Title: Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B
Version: 0 Date: 09 Mar 2024
Reviewer's report:
The text provides a comprehensive overview of the significance of hepatitis B virus (HBV)
infection as a global health issue, particularly its impact on chronic liver disease and the
development of liver fibrosis. It highlights the importance of early diagnosis and intervention in
managing chronic hepatitis B (CHB) to prevent progression to more severe conditions such as
liver fibrosis, cirrhosis, and hepatocellular carcinoma.
The study design and methodology are detailed, including the selection criteria for participants,
laboratory testing procedures, and histological examination methods. The inclusion of a large
sample size (1210 patients with CHB) from a single hospital strengthens the study's statistical
power, although the reliance on retrospective data may introduce selection bias.
I have some suggestions in order to improve the quality of the manuscript.
Please define your groups correctly-. On page 3 you are talking about …” Six hundred and
thirty-one (52.1%) and 275 (22.7%) patients had significant fibrosis (#S2) and advanced fibrosis
(#S3), respectively….”  This numbers equal to 906 patients, where are the rest 304 patients?
On page 6 in Results your statement is …” A total of 935 control cases and 275 cases were
included in this study….” Which group was control cases and which group is the cases?
Page 3 In Abstract first line “….glutamic oxaloacetic transaminase (AST)/ alanine transaminase
(ALT)…..”  it is either serum glutamic oxaloacetic transaminase (SGOT) or aspartate
aminotransferase (AST) and ALT should be alanine aminotransferase as mentioned in you
abbreviations (page 1).  In my opinion you should keep the name- aspartate aminotransferase
(AST) not glutamic oxaloacetic transaminase . The same comment applies to page 4 in
Introduction, line 18 “…..These include the glutamic oxaloacetic transaminase (AST)/platelet
count (PLT) ratio index (APRI )…..”Please keep the abbreviations consistent and in line with
the full name of the enzyme(s) through out the whole manuscript as well as in the Figures  and
Tables.
Page 3 in Results: First line: Six hundred and thirty-one (52.1%) and 275 (22.7%) patients…
please keep the same format: either words or numbers
Page 4 in Introduction”…… and the difficulty of generalizing it to primary care hospitals in
China in a short period of time…….”  what do you mean by this? Please rephrase it
Page 4 in Introduction “….AST/ alanine transaminase (ALT),…” in my opinion there is no
need to use alanine transaminase since you have explained the abbreviation in the text above, it
would be better to be only AST/ALT ratio. As a plus, again you are using mixed names alanine
transaminase and above you are referring to it as alanine aminotransferase. Again, please be
consistent throughout the text
Page 4 in Introduction “…..Recently, a series of noninvasive liver fibrosis models have been
developed to partially replace liver puncture biopsy….” Please use liver biopsy or percutaneous
liver biopsy. Please change throughout your text liver puncture with liver biopsy .
Page 5 “….These indicators are calculated and have to be determined from the literature….”
Please elaborate this sentence. What do you mean?
Page 5 …” For routine blood tests, a fully automated hematology analyzer (Myriad 6800PLUS)
was used; for liver function, fasting blood glucose (FBG), lipids, uric acid (UA) and other
indicators, a fully automated biochemical analyzer (Beckman AU5800) was used; for routine
coagulation, a fully automated coagulation analyzer (Wolfen Hemo CELL750) was used…”.
Please be more precise with this paragraph, use the semi colons precisely. What do you mean
by other indicators? Please be precise.  The same is for routine coagulation, what exactly do you
mean with routine coagulation.
Page 6 …” the percentage of HbeAg-positive…” please correct to HBeAg-positive. Please
correct everywhere throughout your manuscript.
Page 8 in Discussion…” Therefore, non-invasive fibrosis assessment based on serology has been
promoted by progressively more scholars”…. Please be precise-it is not serology but serologic
tests.
