Title: Association of Alpha-1 Acid Glycoprotein with Hepatic Steatosis and Liver Fibrosis
Among Women: A Population-Based Study
Version: 2 Date: 31 May 2025
Reviewer's report:
This manuscript explores the association between alpha-1-acid glycoprotein (AGP), an acute-
phase inflammatory marker, and hepatic steatosis and fibrosis among U.S. women using
NHANES data. The authors used multivariable regression and nonlinear modeling to examine
these relationships. The study is well-timed and methodologically sound, and it provides novel
insight into the nonlinear association between AGP and liver stiffness (LSM). However, there
are key areas requiring clarification, especially in the methods, results interpretation, and
presentation. The writing also needs revision to improve clarity and grammar.
Major Comments
Abstract omits key nonlinear finding
The nonlinear association between AGP and liver stiffness is central to the paper but is not
mentioned in the abstract. This result should be included to present a complete summary of the
findings.
Causal language must be avoided
The cross-sectional nature of the study limits causal inference. The authors should revise any
phrases implying causation in the abstract, discussion, and conclusion.
Study population restriction not explained
The analysis is limited to women aged 18–49, but this is not explained in the manuscript. The
reason—data availability in NHANES—should be clearly stated in the Methods section.
Possible overadjustment in multivariable models
Including BMI, waist circumference, and hs-CRP together in Model 3 may introduce
overadjustment. The authors should explain the rationale for including all three and consider a
sensitivity analysis excluding hs-CRP.
Clarify survey design usage
It is unclear whether survey weights, strata, and clusters were applied to all analyses, especially
nonlinear models and subgroup analyses. Please confirm this and state it clearly in the Statistical
Methods section.
Subgroup findings over-interpreted
Subgroup differences (e.g., by BMI and ethnicity) are emphasized in the text despite borderline
interaction p-values. These should be presented more cautiously, noting the possibility of limited
statistical power or false positives.
Threshold value inconsistently reported
The threshold in the nonlinear analysis is stated as both #0.04 g/L and 0.05 g/L. This
inconsistency needs to be corrected and the correct value reported uniformly in the results,
figures, and discussion.
Nonlinear findings underdeveloped in the discussion
The L-shaped association between AGP and LSM deserves further interpretation. Possible
explanations (e.g., reverse causation, medication use, or immunosuppression in advanced
disease) should be discussed in more detail.
Minor Comments
Table formatting
Tables 1 and 2 could be reformatted for readability. Align columns, standardize row labels (e.g.,
race/ethnicity), and define all abbreviations in footnotes.
Figure captions need clarification
For Figures 2 and 3, clearly state that the plots are based on fully adjusted models and list which
covariates were included.
Improve clarity in writing
The manuscript still contains awkward sentence structures and grammatical errors. Some
sections (especially the discussion) are repetitive. A professional language edit is strongly
recommended.
Conclusion should reflect nonlinear result
The conclusion currently focuses on CAP. A brief mention of the nonlinear finding with LSM
and the need for further study would strengthen the message.
Reference AGP mechanism more concisely in the introduction
The introduction spends several paragraphs on inflammation and liver disease but should
focus more clearly on AGP’s proposed biological role and prior evidence linking it to hepatic
outcomes.
Title: Association of Alpha-1 Acid Glycoprotein with Hepatic Steatosis and Liver Fibrosis
Among Women: A Population-Based Study
Version: 2 Date: 31 May 2025
Reviewer's report:
This manuscript explores the association between alpha-1-acid glycoprotein (AGP), an acute-
phase inflammatory marker, and hepatic steatosis and fibrosis among U.S. women using
NHANES data. The authors used multivariable regression and nonlinear modeling to examine
these relationships. The study is well-timed and methodologically sound, and it provides novel
insight into the nonlinear association between AGP and liver stiffness (LSM). However, there
are key areas requiring clarification, especially in the methods, results interpretation, and
presentation. The writing also needs revision to improve clarity and grammar.
Major Comments
Abstract omits key nonlinear finding
The nonlinear association between AGP and liver stiffness is central to the paper but is not
mentioned in the abstract. This result should be included to present a complete summary of the
findings.
Causal language must be avoided
The cross-sectional nature of the study limits causal inference. The authors should revise any
phrases implying causation in the abstract, discussion, and conclusion.
Study population restriction not explained
The analysis is limited to women aged 18–49, but this is not explained in the manuscript. The
reason—data availability in NHANES—should be clearly stated in the Methods section.
Possible overadjustment in multivariable models
Including BMI, waist circumference, and hs-CRP together in Model 3 may introduce
overadjustment. The authors should explain the rationale for including all three and consider a
sensitivity analysis excluding hs-CRP.
Clarify survey design usage
It is unclear whether survey weights, strata, and clusters were applied to all analyses, especially
nonlinear models and subgroup analyses. Please confirm this and state it clearly in the Statistical
Methods section.
