Title: AISI and MASLD: A Nonlinear Association in U.S. Adults (NHANES 2017-2020)
Version: 1 Date: 16 Jun 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I would like to congratulate the authors on their work, "Exploring the Nonlinear Relationship
Between Systemic Inflammation and Hepatic Steatosis: Evidence from NHANES 2017-2020."
In this study, Xiao et al. aimed to investigates the relationship between systemic inflammation,
measured by the Aggregate Index of Systemic Inflammation (AISI), and nonalcoholic fatty liver
disease (NAFLD) in a representative U.S. adult population. By leveraging NHANES data, the
authors aim to fill a gap in understanding how this novel composite biomarker correlates with
NAFLD prevalence, particularly exploring nonlinear associations and potential clinical utility.
The study’s focus on AISI, a low-cost, readily available metric—adds practical value for early
NAFLD detection in resource-limited settings.
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most prevalent chronic liver
disease, impacting about 30% of global individuals, with the potential to progress to advanced
hepatic fibrosis and end-stage liver diseases eventually [*]. In June 2023, a multi-society
committee of international experts was gathered, and new terminology was adopted to reduce
stigma and increase disease awareness [**]. A new terminology, Steatotic liver disease (SLD),
replaces “fatty liver disease” as the umbrella term. Under subgroups of SLD, NAFLD has been
renamed as metabolic dysfunction-associated Steatotic liver disease (MASLD) [**]. NAFLD/
MASLD is closely related to metabolic syndrome (MetS) and its associated components of
hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity[***].
(*:doi: 10.1097/HEP.0000000000000004, **: doi: 10.1016/j.jhep.2023.06.003, ***  doi:
10.1111/apt.17308).
The authors tried to contribute to this field of research with new findings; nevertheless, there is
an observation for which sufficient justification must be obtained.
In general:
1. The language is generally clear, but some minor grammatical errors and awkward phrasings
could be improved.
- Replace phrases like "multivariable logistic regression" with simpler terms (e.g., "adjusted
analysis") where possible.
- Some sentences are overly long (e.g., the Introduction’s first paragraph). Break them up for
clarity.
- Consider having the manuscript proofread by a native English speaker or a professional editing
service.
2. Abbreviations must be fully written at their first appearance.
In Title:
1. The title should indicate the age and locality of the study population at which the National
Health and Nutrition Examination Survey (NHANES) was performed. The title is informative,
but could be more concise. I suggest “ AISI and NAFLD: A Nonlinear Association in U.S.
Adults (NHANES 2017-2020).”.
In Abstract section
2. The background subsection in the abstract :
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject, and hence what the study intended to examine (or what the paper seeks to
present)? Please reconstruct it properly.
3.  The type of study: a population-based study.
4. In the method subsection in the abstract :
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
- Clarify study design and analysis techniques: “This cross-sectional study analyzed NHANES
data (2017–2020) using …….. analysis.”
5. In the results subsection in the abstract :
-   Improve numerical clarity and conciseness.
6. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "AISI may serve as an accessible biomarker
for NAFLD risk stratification in primary care."
In the Introduction section:
7. Try to provide a summarized description of the National Health and Nutrition Examination
Survey (NHANES) in the background section. You may use the following: “NHANES
(www.cdc.gov/nchs/nhanes) is designed to assess the health and nutritional status of adults
and children in the United States. The survey is distinctive in that it incorporates both
physical examinations and interviews. Several cross-sectional, nationally representative health
examination surveys are part of the NHANES program. Questions about demographics,
health insurance status, dietary habits, acute and chronic medical issues, mental health, and
prescription drug use are all included in the health interview. Exam components can change
between survey cycles but typically include blood pressure, dental exams, vision, hearing,
dermatology, fitness, balance and strength testing, respiratory testing, taste and smell, and
body measurements (weight, height, skin folds, body composition scans). Hematology, organ
and endocrine function (e.g., thyroid, kidney), environmental exposure, dietary biomarkers,
metabolic and cardiovascular health, and infectious disease are a few examples of laboratory
components.
8. MAFLD must replace NAFLD:
“In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes, such
as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected the
disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
9. Introductio devotes much space to MAFLD pathophysiology; you should balance that with
AISI’s novelty.
10. Why AISI’s role in MAFLD is understudied, and how this study addresses that (Study gap).
In the Methods section:
11. Please move the sentences defining the NHANES to the introduction section rather than the
methodology section.
12. The study utilized the 2017-2020 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
13. Please provide the participants' sociodemographic data.
14. How the sample size was calculated.
15. Mention ethical approval earlier in the methodology to emphasize compliance.
16. Provide more details on the exclusion criteria to ensure reproducibility.
17. How were outliers handled (e.g., ±3 SD exclusion), and justify the choice of log#
transformation?