Page 8 in Discussion..” were significantly higher and PT was significantly lower than those
in the non-significant fibrosis group, suggesting that the liver tissue in the significant fibrosis
group was more severely damaged and the WBC was significantly abnormal…” This is the first
time that you are mentioning the white blood cells and they are not included in your table(s).
Please show the relevance of your comment, and if it is relevant to your study please include
the data in the Tables.
Page 9 in Discussion …” The results of clinical studies that included 312 and 135 patients with
CHB, showed that the diagnostic performance of GRP was superior to that of APRI and FIB-4,
respectively, and the AUC for diagnosing liver fibrosis at stage F # 2 was…” What was? The
sentence is not finished.
Page 9 In discussion ….” Our further study also found that the AUC of the four noninvasive
predictors, AST/ALT, APRI, FIB-4 and GPR, were significantly higher for HBeAg-positive
than for HBeAg-negative AUCs, suggesting that the predictive efficacy of these predictors for
HBeAg-positive patients was better than for HBeAg-negative patients and the predictive value
of GPR was better than the other predictors. This result is also consistent with the natural course
of patients with CHB, who have a short duration of immune tolerance, mild immune response,
HBeAg positivity, and mild liver tissue inflammation and fibrosis. 31-33……”
Please elaborate on why these non-invasive tests exhibit better predictive efficacy in HBeAg-
positive patients compared to HBeAg-negative patients. I don't believe this discrepancy is solely
due to the duration of the HBeAg-positive phase, which can be divided into the immunotolerant
and immune active phases, not just immunotolerant. The latter phase is not always characterized
by mild liver tissue inflammation. In my view, the explanation should be sought in other
characteristics unique to these distinct phases of chronic hepatitis B (CHB), both in the HBeAg-
positive and HBeAg-negative phases. Given that your patient cohort includes individuals aged
16 years and above, it is anticipated that younger age groups, if HBeAg-positive, would likely
fall into the immunotolerant phase. To enhance the quality of data and predictive ability of non-
invasive tests, I suggest stratifying patients into different stages of chronic hepatitis B within the
HBeAg-positive and HBeAg-negative groups. This stratification would better reflect the natural
history of the disease, especially considering one of your exclusion criteria pertains to treated
patients (either with interferon therapy or NUCs)
In the discussion, please pay attention to all four non-invasive diagnostic tests being explored
in your manuscript, and compare your findings with those reported in the literature.
In Tables; There is no data about Female
In Tables: There is a graph for smoking and drinking. One of your exclusion criteria was history
of smoking and alcohol abuse. Why are those patients included in your study?
Please improve the quality of the English language.
Title: Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B
Version: 0 Date: 09 Mar 2024
Reviewer's report:
The text provides a comprehensive overview of the significance of hepatitis B virus (HBV)
infection as a global health issue, particularly its impact on chronic liver disease and the
development of liver fibrosis. It highlights the importance of early diagnosis and intervention in
managing chronic hepatitis B (CHB) to prevent progression to more severe conditions such as
liver fibrosis, cirrhosis, and hepatocellular carcinoma.
The study design and methodology are detailed, including the selection criteria for participants,
laboratory testing procedures, and histological examination methods. The inclusion of a large
sample size (1210 patients with CHB) from a single hospital strengthens the study's statistical
power, although the reliance on retrospective data may introduce selection bias.
I have some suggestions in order to improve the quality of the manuscript.
Please define your groups correctly-. On page 3 you are talking about …” Six hundred and
thirty-one (52.1%) and 275 (22.7%) patients had significant fibrosis (#S2) and advanced fibrosis
(#S3), respectively….”  This numbers equal to 906 patients, where are the rest 304 patients?
On page 6 in Results your statement is …” A total of 935 control cases and 275 cases were
included in this study….” Which group was control cases and which group is the cases?
