Title: AISI and MASLD: A Nonlinear Association in U.S. Adults (NHANES 2017-2020)
Version: 1 Date: 16 Jun 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Cross-Sectional Design Limits Causal Inference
The study relies on cross-sectional NHANES data, which inherently prevents establishing
temporal or causal relationships between systemic inflammation and hepatic steatosis. While
this limitation is acknowledged, the implications for clinical interpretation should be discussed
in greater depth.
-Lack of Longitudinal Validation or Prognostic Value
The manuscript suggests that AISI could serve as a predictive or early-detection biomarker, yet
no longitudinal or prospective data are available to support this claim. Assertions about AISI’s
utility in early-stage NAFLD detection may be premature.
-No Histologic Confirmation of NAFLD
Although VCTE-derived CAP scores are non-invasive and validated, they lack the specificity
and granularity of liver biopsy, especially in distinguishing simple steatosis from steatohepatitis
or fibrosis. The study does not account for the histologic heterogeneity of NAFLD.
-Potential Confounding by Acute Inflammation or Comorbid Conditions
AISI can be elevated in various acute or chronic inflammatory states unrelated to NAFLD (e.g.,
infections, malignancies, autoimmune disease). The manuscript does not fully address how such
confounders were accounted for or ruled out.
-Use of AISI as an Unfamiliar Metric in Hepatology
While AISI is well-studied in oncology and cardiovascular disease, its application in liver
disease is novel. The rationale for selecting AISI over more established markers (e.g., NLR,
CRP, IL-6) is somewhat underdeveloped and requires stronger justification.
-Overstated Clinical Utility
The conclusion proposes that AISI could be readily adopted for NAFLD screening in primary
care and community settings. However, given the modest effect sizes, nonlinear associations,
and potential nonspecificity of AISI, such recommendations appear overreaching without
external validation.
-Restricted Subgroup Interpretation
Subgroup findings (e.g., stronger association in younger adults and those without hypertension)
are intriguing but inadequately contextualized. The biological rationale is speculative, and effect
modification by other unmeasured factors cannot be ruled out.
-Limited Adjustment for Lifestyle and Nutritional Factors
Important lifestyle variables such as dietary intake, physical activity, medication use (e.g.,
statins, corticosteroids), and socioeconomic status are either missing or insufficiently addressed,
which may introduce residual confounding.
-The formula for AISI Is Misstated
The manuscript provides the AISI formula as
AISI=Lymphocyte Count2×Neutrophil Count×Platelet Count×Monocyte Count
\text{AISI} = \frac{\text{Lymphocyte Count}}{2 \times \text{Neutrophil
Count} \times \text{Platelet Count} \times \text{Monocyte
Count}}AISI=2×Neutrophil Count×Platelet Count×Monocyte CountLymphocyte CountThis
appears inconsistent with published literature, where the denominator and numerator are
reversed in most definitions. Clarification is urgently needed for reproducibility.
-Discussion of Nonlinear Relationship Is Limited
The observed nonlinear association and plateau at high AISI levels is interesting but not
sufficiently explored. The potential biological or statistical reasons for this trend are only briefly
hypothesized without rigorous investigation.
-Absence of External or Sensitivity Analyses
The study does not include internal or external validation cohorts, nor are sensitivity analyses
(e.g., excluding subjects with CRP >10 mg/L, or known cancer) presented to test the robustness
of the AISI–NAFLD relationship.
-Typographical and Structural Issues
The manuscript has inconsistent formatting (e.g., scattered line numbers, misplaced section
headers like “2 Methods” appearing mid-paragraph), which detracts from readability and
professionalism.
Title: AISI and MASLD: A Nonlinear Association in U.S. Adults (NHANES 2017-2020)
Version: 1 Date: 16 Jun 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Cross-Sectional Design Limits Causal Inference
The study relies on cross-sectional NHANES data, which inherently prevents establishing
temporal or causal relationships between systemic inflammation and hepatic steatosis. While
this limitation is acknowledged, the implications for clinical interpretation should be discussed
in greater depth.
-Lack of Longitudinal Validation or Prognostic Value
The manuscript suggests that AISI could serve as a predictive or early-detection biomarker, yet
no longitudinal or prospective data are available to support this claim. Assertions about AISI’s
utility in early-stage NAFLD detection may be premature.
-No Histologic Confirmation of NAFLD
Although VCTE-derived CAP scores are non-invasive and validated, they lack the specificity
and granularity of liver biopsy, especially in distinguishing simple steatosis from steatohepatitis
or fibrosis. The study does not account for the histologic heterogeneity of NAFLD.
-Potential Confounding by Acute Inflammation or Comorbid Conditions
AISI can be elevated in various acute or chronic inflammatory states unrelated to NAFLD (e.g.,
infections, malignancies, autoimmune disease). The manuscript does not fully address how such
confounders were accounted for or ruled out.
-Use of AISI as an Unfamiliar Metric in Hepatology
While AISI is well-studied in oncology and cardiovascular disease, its application in liver
disease is novel. The rationale for selecting AISI over more established markers (e.g., NLR,
CRP, IL-6) is somewhat underdeveloped and requires stronger justification.
-Overstated Clinical Utility
The conclusion proposes that AISI could be readily adopted for NAFLD screening in primary
care and community settings. However, given the modest effect sizes, nonlinear associations,
and potential nonspecificity of AISI, such recommendations appear overreaching without
external validation.