18. Provide the exact formula for AISI in the main text (currently buried in supplemental
material).
19. Why was AST included but not ALT, given that both are liver enzymes?
In the Results section:
20. In all tables, please explain the abbreviations under the tables.
21. You can title the statistical test column as “Test of significance” and use U= for the Mann–
Whitney U test, T= for the T-test, and #2 = for the Chi-square test, etc.
22. Ensure that table captions succinctly describe the content for standalone clarity.
23. The RCS curve (Fig. 2) is critical but lacks axis labels or a clear inflection point marker.
Add these for readability.
24. Highlight the age and hypertension interaction (Subgroup Analysis) earlier in the results, as
these are key findings.
25. Simplify Table 1 by removing redundant "%" symbols (e.g., "Female" already implies
percentage).
26. Ensure all confidence intervals in Table 2 align vertically for readability.
In the Discussion section:
27. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
28. Discuss why AISI’s nonlinearity might occur (e.g., compensatory anti-inflammatory
responses). Link this to existing literature.
29. Discuss how nurses or primary care providers could integrate AISI into practice.
30. Potential confounding by physical activity/diet, which are relevant to MAFLD but
unmeasured in NHANES, should be considered a limitation.
The manuscript is well-structured and addresses an important gap in MAFLD research. With
minor refinements to clarity, focus, and visual presentation, it could better highlight its
contributions to both science and clinical practice.
Title: AISI and MASLD: A Nonlinear Association in U.S. Adults (NHANES 2017-2020)
Version: 1 Date: 16 Jun 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I would like to congratulate the authors on their work, "Exploring the Nonlinear Relationship
Between Systemic Inflammation and Hepatic Steatosis: Evidence from NHANES 2017-2020."
In this study, Xiao et al. aimed to investigates the relationship between systemic inflammation,
measured by the Aggregate Index of Systemic Inflammation (AISI), and nonalcoholic fatty liver
disease (NAFLD) in a representative U.S. adult population. By leveraging NHANES data, the
authors aim to fill a gap in understanding how this novel composite biomarker correlates with
NAFLD prevalence, particularly exploring nonlinear associations and potential clinical utility.
The study’s focus on AISI, a low-cost, readily available metric—adds practical value for early
NAFLD detection in resource-limited settings.
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most prevalent chronic liver
disease, impacting about 30% of global individuals, with the potential to progress to advanced
hepatic fibrosis and end-stage liver diseases eventually [*]. In June 2023, a multi-society
committee of international experts was gathered, and new terminology was adopted to reduce
stigma and increase disease awareness [**]. A new terminology, Steatotic liver disease (SLD),
replaces “fatty liver disease” as the umbrella term. Under subgroups of SLD, NAFLD has been
renamed as metabolic dysfunction-associated Steatotic liver disease (MASLD) [**]. NAFLD/
MASLD is closely related to metabolic syndrome (MetS) and its associated components of
hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity[***].
(*:doi: 10.1097/HEP.0000000000000004, **: doi: 10.1016/j.jhep.2023.06.003, ***  doi:
10.1111/apt.17308).
The authors tried to contribute to this field of research with new findings; nevertheless, there is
an observation for which sufficient justification must be obtained.
In general:
1. The language is generally clear, but some minor grammatical errors and awkward phrasings
could be improved.
- Replace phrases like "multivariable logistic regression" with simpler terms (e.g., "adjusted
analysis") where possible.
- Some sentences are overly long (e.g., the Introduction’s first paragraph). Break them up for
clarity.
- Consider having the manuscript proofread by a native English speaker or a professional editing
service.
2. Abbreviations must be fully written at their first appearance.
In Title:
1. The title should indicate the age and locality of the study population at which the National
Health and Nutrition Examination Survey (NHANES) was performed. The title is informative,
but could be more concise. I suggest “ AISI and NAFLD: A Nonlinear Association in U.S.
Adults (NHANES 2017-2020).”.
In Abstract section
2. The background subsection in the abstract :
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject, and hence what the study intended to examine (or what the paper seeks to
present)? Please reconstruct it properly.
3.  The type of study: a population-based study.
4. In the method subsection in the abstract :
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
- Clarify study design and analysis techniques: “This cross-sectional study analyzed NHANES
data (2017–2020) using …….. analysis.”
5. In the results subsection in the abstract :
-   Improve numerical clarity and conciseness.
6. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "AISI may serve as an accessible biomarker
for NAFLD risk stratification in primary care."
