Reviewer ’s report  
 
Title: Risk prediction models for colorectal cancer in people with symptoms: a systematic 
review  
 
 
Version: 1 Date: 05 Feb 2016  
 
 
Reviewer: Andrzej  Wincewicz  
 
 
Reviewer's report:  
 
The revised version of paper numbered BMGE -D-15-00187R1 contains some necessary 
corrections and overall a bit more details on commented primary studies for establishment of risk 
prediction models for colorectal cancer. It add itionally is enriched in a fine remark on study 
group designs: namely this one on case control designs versus cohort studies. Thus, the paper 
contains an important call for more serious involvement of experienced epidemiologists in such 
kind of studies.  
 
 
The whole added piece of could be completely misunderstood by readers, the purpose and utility 
of the whole quoted paragraph is unclear:  
 
 
"Further work is also needed to consider whether CRC alone or in combination with advanced 
colorectal neoplasia or adenom a is the most appropriate outcome. This review focused on risk 
prediction models for CRC and only two models, which both reported only limited performance 
data and have not been validated, included advanced colorectal neoplasia or adenoma in addition 
to CR C[20,28]. It is, therefore, not possible from this review alone to know how the addition of 
advanced colorectal neoplasia to CRC as an outcome affects the ability of models to identify 
those with CRC. One study, however, reported the performance of risk mo dels for CRC, 
advanced adenoma, or adenomas 6 -9mm in diameter separately within the same population[31]. 
The discrimination for the CRC model was substantially better (AUROC 0.87 compared to 0.70 
and 0.67 for advanced adenoma and adenomas 6 -9mm in diameter  respectively). This probably 
reflects the fact that many adenomas are asymptomatic and the discriminatory performance for 
advanced adenoma in this symptomatic population is comparable with risk models developed for 
asymptomatic individuals[43]. This sugge sts that models with a combined outcome of advanced 
colorectal neoplasia and CRC may identify those with CRC less well than models with CRC as a 
single outcome. As the priority in patients with symptoms is likely to be identifying those with 
CRC, models fo cusing only on CRC may, therefore, have greater utility in clinical practice."  
 
 
"This suggests that models with a combined outcome of advanced colorectal neoplasia and CRC 
may identify those with CRC less well than models with CRC as a single outcome". Mayb e 
models with a combined outcome of advanced colorectal neoplasia are not completely oriented 
to exclusive identification of pure invasive cases which truly colorectal cancers according to 
WHO definition but also all the cases of high grade colorectal neop lasia with different status of 
invasion according to Stolte et al, later modified Vienna classification ( such lesions progress to 
invasive life threatening disease in inevitable way). In any risk model the clue is also the strict 
definition what is colore ctal carcinoma: in WHO definition it is an epithelial neoplastic growth, 
that invaded through lamina muscularis tunicae mucosae of large intestine (muscularis mucosae) 
into submucosal tunica of large intestine. As for me as pathologist, it is simply clear that 
colorectal adenocarcinoma is usually born from adenoma in adenoma -cancer colorectal 
tumorigenesis pathway. Thus, screening for early lesions like dysplastic ACF and all sorts of 
dysplasia in polyps is of high value in limitation of further progression  of these lesions into 
malignancy. In divagation, we should not lose this primary truth. The risk models are for sure 
somewhere in between… and should be useful. I put it under consideration of the Authors to 
hope that on this stage of the re -review they a re going to find a wise solution for this truly fragile 
and controversial -appearing piece of text. Please emphasize the highlights of your study in the 
text of manuscript: maybe re -writing conclusions as point by point ( points of take home 
message) would provide a much clearer final message to readers.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the ma nuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees,  funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial com peting interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
No competing interest  
 
I agree t o the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Risk prediction models for colorectal cancer in people with symptoms: a systematic 
review  
 
 
Version: 1 Date: 05 Feb 2016  
 
 
Reviewer: Andrzej  Wincewicz  
 
 
Reviewer's report:  
 
The revised version of paper numbered BMGE -D-15-00187R1 contains some necessary 
corrections and overall a bit more details on commented primary studies for establishment of risk 
prediction models for colorectal cancer. It add itionally is enriched in a fine remark on study 
group designs: namely this one on case control designs versus cohort studies. Thus, the paper 
contains an important call for more serious involvement of experienced epidemiologists in such 
kind of studies.  
 
 
The whole added piece of could be completely misunderstood by readers, the purpose and utility 
of the whole quoted paragraph is unclear:  
 
 
"Further work is also needed to consider whether CRC alone or in combination with advanced 
colorectal neoplasia or adenom a is the most appropriate outcome. This review focused on risk 
prediction models for CRC and only two models, which both reported only limited performance 
data and have not been validated, included advanced colorectal neoplasia or adenoma in addition 
to CR C[20,28]. It is, therefore, not possible from this review alone to know how the addition of 
advanced colorectal neoplasia to CRC as an outcome affects the ability of models to identify 
those with CRC. One study, however, reported the performance of risk mo dels for CRC, 
advanced adenoma, or adenomas 6 -9mm in diameter separately within the same population[31]. 
The discrimination for the CRC model was substantially better (AUROC 0.87 compared to 0.70 
and 0.67 for advanced adenoma and adenomas 6 -9mm in diameter  respectively). This probably 
reflects the fact that many adenomas are asymptomatic and the discriminatory performance for 
advanced adenoma in this symptomatic population is comparable with risk models developed for 
asymptomatic individuals[43]. This sugge sts that models with a combined outcome of advanced 
colorectal neoplasia and CRC may identify those with CRC less well than models with CRC as a 
single outcome. As the priority in patients with symptoms is likely to be identifying those with 
CRC, models fo cusing only on CRC may, therefore, have greater utility in clinical practice."  
 
