Title: Diagnostic performance of a new algorithm combining simple, non-invasive and
inexpensive tests for predicting the presence of advanced liver fibrosis in patients with chronic
hepatitis B.
Version: 6 Date: 11 Jan 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have addressed the points but not adequately. Similarly,
changes are incomplete. The manuscript still needs major revision.
REQUESTED REVISIONS:
Although the paper has been revised and has improved considerably, but there are still many
points that need correction. Importantly, the presentation of the paper is too complicated for the
readers to follow it. I suggest the authors should stick to just one diagnostic target, eg. either
significant fibrosis or advanced fibrosis in this paper and may produce another paper on the
other target in future. This will make it easier for readers to understand it. The specific points
are given below:
1. In abstract, five variables are given as prothrombin time, platelet count, alanine
aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels, and age. Whereas in
main paper, six variables are given. Which one is correct?
2. In abstract results (line 2), decision tree is written as decision three.
3. Where are the nine leaves of the algorithm?
4. In abstract results, only specificity and NPV are given. Why not other parameters of diagnostic
evaluation such as sensitivity, PPV and accuracy?
5. The primary diagnostic endpoint is unclear. Is it i) a prediction of severe fibrosis, ii) ruling out
severe fibrosis or iii) differentiating among different grades of fibrosis? At some places, three
categories of fibrosis are used in the analysis eg. Figure 1, whereas at other places, a dichotomous
division is provided, eg. #F2 and #3 as relevant diagnostic targets. This creates confusion in
the minds of readers. This should be simplified for the readers to follow. For example, keep
advanced fibrosis as the main outcome measure or significant fibrosis. Currently, both are being
used. Remove the term severe fibrosis.
6. The term severe fibrosis is still being used at multiple places instead of advanced fibrosis.
7. In introduction (main paper), there is no reference for 2015 figures of viral hepatitis and other
infectious diseases causing deaths.
8. All abbreviations must be fully spelled out on first use, eg. HBV, HIV, ALT, AST, GGT, etc.
9. Chronic HBV is abbreviated in Introduction as CHB, but again full terms of chronic HBV
infection are used repeatedly. There should be consistency in the use of abbreviations.
10. In introduction, second paragraph, gamma-glutamyl transpeptidase  is written instead of
gamma-glutamyl transferase (GGT).
11. Write aim of this study instead of aim of our study was----.
12. How and why this is an ancillary study and to what?
13. Reference to Metavir scoring system should be given.
14. In liver biopsy section, it is mentioned that liver biopsies were read by a senior pathologist.
Later on, it is also stated that sections were retrospectively reviewed by a senior pathologist. Was
this pathologist the same one who previously read the biopsies and why this review was needed?
15. In normal tests, only normal values of ALT are given. Why not of PT, Platelet count, AST
and GGT, etc.
16.  A detailed figure legend explaining the decision algorithm be provided with Figure 1 as to
what the numbers in boxes indicate. Give × before 109 of platelet values. Moreover, PT does
not appear anywhere in this algorithm.
17. Did you test for gender and race in the algorithm?
18. In the main results, give values of IQR along with median values of the ages in both groups.
19. In the main results (platelets <192 and ALT <116) should be corrected to (platelets >192
and ALT <116).
20.  In Table 1, last entry is given as F3-F2-F4, which should be F2-F3-F4.
21. All abbreviations  in Tables should be fully spelled out at the bottom in footnotes.
22. Platelet count is given in 103/mm3 in Table 1, while in the main text and algorithm, they
are given as 109.
23. What will happen to patients whose platelets are >192 and <184 according to the algorithm.
Suppose one patient has a platelet count of 186, how to use the algorithm in this case?
24. Explanation of other cut-off points besides platelet and ALT is not given in text in results
as advised by one of the reviewers previously.
25. The numbers and percentages of patients with platelets <184 and age < 38 are not correct
and do not match the numbers given in Figure 1. Rectify these.
26. The number 2226 (85%) is incorrect.
27. The results in text for ROC curves and Figure 1 labeling are incorrect. While Figure A1
shows the AUROC of 0.83 for F0-F1, in the text it is mentioned for significant fibrosis.
28. In the text, it is mentioned that diagnostic thresholds are given in Tables 2 and 3. These are
not diagnostic thresholds but diagnostic results. Moreover, the tables also results for advanced
fibrosis, which are not reflected in the text.
ADDITIONAL REQUESTS/SUGGESTIONS:
The same as listed previously.