In the Introduction section:
7. Try to provide a summarized description of the National Health and Nutrition Examination
Survey (NHANES) in the background section. You may use the following: “NHANES
(www.cdc.gov/nchs/nhanes) is designed to assess the health and nutritional status of adults
and children in the United States. The survey is distinctive in that it incorporates both
physical examinations and interviews. Several cross-sectional, nationally representative health
examination surveys are part of the NHANES program. Questions about demographics,
health insurance status, dietary habits, acute and chronic medical issues, mental health, and
prescription drug use are all included in the health interview. Exam components can change
between survey cycles but typically include blood pressure, dental exams, vision, hearing,
dermatology, fitness, balance and strength testing, respiratory testing, taste and smell, and
body measurements (weight, height, skin folds, body composition scans). Hematology, organ
and endocrine function (e.g., thyroid, kidney), environmental exposure, dietary biomarkers,
metabolic and cardiovascular health, and infectious disease are a few examples of laboratory
components.
8. MAFLD must replace NAFLD:
“In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes, such
as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected the
disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
9. Introductio devotes much space to MAFLD pathophysiology; you should balance that with
AISI’s novelty.
10. Why AISI’s role in MAFLD is understudied, and how this study addresses that (Study gap).
In the Methods section:
11. Please move the sentences defining the NHANES to the introduction section rather than the
methodology section.
12. The study utilized the 2017-2020 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
13. Please provide the participants' sociodemographic data.
14. How the sample size was calculated.
15. Mention ethical approval earlier in the methodology to emphasize compliance.
16. Provide more details on the exclusion criteria to ensure reproducibility.
17. How were outliers handled (e.g., ±3 SD exclusion), and justify the choice of log#
transformation?
18. Provide the exact formula for AISI in the main text (currently buried in supplemental
material).
19. Why was AST included but not ALT, given that both are liver enzymes?
In the Results section:
20. In all tables, please explain the abbreviations under the tables.
21. You can title the statistical test column as “Test of significance” and use U= for the Mann–
Whitney U test, T= for the T-test, and #2 = for the Chi-square test, etc.
22. Ensure that table captions succinctly describe the content for standalone clarity.
23. The RCS curve (Fig. 2) is critical but lacks axis labels or a clear inflection point marker.
Add these for readability.
24. Highlight the age and hypertension interaction (Subgroup Analysis) earlier in the results, as
these are key findings.
25. Simplify Table 1 by removing redundant "%" symbols (e.g., "Female" already implies
percentage).
26. Ensure all confidence intervals in Table 2 align vertically for readability.
In the Discussion section:
27. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
28. Discuss why AISI’s nonlinearity might occur (e.g., compensatory anti-inflammatory
responses). Link this to existing literature.
29. Discuss how nurses or primary care providers could integrate AISI into practice.
30. Potential confounding by physical activity/diet, which are relevant to MAFLD but
unmeasured in NHANES, should be considered a limitation.
The manuscript is well-structured and addresses an important gap in MAFLD research. With
minor refinements to clarity, focus, and visual presentation, it could better highlight its
contributions to both science and clinical practice.
Please review this paper.
user
Title: AISI and MASLD: A Nonlinear Association in U.S. Adults (NHANES 2017-2020)
Version: 1 Date: 16 Jun 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I would like to congratulate the authors on their work, "Exploring the Nonlinear Relationship
Between Systemic Inflammation and Hepatic Steatosis: Evidence from NHANES 2017-2020."
In this study, Xiao et al. aimed to investigates the relationship between systemic inflammation,
measured by the Aggregate Index of Systemic Inflammation (AISI), and nonalcoholic fatty liver
disease (NAFLD) in a representative U.S. adult population. By leveraging NHANES data, the
authors aim to fill a gap in understanding how this novel composite biomarker correlates with
NAFLD prevalence, particularly exploring nonlinear associations and potential clinical utility.
The study’s focus on AISI, a low-cost, readily available metric—adds practical value for early
NAFLD detection in resource-limited settings.
Non-alcoholic fatty liver disease (NAFLD) is recognized as the most prevalent chronic liver
disease, impacting about 30% of global individuals, with the potential to progress to advanced
hepatic fibrosis and end-stage liver diseases eventually [*]. In June 2023, a multi-society
committee of international experts was gathered, and new terminology was adopted to reduce
stigma and increase disease awareness [**]. A new terminology, Steatotic liver disease (SLD),
replaces “fatty liver disease” as the umbrella term. Under subgroups of SLD, NAFLD has been
renamed as metabolic dysfunction-associated Steatotic liver disease (MASLD) [**]. NAFLD/
MASLD is closely related to metabolic syndrome (MetS) and its associated components of
hypertension, type 2 diabetes mellitus, dyslipidemia, and obesity[***].
(*:doi: 10.1097/HEP.0000000000000004, **: doi: 10.1016/j.jhep.2023.06.003, ***  doi:
10.1111/apt.17308).
The authors tried to contribute to this field of research with new findings; nevertheless, there is
an observation for which sufficient justification must be obtained.
