Detecting Advanced Colorectal Neoplasia at Colonoscopy
Detecting Advanced Colorectal Neoplasia at Colonoscopy
Our previous study found that male sex, age of 50 years or more and family history of colorectal cancer were independent risk factors for detecting advanced colorectal neoplasia. In the ensuing discussion, it has been suggested that the observed disparity of advanced neoplasia risk between men and women might have merely reflected sex-based differences in smoking patterns. In the present study, we used a new dataset to derive and validate a model for the detection of advanced colorectal neoplasia that included smoking status and other potential confounders, such as age, sex, family history of colorectal cancer, and Body Mass Index. We confirmed previously identified associations, and also found that smoking ≥10 pack-years, and Body Mass Index ≥30 kg/m were independent risk factors for detecting advanced colorectal neoplasia. Our study corroborated previously identified risk factors for advanced colorectal neoplasia; it also, for the first time, combined all five important factors and their categories in a multivariate analysis and confirmed obtained results in a validation set.
The present model was well calibrated overall, as well as in men and women, as verified in the validation set, which means that the observed risk of advanced colorectal neoplasia well fitted the expected risk. Therefore, we used the model to develop a simple score for the detection of advanced colorectal neoplasia in asymptomatic patients. The score, based on age, sex, family history of colorectal cancer, smoking status and Body Mass Index, estimated the likelihood of detecting advanced colorectal neoplasia in the validation set from 1.32% to 19.12% in patients with 0 to 7–8 points, respectively. The estimation of individual risk of detecting advanced colorectal neoplasia may help asymptomatic patients and healthcare providers to make informed decisions about screening. For example, the likelihood of detecting advanced colorectal neoplasia in a 53-year-old, overweight, never-smoking woman, with one first-degree relative 60 years of age or older with colorectal cancer, is difficult to compare with that of a 56-year-old man who smoked for 20 pack-years, but has healthy weight and no family history of colorectal cancer. However, based on the results of the present model, the respective likelihood of detecting advanced neoplasia for two such patients are 4.65% and 12.46% (or 4.57% and 11.27%, respectively, using simplified scoring). Such results do not mean that one should discourage the woman from participation in an existing screening programme in a given country aiming at average risk group; rather they indicate that the man should be specifically encouraged to be screened, because the likelihood of detecting advanced neoplasia in his colorectum is almost twice that of the average screening population. For ease of clinical application, the present model could be transformed into an online calculator of the likelihood of detecting advanced colorectal neoplasia and used in mobile easy access media. Although lack of symptoms and low perceived risk of colorectal cancer are considered major barriers to screening, it is unknown, whether providing the estimate of individual risk could facilitate the informed decision to undergo endoscopy screening in a similar way as it worked for prostate cancer screening. It is particularly unknown, what kind of effect on participation in screening, would have the lower than average estimate of likelihood of detecting advanced colorectal neoplasia.
Another potential application of a model for the detection of advanced colorectal neoplasia is to guide practical recommendations for mass screening; however, this application would require a model with high discriminatory power. The present model had only moderate concordance statistic value, comparable to that of previously published models for the detection of advanced colorectal neoplasia in Western populations, even though the present model included more risk factors than previous models did. Three issues may explain this observation. First, the model of Betes et al lacked validation, which may have led to overestimation of its discriminatory power. Second, the models of Betes et al and Lin et al were derived from populations with a broader age range, which may have increased their discriminatory power, because age is the most powerful clinical risk factor for advanced colorectal neoplasia. Third, additional independent risk factors included in the present model were too weak to significantly change its discriminatory power. The models for the detection of advanced colorectal neoplasia in East Asian populations demonstrated variable discriminatory power. The model by Yeoh et al demonstrated discriminatory power comparable to that achieved in Western populations, while the model by Cai QC et al demonstrated better discrimination. The latter model missed family history of colorectal cancer but included various dietary factors, which (in contrast to previous studies) showed strong association with the risk of advanced colorectal neoplasia; however, these factors are prone to recall bias. Therefore, it is rather unlikely that a model based on simple, reliable clinical factors alone would ever have sufficient discriminatory power to limit the target population for screening. It is corroborated by the results of a very recent study by Tao S et al. The model that included risk factors missing in the present study (alcohol consumption, red meat consumption, ever regular use of non-steroidal anti-inflammatory drugs, previous colonoscopy and previous detection of polyps), also demonstrated moderate discriminatory value. On the other hand, indirect comparison suggests that the present model's sensitivity and specificity for advanced colorectal neoplasia may be comparable with a single round guaiac faecal occult blood test (mostly due to poor diagnostic performance of guaiac faecal occult blood test for detection of advanced adenomas). Although the model has considerably lower discriminatory power for advanced colorectal neoplasia compared to the one reported for faecal immunochemical tests, it has been shown that combining clinical risk factors with faecal immunochemical test outcome results in improved discrimination. Therefore, it is likely that in the future the clinical factors identified in the model will be combined with results of faecal immunochemical test and/or blood-based biomarkers to select a target population for colonoscopy.