Title: Diagnostic performance of a new algorithm combining simple, non-invasive and
inexpensive tests for predicting the presence of advanced liver fibrosis in patients with chronic
hepatitis B.
Version: 6 Date: 11 Jan 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have addressed the points but not adequately. Similarly,
changes are incomplete. The manuscript still needs major revision.
REQUESTED REVISIONS:
Although the paper has been revised and has improved considerably, but there are still many
points that need correction. Importantly, the presentation of the paper is too complicated for the
readers to follow it. I suggest the authors should stick to just one diagnostic target, eg. either
significant fibrosis or advanced fibrosis in this paper and may produce another paper on the
other target in future. This will make it easier for readers to understand it. The specific points
are given below:
1. In abstract, five variables are given as prothrombin time, platelet count, alanine
aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels, and age. Whereas in
main paper, six variables are given. Which one is correct?
2. In abstract results (line 2), decision tree is written as decision three.
3. Where are the nine leaves of the algorithm?
4. In abstract results, only specificity and NPV are given. Why not other parameters of diagnostic
evaluation such as sensitivity, PPV and accuracy?
5. The primary diagnostic endpoint is unclear. Is it i) a prediction of severe fibrosis, ii) ruling out
severe fibrosis or iii) differentiating among different grades of fibrosis? At some places, three
categories of fibrosis are used in the analysis eg. Figure 1, whereas at other places, a dichotomous
division is provided, eg. #F2 and #3 as relevant diagnostic targets. This creates confusion in
the minds of readers. This should be simplified for the readers to follow. For example, keep
advanced fibrosis as the main outcome measure or significant fibrosis. Currently, both are being
used. Remove the term severe fibrosis.
6. The term severe fibrosis is still being used at multiple places instead of advanced fibrosis.
7. In introduction (main paper), there is no reference for 2015 figures of viral hepatitis and other
infectious diseases causing deaths.
8. All abbreviations must be fully spelled out on first use, eg. HBV, HIV, ALT, AST, GGT, etc.
9. Chronic HBV is abbreviated in Introduction as CHB, but again full terms of chronic HBV
infection are used repeatedly. There should be consistency in the use of abbreviations.
10. In introduction, second paragraph, gamma-glutamyl transpeptidase  is written instead of
gamma-glutamyl transferase (GGT).
11. Write aim of this study instead of aim of our study was----.
12. How and why this is an ancillary study and to what?
13. Reference to Metavir scoring system should be given.
14. In liver biopsy section, it is mentioned that liver biopsies were read by a senior pathologist.
Later on, it is also stated that sections were retrospectively reviewed by a senior pathologist. Was
this pathologist the same one who previously read the biopsies and why this review was needed?
15. In normal tests, only normal values of ALT are given. Why not of PT, Platelet count, AST
and GGT, etc.
16.  A detailed figure legend explaining the decision algorithm be provided with Figure 1 as to
what the numbers in boxes indicate. Give × before 109 of platelet values. Moreover, PT does
not appear anywhere in this algorithm.
17. Did you test for gender and race in the algorithm?
18. In the main results, give values of IQR along with median values of the ages in both groups.
19. In the main results (platelets <192 and ALT <116) should be corrected to (platelets >192
and ALT <116).
20.  In Table 1, last entry is given as F3-F2-F4, which should be F2-F3-F4.
21. All abbreviations  in Tables should be fully spelled out at the bottom in footnotes.
22. Platelet count is given in 103/mm3 in Table 1, while in the main text and algorithm, they
are given as 109.
23. What will happen to patients whose platelets are >192 and <184 according to the algorithm.
Suppose one patient has a platelet count of 186, how to use the algorithm in this case?
24. Explanation of other cut-off points besides platelet and ALT is not given in text in results
as advised by one of the reviewers previously.
25. The numbers and percentages of patients with platelets <184 and age < 38 are not correct
and do not match the numbers given in Figure 1. Rectify these.
26. The number 2226 (85%) is incorrect.
27. The results in text for ROC curves and Figure 1 labeling are incorrect. While Figure A1
shows the AUROC of 0.83 for F0-F1, in the text it is mentioned for significant fibrosis.
28. In the text, it is mentioned that diagnostic thresholds are given in Tables 2 and 3. These are
not diagnostic thresholds but diagnostic results. Moreover, the tables also results for advanced
fibrosis, which are not reflected in the text.
ADDITIONAL REQUESTS/SUGGESTIONS:
The same as listed previously.
