Reviewer ’s report  
 
Title: Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic 
review and me ta-analysis of randomized controlled trials  
 
Version: 0 Date: 28 Sep 2016  
 
Reviewer: Sajan Jiv Singh Nagpal  
 
Reviewer's report:  
 
The meta -analysis is done very methodically and systematically. However, I do have concerns 
regarding the generalizability of the results. The authors correctly point out that the study 
involves only Japanese pati ents. Even after that is taken into account, it should be noted that the 
4 randomized control trials eventually included are actually just by 2 groups of investigators.  
Secondly, meta -analyses are done with the intent of pooling data together to resolve c onflicting 
signals from existing literature. In this case it appears that all the 4 studies included already show 
consistent benefits of the drug in question, so I am not sure what the authors intend to achieve. In 
its current form, it only serves the purp ose of a useful review article.  The only instance among 
all the Forest plots, where the total risk ratio is different from one of the included studies, is in 
the case of Total Adverse events, and even in that case, it is not significant. The overall resul ts 
are expected because of the obviously apparent results of the included RCTs.  
Thirdly, due to the difference in the sample size of the component RCTs, a sensitivity analysis 
should be performed to ensure one of the studies is not having an undue influen ce on the final 
relative risk. One way to do this would be to exclude each of the studies at a time and re -analyze 
the remaining. In this case, I anticipate that although the relative risk might change, the 
conclusions will be the same.  
Lastly, even thoug h the included studies are randomized control trials, the authors have not used 
a formal scale for study assessment (e.g the Newcastle Ottawa scale) to comment on study 
quality. The authors have also not commented on the coefficient of agreement between th e 
authors in the section where 'disagreements were resolved by discussion' -Page 6, Line 14.  
Overall, although I feel that the study adds somewhat to the existing literature by combining the 
limited existing literature on Ramisetron, a more appropriate tim e to do this study would be 
when we have more (and possibly conflicting) data on Ramisetron  
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 neces sary controls?  
If not, please specify 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.  
 
Yes 
 
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 am able to assess the statis tics 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
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 o f 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  
 
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 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: Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic 
review and me ta-analysis of randomized controlled trials  
 
Version: 0 Date: 28 Sep 2016  
 
Reviewer: Sajan Jiv Singh Nagpal  
 
Reviewer's report:  
 
The meta -analysis is done very methodically and systematically. However, I do have concerns 
regarding the generalizability of the results. The authors correctly point out that the study 
involves only Japanese pati ents. Even after that is taken into account, it should be noted that the 
4 randomized control trials eventually included are actually just by 2 groups of investigators.  
Secondly, meta -analyses are done with the intent of pooling data together to resolve c onflicting 
signals from existing literature. In this case it appears that all the 4 studies included already show 
consistent benefits of the drug in question, so I am not sure what the authors intend to achieve. In 
its current form, it only serves the purp ose of a useful review article.  The only instance among 
all the Forest plots, where the total risk ratio is different from one of the included studies, is in 
the case of Total Adverse events, and even in that case, it is not significant. The overall resul ts 
are expected because of the obviously apparent results of the included RCTs.  
Thirdly, due to the difference in the sample size of the component RCTs, a sensitivity analysis 
should be performed to ensure one of the studies is not having an undue influen ce on the final 
relative risk. One way to do this would be to exclude each of the studies at a time and re -analyze 
the remaining. In this case, I anticipate that although the relative risk might change, the 
conclusions will be the same.  
Lastly, even thoug h the included studies are randomized control trials, the authors have not used 
a formal scale for study assessment (e.g the Newcastle Ottawa scale) to comment on study 
quality. The authors have also not commented on the coefficient of agreement between th e 
authors in the section where 'disagreements were resolved by discussion' -Page 6, Line 14.  
Overall, although I feel that the study adds somewhat to the existing literature by combining the 
limited existing literature on Ramisetron, a more appropriate tim e to do this study would be 
when we have more (and possibly conflicting) data on Ramisetron  
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 neces sary controls?  
If not, please specify 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.  
 
Yes 
 
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 am able to assess the statis tics 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
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 o f 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  
 
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 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: Ramosetron for the treatment of irritable bowel syndrome with diarrhea: a systematic 
review and me ta-analysis of randomized controlled trials  
 
Version: 0 Date: 28 Sep 2016  
 
Reviewer: Sajan Jiv Singh Nagpal  
 
Reviewer's report:  
 
The meta -analysis is done very methodically and systematically. However, I do have concerns 
regarding the generalizability of the results. The authors correctly point out that the study 
involves only Japanese pati ents. Even after that is taken into account, it should be noted that the 
4 randomized control trials eventually included are actually just by 2 groups of investigators.  
Secondly, meta -analyses are done with the intent of pooling data together to resolve c onflicting 
signals from existing literature. In this case it appears that all the 4 studies included already show 
consistent benefits of the drug in question, so I am not sure what the authors intend to achieve. In 
its current form, it only serves the purp ose of a useful review article.  The only instance among 
all the Forest plots, where the total risk ratio is different from one of the included studies, is in 
the case of Total Adverse events, and even in that case, it is not significant. The overall resul ts 
are expected because of the obviously apparent results of the included RCTs.  
Thirdly, due to the difference in the sample size of the component RCTs, a sensitivity analysis 
should be performed to ensure one of the studies is not having an undue influen ce on the final 
relative risk. One way to do this would be to exclude each of the studies at a time and re -analyze 
the remaining. In this case, I anticipate that although the relative risk might change, the 
conclusions will be the same.  
Lastly, even thoug h the included studies are randomized control trials, the authors have not used 
a formal scale for study assessment (e.g the Newcastle Ottawa scale) to comment on study 
quality. The authors have also not commented on the coefficient of agreement between th e 
authors in the section where 'disagreements were resolved by discussion' -Page 6, Line 14.  
Overall, although I feel that the study adds somewhat to the existing literature by combining the 
limited existing literature on Ramisetron, a more appropriate tim e to do this study would be 
when we have more (and possibly conflicting) data on Ramisetron  
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 neces sary controls?  
If not, please specify 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.  
 
Yes 
 
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 am able to assess the statis tics 
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
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 o f 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  
 
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 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