Reviewer’s report
Title: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
3 
Date: 
19 Nov 2020
Reviewer's report:
Thank you for the revision. The manuscript has been improved substantially.
Still, I think some of the tables should be refined, and it would be better to have
less tables and figures in the manuscript.
e.g. 
- There were multiple or a combination of figures and tables under the same
name (for example, Figure 12 actually had 2 figures and 1 table).
- The table at the bottom of Table 2 can be dismissed, because all of the
information were explained in the text of the manuscript.
- The threshold table for the ROC curve (table 3) is not really necessary, and
might be omitted; the ROC should be sorted under "Figure", not "Table".
Under the COMPARISON OF PRE-OPERATIVE AND POST-OPERATIVE
DAY 7 TOTAL BILIRUBIN LEVEL section
- I think it would be better to separately compare the the changes between pre-
and post-operative total bilirubin in the complicated and uncomplicated group,
rather than in all patients.
I believe it would give a clearer picture about the role of total hyperbilirubinemia
in complicated appendicitis (total bilirubinemia in the the complicated group
reduced significantly, while the level remained the same in the uncomplicated
group).
- Please change the data in the Table 2 accordingly.
For the multivariable analysis
- There were too many variable included, and that might make the model
unstable. Please considered adding only the variables that were significant in
univariate analysis (for example, ALT, AST, ALP were not significant, and
shouldn't be included in the model). Likewise, please also consider adding the
variable that seems strongly significant in the univariate analysis to the model
(e.g. fecolith and periappendiceal collection).
- Some continuous variable that did not have an exact cut-off point (for example:
appendix diameter in USG (mm), duration of pain (hrs)), should be included as
is. The logistic regression can accept and analyze continuous variable. Don't
make up a cut-off point unless a proper statistical analysis of those cut-off had
been done
for example:
(i) the 9 hrs cut-off for the duration of pain --> 9 hours is the means of the
duration in the uncomplicated group; that means approximately half of patients
with uncomplicated appendicitis would have pain more than 9 hours. So this is
not an appropriate cut-off value.
(ii) the 8 mm cut-off for the appendiceal diameter --> the cut-off diameter used
in the univariate analysis was 7.6 mm, why choosing 8 mm in the multivariate
analysis? 
Thank you
Publons Reviewer Recognition
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Publons’ privacy policy 
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Yes
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
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: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
3 
Date: 
19 Nov 2020
Reviewer's report:
Thank you for the revision. The manuscript has been improved substantially.
Still, I think some of the tables should be refined, and it would be better to have
less tables and figures in the manuscript.
e.g. 
- There were multiple or a combination of figures and tables under the same
name (for example, Figure 12 actually had 2 figures and 1 table).
- The table at the bottom of Table 2 can be dismissed, because all of the
information were explained in the text of the manuscript.
- The threshold table for the ROC curve (table 3) is not really necessary, and
might be omitted; the ROC should be sorted under "Figure", not "Table".
Under the COMPARISON OF PRE-OPERATIVE AND POST-OPERATIVE
DAY 7 TOTAL BILIRUBIN LEVEL section
- I think it would be better to separately compare the the changes between pre-
and post-operative total bilirubin in the complicated and uncomplicated group,
rather than in all patients.
I believe it would give a clearer picture about the role of total hyperbilirubinemia
in complicated appendicitis (total bilirubinemia in the the complicated group
reduced significantly, while the level remained the same in the uncomplicated
group).
- Please change the data in the Table 2 accordingly.
For the multivariable analysis
- There were too many variable included, and that might make the model
unstable. Please considered adding only the variables that were significant in
univariate analysis (for example, ALT, AST, ALP were not significant, and
shouldn't be included in the model). Likewise, please also consider adding the
variable that seems strongly significant in the univariate analysis to the model
(e.g. fecolith and periappendiceal collection).
- Some continuous variable that did not have an exact cut-off point (for example:
appendix diameter in USG (mm), duration of pain (hrs)), should be included as
is. The logistic regression can accept and analyze continuous variable. Don't
make up a cut-off point unless a proper statistical analysis of those cut-off had
been done
for example:
(i) the 9 hrs cut-off for the duration of pain --> 9 hours is the means of the
duration in the uncomplicated group; that means approximately half of patients
with uncomplicated appendicitis would have pain more than 9 hours. So this is
not an appropriate cut-off value.
(ii) the 8 mm cut-off for the appendiceal diameter --> the cut-off diameter used
in the univariate analysis was 7.6 mm, why choosing 8 mm in the multivariate
analysis? 
Thank you
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
Yes
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
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: 
Evaluation of Role of Hyperbilirubinemia as a New Diagnostic Marker of
Complicated Appendicitis.
Version: 
3 
Date: 
19 Nov 2020
Reviewer's report:
Thank you for the revision. The manuscript has been improved substantially.
Still, I think some of the tables should be refined, and it would be better to have
less tables and figures in the manuscript.
e.g. 
- There were multiple or a combination of figures and tables under the same
name (for example, Figure 12 actually had 2 figures and 1 table).
- The table at the bottom of Table 2 can be dismissed, because all of the
information were explained in the text of the manuscript.
- The threshold table for the ROC curve (table 3) is not really necessary, and
might be omitted; the ROC should be sorted under "Figure", not "Table".
Under the COMPARISON OF PRE-OPERATIVE AND POST-OPERATIVE
DAY 7 TOTAL BILIRUBIN LEVEL section
- I think it would be better to separately compare the the changes between pre-
and post-operative total bilirubin in the complicated and uncomplicated group,
rather than in all patients.
I believe it would give a clearer picture about the role of total hyperbilirubinemia
in complicated appendicitis (total bilirubinemia in the the complicated group
reduced significantly, while the level remained the same in the uncomplicated
group).
- Please change the data in the Table 2 accordingly.
For the multivariable analysis
- There were too many variable included, and that might make the model
unstable. Please considered adding only the variables that were significant in
univariate analysis (for example, ALT, AST, ALP were not significant, and
shouldn't be included in the model). Likewise, please also consider adding the
variable that seems strongly significant in the univariate analysis to the model
(e.g. fecolith and periappendiceal collection).
- Some continuous variable that did not have an exact cut-off point (for example:
appendix diameter in USG (mm), duration of pain (hrs)), should be included as
is. The logistic regression can accept and analyze continuous variable. Don't
make up a cut-off point unless a proper statistical analysis of those cut-off had
been done
for example:
(i) the 9 hrs cut-off for the duration of pain --> 9 hours is the means of the
duration in the uncomplicated group; that means approximately half of patients
with uncomplicated appendicitis would have pain more than 9 hours. So this is
not an appropriate cut-off value.
(ii) the 8 mm cut-off for the appendiceal diameter --> the cut-off diameter used
in the univariate analysis was 7.6 mm, why choosing 8 mm in the multivariate
analysis? 
Thank you
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
Yes
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
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
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