Subgroup findings over-interpreted
Subgroup differences (e.g., by BMI and ethnicity) are emphasized in the text despite borderline
interaction p-values. These should be presented more cautiously, noting the possibility of limited
statistical power or false positives.
Threshold value inconsistently reported
The threshold in the nonlinear analysis is stated as both #0.04 g/L and 0.05 g/L. This
inconsistency needs to be corrected and the correct value reported uniformly in the results,
figures, and discussion.
Nonlinear findings underdeveloped in the discussion
The L-shaped association between AGP and LSM deserves further interpretation. Possible
explanations (e.g., reverse causation, medication use, or immunosuppression in advanced
disease) should be discussed in more detail.
Minor Comments
Table formatting
Tables 1 and 2 could be reformatted for readability. Align columns, standardize row labels (e.g.,
race/ethnicity), and define all abbreviations in footnotes.
Figure captions need clarification
For Figures 2 and 3, clearly state that the plots are based on fully adjusted models and list which
covariates were included.
Improve clarity in writing
The manuscript still contains awkward sentence structures and grammatical errors. Some
sections (especially the discussion) are repetitive. A professional language edit is strongly
recommended.
Conclusion should reflect nonlinear result
The conclusion currently focuses on CAP. A brief mention of the nonlinear finding with LSM
and the need for further study would strengthen the message.
Reference AGP mechanism more concisely in the introduction
The introduction spends several paragraphs on inflammation and liver disease but should
focus more clearly on AGP’s proposed biological role and prior evidence linking it to hepatic
outcomes.
Please review this paper.
user
Title: Association of Alpha-1 Acid Glycoprotein with Hepatic Steatosis and Liver Fibrosis
Among Women: A Population-Based Study
Version: 2 Date: 31 May 2025
Reviewer's report:
This manuscript explores the association between alpha-1-acid glycoprotein (AGP), an acute-
phase inflammatory marker, and hepatic steatosis and fibrosis among U.S. women using
NHANES data. The authors used multivariable regression and nonlinear modeling to examine
these relationships. The study is well-timed and methodologically sound, and it provides novel
insight into the nonlinear association between AGP and liver stiffness (LSM). However, there
are key areas requiring clarification, especially in the methods, results interpretation, and
presentation. The writing also needs revision to improve clarity and grammar.
Major Comments
Abstract omits key nonlinear finding
The nonlinear association between AGP and liver stiffness is central to the paper but is not
mentioned in the abstract. This result should be included to present a complete summary of the
findings.
Causal language must be avoided
The cross-sectional nature of the study limits causal inference. The authors should revise any
phrases implying causation in the abstract, discussion, and conclusion.
Study population restriction not explained
The analysis is limited to women aged 18–49, but this is not explained in the manuscript. The
reason—data availability in NHANES—should be clearly stated in the Methods section.
Possible overadjustment in multivariable models
Including BMI, waist circumference, and hs-CRP together in Model 3 may introduce
overadjustment. The authors should explain the rationale for including all three and consider a
sensitivity analysis excluding hs-CRP.
Clarify survey design usage
It is unclear whether survey weights, strata, and clusters were applied to all analyses, especially
nonlinear models and subgroup analyses. Please confirm this and state it clearly in the Statistical
Methods section.
Subgroup findings over-interpreted
Subgroup differences (e.g., by BMI and ethnicity) are emphasized in the text despite borderline
interaction p-values. These should be presented more cautiously, noting the possibility of limited
statistical power or false positives.
Threshold value inconsistently reported
The threshold in the nonlinear analysis is stated as both #0.04 g/L and 0.05 g/L. This
inconsistency needs to be corrected and the correct value reported uniformly in the results,
figures, and discussion.
Nonlinear findings underdeveloped in the discussion
The L-shaped association between AGP and LSM deserves further interpretation. Possible
explanations (e.g., reverse causation, medication use, or immunosuppression in advanced
disease) should be discussed in more detail.
Minor Comments
Table formatting
Tables 1 and 2 could be reformatted for readability. Align columns, standardize row labels (e.g.,
race/ethnicity), and define all abbreviations in footnotes.
Figure captions need clarification
For Figures 2 and 3, clearly state that the plots are based on fully adjusted models and list which
covariates were included.
Improve clarity in writing
The manuscript still contains awkward sentence structures and grammatical errors. Some
sections (especially the discussion) are repetitive. A professional language edit is strongly
recommended.
Conclusion should reflect nonlinear result
The conclusion currently focuses on CAP. A brief mention of the nonlinear finding with LSM
and the need for further study would strengthen the message.
Reference AGP mechanism more concisely in the introduction
The introduction spends several paragraphs on inflammation and liver disease but should
focus more clearly on AGP’s proposed biological role and prior evidence linking it to hepatic
outcomes.
assistant