Title: Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis
Version: 0 Date: 04 May 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Zhou et al. aimed to explore
into the potential of the pan-immune-inflammation value (PIV) as a prognostic marker for
mortality risk in individuals with metabolic dysfunction-associated steatotic liver disease
(MASLD). By leveraging data from the NHANES database, the authors explore the nonlinear
relationships between PIV and both all-cause and cardiovascular mortality, while also examining
how socioeconomic factors like poverty-income ratio (PIR) modulate these associations. The
findings could offer valuable insights for risk stratification and personalized interventions in this
high-risk population.
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 handled the reviewer comments satisfactorily, 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. 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.
3. Check consistency in terminology (e.g., "MASLD" vs "MASH" in the Introduction).
In Title:
1. The title is clear but somewhat lengthy.
2. 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 US Adult). I suggest:
"Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis."
In the Abstract section
3. 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.
- Why PIV is a superior or novel marker compared to existing inflammatory indices (e.g., NLR,
SII).
4.  The type of study: a population-based study.
5. 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
6. In the results subsection in the abstract :
-   Highlight the clinical implications of the U-shaped & J-shaped relationships early in the
abstract to emphasize their significance.
7. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "PIV may aid in identifying high-risk
MASLD patients, particularly in low-income populations."
In the Introduction section:
8. 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.”.
9. 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).
10. State the gap in knowledge regarding PIV’s role in MASLD mortality.
In the Methods section:
11. The study utilized the 1999-2018 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
12. Please provide the participants' sociodemographic data.
13. Why certain exclusions (e.g., pregnant individuals, missing covariates) were necessary and
how they might bias results.
14.  Put the formula for PIV in the Methods section (currently only in the Abstract).
15. Why was dietary energy intake included but not alcohol use?
16. Explain the rationale for using natural log transformation (lnPIV) and how knot selection
was optimized for RCS.
In the Results section:
17. In all tables, please explain the abbreviations under the tables.
18. 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.. Although the Chi-square
test was used to compare observed and expected results, nothing was mentioned in the statistical
analysis section.
19. Ensure that table captions succinctly describe the content for standalone clarity.
20. Table S1 should be summarized in the main text to highlight key trends (e.g., Higher PIV
quartiles correlated with younger age but higher metabolic comorbidities).
21. Emphasize the clinical relevance of the inflection points (e.g., PIV > 409.868 [Q4] signaled
a 27.3% increase in mortality).
22. Why PIR < 1 amplified PIV’s mortality risk (e.g., healthcare access, chronic stress.
23. Should add a simplified schematic of PIV’s mechanistic role in MASLD progression for
visual impact.
In the Discussion section:
24. 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.
25. Discuss how neutrophil activation exacerbates hepatic fibrosis, linking these to PIV’s
components.
26. Unmeasured genetic or lifestyle factors, and the lack of external validation, should be in the
limitations section.
27. Avoid repeated phrases: future studies are needed was repeated several times.
Title: Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis
Version: 0 Date: 04 May 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Zhou et al. aimed to explore
into the potential of the pan-immune-inflammation value (PIV) as a prognostic marker for
mortality risk in individuals with metabolic dysfunction-associated steatotic liver disease
(MASLD). By leveraging data from the NHANES database, the authors explore the nonlinear
relationships between PIV and both all-cause and cardiovascular mortality, while also examining
how socioeconomic factors like poverty-income ratio (PIR) modulate these associations. The
findings could offer valuable insights for risk stratification and personalized interventions in this
high-risk population.
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 handled the reviewer comments satisfactorily, 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. 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.
3. Check consistency in terminology (e.g., "MASLD" vs "MASH" in the Introduction).
In Title:
1. The title is clear but somewhat lengthy.
2. 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 US Adult). I suggest:
"Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis."
In the Abstract section
3. 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.
- Why PIV is a superior or novel marker compared to existing inflammatory indices (e.g., NLR,
SII).
4.  The type of study: a population-based study.
5. 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
6. In the results subsection in the abstract :
-   Highlight the clinical implications of the U-shaped & J-shaped relationships early in the
abstract to emphasize their significance.
7. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "PIV may aid in identifying high-risk
MASLD patients, particularly in low-income populations."
In the Introduction section:
8. 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.”.
9. 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).
10. State the gap in knowledge regarding PIV’s role in MASLD mortality.
In the Methods section:
11. The study utilized the 1999-2018 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
12. Please provide the participants' sociodemographic data.
13. Why certain exclusions (e.g., pregnant individuals, missing covariates) were necessary and
how they might bias results.
