Title: Association of alkaline phosphatase to albumin ratio with all-cause mortality in critically
ill patients with cirrhosis: a retrospective study
Version: 1 Date: 27 Mar 2025
Reviewer's report:
Comment 1
Line 45-46:  Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> The conclusion of the abstract is far reaching and inaccurate. APAR is an index that is
associated with increased all-cause mortality risk in patients with cirrhosis. This study does not
provide evidence that monitoring of APAR would reduce the risk of death.
Comment 2
Line 53-56: As the end stage of multiple chronic liver diseases, cirrhosis can not only cause a
series of serious complications such as portal hypertension (PHT), hepatorenal syndrome (HRS),
and ascites, but also significantly increase the risk of diabetes mellitus (DM ), chronic kidney
disease (CKD), and adverse cardiovascular events, which seriously affects patients' quality of
life [2-4].
> This statement is not accurate - there is no evidence that cirrhosis significantly increases the
risk of diabetes mellitus
Comment 3
I would like to know greater details about the IRB approval process for this study as the study is
a retrospective analysis of a database of medical records from patients admitted to ICU of Beth
Israel Deaconess Medical Centre in Boston, but none of the authors are from that institution.
Comment 4
It is not clear which ALP and albumin values were used to calculate the APAR. I would assume
it would be the first ALP and albumin values that were done on admission to the ICU. The
authors should state this explicitly for clarity for the readers.
Comment 5
What was the reasoning for dividing the cohort into 3 equal groups based on the APAR levels?
Why not just evaluate the APAR as a continuous variable to study its impact on all-cause
mortality?
Comment 6
Was the APAR (as a continuous variable) a significant predictor of 365-day mortality? This
sentence states that it was a significant predictor for 28-day and 90-day mortality but does not
mention 365-day mortality although the data in Table 2 seems to suggest it is. Can the authors
please clarify this?
Comment 7
Line 228-229: In this retrospective cohort study, which included 2109 patients, we observed a
higher risk of all-cause mortality in patients with severe cirrhosis  who had higher APAR levels
> This statement is not data-supported as this study did not stratify patients according to severity
of cirrhosis. There is no data on the Child Pugh score or MELD score of the cohort.
Comment 8
Line 237-254: This whole paragraph needs to be rewritten as it is very confusing. The authors
have studied ALP/albumin ratio (APAR) and have shown that high APAR is associated with
higher mortality. However, they are comparing their results with other publications [15-19] that
report albumin/ALP ratio (AAPR). Hence AAPR is not synonymous with APAR since one
is the inverse of the other, and it is misleading to present it as the authors have done in this
paragraph, stating that “AAPR/APAR, a newly discovered biomarker for assessing the prognosis
of critically ill patients …”
Comment 9
How does the AAPR compare with MELD and ALBI scores in the prediction of all-cause
mortality?
Comment 10
Line 326-328: Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> Suggest to rephrase this conclusion statement in the abstract and manuscript as the data in
this study has shown that monitoring of APAR can identify high-risk groups at an early stage,
but the ability to “achieve accurate management” and “reduce the risk of death” by monitoring
APAR is speculative and unproven hence should be removed from the concluding statement.
Title: Association of alkaline phosphatase to albumin ratio with all-cause mortality in critically
ill patients with cirrhosis: a retrospective study
Version: 1 Date: 27 Mar 2025
Reviewer's report:
Comment 1
Line 45-46:  Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> The conclusion of the abstract is far reaching and inaccurate. APAR is an index that is
associated with increased all-cause mortality risk in patients with cirrhosis. This study does not
provide evidence that monitoring of APAR would reduce the risk of death.
Comment 2
Line 53-56: As the end stage of multiple chronic liver diseases, cirrhosis can not only cause a
series of serious complications such as portal hypertension (PHT), hepatorenal syndrome (HRS),
and ascites, but also significantly increase the risk of diabetes mellitus (DM ), chronic kidney
disease (CKD), and adverse cardiovascular events, which seriously affects patients' quality of
life [2-4].
> This statement is not accurate - there is no evidence that cirrhosis significantly increases the
risk of diabetes mellitus
Comment 3
I would like to know greater details about the IRB approval process for this study as the study is
a retrospective analysis of a database of medical records from patients admitted to ICU of Beth
Israel Deaconess Medical Centre in Boston, but none of the authors are from that institution.
Comment 4
It is not clear which ALP and albumin values were used to calculate the APAR. I would assume
it would be the first ALP and albumin values that were done on admission to the ICU. The
authors should state this explicitly for clarity for the readers.
Comment 5
What was the reasoning for dividing the cohort into 3 equal groups based on the APAR levels?
Why not just evaluate the APAR as a continuous variable to study its impact on all-cause
mortality?
