Reviewer’s report  
Title: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Neil Shah  
Reviewer’s report:  
This is an important paper and it is from two well recognised units with excellent IBD 
experience and the idea is a good foundation to more prospective studies in this area. As much as 
i would like  to accepted this paper it is not acceptable in its current form which is great shame 
for such an excellent idea. I would have like the authors to have another go if they are able to 
answer the concerns because of the importance of what the authors are try ing to demonstrate.  
 
Major concerns  
 
1. The paper is hard to read and the English in several places is poor especially the 
discussion which also has several typos within it and the discussion either looks like it 
has been rushed or has run out of ideas  
 
2. The two centre approach to get numbers for the study to be significant is a good approach 
but the outcomes being assessed very much depend on some attempt to identify that the 
two centres have similar outcome approaches. The paper goes into a lot of asses sment on 
bloods parameters, clinical and biological ones but this is not what should be assessed as 
this is universal to both centres. There is clear differences of practice in use of antibiotics 
and Thiopurines and steroids but the outcomes suggested also  hint that centres like Italy 
are more willing to "top Down" rather than British approach so it would be nice to know 
how uniform the management was, also endoscopy very much depends on the threshold 
of the individual so some comparator of practice needs t o be made on endoscopy decision 
pathways if it is to be an outcome measure of severity and I cannot see how the two 
groups can be merged if there is clear practice differences between the units - It will need 
some facts behind it rather than a plain statem ent saying the indications were the same  
 
3. The stats really need some working over , terminology is unclear - multivariate, multiple 
lines regression or multivariable analysis is confused and needs to be written more clearly 
which stats were being used w here with methodology being much clearer than 
currently.Both independent (unpaired) and paired samples were compared. Can they 
clarify when they used paired sample? Chi -square test was used to compare normally 
distributed populations for categorical variab les; Fisher's exact test was used to compare 
non-normally distributed populations for categorical variables;Normal or abnormal 
distribution is in regards of continuous data. We use chi -square test when two variables 
are categorical. Fisher's exact test is used when table have a small expected number of 
cases, which in general means smaller sample. So Chi -Square and Fisher's has got 
nothing in common with normal distribution.The sections about regression are the most 
obscure. It might be correct, it's just a  lack of information what makes it hard to judge e.g  
The children in Group A presented at diagnosis with a more severe disease activity score 
(PCDAI: Mean 38.75 ± 2.7; PUCAI: Mean 47.2 ± 2.5), compared to those in Group B 
(PCDAI: Mean 30.76 ± 2.02; PUCAI:  Mean 41.36 ± 1.8) (p=0.05 for CD, p=0.03 for 
UC) (Table 1A). Nevertheless, the multiple logistic regression analysis did not highlight 
such a strong discrepancy between the two age groups (OR 1.09, 95% CI 1.02 - 1.1) 
(Table 1A).Outcome variable is age gro up and explanatory variable . I'm not really sure 
of the data here and what is being applied where and this needs rethink perhaps with a 
statistician to help.  
 
4. How many cases of IBDU were identified as ever in older children I would have 
expected to se m ore cases of IBDU which is probably  more  in 5 -10 year  
 
5. The lack of data on inpatient and outpatient stays also suggest that there may be 
significant practice differences and approaches to esc escalation of treatment.  
 
6. I wonder if the complexity but advantages of the two centres and trying to merge them 
could be offset by a different strategy where the 40 VS 40 in both units are compared for 
5-10 and >10 and that way the problems of two centre practices being different could be 
overcome as that way  you retain the numbers but the major confounder i.e clinical 
practice could be resolved  
 
7. There are numerous typos and the discussion could do with a lot of improving  
 
8. The conclusion is not borne out by the facts and is a statement that needs to be c larified. 
It needs modifying as the analysis does not lead to the clear stamen that there is no 
difference when biologically there clearly is in terms of bloods, clinical score and 
distribution and i` suspect the way  analysis has been  confounds the biolo gical 
plausibility that there  is  a difference between the groups  
 
9. There are no details on calprotectin numbers and it would be fair enough to have only a 
few values as not commonplace in the early part of this study  
 
10. The retrospective nature is of c ourse a huge problem but I would allow for this as this is a 
foundation paper to looking at other prospective studies so the authors should be too 
concerned as although a clear problem this should be accepted as a start point in an 
important area  
 
11. I rea lly would like to see this paper get through , it has good numbers in a good area it 
needs rewriting , reanalysing and where the data is insufficient that to be highlighted not 
passed over in the text as this is a problem with many studies and should impac t on the 
possible message that these tow units are trying to say  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please spe cify which controls are required in your comments to the authors.  
 
Yes 
 
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 manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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.  
 
I declare that I have no competing interests  
 
I agree to 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 inc luded 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: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Neil Shah  
Reviewer’s report:  
This is an important paper and it is from two well recognised units with excellent IBD 
experience and the idea is a good foundation to more prospective studies in this area. As much as 
i would like  to accepted this paper it is not acceptable in its current form which is great shame 
for such an excellent idea. I would have like the authors to have another go if they are able to 
answer the concerns because of the importance of what the authors are try ing to demonstrate.  
 