14.  Put the formula for PIV in the Methods section (currently only in the Abstract).
15. Why was dietary energy intake included but not alcohol use?
16. Explain the rationale for using natural log transformation (lnPIV) and how knot selection
was optimized for RCS.
In the Results section:
17. In all tables, please explain the abbreviations under the tables.
18. 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.. Although the Chi-square
test was used to compare observed and expected results, nothing was mentioned in the statistical
analysis section.
19. Ensure that table captions succinctly describe the content for standalone clarity.
20. Table S1 should be summarized in the main text to highlight key trends (e.g., Higher PIV
quartiles correlated with younger age but higher metabolic comorbidities).
21. Emphasize the clinical relevance of the inflection points (e.g., PIV > 409.868 [Q4] signaled
a 27.3% increase in mortality).
22. Why PIR < 1 amplified PIV’s mortality risk (e.g., healthcare access, chronic stress.
23. Should add a simplified schematic of PIV’s mechanistic role in MASLD progression for
visual impact.
In the Discussion section:
24. 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.
25. Discuss how neutrophil activation exacerbates hepatic fibrosis, linking these to PIV’s
components.
26. Unmeasured genetic or lifestyle factors, and the lack of external validation, should be in the
limitations section.
27. Avoid repeated phrases: future studies are needed was repeated several times.
Please review this paper.
user
Title: Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis
Version: 0 Date: 04 May 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work. In this study, Zhou et al. aimed to explore
into the potential of the pan-immune-inflammation value (PIV) as a prognostic marker for
mortality risk in individuals with metabolic dysfunction-associated steatotic liver disease
(MASLD). By leveraging data from the NHANES database, the authors explore the nonlinear
relationships between PIV and both all-cause and cardiovascular mortality, while also examining
how socioeconomic factors like poverty-income ratio (PIR) modulate these associations. The
findings could offer valuable insights for risk stratification and personalized interventions in this
high-risk population.
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 handled the reviewer comments satisfactorily, 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. 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.
3. Check consistency in terminology (e.g., "MASLD" vs "MASH" in the Introduction).
In Title:
1. The title is clear but somewhat lengthy.
2. 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 US Adult). I suggest:
"Pan-Immune-Inflammation Value and Mortality in The US Adult MASLD: A Nonlinear
NHANES Analysis."
In the Abstract section
3. 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.
- Why PIV is a superior or novel marker compared to existing inflammatory indices (e.g., NLR,
SII).
4.  The type of study: a population-based study.
5. 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
6. In the results subsection in the abstract :
-   Highlight the clinical implications of the U-shaped & J-shaped relationships early in the
abstract to emphasize their significance.
7. In the conclusion subsection in the abstract :
- Emphasize the clinical significance of your study: "PIV may aid in identifying high-risk
MASLD patients, particularly in low-income populations."
In the Introduction section:
8. 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.”.
9. 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).
10. State the gap in knowledge regarding PIV’s role in MASLD mortality.
In the Methods section:
11. The study utilized the 1999-2018 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
12. Please provide the participants' sociodemographic data.
13. Why certain exclusions (e.g., pregnant individuals, missing covariates) were necessary and
how they might bias results.
14.  Put the formula for PIV in the Methods section (currently only in the Abstract).
15. Why was dietary energy intake included but not alcohol use?
16. Explain the rationale for using natural log transformation (lnPIV) and how knot selection
was optimized for RCS.
In the Results section:
17. In all tables, please explain the abbreviations under the tables.
18. 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.. Although the Chi-square
test was used to compare observed and expected results, nothing was mentioned in the statistical
analysis section.
19. Ensure that table captions succinctly describe the content for standalone clarity.
20. Table S1 should be summarized in the main text to highlight key trends (e.g., Higher PIV
quartiles correlated with younger age but higher metabolic comorbidities).
21. Emphasize the clinical relevance of the inflection points (e.g., PIV > 409.868 [Q4] signaled
a 27.3% increase in mortality).
22. Why PIR < 1 amplified PIV’s mortality risk (e.g., healthcare access, chronic stress.
23. Should add a simplified schematic of PIV’s mechanistic role in MASLD progression for
visual impact.
In the Discussion section:
24. 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.
25. Discuss how neutrophil activation exacerbates hepatic fibrosis, linking these to PIV’s
components.
26. Unmeasured genetic or lifestyle factors, and the lack of external validation, should be in the
limitations section.
27. Avoid repeated phrases: future studies are needed was repeated several times.
assistant