Page 3 In Abstract first line “….glutamic oxaloacetic transaminase (AST)/ alanine transaminase
(ALT)…..”  it is either serum glutamic oxaloacetic transaminase (SGOT) or aspartate
aminotransferase (AST) and ALT should be alanine aminotransferase as mentioned in you
abbreviations (page 1).  In my opinion you should keep the name- aspartate aminotransferase
(AST) not glutamic oxaloacetic transaminase . The same comment applies to page 4 in
Introduction, line 18 “…..These include the glutamic oxaloacetic transaminase (AST)/platelet
count (PLT) ratio index (APRI )…..”Please keep the abbreviations consistent and in line with
the full name of the enzyme(s) through out the whole manuscript as well as in the Figures  and
Tables.
Page 3 in Results: First line: Six hundred and thirty-one (52.1%) and 275 (22.7%) patients…
please keep the same format: either words or numbers
Page 4 in Introduction”…… and the difficulty of generalizing it to primary care hospitals in
China in a short period of time…….”  what do you mean by this? Please rephrase it
Page 4 in Introduction “….AST/ alanine transaminase (ALT),…” in my opinion there is no
need to use alanine transaminase since you have explained the abbreviation in the text above, it
would be better to be only AST/ALT ratio. As a plus, again you are using mixed names alanine
transaminase and above you are referring to it as alanine aminotransferase. Again, please be
consistent throughout the text
Page 4 in Introduction “…..Recently, a series of noninvasive liver fibrosis models have been
developed to partially replace liver puncture biopsy….” Please use liver biopsy or percutaneous
liver biopsy. Please change throughout your text liver puncture with liver biopsy .
Page 5 “….These indicators are calculated and have to be determined from the literature….”
Please elaborate this sentence. What do you mean?
Page 5 …” For routine blood tests, a fully automated hematology analyzer (Myriad 6800PLUS)
was used; for liver function, fasting blood glucose (FBG), lipids, uric acid (UA) and other
indicators, a fully automated biochemical analyzer (Beckman AU5800) was used; for routine
coagulation, a fully automated coagulation analyzer (Wolfen Hemo CELL750) was used…”.
Please be more precise with this paragraph, use the semi colons precisely. What do you mean
by other indicators? Please be precise.  The same is for routine coagulation, what exactly do you
mean with routine coagulation.
Page 6 …” the percentage of HbeAg-positive…” please correct to HBeAg-positive. Please
correct everywhere throughout your manuscript.
Page 8 in Discussion…” Therefore, non-invasive fibrosis assessment based on serology has been
promoted by progressively more scholars”…. Please be precise-it is not serology but serologic
tests.
Page 8 in Discussion..” were significantly higher and PT was significantly lower than those
in the non-significant fibrosis group, suggesting that the liver tissue in the significant fibrosis
group was more severely damaged and the WBC was significantly abnormal…” This is the first
time that you are mentioning the white blood cells and they are not included in your table(s).
Please show the relevance of your comment, and if it is relevant to your study please include
the data in the Tables.
Page 9 in Discussion …” The results of clinical studies that included 312 and 135 patients with
CHB, showed that the diagnostic performance of GRP was superior to that of APRI and FIB-4,
respectively, and the AUC for diagnosing liver fibrosis at stage F # 2 was…” What was? The
sentence is not finished.