Major concerns  
 
1. The paper is hard to read and the English in several places is poor especially the 
discussion which also has several typos within it and the discussion either looks like it 
has been rushed or has run out of ideas  
 
2. The two centre approach to get numbers for the study to be significant is a good approach 
but the outcomes being assessed very much depend on some attempt to identify that the 
two centres have similar outcome approaches. The paper goes into a lot of asses sment on 
bloods parameters, clinical and biological ones but this is not what should be assessed as 
this is universal to both centres. There is clear differences of practice in use of antibiotics 
and Thiopurines and steroids but the outcomes suggested also  hint that centres like Italy 
are more willing to "top Down" rather than British approach so it would be nice to know 
how uniform the management was, also endoscopy very much depends on the threshold 
of the individual so some comparator of practice needs t o be made on endoscopy decision 
pathways if it is to be an outcome measure of severity and I cannot see how the two 
groups can be merged if there is clear practice differences between the units - It will need 
some facts behind it rather than a plain statem ent saying the indications were the same  
 
3. The stats really need some working over , terminology is unclear - multivariate, multiple 
lines regression or multivariable analysis is confused and needs to be written more clearly 
which stats were being used w here with methodology being much clearer than 
currently.Both independent (unpaired) and paired samples were compared. Can they 
clarify when they used paired sample? Chi -square test was used to compare normally 
distributed populations for categorical variab les; Fisher's exact test was used to compare 
non-normally distributed populations for categorical variables;Normal or abnormal 
distribution is in regards of continuous data. We use chi -square test when two variables 
are categorical. Fisher's exact test is used when table have a small expected number of 
cases, which in general means smaller sample. So Chi -Square and Fisher's has got 
nothing in common with normal distribution.The sections about regression are the most 
obscure. It might be correct, it's just a  lack of information what makes it hard to judge e.g  
The children in Group A presented at diagnosis with a more severe disease activity score 
(PCDAI: Mean 38.75 ± 2.7; PUCAI: Mean 47.2 ± 2.5), compared to those in Group B 
(PCDAI: Mean 30.76 ± 2.02; PUCAI:  Mean 41.36 ± 1.8) (p=0.05 for CD, p=0.03 for 
UC) (Table 1A). Nevertheless, the multiple logistic regression analysis did not highlight 
such a strong discrepancy between the two age groups (OR 1.09, 95% CI 1.02 - 1.1) 
(Table 1A).Outcome variable is age gro up and explanatory variable . I'm not really sure 
of the data here and what is being applied where and this needs rethink perhaps with a 
statistician to help.  
 
4. How many cases of IBDU were identified as ever in older children I would have 
expected to se m ore cases of IBDU which is probably  more  in 5 -10 year  
 
5. The lack of data on inpatient and outpatient stays also suggest that there may be 
significant practice differences and approaches to esc escalation of treatment.  
 
6. I wonder if the complexity but advantages of the two centres and trying to merge them 
could be offset by a different strategy where the 40 VS 40 in both units are compared for 
5-10 and >10 and that way the problems of two centre practices being different could be 
overcome as that way  you retain the numbers but the major confounder i.e clinical 
practice could be resolved  
 
7. There are numerous typos and the discussion could do with a lot of improving  
 
8. The conclusion is not borne out by the facts and is a statement that needs to be c larified. 
It needs modifying as the analysis does not lead to the clear stamen that there is no 
difference when biologically there clearly is in terms of bloods, clinical score and 
distribution and i` suspect the way  analysis has been  confounds the biolo gical 
plausibility that there  is  a difference between the groups  
 
9. There are no details on calprotectin numbers and it would be fair enough to have only a 
few values as not commonplace in the early part of this study  
 
10. The retrospective nature is of c ourse a huge problem but I would allow for this as this is a 
foundation paper to looking at other prospective studies so the authors should be too 
concerned as although a clear problem this should be accepted as a start point in an 
important area  
 
11. I rea lly would like to see this paper get through , it has good numbers in a good area it 
needs rewriting , reanalysing and where the data is insufficient that to be highlighted not 
passed over in the text as this is a problem with many studies and should impac t on the 
possible message that these tow units are trying to say  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please spe cify which controls are required in your comments to the authors.  
 
Yes 
 
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 manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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.  
 
I declare that I have no competing interests  
 
I agree to 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 inc luded 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: Clinical course and outcomes of diagnosing Inflammatory Bowel Disease in children 10  
years and under. Retrospective cohort study from t wo tertiary centres in the United Kingdom and  
in Italy.  
 
Version: 0 Date: 15 Oct 2015  
 
Reviewer: Neil Shah  
Reviewer’s report:  
This is an important paper and it is from two well recognised units with excellent IBD 
experience and the idea is a good foundation to more prospective studies in this area. As much as 
i would like  to accepted this paper it is not acceptable in its current form which is great shame 
for such an excellent idea. I would have like the authors to have another go if they are able to 
answer the concerns because of the importance of what the authors are try ing to demonstrate.  
 