Our study has certain notable features. Despite a large sample size, we have not identified any statistically significant association between diabetes mellitus or aspirin use and the risk of advanced colorectal neoplasia. Although diabetes mellitus is a known risk factor for colorectal cancer, its association with advanced colorectal neoplasia is less certain. The observed lack of association may also be due to the lower-than-expected prevalence of diabetes mellitus in the study cohort, which likely reflects recall bias or self-selection to opportunistic screening.
The lack of a statistically significant association between aspirin use and the risk of advanced colorectal neoplasia in our study may be due to recall bias or missing data regarding the dose and regularity of aspirin use. Moreover, we have not collected the data on other non-steroid anti-inflammatory drugs, which in some studies were analysed together with aspirin.
Advanced neoplasia, not just cancer, was chosen for analysis because it has been suggested as the most appropriate target for endoscopy screening. Although some previous risk prediction models were developed for cancer alone, cancers and advanced neoplasia are surrogate endpoints of primary cancer screening endpoint, which is colorectal cancer mortality. Early detection and treatment of colorectal cancer is associated with a reduction in colorectal cancer mortality, but a detection and removal of adenomas, especially advanced ones, is associated with additional reduction in colorectal cancer incidence and mortality. Therefore, it is uncertain, whether cancer alone or advanced neoplasia is a better endpoint for risk prediction models, but the latter may be particularly suited for use in endoscopy screening.
The primary endpoint of our model was advanced neoplasia located anywhere in the colorectum, therefore, the risk score is not optimised for sigmoidoscopy screening. Nevertheless, we built an additional model to investigate risk factors for detecting distal advanced neoplasia, using sigmoid-descending colon junction as an artificial boundary between distal and proximal colon. The model for the detection of distal advanced neoplasia identified the same risk factors and showed comparable discriminatory power (data not shown).
The limitations of our study require comment. First, the validation process was limited because it was performed in a dataset that was randomly selected from a population recruited in the same setting. The model's performance has not been tested outside Poland or in non-Caucasians. Nonetheless, the National Colorectal Cancer Screening Program recruited participants in 73 centres located in all administrative and geographic regions of Poland, and was open free of charge to all eligible Polish citizens, providing our study with sociodemographic diversity. Moreover, the prevalence of advanced colorectal neoplasia identified in our study was 7.1%, which is within the range of values reported in studies performed in the USA and Europe. Additionally, the adjusted ORs for detecting advanced colorectal neoplasia in various categories of risk factors in our study are similar to that reported in previously published large studies. Notably, in our previous study, performed several years before and in different endoscopy centres, we used the same key to categorise age, family history of colorectal cancer and gender and yielded virtually the same adjusted ORs for each category of variables.
Second, our cohort does not fully cover the recommended age range for screening (people aged 67–75 years were not included) what may limit the applicability of the results for the entire population eligible for screening. On the other hand, by including people at the lower age range for screening (people aged 40–49 years with family history of cancer), this model may help to identify and encourage younger people at considerable risk to undergo screening.
Third, given the cross-sectional design of the study, our risk score is suitable only to predict the detection of advanced neoplasia at the present time, and not the future risk of developing advanced colorectal neoplasia or dying from colorectal cancer.
In summary, we derived and internally validated a model that predicts the likelihood of detecting advanced colorectal neoplasia in asymptomatic Caucasian patients based on age, sex, smoking habits, Body Mass Index, and family history of colorectal cancer. The results of the model were used to develop a simple score that estimates the likelihood of detecting advanced colorectal neoplasia. Once externally validated, the score may be useful for counselling or designing primary prevention studies.
