Reviewer ’s report  
 
Title: A Novel Collagen Area Fraction Index to Quantitatively As sess Bowel Fibrosis in patients 
with Crohn's Disease  
 
Version: 0 Date: 09 Jul 2018  
 
Reviewer: Antonio Di Sabatino  
 
Reviewer's report:  
 
Aim of Li et al. in this study was to develop and verify a histopathological index, i.e. the 
collagen area fraction, to quantify intestinal fibrosis in Crohn's disease (CD). The manuscript 
showed that the collagen area fraction had a  higher correlation with the degree of stricture 
evaluated macroscopically than with the histological fibrosis score. In addition, the ROC curve 
analysis demonstrated that the collagen area fraction had a slightly higher accuracy for 
diagnosing CD strictur es in comparison to the histological fibrosis score. The repeatability of 
collagen area fraction was also high. On this basis, the Authors concluded that the collagen area 
fraction is a simple and reliable index to quantify the severity of intestinal fibro sis in CD. This 
manuscript suffers from major issues listed below so that it is not worth publishing in this 
Journal.  
 
Major issues  
1. In the introduction Authors argue that a histopathological score is crucial to verify the 
utility of cross -sectional imagi ng and to assess the efficacy of anti -fibrotic drugs. However, the 
prediction of histopathological composition from imaging techniques has been already validated 
in CD fibrosis (Wagner M et al. J Crohns Colitis 2018). Moreover, two papers recently publishe d 
by two groups of international experts on intestinal fibrosis (Danese S et al. Gastroenterology 
2018; Rieder F et al. Aliment Pharmacol Ther 2018) did not include histology as an endpoint in 
trials for anti -fibrotic therapies in CD. Briefly, what is the clinical relevance and utility for this 
histopathological score of intestinal fibrosis in CD?  
 
2. The Authors have to justify the increased CRP and ESR in CD patients. It would mean 
that these patients have a concomitant inflammatory and/or penetrating phen otype. A new index 
to assess intestinal fibrosis would loss accuracy and reliability in CD patients with mixed 
phenotypes rather than in those with purely stricturing phenotype.  
3. The previously published semi -quantitatively histopathological grading sche me (Ref. 9) 
has not been fully validated. Accordingly, using it as grade of fibrosis to assess the efficacy of 
the new histopathological index might be weak and debatable.  
 
Minor issues  
1. In the introduction the Authors do not comment the clinical need to  validate other 
biomarkers of intestinal fibrosis, such as serum microRNAs, serum extracellular matrix proteins, 
serum growth factor and serum antimicrobial antibodies, by citing the manuscript Giuffrida P et 
al. United European Gastroenterol J 2016.  
 
2. The Authors have to specify smoking habit and previous medical therapies in Table 2.  
 
 
 
Are the methods appropriate and well described?  
If not, please specif y what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects requir e further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing inte rests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, 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 t hat 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 competing inter ests 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 you r reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understan d 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 in cluded 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: A Novel Collagen Area Fraction Index to Quantitatively As sess Bowel Fibrosis in patients 
with Crohn's Disease  
 
Version: 0 Date: 09 Jul 2018  
 
Reviewer: Antonio Di Sabatino  
 
Reviewer's report:  
 
Aim of Li et al. in this study was to develop and verify a histopathological index, i.e. the 
collagen area fraction, to quantify intestinal fibrosis in Crohn's disease (CD). The manuscript 
showed that the collagen area fraction had a  higher correlation with the degree of stricture 
evaluated macroscopically than with the histological fibrosis score. In addition, the ROC curve 
analysis demonstrated that the collagen area fraction had a slightly higher accuracy for 
diagnosing CD strictur es in comparison to the histological fibrosis score. The repeatability of 
collagen area fraction was also high. On this basis, the Authors concluded that the collagen area 
fraction is a simple and reliable index to quantify the severity of intestinal fibro sis in CD. This 
manuscript suffers from major issues listed below so that it is not worth publishing in this 
Journal.  
 
Major issues  
1. In the introduction Authors argue that a histopathological score is crucial to verify the 
utility of cross -sectional imagi ng and to assess the efficacy of anti -fibrotic drugs. However, the 
prediction of histopathological composition from imaging techniques has been already validated 
in CD fibrosis (Wagner M et al. J Crohns Colitis 2018). Moreover, two papers recently publishe d 
by two groups of international experts on intestinal fibrosis (Danese S et al. Gastroenterology 
2018; Rieder F et al. Aliment Pharmacol Ther 2018) did not include histology as an endpoint in 
trials for anti -fibrotic therapies in CD. Briefly, what is the clinical relevance and utility for this 
histopathological score of intestinal fibrosis in CD?  
 