Major concerns  
 
1. The paper is hard to read and the English in several places is poor especially the 
discussion which also has several typos within it and the discussion either looks like it 
has been rushed or has run out of ideas  
 
2. The two centre approach to get numbers for the study to be significant is a good approach 
but the outcomes being assessed very much depend on some attempt to identify that the 
two centres have similar outcome approaches. The paper goes into a lot of asses sment on 
bloods parameters, clinical and biological ones but this is not what should be assessed as 
this is universal to both centres. There is clear differences of practice in use of antibiotics 
and Thiopurines and steroids but the outcomes suggested also  hint that centres like Italy 
are more willing to "top Down" rather than British approach so it would be nice to know 
how uniform the management was, also endoscopy very much depends on the threshold 
of the individual so some comparator of practice needs t o be made on endoscopy decision 
pathways if it is to be an outcome measure of severity and I cannot see how the two 
groups can be merged if there is clear practice differences between the units - It will need 
some facts behind it rather than a plain statem ent saying the indications were the same  
 
3. The stats really need some working over , terminology is unclear - multivariate, multiple 
lines regression or multivariable analysis is confused and needs to be written more clearly 
which stats were being used w here with methodology being much clearer than 
currently.Both independent (unpaired) and paired samples were compared. Can they 
clarify when they used paired sample? Chi -square test was used to compare normally 
distributed populations for categorical variab les; Fisher's exact test was used to compare 
non-normally distributed populations for categorical variables;Normal or abnormal 
distribution is in regards of continuous data. We use chi -square test when two variables 
are categorical. Fisher's exact test is used when table have a small expected number of 
cases, which in general means smaller sample. So Chi -Square and Fisher's has got 
nothing in common with normal distribution.The sections about regression are the most 
obscure. It might be correct, it's just a  lack of information what makes it hard to judge e.g  
The children in Group A presented at diagnosis with a more severe disease activity score 
(PCDAI: Mean 38.75 ± 2.7; PUCAI: Mean 47.2 ± 2.5), compared to those in Group B 
(PCDAI: Mean 30.76 ± 2.02; PUCAI:  Mean 41.36 ± 1.8) (p=0.05 for CD, p=0.03 for 
UC) (Table 1A). Nevertheless, the multiple logistic regression analysis did not highlight 
such a strong discrepancy between the two age groups (OR 1.09, 95% CI 1.02 - 1.1) 
(Table 1A).Outcome variable is age gro up and explanatory variable . I'm not really sure 
of the data here and what is being applied where and this needs rethink perhaps with a 
statistician to help.  
 
4. How many cases of IBDU were identified as ever in older children I would have 
expected to se m ore cases of IBDU which is probably  more  in 5 -10 year  
 
5. The lack of data on inpatient and outpatient stays also suggest that there may be 
significant practice differences and approaches to esc escalation of treatment.  
 
6. I wonder if the complexity but advantages of the two centres and trying to merge them 
could be offset by a different strategy where the 40 VS 40 in both units are compared for 
5-10 and >10 and that way the problems of two centre practices being different could be 
overcome as that way  you retain the numbers but the major confounder i.e clinical 
practice could be resolved  
 
7. There are numerous typos and the discussion could do with a lot of improving  
 
8. The conclusion is not borne out by the facts and is a statement that needs to be c larified. 
It needs modifying as the analysis does not lead to the clear stamen that there is no 
difference when biologically there clearly is in terms of bloods, clinical score and 
distribution and i` suspect the way  analysis has been  confounds the biolo gical 
plausibility that there  is  a difference between the groups  
 
9. There are no details on calprotectin numbers and it would be fair enough to have only a 
few values as not commonplace in the early part of this study  
 
10. The retrospective nature is of c ourse a huge problem but I would allow for this as this is a 
foundation paper to looking at other prospective studies so the authors should be too 
concerned as although a clear problem this should be accepted as a start point in an 
important area  
 
11. I rea lly would like to see this paper get through , it has good numbers in a good area it 
needs rewriting , reanalysing and where the data is insufficient that to be highlighted not 
passed over in the text as this is a problem with many studies and should impac t on the 
possible message that these tow units are trying to say  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
Does the work include the necessary controls?  
If not, please spe cify which controls are required in your comments to the authors.  
 
Yes 
 
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 manuscript o r 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 statist ical review  
 
Quality of written Engl ish 
Please indicate the quality of language in the manuscript:  
 
Not suitable for publication unless extensively edited  
 
Declaration of competing interests  
Please complete a declaration of competing interests, consideri ng 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, e ither now or in the future?  
 
2. Do you hold any stocks or shares in an organis ation that may in any way gain or lose 
financially from the publication of this manuscript, e ither 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 fin ancial competing interests?  
 
6. Do you have any non -financial competing interests  in relation to this pa per? 
 
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.  
 
I declare that I have no competing interests  
 
I agree to 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 inc luded 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