 
"This suggests that models with a combined outcome of advanced colorectal neoplasia and CRC 
may identify those with CRC less well than models with CRC as a single outcome". Mayb e 
models with a combined outcome of advanced colorectal neoplasia are not completely oriented 
to exclusive identification of pure invasive cases which truly colorectal cancers according to 
WHO definition but also all the cases of high grade colorectal neop lasia with different status of 
invasion according to Stolte et al, later modified Vienna classification ( such lesions progress to 
invasive life threatening disease in inevitable way). In any risk model the clue is also the strict 
definition what is colore ctal carcinoma: in WHO definition it is an epithelial neoplastic growth, 
that invaded through lamina muscularis tunicae mucosae of large intestine (muscularis mucosae) 
into submucosal tunica of large intestine. As for me as pathologist, it is simply clear that 
colorectal adenocarcinoma is usually born from adenoma in adenoma -cancer colorectal 
tumorigenesis pathway. Thus, screening for early lesions like dysplastic ACF and all sorts of 
dysplasia in polyps is of high value in limitation of further progression  of these lesions into 
malignancy. In divagation, we should not lose this primary truth. The risk models are for sure 
somewhere in between… and should be useful. I put it under consideration of the Authors to 
hope that on this stage of the re -review they a re going to find a wise solution for this truly fragile 
and controversial -appearing piece of text. Please emphasize the highlights of your study in the 
text of manuscript: maybe re -writing conclusions as point by point ( points of take home 
message) would provide a much clearer final message to readers.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the ma nuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees,  funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial com peting interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
No competing interest  
 
I agree t o the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Risk prediction models for colorectal cancer in people with symptoms: a systematic 
review  
 
 
Version: 1 Date: 05 Feb 2016  
 
 
Reviewer: Andrzej  Wincewicz  
 
 
Reviewer's report:  
 
The revised version of paper numbered BMGE -D-15-00187R1 contains some necessary 
corrections and overall a bit more details on commented primary studies for establishment of risk 
prediction models for colorectal cancer. It add itionally is enriched in a fine remark on study 
group designs: namely this one on case control designs versus cohort studies. Thus, the paper 
contains an important call for more serious involvement of experienced epidemiologists in such 
kind of studies.  
 
 
The whole added piece of could be completely misunderstood by readers, the purpose and utility 
of the whole quoted paragraph is unclear:  
 
 
"Further work is also needed to consider whether CRC alone or in combination with advanced 
colorectal neoplasia or adenom a is the most appropriate outcome. This review focused on risk 
prediction models for CRC and only two models, which both reported only limited performance 
data and have not been validated, included advanced colorectal neoplasia or adenoma in addition 
to CR C[20,28]. It is, therefore, not possible from this review alone to know how the addition of 
advanced colorectal neoplasia to CRC as an outcome affects the ability of models to identify 
those with CRC. One study, however, reported the performance of risk mo dels for CRC, 
advanced adenoma, or adenomas 6 -9mm in diameter separately within the same population[31]. 
The discrimination for the CRC model was substantially better (AUROC 0.87 compared to 0.70 
and 0.67 for advanced adenoma and adenomas 6 -9mm in diameter  respectively). This probably 
reflects the fact that many adenomas are asymptomatic and the discriminatory performance for 
advanced adenoma in this symptomatic population is comparable with risk models developed for 
asymptomatic individuals[43]. This sugge sts that models with a combined outcome of advanced 
colorectal neoplasia and CRC may identify those with CRC less well than models with CRC as a 
single outcome. As the priority in patients with symptoms is likely to be identifying those with 
CRC, models fo cusing only on CRC may, therefore, have greater utility in clinical practice."  
 
 
"This suggests that models with a combined outcome of advanced colorectal neoplasia and CRC 
may identify those with CRC less well than models with CRC as a single outcome". Mayb e 
models with a combined outcome of advanced colorectal neoplasia are not completely oriented 
to exclusive identification of pure invasive cases which truly colorectal cancers according to 
WHO definition but also all the cases of high grade colorectal neop lasia with different status of 
invasion according to Stolte et al, later modified Vienna classification ( such lesions progress to 
invasive life threatening disease in inevitable way). In any risk model the clue is also the strict 
definition what is colore ctal carcinoma: in WHO definition it is an epithelial neoplastic growth, 
that invaded through lamina muscularis tunicae mucosae of large intestine (muscularis mucosae) 
into submucosal tunica of large intestine. As for me as pathologist, it is simply clear that 
colorectal adenocarcinoma is usually born from adenoma in adenoma -cancer colorectal 
tumorigenesis pathway. Thus, screening for early lesions like dysplastic ACF and all sorts of 
dysplasia in polyps is of high value in limitation of further progression  of these lesions into 
malignancy. In divagation, we should not lose this primary truth. The risk models are for sure 
somewhere in between… and should be useful. I put it under consideration of the Authors to 
hope that on this stage of the re -review they a re going to find a wise solution for this truly fragile 
and controversial -appearing piece of text. Please emphasize the highlights of your study in the 
text of manuscript: maybe re -writing conclusions as point by point ( points of take home 
message) would provide a much clearer final message to readers.  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Unable to assess  
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects require further  
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indicate the quality of language in the ma nuscript:  
 
Acceptable  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees,  funding, or salary from 
an organisation that may in any way gain or lose financially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial com peting interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If your reply is yes to any, please give details below.  
 
No competing interest  
 
I agree t o the open peer review policy of the journal. I understand that my name will be included  
on my report to the authors and, if the manuscript is accepted for publication, my named report  
including any attachments I upload will be posted on the website along with the authors'  
responses. I agree for my report to be made available under an Open Access Creative Commons  
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments  
which I do not wish to be included in my named report can be included as confidential comments  
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant