Reviewer’s report
Title: 
Abdominal pain in patients with inflammatory bowel disease – Association with single-nucleotide
polymorphisms prevalent in irritable bowel syndrome and clinical management
Version: 
3 
Date: 
25 Sep 2020
Reviewer's report:
The authors have attempted to address each of the major criticisms I previously provided. 
While the
current version is improved, I still have concerns about the conceptual underpinnings of this work and
how the current version of this manuscript is constructed.
1) Background, pages 4-5 -> While the authors have revised and added sentences relating to the purpose
for undertaking this study, the rationale for looking at SNPs associated with IBS as potential predictors of
any outcomes in IBD (pain or otherwise) still remains confusing and convoluted. The authors focus much
of their text on relating the fact that abdominal pain is common to both IBS and IBD but nothing on
potential underlying pathophysiological factors that might make that the case. 
Although they are
purportedly looking for genetic factors/signals shared by IBS and IBD that might predict certain outcomes
in the latter, they do not spend much time providing hypotheses as to why these conditions should
demonstrate commonality in this regard. 
There are certainly no shortage of potential reasons out there,
either. 
Examples could include infectious etiologies, alterations in epithelial barrier function and/or
abnormalities in brain/nerve/gut interactions, to name a few. 
The authors state in their response letter that
their real focus is looking at pain in IBD. 
Clarifying that identification of IBD-IBS patients was not the
goal was helpful. However, too little is known about how the IBS-associated SNPs described actually
influence IBS pathogenesis to necessarily infer that any or all of them necessarily affect abdominal pain
perception (the primary objective described at the end of the Background section). 
This also makes
explaining the choice of SNPs for this analysis more confusing than it has to be (see below).
2) Methods, pages 8-9 -> The decision-making regarding the choice of SNPs is still a bit unclear. For the
purposes of this particular study, why not focus only on genes or SNPs common to both IBS and IBD
identified in the GWAS studies the authors reference? 
For other targets, the authors should clearly explain
how they were chosen. Additionally, while the authors have beefed up their analysis related to patient pain
experience, the rationale behind using maximum pain as the primary assessment of this symptom (as
opposed to a simpler binary measure such as the presence or absence of abdominal pain) still remains
unclear. 
They include one reference demonstrating an inverse correlation between abdominal pain severity
and quality of life in IBS. While this point is reasonably important in general, it doesn't make use of a
continuous variable like maximum pain particularly easy to apply in this analysis. 
3) Additionally, there are several instances of missing articles or inappropriate use of words. 
I would work
through the manuscript with an independent reviewer/editor to identify and correct these as appropriate.
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons upon
publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt
of this review and update your profile 
as per your settings and their policy. If you are not registered with
Publons, you will receive an email from them asking you to register in order for them to be able to
recognize your review on your new profile page. Publons may use the Review Data to generate derivative
metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such
information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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 competing 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.
I declare that I have no competing interests
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Reviewer’s report
Title: 
Abdominal pain in patients with inflammatory bowel disease – Association with single-nucleotide
polymorphisms prevalent in irritable bowel syndrome and clinical management
Version: 
3 
Date: 
25 Sep 2020
Reviewer's report:
The authors have attempted to address each of the major criticisms I previously provided. 
While the
current version is improved, I still have concerns about the conceptual underpinnings of this work and
how the current version of this manuscript is constructed.
1) Background, pages 4-5 -> While the authors have revised and added sentences relating to the purpose
for undertaking this study, the rationale for looking at SNPs associated with IBS as potential predictors of
any outcomes in IBD (pain or otherwise) still remains confusing and convoluted. The authors focus much
of their text on relating the fact that abdominal pain is common to both IBS and IBD but nothing on
potential underlying pathophysiological factors that might make that the case. 
Although they are
purportedly looking for genetic factors/signals shared by IBS and IBD that might predict certain outcomes
in the latter, they do not spend much time providing hypotheses as to why these conditions should
demonstrate commonality in this regard. 
There are certainly no shortage of potential reasons out there,
either. 
Examples could include infectious etiologies, alterations in epithelial barrier function and/or
abnormalities in brain/nerve/gut interactions, to name a few. 
The authors state in their response letter that
their real focus is looking at pain in IBD. 
Clarifying that identification of IBD-IBS patients was not the
goal was helpful. However, too little is known about how the IBS-associated SNPs described actually
influence IBS pathogenesis to necessarily infer that any or all of them necessarily affect abdominal pain
perception (the primary objective described at the end of the Background section). 
This also makes
explaining the choice of SNPs for this analysis more confusing than it has to be (see below).
2) Methods, pages 8-9 -> The decision-making regarding the choice of SNPs is still a bit unclear. For the
purposes of this particular study, why not focus only on genes or SNPs common to both IBS and IBD
identified in the GWAS studies the authors reference? 
For other targets, the authors should clearly explain
how they were chosen. Additionally, while the authors have beefed up their analysis related to patient pain
experience, the rationale behind using maximum pain as the primary assessment of this symptom (as
opposed to a simpler binary measure such as the presence or absence of abdominal pain) still remains
unclear. 
They include one reference demonstrating an inverse correlation between abdominal pain severity
and quality of life in IBS. While this point is reasonably important in general, it doesn't make use of a
continuous variable like maximum pain particularly easy to apply in this analysis. 
3) Additionally, there are several instances of missing articles or inappropriate use of words. 
I would work
through the manuscript with an independent reviewer/editor to identify and correct these as appropriate.
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons upon
publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt
of this review and update your profile 
as per your settings and their policy. If you are not registered with
Publons, you will receive an email from them asking you to register in order for them to be able to
recognize your review on your new profile page. Publons may use the Review Data to generate derivative
metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such
information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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 competing 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.
I declare that I have no competing interests
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Abdominal pain in patients with inflammatory bowel disease – Association with single-nucleotide
polymorphisms prevalent in irritable bowel syndrome and clinical management
Version: 
3 
Date: 
25 Sep 2020
Reviewer's report:
The authors have attempted to address each of the major criticisms I previously provided. 
While the
current version is improved, I still have concerns about the conceptual underpinnings of this work and
how the current version of this manuscript is constructed.
1) Background, pages 4-5 -> While the authors have revised and added sentences relating to the purpose
for undertaking this study, the rationale for looking at SNPs associated with IBS as potential predictors of
any outcomes in IBD (pain or otherwise) still remains confusing and convoluted. The authors focus much
of their text on relating the fact that abdominal pain is common to both IBS and IBD but nothing on
potential underlying pathophysiological factors that might make that the case. 
Although they are
purportedly looking for genetic factors/signals shared by IBS and IBD that might predict certain outcomes
in the latter, they do not spend much time providing hypotheses as to why these conditions should
demonstrate commonality in this regard. 
There are certainly no shortage of potential reasons out there,
either. 
Examples could include infectious etiologies, alterations in epithelial barrier function and/or
abnormalities in brain/nerve/gut interactions, to name a few. 
The authors state in their response letter that
their real focus is looking at pain in IBD. 
Clarifying that identification of IBD-IBS patients was not the
goal was helpful. However, too little is known about how the IBS-associated SNPs described actually
influence IBS pathogenesis to necessarily infer that any or all of them necessarily affect abdominal pain
perception (the primary objective described at the end of the Background section). 
This also makes
explaining the choice of SNPs for this analysis more confusing than it has to be (see below).
2) Methods, pages 8-9 -> The decision-making regarding the choice of SNPs is still a bit unclear. For the
purposes of this particular study, why not focus only on genes or SNPs common to both IBS and IBD
identified in the GWAS studies the authors reference? 
For other targets, the authors should clearly explain
how they were chosen. Additionally, while the authors have beefed up their analysis related to patient pain
experience, the rationale behind using maximum pain as the primary assessment of this symptom (as
opposed to a simpler binary measure such as the presence or absence of abdominal pain) still remains
unclear. 
They include one reference demonstrating an inverse correlation between abdominal pain severity
and quality of life in IBS. While this point is reasonably important in general, it doesn't make use of a
continuous variable like maximum pain particularly easy to apply in this analysis. 
3) Additionally, there are several instances of missing articles or inappropriate use of words. 
I would work
through the manuscript with an independent reviewer/editor to identify and correct these as appropriate.
Publons Reviewer Recognition
. Springer Nature can send verification of this review directly to Publons
(a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on
the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted to Publons upon
publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt
of this review and update your profile 
as per your settings and their policy. If you are not registered with
Publons, you will receive an email from them asking you to register in order for them to be able to
recognize your review on your new profile page. Publons may use the Review Data to generate derivative
metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such
information. For example, Publons may verify your record as a reviewer by updating your profile
published on its webservice if you have registered for such service or help editors to identify candidate
reviewers. Please find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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 competing 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.
I declare that I have no competing interests
Reviewer Publication Consent.
 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
) if this manuscript is
accepted for publication. Any comments that I do not wish to be included in the published report have
been included as confidential comments to the editor, which will not be published.
If you are not happy for us to publish this report, please contact the editorial office before completing
the review.
If you wish, you can include your name in your published report. Please note you must decide whether
to include your name at the start of the process and confirm this decision whenever prompted. If you
change your decision later, we will not be able to publish your name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name with my report. (default)
Is the study design appropriate to answer the research question (including the use of appropriate controls),
and are the conclusions supported by the evidence presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free from apparent
manipulation?
Yes
assistant