Page 9 In discussion ….” Our further study also found that the AUC of the four noninvasive
predictors, AST/ALT, APRI, FIB-4 and GPR, were significantly higher for HBeAg-positive
than for HBeAg-negative AUCs, suggesting that the predictive efficacy of these predictors for
HBeAg-positive patients was better than for HBeAg-negative patients and the predictive value
of GPR was better than the other predictors. This result is also consistent with the natural course
of patients with CHB, who have a short duration of immune tolerance, mild immune response,
HBeAg positivity, and mild liver tissue inflammation and fibrosis. 31-33……”
Please elaborate on why these non-invasive tests exhibit better predictive efficacy in HBeAg-
positive patients compared to HBeAg-negative patients. I don't believe this discrepancy is solely
due to the duration of the HBeAg-positive phase, which can be divided into the immunotolerant
and immune active phases, not just immunotolerant. The latter phase is not always characterized
by mild liver tissue inflammation. In my view, the explanation should be sought in other
characteristics unique to these distinct phases of chronic hepatitis B (CHB), both in the HBeAg-
positive and HBeAg-negative phases. Given that your patient cohort includes individuals aged
16 years and above, it is anticipated that younger age groups, if HBeAg-positive, would likely
fall into the immunotolerant phase. To enhance the quality of data and predictive ability of non-
invasive tests, I suggest stratifying patients into different stages of chronic hepatitis B within the
HBeAg-positive and HBeAg-negative groups. This stratification would better reflect the natural
history of the disease, especially considering one of your exclusion criteria pertains to treated
patients (either with interferon therapy or NUCs)
In the discussion, please pay attention to all four non-invasive diagnostic tests being explored
in your manuscript, and compare your findings with those reported in the literature.
In Tables; There is no data about Female
In Tables: There is a graph for smoking and drinking. One of your exclusion criteria was history
of smoking and alcohol abuse. Why are those patients included in your study?
Please improve the quality of the English language.
Please review this paper.
user
Title: Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B
Version: 0 Date: 09 Mar 2024
Reviewer's report:
The text provides a comprehensive overview of the significance of hepatitis B virus (HBV)
infection as a global health issue, particularly its impact on chronic liver disease and the
development of liver fibrosis. It highlights the importance of early diagnosis and intervention in
managing chronic hepatitis B (CHB) to prevent progression to more severe conditions such as
liver fibrosis, cirrhosis, and hepatocellular carcinoma.
The study design and methodology are detailed, including the selection criteria for participants,
laboratory testing procedures, and histological examination methods. The inclusion of a large
sample size (1210 patients with CHB) from a single hospital strengthens the study's statistical
power, although the reliance on retrospective data may introduce selection bias.
I have some suggestions in order to improve the quality of the manuscript.
Please define your groups correctly-. On page 3 you are talking about …” Six hundred and
thirty-one (52.1%) and 275 (22.7%) patients had significant fibrosis (#S2) and advanced fibrosis
(#S3), respectively….”  This numbers equal to 906 patients, where are the rest 304 patients?
On page 6 in Results your statement is …” A total of 935 control cases and 275 cases were
included in this study….” Which group was control cases and which group is the cases?
Page 3 In Abstract first line “….glutamic oxaloacetic transaminase (AST)/ alanine transaminase
(ALT)…..”  it is either serum glutamic oxaloacetic transaminase (SGOT) or aspartate
aminotransferase (AST) and ALT should be alanine aminotransferase as mentioned in you
abbreviations (page 1).  In my opinion you should keep the name- aspartate aminotransferase
(AST) not glutamic oxaloacetic transaminase . The same comment applies to page 4 in
Introduction, line 18 “…..These include the glutamic oxaloacetic transaminase (AST)/platelet
count (PLT) ratio index (APRI )…..”Please keep the abbreviations consistent and in line with
the full name of the enzyme(s) through out the whole manuscript as well as in the Figures  and
Tables.
Page 3 in Results: First line: Six hundred and thirty-one (52.1%) and 275 (22.7%) patients…
please keep the same format: either words or numbers
Page 4 in Introduction”…… and the difficulty of generalizing it to primary care hospitals in
China in a short period of time…….”  what do you mean by this? Please rephrase it
Page 4 in Introduction “….AST/ alanine transaminase (ALT),…” in my opinion there is no
need to use alanine transaminase since you have explained the abbreviation in the text above, it
would be better to be only AST/ALT ratio. As a plus, again you are using mixed names alanine
transaminase and above you are referring to it as alanine aminotransferase. Again, please be
consistent throughout the text
Page 4 in Introduction “…..Recently, a series of noninvasive liver fibrosis models have been
developed to partially replace liver puncture biopsy….” Please use liver biopsy or percutaneous
liver biopsy. Please change throughout your text liver puncture with liver biopsy .