-Restricted Subgroup Interpretation
Subgroup findings (e.g., stronger association in younger adults and those without hypertension)
are intriguing but inadequately contextualized. The biological rationale is speculative, and effect
modification by other unmeasured factors cannot be ruled out.
-Limited Adjustment for Lifestyle and Nutritional Factors
Important lifestyle variables such as dietary intake, physical activity, medication use (e.g.,
statins, corticosteroids), and socioeconomic status are either missing or insufficiently addressed,
which may introduce residual confounding.
-The formula for AISI Is Misstated
The manuscript provides the AISI formula as
AISI=Lymphocyte Count2×Neutrophil Count×Platelet Count×Monocyte Count
\text{AISI} = \frac{\text{Lymphocyte Count}}{2 \times \text{Neutrophil
Count} \times \text{Platelet Count} \times \text{Monocyte
Count}}AISI=2×Neutrophil Count×Platelet Count×Monocyte CountLymphocyte CountThis
appears inconsistent with published literature, where the denominator and numerator are
reversed in most definitions. Clarification is urgently needed for reproducibility.
-Discussion of Nonlinear Relationship Is Limited
The observed nonlinear association and plateau at high AISI levels is interesting but not
sufficiently explored. The potential biological or statistical reasons for this trend are only briefly
hypothesized without rigorous investigation.
-Absence of External or Sensitivity Analyses
The study does not include internal or external validation cohorts, nor are sensitivity analyses
(e.g., excluding subjects with CRP >10 mg/L, or known cancer) presented to test the robustness
of the AISI–NAFLD relationship.
-Typographical and Structural Issues
The manuscript has inconsistent formatting (e.g., scattered line numbers, misplaced section
headers like “2 Methods” appearing mid-paragraph), which detracts from readability and
professionalism.
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:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Cross-Sectional Design Limits Causal Inference
The study relies on cross-sectional NHANES data, which inherently prevents establishing
temporal or causal relationships between systemic inflammation and hepatic steatosis. While
this limitation is acknowledged, the implications for clinical interpretation should be discussed
in greater depth.
-Lack of Longitudinal Validation or Prognostic Value
The manuscript suggests that AISI could serve as a predictive or early-detection biomarker, yet
no longitudinal or prospective data are available to support this claim. Assertions about AISI’s
utility in early-stage NAFLD detection may be premature.
-No Histologic Confirmation of NAFLD
Although VCTE-derived CAP scores are non-invasive and validated, they lack the specificity
and granularity of liver biopsy, especially in distinguishing simple steatosis from steatohepatitis
or fibrosis. The study does not account for the histologic heterogeneity of NAFLD.
-Potential Confounding by Acute Inflammation or Comorbid Conditions
AISI can be elevated in various acute or chronic inflammatory states unrelated to NAFLD (e.g.,
infections, malignancies, autoimmune disease). The manuscript does not fully address how such
confounders were accounted for or ruled out.
-Use of AISI as an Unfamiliar Metric in Hepatology
While AISI is well-studied in oncology and cardiovascular disease, its application in liver
disease is novel. The rationale for selecting AISI over more established markers (e.g., NLR,
CRP, IL-6) is somewhat underdeveloped and requires stronger justification.
-Overstated Clinical Utility
The conclusion proposes that AISI could be readily adopted for NAFLD screening in primary
care and community settings. However, given the modest effect sizes, nonlinear associations,
and potential nonspecificity of AISI, such recommendations appear overreaching without
external validation.
-Restricted Subgroup Interpretation
Subgroup findings (e.g., stronger association in younger adults and those without hypertension)
are intriguing but inadequately contextualized. The biological rationale is speculative, and effect
modification by other unmeasured factors cannot be ruled out.
-Limited Adjustment for Lifestyle and Nutritional Factors
Important lifestyle variables such as dietary intake, physical activity, medication use (e.g.,
statins, corticosteroids), and socioeconomic status are either missing or insufficiently addressed,
which may introduce residual confounding.
-The formula for AISI Is Misstated
The manuscript provides the AISI formula as
AISI=Lymphocyte Count2×Neutrophil Count×Platelet Count×Monocyte Count
\text{AISI} = \frac{\text{Lymphocyte Count}}{2 \times \text{Neutrophil
Count} \times \text{Platelet Count} \times \text{Monocyte
Count}}AISI=2×Neutrophil Count×Platelet Count×Monocyte CountLymphocyte CountThis
appears inconsistent with published literature, where the denominator and numerator are
reversed in most definitions. Clarification is urgently needed for reproducibility.
-Discussion of Nonlinear Relationship Is Limited
The observed nonlinear association and plateau at high AISI levels is interesting but not
sufficiently explored. The potential biological or statistical reasons for this trend are only briefly
hypothesized without rigorous investigation.
-Absence of External or Sensitivity Analyses
The study does not include internal or external validation cohorts, nor are sensitivity analyses
(e.g., excluding subjects with CRP >10 mg/L, or known cancer) presented to test the robustness
of the AISI–NAFLD relationship.
-Typographical and Structural Issues
The manuscript has inconsistent formatting (e.g., scattered line numbers, misplaced section
headers like “2 Methods” appearing mid-paragraph), which detracts from readability and
professionalism.
assistant