref PubMed Scopus (76) Google Scholar who showed that 191 colorectal cancers and 890 adenomas were detected at colonoscopy in 2597 FIT-positive individuals, and, among adenomas, higher fecal Hb concentration was associated significantly with size, presence of severe dysplasia, and presence of a villous component.9Ciatto S. Martinelli F. Castiglione G. et al.Association of FOBT-assessed faecal Hb content with colonic lesions detected in the Florence screening programme.Br J Cancer. 2007; 96: 218-221Crossref PubMed Scopus (76) Google Scholar Further studies have shown that fecal Hb concentration increases in individuals with no colonic neoplasia as disease becomes more severe through clinically less important lesions through nonadvanced and small adenomas through larger and more advanced adenomas to cancer, although there is considerable overlap between these groups.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar Indeed, screening using FITs would be successful only if a relationship existed between fecal Hb concentration and disease. The work of Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar provides additional support for this relationship by showing that small and early lesions have negative FIT results, equivalent to low fecal Hb concentrations. A number of studies have investigated the effect of fecal Hb cut-off concentration on the performance characteristics of FITs: these have used quantitative FITs, which usually involve automated immunoturbidimetry.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar As the cut-off Hb concentration is decreased, the positivity rate and sensitivity for neoplasia increase, but at the expense of specificity and positive predictive value. Thus, as pointed out by Chiu et al,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar their documented sensitivity and specificity for adenomas and cancer could be modified by changing the cut-off fecal Hb concentration. Qualitative FITs do not allow this desirable opportunity. In contrast, quantitative FITs have the major advantage, particularly for countries with national programmatic screening approaches, that the organizers of screening programs can select the cut-off Hb concentration that fulfills their preset objectives. Moreover, instead of taking more than one sample or decreasing the interscreening interval as mentioned,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar the cut-off Hb concentration simply could be made lower to achieve the stated desirable outcome of increased sensitivity. Although the assays require automated analytical systems and are more costly overall, quantitative FITs have so many advantages compared with qualitative FITs10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar that they ought to be available everywhere, particularly recommended in all CRC screening guidelines, and approved for use by all relevant regulatory bodies. Third, what would be gained by using different cut-off fecal Hb concentrations for different groups? It has become well recognized that fecal Hb concentration is affected by age, with older people having a higher concentration than younger people, and by sex, with men having a higher concentration than women.10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar Indeed, many10Fraser C.G. A future for faecal haemoglobin measurements in the medical laboratory.Ann Clin Biochem. 2012; 49: 518-526Crossref PubMed Scopus (21) Google Scholar have commented that these relationships should affect the design of FIT-based screening programs. Although undoubtedly difficult to institute in practice, it is likely that programs would benefit considerably if different cut-off fecal Hb concentrations were used as criteria for the initiation of further investigation, usually colonoscopy, for different groups. Selecting the appropriate cut-off Hb concentrations for different groups would be based on the FIT performance characteristic that was decided to be the most important by the individual program organizers, such as positivity rate, sensitivity, specificity, or positive predictive value. By using a qualitative FIT, Chiu et al5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar treated their large study population as a single entity. It would be of interest to examine the influence of age and sex on false-negative FIT results with quantitative FITs using different cut-off fecal Hb concentrations. Finally, how correct is the often-quoted take-away message that FITs are not good screening tests because they have high false-negative rates for small and nonpolypoid adenomas and early cancers? This conclusion does not take into consideration that the reported sensitivities5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar are examples of test application sensitivity (test once only) and not test programmatic sensitivity (test repeatedly performed in a program of repeated screening episodes over time) as per recommendations for population screening with FITs. As pointed out by Chiu et al,5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar good programmatic sensitivity allows for missed advanced adenomas and early cancers to be detected in subsequent screens before they become fatal cancers. It is also important to explain that the term advanced neoplasms, as used in the gastroenterology literature, actually refers most commonly to advanced adenomas and not cancers. Advanced adenomas are benign lesions of a certain size and histology and their natural history is unknown. Only a very few actually become fatal cancers. Labeling these neoplasms as advanced is a form of overdiagnosis for most of them. Overdiagnosis is the detection of lesions that require treatment for which the treatment will confer no benefit to survival in the course of the patient's lifetime. This study5Chiu H.M. Lee Y.C. Tu C.H. et al.Association between early stage colon neoplasms and false-negative results from the fecal immunochemical test.Clin Gastroenterol Hepatol. 2013; 11: 832-838Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar is a valuable addition to the literature on FITs for screening. It adds some information on sensitivity of the FITs used for proximal and distal advanced neoplasms as well as for polypoid vs flat neoplasms. It raises important questions that we hope will be answered by investigators using quantitative FITs and standardized reporting of FIT results. We then will be closer to the day when guidelines can make evidence-based recommendations on which FITs are best for any given screening strategy. Association Between Early Stage Colon Neoplasms and False-negative Results From the Fecal Immunochemical TestClinical Gastroenterology and HepatologyVol. 11Issue 7PreviewThe fecal immunochemical test (FIT) can identify patients with advanced colorectal neoplasms, but it also has a high rate of false-negative results. It would be helpful to characterize colorectal neoplasms that are not detected by FIT to aid in development of new tests. We characterized colorectal neoplasms from patients who had negative results from the FIT. Full-Text PDF