Title: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio
as a predictor of all cause and cardiovascular mortality in United States adults with NAFLD:
a prospective cohort study
Version: 1 Date: 15 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Although the US-FLI (U.S. Fatty Liver Index) is a non-invasive and validated tool for
diagnosing NAFLD, its accuracy compared to liver biopsy (the gold standard) is limited. While
it is appropriate for large-scale epidemiological studies, its performance in identifying early-
stage or less severe forms of NAFLD might not be perfect, potentially affecting the study's
results. The absence of actual liver biopsy data could limit the precision of the findings in terms
of NAFLD severity.
-Given that abdominal ultrasound is a common and relatively accessible tool for diagnosing
NAFLD, the absence of this data in NHANES limits the study's ability to accurately categorize
NAFLD. While the US-FLI is an alternative, combining it with ultrasound would have
strengthened the study’s diagnostic rigor.
-While the study adjusts for many potential confounders, there may still be residual confounding
due to unmeasured factors, such as dietary habits, medication usage (other than those for diabetes
or hypertension), and other lifestyle variables (e.g., sedentary behaviors). These factors could
affect lipid profiles and mortality outcomes and may not have been fully controlled for in the
analyses.
-The study primarily categorizes participants with NAFLD based on the US-FLI without further
stratification based on liver fibrosis stage or the presence of non-alcoholic steatohepatitis
(NASH). This lack of attention to NAFLD staging (e.g., mild steatosis vs. advanced fibrosis)
could overlook significant variations in mortality risk, as more advanced stages of NAFLD are
associated with higher mortality rates. A more detailed analysis of the stages of NAFLD could
offer more refined insights into the relationship between NHHR and mortality.
-While the study uses the NHANES database, which is specific to the U.S. population,
the findings may not be directly applicable to other populations with different genetic
backgrounds, dietary habits, or healthcare systems. Replication studies in other countries or
diverse populations would be necessary to confirm the applicability of NHHR as a universal
biomarker for NAFLD mortality risk.
-The authors briefly mention NHHR's correlation with the FIB-4 score and ALT levels, but the
mechanistic link between NHHR and liver fibrosis progression in NAFLD could be explored in
more detail. Since liver fibrosis is a key factor in NAFLD-related mortality, further discussion
of how NHHR could serve as an indirect marker for liver disease severity would be beneficial.
Title: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio
as a predictor of all cause and cardiovascular mortality in United States adults with NAFLD:
a prospective cohort study
Version: 1 Date: 15 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Although the US-FLI (U.S. Fatty Liver Index) is a non-invasive and validated tool for
diagnosing NAFLD, its accuracy compared to liver biopsy (the gold standard) is limited. While
it is appropriate for large-scale epidemiological studies, its performance in identifying early-
stage or less severe forms of NAFLD might not be perfect, potentially affecting the study's
results. The absence of actual liver biopsy data could limit the precision of the findings in terms
of NAFLD severity.
-Given that abdominal ultrasound is a common and relatively accessible tool for diagnosing
NAFLD, the absence of this data in NHANES limits the study's ability to accurately categorize
NAFLD. While the US-FLI is an alternative, combining it with ultrasound would have
strengthened the study’s diagnostic rigor.
-While the study adjusts for many potential confounders, there may still be residual confounding
due to unmeasured factors, such as dietary habits, medication usage (other than those for diabetes
or hypertension), and other lifestyle variables (e.g., sedentary behaviors). These factors could
affect lipid profiles and mortality outcomes and may not have been fully controlled for in the
analyses.
-The study primarily categorizes participants with NAFLD based on the US-FLI without further
stratification based on liver fibrosis stage or the presence of non-alcoholic steatohepatitis
(NASH). This lack of attention to NAFLD staging (e.g., mild steatosis vs. advanced fibrosis)
could overlook significant variations in mortality risk, as more advanced stages of NAFLD are
associated with higher mortality rates. A more detailed analysis of the stages of NAFLD could
offer more refined insights into the relationship between NHHR and mortality.
-While the study uses the NHANES database, which is specific to the U.S. population,
the findings may not be directly applicable to other populations with different genetic
backgrounds, dietary habits, or healthcare systems. Replication studies in other countries or
diverse populations would be necessary to confirm the applicability of NHHR as a universal
biomarker for NAFLD mortality risk.
-The authors briefly mention NHHR's correlation with the FIB-4 score and ALT levels, but the
mechanistic link between NHHR and liver fibrosis progression in NAFLD could be explored in
more detail. Since liver fibrosis is a key factor in NAFLD-related mortality, further discussion
of how NHHR could serve as an indirect marker for liver disease severity would be beneficial.
Please review this paper.
user
Title: The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio
as a predictor of all cause and cardiovascular mortality in United States adults with NAFLD:
a prospective cohort study
Version: 1 Date: 15 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-Although the US-FLI (U.S. Fatty Liver Index) is a non-invasive and validated tool for
diagnosing NAFLD, its accuracy compared to liver biopsy (the gold standard) is limited. While
it is appropriate for large-scale epidemiological studies, its performance in identifying early-
stage or less severe forms of NAFLD might not be perfect, potentially affecting the study's
results. The absence of actual liver biopsy data could limit the precision of the findings in terms
of NAFLD severity.
-Given that abdominal ultrasound is a common and relatively accessible tool for diagnosing
NAFLD, the absence of this data in NHANES limits the study's ability to accurately categorize
NAFLD. While the US-FLI is an alternative, combining it with ultrasound would have
strengthened the study’s diagnostic rigor.
-While the study adjusts for many potential confounders, there may still be residual confounding
due to unmeasured factors, such as dietary habits, medication usage (other than those for diabetes
or hypertension), and other lifestyle variables (e.g., sedentary behaviors). These factors could
affect lipid profiles and mortality outcomes and may not have been fully controlled for in the
analyses.
-The study primarily categorizes participants with NAFLD based on the US-FLI without further
stratification based on liver fibrosis stage or the presence of non-alcoholic steatohepatitis
(NASH). This lack of attention to NAFLD staging (e.g., mild steatosis vs. advanced fibrosis)
could overlook significant variations in mortality risk, as more advanced stages of NAFLD are
associated with higher mortality rates. A more detailed analysis of the stages of NAFLD could
offer more refined insights into the relationship between NHHR and mortality.
-While the study uses the NHANES database, which is specific to the U.S. population,
the findings may not be directly applicable to other populations with different genetic
backgrounds, dietary habits, or healthcare systems. Replication studies in other countries or
diverse populations would be necessary to confirm the applicability of NHHR as a universal
biomarker for NAFLD mortality risk.
-The authors briefly mention NHHR's correlation with the FIB-4 score and ALT levels, but the
mechanistic link between NHHR and liver fibrosis progression in NAFLD could be explored in
more detail. Since liver fibrosis is a key factor in NAFLD-related mortality, further discussion
of how NHHR could serve as an indirect marker for liver disease severity would be beneficial.
assistant