2. The Authors have to justify the increased CRP and ESR in CD patients. It would mean 
that these patients have a concomitant inflammatory and/or penetrating phen otype. A new index 
to assess intestinal fibrosis would loss accuracy and reliability in CD patients with mixed 
phenotypes rather than in those with purely stricturing phenotype.  
3. The previously published semi -quantitatively histopathological grading sche me (Ref. 9) 
has not been fully validated. Accordingly, using it as grade of fibrosis to assess the efficacy of 
the new histopathological index might be weak and debatable.  
 
Minor issues  
1. In the introduction the Authors do not comment the clinical need to  validate other 
biomarkers of intestinal fibrosis, such as serum microRNAs, serum extracellular matrix proteins, 
serum growth factor and serum antimicrobial antibodies, by citing the manuscript Giuffrida P et 
al. United European Gastroenterol J 2016.  
 
2. The Authors have to specify smoking habit and previous medical therapies in Table 2.  
 
 
 
Are the methods appropriate and well described?  
If not, please specif y what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects requir e further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing inte rests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, 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 t hat 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 competing inter ests 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 you r reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understan d 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 in cluded 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: A Novel Collagen Area Fraction Index to Quantitatively As sess Bowel Fibrosis in patients 
with Crohn's Disease  
 
Version: 0 Date: 09 Jul 2018  
 
Reviewer: Antonio Di Sabatino  
 
Reviewer's report:  
 
Aim of Li et al. in this study was to develop and verify a histopathological index, i.e. the 
collagen area fraction, to quantify intestinal fibrosis in Crohn's disease (CD). The manuscript 
showed that the collagen area fraction had a  higher correlation with the degree of stricture 
evaluated macroscopically than with the histological fibrosis score. In addition, the ROC curve 
analysis demonstrated that the collagen area fraction had a slightly higher accuracy for 
diagnosing CD strictur es in comparison to the histological fibrosis score. The repeatability of 
collagen area fraction was also high. On this basis, the Authors concluded that the collagen area 
fraction is a simple and reliable index to quantify the severity of intestinal fibro sis in CD. This 
manuscript suffers from major issues listed below so that it is not worth publishing in this 
Journal.  
 
Major issues  
1. In the introduction Authors argue that a histopathological score is crucial to verify the 
utility of cross -sectional imagi ng and to assess the efficacy of anti -fibrotic drugs. However, the 
prediction of histopathological composition from imaging techniques has been already validated 
in CD fibrosis (Wagner M et al. J Crohns Colitis 2018). Moreover, two papers recently publishe d 
by two groups of international experts on intestinal fibrosis (Danese S et al. Gastroenterology 
2018; Rieder F et al. Aliment Pharmacol Ther 2018) did not include histology as an endpoint in 
trials for anti -fibrotic therapies in CD. Briefly, what is the clinical relevance and utility for this 
histopathological score of intestinal fibrosis in CD?  
 
2. The Authors have to justify the increased CRP and ESR in CD patients. It would mean 
that these patients have a concomitant inflammatory and/or penetrating phen otype. A new index 
to assess intestinal fibrosis would loss accuracy and reliability in CD patients with mixed 
phenotypes rather than in those with purely stricturing phenotype.  
3. The previously published semi -quantitatively histopathological grading sche me (Ref. 9) 
has not been fully validated. Accordingly, using it as grade of fibrosis to assess the efficacy of 
the new histopathological index might be weak and debatable.  
 
Minor issues  
1. In the introduction the Authors do not comment the clinical need to  validate other 
biomarkers of intestinal fibrosis, such as serum microRNAs, serum extracellular matrix proteins, 
serum growth factor and serum antimicrobial antibodies, by citing the manuscript Giuffrida P et 
al. United European Gastroenterol J 2016.  
 
2. The Authors have to specify smoking habit and previous medical therapies in Table 2.  
 
 
 
Are the methods appropriate and well described?  
If not, please specif y what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical review?  
If an additional statistical review is recommended, please specify what aspects requir e further 
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing inte rests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, f ees, 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 t hat 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 competing inter ests 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 you r reply is yes to any, please give details below.  
 
I declare that I have no competing interests.  
 
I agree to the open peer review policy of the journal. I understan d 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 in cluded as confidential comments 
to the editors, which will not be published.  
 
I agree to the open peer review policy of the journal  
assistant