Page 5 “….These indicators are calculated and have to be determined from the literature….”
Please elaborate this sentence. What do you mean?
Page 5 …” For routine blood tests, a fully automated hematology analyzer (Myriad 6800PLUS)
was used; for liver function, fasting blood glucose (FBG), lipids, uric acid (UA) and other
indicators, a fully automated biochemical analyzer (Beckman AU5800) was used; for routine
coagulation, a fully automated coagulation analyzer (Wolfen Hemo CELL750) was used…”.
Please be more precise with this paragraph, use the semi colons precisely. What do you mean
by other indicators? Please be precise.  The same is for routine coagulation, what exactly do you
mean with routine coagulation.
Page 6 …” the percentage of HbeAg-positive…” please correct to HBeAg-positive. Please
correct everywhere throughout your manuscript.
Page 8 in Discussion…” Therefore, non-invasive fibrosis assessment based on serology has been
promoted by progressively more scholars”…. Please be precise-it is not serology but serologic
tests.
Page 8 in Discussion..” were significantly higher and PT was significantly lower than those
in the non-significant fibrosis group, suggesting that the liver tissue in the significant fibrosis
group was more severely damaged and the WBC was significantly abnormal…” This is the first
time that you are mentioning the white blood cells and they are not included in your table(s).
Please show the relevance of your comment, and if it is relevant to your study please include
the data in the Tables.
Page 9 in Discussion …” The results of clinical studies that included 312 and 135 patients with
CHB, showed that the diagnostic performance of GRP was superior to that of APRI and FIB-4,
respectively, and the AUC for diagnosing liver fibrosis at stage F # 2 was…” What was? The
sentence is not finished.
Page 9 In discussion ….” Our further study also found that the AUC of the four noninvasive
predictors, AST/ALT, APRI, FIB-4 and GPR, were significantly higher for HBeAg-positive
than for HBeAg-negative AUCs, suggesting that the predictive efficacy of these predictors for
HBeAg-positive patients was better than for HBeAg-negative patients and the predictive value
of GPR was better than the other predictors. This result is also consistent with the natural course
of patients with CHB, who have a short duration of immune tolerance, mild immune response,
HBeAg positivity, and mild liver tissue inflammation and fibrosis. 31-33……”
Please elaborate on why these non-invasive tests exhibit better predictive efficacy in HBeAg-
positive patients compared to HBeAg-negative patients. I don't believe this discrepancy is solely
due to the duration of the HBeAg-positive phase, which can be divided into the immunotolerant
and immune active phases, not just immunotolerant. The latter phase is not always characterized
by mild liver tissue inflammation. In my view, the explanation should be sought in other
characteristics unique to these distinct phases of chronic hepatitis B (CHB), both in the HBeAg-
positive and HBeAg-negative phases. Given that your patient cohort includes individuals aged
16 years and above, it is anticipated that younger age groups, if HBeAg-positive, would likely
fall into the immunotolerant phase. To enhance the quality of data and predictive ability of non-
invasive tests, I suggest stratifying patients into different stages of chronic hepatitis B within the
HBeAg-positive and HBeAg-negative groups. This stratification would better reflect the natural
history of the disease, especially considering one of your exclusion criteria pertains to treated
patients (either with interferon therapy or NUCs)
In the discussion, please pay attention to all four non-invasive diagnostic tests being explored
in your manuscript, and compare your findings with those reported in the literature.
In Tables; There is no data about Female
In Tables: There is a graph for smoking and drinking. One of your exclusion criteria was history
of smoking and alcohol abuse. Why are those patients included in your study?
Please improve the quality of the English language.
assistant