Discussion
Our previous study found that male sex, age of 50 years or more and family history of colorectal cancer were independent risk factors for detecting advanced colorectal neoplasia. In the ensuing discussion, it has been suggested that the observed disparity of advanced neoplasia risk between men and women might have merely reflected sex-based differences in smoking patterns. In the present study, we used a new dataset to derive and validate a model for the detection of advanced colorectal neoplasia that included smoking status and other potential confounders, such as age, sex, family history of colorectal cancer, and Body Mass Index. We confirmed previously identified associations, and also found that smoking ≥10 pack-years, and Body Mass Index ≥30 kg/m were independent risk factors for detecting advanced colorectal neoplasia. Our study corroborated previously identified risk factors for advanced colorectal neoplasia; it also, for the first time, combined all five important factors and their categories in a multivariate analysis and confirmed obtained results in a validation set.
The present model was well calibrated overall, as well as in men and women, as verified in the validation set, which means that the observed risk of advanced colorectal neoplasia well fitted the expected risk. Therefore, we used the model to develop a simple score for the detection of advanced colorectal neoplasia in asymptomatic patients. The score, based on age, sex, family history of colorectal cancer, smoking status and Body Mass Index, estimated the likelihood of detecting advanced colorectal neoplasia in the validation set from 1.32% to 19.12% in patients with 0 to 7–8 points, respectively. The estimation of individual risk of detecting advanced colorectal neoplasia may help asymptomatic patients and healthcare providers to make informed decisions about screening. For example, the likelihood of detecting advanced colorectal neoplasia in a 53-year-old, overweight, never-smoking woman, with one first-degree relative 60 years of age or older with colorectal cancer, is difficult to compare with that of a 56-year-old man who smoked for 20 pack-years, but has healthy weight and no family history of colorectal cancer. However, based on the results of the present model, the respective likelihood of detecting advanced neoplasia for two such patients are 4.65% and 12.46% (or 4.57% and 11.27%, respectively, using simplified scoring). Such results do not mean that one should discourage the woman from participation in an existing screening programme in a given country aiming at average risk group; rather they indicate that the man should be specifically encouraged to be screened, because the likelihood of detecting advanced neoplasia in his colorectum is almost twice that of the average screening population. For ease of clinical application, the present model could be transformed into an online calculator of the likelihood of detecting advanced colorectal neoplasia and used in mobile easy access media. Although lack of symptoms and low perceived risk of colorectal cancer are considered major barriers to screening, it is unknown, whether providing the estimate of individual risk could facilitate the informed decision to undergo endoscopy screening in a similar way as it worked for prostate cancer screening. It is particularly unknown, what kind of effect on participation in screening, would have the lower than average estimate of likelihood of detecting advanced colorectal neoplasia.
Another potential application of a model for the detection of advanced colorectal neoplasia is to guide practical recommendations for mass screening; however, this application would require a model with high discriminatory power. The present model had only moderate concordance statistic value, comparable to that of previously published models for the detection of advanced colorectal neoplasia in Western populations, even though the present model included more risk factors than previous models did. Three issues may explain this observation. First, the model of Betes et al lacked validation, which may have led to overestimation of its discriminatory power. Second, the models of Betes et al and Lin et al were derived from populations with a broader age range, which may have increased their discriminatory power, because age is the most powerful clinical risk factor for advanced colorectal neoplasia. Third, additional independent risk factors included in the present model were too weak to significantly change its discriminatory power. The models for the detection of advanced colorectal neoplasia in East Asian populations demonstrated variable discriminatory power. The model by Yeoh et al demonstrated discriminatory power comparable to that achieved in Western populations, while the model by Cai QC et al demonstrated better discrimination. The latter model missed family history of colorectal cancer but included various dietary factors, which (in contrast to previous studies) showed strong association with the risk of advanced colorectal neoplasia; however, these factors are prone to recall bias. Therefore, it is rather unlikely that a model based on simple, reliable clinical factors alone would ever have sufficient discriminatory power to limit the target population for screening. It is corroborated by the results of a very recent study by Tao S et al. The model that included risk factors missing in the present study (alcohol consumption, red meat consumption, ever regular use of non-steroidal anti-inflammatory drugs, previous colonoscopy and previous detection of polyps), also demonstrated moderate discriminatory value. On the other hand, indirect comparison suggests that the present model's sensitivity and specificity for advanced colorectal neoplasia may be comparable with a single round guaiac faecal occult blood test (mostly due to poor diagnostic performance of guaiac faecal occult blood test for detection of advanced adenomas). Although the model has considerably lower discriminatory power for advanced colorectal neoplasia compared to the one reported for faecal immunochemical tests, it has been shown that combining clinical risk factors with faecal immunochemical test outcome results in improved discrimination. Therefore, it is likely that in the future the clinical factors identified in the model will be combined with results of faecal immunochemical test and/or blood-based biomarkers to select a target population for colonoscopy.