Comment 6
Was the APAR (as a continuous variable) a significant predictor of 365-day mortality? This
sentence states that it was a significant predictor for 28-day and 90-day mortality but does not
mention 365-day mortality although the data in Table 2 seems to suggest it is. Can the authors
please clarify this?
Comment 7
Line 228-229: In this retrospective cohort study, which included 2109 patients, we observed a
higher risk of all-cause mortality in patients with severe cirrhosis  who had higher APAR levels
> This statement is not data-supported as this study did not stratify patients according to severity
of cirrhosis. There is no data on the Child Pugh score or MELD score of the cohort.
Comment 8
Line 237-254: This whole paragraph needs to be rewritten as it is very confusing. The authors
have studied ALP/albumin ratio (APAR) and have shown that high APAR is associated with
higher mortality. However, they are comparing their results with other publications [15-19] that
report albumin/ALP ratio (AAPR). Hence AAPR is not synonymous with APAR since one
is the inverse of the other, and it is misleading to present it as the authors have done in this
paragraph, stating that “AAPR/APAR, a newly discovered biomarker for assessing the prognosis
of critically ill patients …”
Comment 9
How does the AAPR compare with MELD and ALBI scores in the prediction of all-cause
mortality?
Comment 10
Line 326-328: Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> Suggest to rephrase this conclusion statement in the abstract and manuscript as the data in
this study has shown that monitoring of APAR can identify high-risk groups at an early stage,
but the ability to “achieve accurate management” and “reduce the risk of death” by monitoring
APAR is speculative and unproven hence should be removed from the concluding statement.
Please review this paper.
user
Title: Association of alkaline phosphatase to albumin ratio with all-cause mortality in critically
ill patients with cirrhosis: a retrospective study
Version: 1 Date: 27 Mar 2025
Reviewer's report:
Comment 1
Line 45-46:  Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> The conclusion of the abstract is far reaching and inaccurate. APAR is an index that is
associated with increased all-cause mortality risk in patients with cirrhosis. This study does not
provide evidence that monitoring of APAR would reduce the risk of death.
Comment 2
Line 53-56: As the end stage of multiple chronic liver diseases, cirrhosis can not only cause a
series of serious complications such as portal hypertension (PHT), hepatorenal syndrome (HRS),
and ascites, but also significantly increase the risk of diabetes mellitus (DM ), chronic kidney
disease (CKD), and adverse cardiovascular events, which seriously affects patients' quality of
life [2-4].
> This statement is not accurate - there is no evidence that cirrhosis significantly increases the
risk of diabetes mellitus
Comment 3
I would like to know greater details about the IRB approval process for this study as the study is
a retrospective analysis of a database of medical records from patients admitted to ICU of Beth
Israel Deaconess Medical Centre in Boston, but none of the authors are from that institution.
Comment 4
It is not clear which ALP and albumin values were used to calculate the APAR. I would assume
it would be the first ALP and albumin values that were done on admission to the ICU. The
authors should state this explicitly for clarity for the readers.
Comment 5
What was the reasoning for dividing the cohort into 3 equal groups based on the APAR levels?
Why not just evaluate the APAR as a continuous variable to study its impact on all-cause
mortality?
Comment 6
Was the APAR (as a continuous variable) a significant predictor of 365-day mortality? This
sentence states that it was a significant predictor for 28-day and 90-day mortality but does not
mention 365-day mortality although the data in Table 2 seems to suggest it is. Can the authors
please clarify this?
Comment 7
Line 228-229: In this retrospective cohort study, which included 2109 patients, we observed a
higher risk of all-cause mortality in patients with severe cirrhosis  who had higher APAR levels
> This statement is not data-supported as this study did not stratify patients according to severity
of cirrhosis. There is no data on the Child Pugh score or MELD score of the cohort.
Comment 8
Line 237-254: This whole paragraph needs to be rewritten as it is very confusing. The authors
have studied ALP/albumin ratio (APAR) and have shown that high APAR is associated with
higher mortality. However, they are comparing their results with other publications [15-19] that
report albumin/ALP ratio (AAPR). Hence AAPR is not synonymous with APAR since one
is the inverse of the other, and it is misleading to present it as the authors have done in this
paragraph, stating that “AAPR/APAR, a newly discovered biomarker for assessing the prognosis
of critically ill patients …”
Comment 9
How does the AAPR compare with MELD and ALBI scores in the prediction of all-cause
mortality?
Comment 10
Line 326-328: Dynamic monitoring of APAR can help to identify high-risk groups at an early
stage, achieve accurate management, and reduce the risk of death in patients with severe liver
cirrhosis.
> Suggest to rephrase this conclusion statement in the abstract and manuscript as the data in
this study has shown that monitoring of APAR can identify high-risk groups at an early stage,
but the ability to “achieve accurate management” and “reduce the risk of death” by monitoring
APAR is speculative and unproven hence should be removed from the concluding statement.
assistant