Please review this paper.
user
Title: Diagnostic performance of a new algorithm combining simple, non-invasive and
inexpensive tests for predicting the presence of advanced liver fibrosis in patients with chronic
hepatitis B.
Version: 6 Date: 11 Jan 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
Yes - the approach is appropriate
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors have addressed the points but not adequately. Similarly,
changes are incomplete. The manuscript still needs major revision.
REQUESTED REVISIONS:
Although the paper has been revised and has improved considerably, but there are still many
points that need correction. Importantly, the presentation of the paper is too complicated for the
readers to follow it. I suggest the authors should stick to just one diagnostic target, eg. either
significant fibrosis or advanced fibrosis in this paper and may produce another paper on the
other target in future. This will make it easier for readers to understand it. The specific points
are given below:
1. In abstract, five variables are given as prothrombin time, platelet count, alanine
aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels, and age. Whereas in
main paper, six variables are given. Which one is correct?
2. In abstract results (line 2), decision tree is written as decision three.
3. Where are the nine leaves of the algorithm?
4. In abstract results, only specificity and NPV are given. Why not other parameters of diagnostic
evaluation such as sensitivity, PPV and accuracy?
5. The primary diagnostic endpoint is unclear. Is it i) a prediction of severe fibrosis, ii) ruling out
severe fibrosis or iii) differentiating among different grades of fibrosis? At some places, three
categories of fibrosis are used in the analysis eg. Figure 1, whereas at other places, a dichotomous
division is provided, eg. #F2 and #3 as relevant diagnostic targets. This creates confusion in
the minds of readers. This should be simplified for the readers to follow. For example, keep
advanced fibrosis as the main outcome measure or significant fibrosis. Currently, both are being
used. Remove the term severe fibrosis.
6. The term severe fibrosis is still being used at multiple places instead of advanced fibrosis.
7. In introduction (main paper), there is no reference for 2015 figures of viral hepatitis and other
infectious diseases causing deaths.
8. All abbreviations must be fully spelled out on first use, eg. HBV, HIV, ALT, AST, GGT, etc.
9. Chronic HBV is abbreviated in Introduction as CHB, but again full terms of chronic HBV
infection are used repeatedly. There should be consistency in the use of abbreviations.
10. In introduction, second paragraph, gamma-glutamyl transpeptidase  is written instead of
gamma-glutamyl transferase (GGT).
11. Write aim of this study instead of aim of our study was----.
12. How and why this is an ancillary study and to what?
13. Reference to Metavir scoring system should be given.
14. In liver biopsy section, it is mentioned that liver biopsies were read by a senior pathologist.
Later on, it is also stated that sections were retrospectively reviewed by a senior pathologist. Was
this pathologist the same one who previously read the biopsies and why this review was needed?
15. In normal tests, only normal values of ALT are given. Why not of PT, Platelet count, AST
and GGT, etc.
16.  A detailed figure legend explaining the decision algorithm be provided with Figure 1 as to
what the numbers in boxes indicate. Give × before 109 of platelet values. Moreover, PT does
not appear anywhere in this algorithm.
17. Did you test for gender and race in the algorithm?
18. In the main results, give values of IQR along with median values of the ages in both groups.
19. In the main results (platelets <192 and ALT <116) should be corrected to (platelets >192
and ALT <116).
20.  In Table 1, last entry is given as F3-F2-F4, which should be F2-F3-F4.
21. All abbreviations  in Tables should be fully spelled out at the bottom in footnotes.
22. Platelet count is given in 103/mm3 in Table 1, while in the main text and algorithm, they
are given as 109.
23. What will happen to patients whose platelets are >192 and <184 according to the algorithm.
Suppose one patient has a platelet count of 186, how to use the algorithm in this case?
24. Explanation of other cut-off points besides platelet and ALT is not given in text in results
as advised by one of the reviewers previously.
25. The numbers and percentages of patients with platelets <184 and age < 38 are not correct
and do not match the numbers given in Figure 1. Rectify these.
26. The number 2226 (85%) is incorrect.
27. The results in text for ROC curves and Figure 1 labeling are incorrect. While Figure A1
shows the AUROC of 0.83 for F0-F1, in the text it is mentioned for significant fibrosis.
28. In the text, it is mentioned that diagnostic thresholds are given in Tables 2 and 3. These are
not diagnostic thresholds but diagnostic results. Moreover, the tables also results for advanced
fibrosis, which are not reflected in the text.
ADDITIONAL REQUESTS/SUGGESTIONS:
The same as listed previously.
assistant