In general:
1. The language is generally clear, but some minor grammatical errors and awkward phrasings
could be improved.
- Replace phrases like "multivariable logistic regression" with simpler terms (e.g., "adjusted
analysis") where possible.
- Some sentences are overly long (e.g., the Introduction’s first paragraph). Break them up for
clarity.
- Consider having the manuscript proofread by a native English speaker or a professional editing
service.
2. Abbreviations must be fully written at their first appearance.
In Title:
1. The title should indicate the age and locality of the study population at which the National
Health and Nutrition Examination Survey (NHANES) was performed. The title is informative,
but could be more concise. I suggest “ AISI and NAFLD: A Nonlinear Association in U.S.
Adults (NHANES 2017-2020).”.
In Abstract section
2. The background subsection in the abstract :
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject, and hence what the study intended to examine (or what the paper seeks to
present)? Please reconstruct it properly.
3.  The type of study: a population-based study.
4. In the method subsection in the abstract :
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
- Clarify study design and analysis techniques: “This cross-sectional study analyzed NHANES
data (2017–2020) using …….. analysis.”
5. In the results subsection in the abstract :
-   Improve numerical clarity and conciseness.
6. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "AISI may serve as an accessible biomarker
for NAFLD risk stratification in primary care."
In the Introduction section:
7. Try to provide a summarized description of the National Health and Nutrition Examination
Survey (NHANES) in the background section. You may use the following: “NHANES
(www.cdc.gov/nchs/nhanes) is designed to assess the health and nutritional status of adults
and children in the United States. The survey is distinctive in that it incorporates both
physical examinations and interviews. Several cross-sectional, nationally representative health
examination surveys are part of the NHANES program. Questions about demographics,
health insurance status, dietary habits, acute and chronic medical issues, mental health, and
prescription drug use are all included in the health interview. Exam components can change
between survey cycles but typically include blood pressure, dental exams, vision, hearing,
dermatology, fitness, balance and strength testing, respiratory testing, taste and smell, and
body measurements (weight, height, skin folds, body composition scans). Hematology, organ
and endocrine function (e.g., thyroid, kidney), environmental exposure, dietary biomarkers,
metabolic and cardiovascular health, and infectious disease are a few examples of laboratory
components.
8. MAFLD must replace NAFLD:
“In contrast to NAFLD, MAFLD does not necessitate ruling out other liver disease causes, such
as viral hepatitis or heavy alcohol use*. The new name chosen to replace NAFLD reflected the
disease etiology better and conveyed a more practical approach in daily clinical practice than
NAFLD, considering its close association with metabolic syndrome**. Please discuss the new
nomenclature in more detail.
(*: Doi: 10.1016/j.jhep.2020.03.039, **: doi: 10.1097/HEP.0000000000000520)
9. Introductio devotes much space to MAFLD pathophysiology; you should balance that with
AISI’s novelty.
10. Why AISI’s role in MAFLD is understudied, and how this study addresses that (Study gap).
In the Methods section:
11. Please move the sentences defining the NHANES to the introduction section rather than the
methodology section.
12. The study utilized the 2017-2020 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
13. Please provide the participants' sociodemographic data.
14. How the sample size was calculated.
15. Mention ethical approval earlier in the methodology to emphasize compliance.
16. Provide more details on the exclusion criteria to ensure reproducibility.
17. How were outliers handled (e.g., ±3 SD exclusion), and justify the choice of log#
transformation?
18. Provide the exact formula for AISI in the main text (currently buried in supplemental
material).
19. Why was AST included but not ALT, given that both are liver enzymes?
In the Results section:
20. In all tables, please explain the abbreviations under the tables.
21. You can title the statistical test column as “Test of significance” and use U= for the Mann–
Whitney U test, T= for the T-test, and #2 = for the Chi-square test, etc.
22. Ensure that table captions succinctly describe the content for standalone clarity.
23. The RCS curve (Fig. 2) is critical but lacks axis labels or a clear inflection point marker.
Add these for readability.
24. Highlight the age and hypertension interaction (Subgroup Analysis) earlier in the results, as
these are key findings.
25. Simplify Table 1 by removing redundant "%" symbols (e.g., "Female" already implies
percentage).
26. Ensure all confidence intervals in Table 2 align vertically for readability.
In the Discussion section:
27. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
28. Discuss why AISI’s nonlinearity might occur (e.g., compensatory anti-inflammatory
responses). Link this to existing literature.
29. Discuss how nurses or primary care providers could integrate AISI into practice.
30. Potential confounding by physical activity/diet, which are relevant to MAFLD but
unmeasured in NHANES, should be considered a limitation.
The manuscript is well-structured and addresses an important gap in MAFLD research. With
minor refinements to clarity, focus, and visual presentation, it could better highlight its
contributions to both science and clinical practice.
assistant