Our study has certain notable features. Despite a large sample size, we have not identified any statistically significant association between diabetes mellitus or aspirin use and the risk of advanced colorectal neoplasia. Although diabetes mellitus is a known risk factor for colorectal cancer, its association with advanced colorectal neoplasia is less certain. The observed lack of association may also be due to the lower-than-expected prevalence of diabetes mellitus in the study cohort, which likely reflects recall bias or self-selection to opportunistic screening.
The lack of a statistically significant association between aspirin use and the risk of advanced colorectal neoplasia in our study may be due to recall bias or missing data regarding the dose and regularity of aspirin use. Moreover, we have not collected the data on other non-steroid anti-inflammatory drugs, which in some studies were analysed together with aspirin.
Advanced neoplasia, not just cancer, was chosen for analysis because it has been suggested as the most appropriate target for endoscopy screening. Although some previous risk prediction models were developed for cancer alone, cancers and advanced neoplasia are surrogate endpoints of primary cancer screening endpoint, which is colorectal cancer mortality. Early detection and treatment of colorectal cancer is associated with a reduction in colorectal cancer mortality, but a detection and removal of adenomas, especially advanced ones, is associated with additional reduction in colorectal cancer incidence and mortality. Therefore, it is uncertain, whether cancer alone or advanced neoplasia is a better endpoint for risk prediction models, but the latter may be particularly suited for use in endoscopy screening.
The primary endpoint of our model was advanced neoplasia located anywhere in the colorectum, therefore, the risk score is not optimised for sigmoidoscopy screening. Nevertheless, we built an additional model to investigate risk factors for detecting distal advanced neoplasia, using sigmoid-descending colon junction as an artificial boundary between distal and proximal colon. The model for the detection of distal advanced neoplasia identified the same risk factors and showed comparable discriminatory power (data not shown).
The limitations of our study require comment. First, the validation process was limited because it was performed in a dataset that was randomly selected from a population recruited in the same setting. The model's performance has not been tested outside Poland or in non-Caucasians. Nonetheless, the National Colorectal Cancer Screening Program recruited participants in 73 centres located in all administrative and geographic regions of Poland, and was open free of charge to all eligible Polish citizens, providing our study with sociodemographic diversity. Moreover, the prevalence of advanced colorectal neoplasia identified in our study was 7.1%, which is within the range of values reported in studies performed in the USA and Europe. Additionally, the adjusted ORs for detecting advanced colorectal neoplasia in various categories of risk factors in our study are similar to that reported in previously published large studies. Notably, in our previous study, performed several years before and in different endoscopy centres, we used the same key to categorise age, family history of colorectal cancer and gender and yielded virtually the same adjusted ORs for each category of variables.
Second, our cohort does not fully cover the recommended age range for screening (people aged 67–75 years were not included) what may limit the applicability of the results for the entire population eligible for screening. On the other hand, by including people at the lower age range for screening (people aged 40–49 years with family history of cancer), this model may help to identify and encourage younger people at considerable risk to undergo screening.
Third, given the cross-sectional design of the study, our risk score is suitable only to predict the detection of advanced neoplasia at the present time, and not the future risk of developing advanced colorectal neoplasia or dying from colorectal cancer.
In summary, we derived and internally validated a model that predicts the likelihood of detecting advanced colorectal neoplasia in asymptomatic Caucasian patients based on age, sex, smoking habits, Body Mass Index, and family history of colorectal cancer. The results of the model were used to develop a simple score that estimates the likelihood of detecting advanced colorectal neoplasia. Once externally validated, the score may be useful for counselling or designing primary prevention studies.
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