Title: Prognostic Significance of Red Cell Distribution Width to Albumin Ratio in ICU Patients
with NAFLD: A Retrospective Analysis
Version: 1 Date: 29 Mar 2025
Reviewer's report:
This retrospective cohort study evaluates the association between the red cell distribution
width to albumin ratio (RAR) and mortality in patients with non-alcoholic fatty liver disease
(NAFLD) admitted to the intensive care unit (ICU), utilizing the MIMIC-IV database. The
primary and secondary outcomes were 365-day and 28-day all-cause mortality, respectively.
RAR was analyzed both as a continuous variable and across quartiles. The study demonstrates
that elevated RAR levels are significantly associated with increased short- and long-term
mortality, even after multivariable adjustment. Additional analyses included Kaplan-Meier
curves, Cox proportional hazards models, restricted cubic spline (RCS) analysis, ROC analysis,
and nomogram development.
Major Points of Evaluation
1. Study Design and Cohort Definition
The study is retrospective in design and relies entirely on secondary data from MIMIC-IV.
The use of ICD-9/10 codes for the identification of NAFLD introduces the possibility of
misclassification bias, particularly in an ICU population where NAFLD may not be accurately
coded. The manuscript does not provide confirmatory laboratory, imaging, or histologic criteria
for NAFLD, which limits diagnostic precision. Moreover, since this is a single-center dataset,
derived from a tertiary academic center in the US, external validity is inherently limited.
2. Exposure Definition and Biomarker Calculation
RAR is calculated as the ratio of red cell distribution width (RDW) to serum albumin (g/
dL). Both RDW and albumin are nonspecific laboratory parameters influenced by acute and
chronic conditions. In ICU settings, albumin is frequently affected by capillary leakage, fluid
resuscitation, sepsis, and liver dysfunction. RDW may reflect systemic inflammation, nutritional
deficiencies, or hematologic stress. Therefore, the RAR value in this context may not reflect a
stable biomarker but rather a dynamic response to critical illness. This complex interplay is not
deeply explored in the manuscript.
3. Outcome Definition and Endpoint Integrity
The study focuses on all-cause mortality at 28 and 365 days. Cause-specific mortality is not
available in the dataset. Thus, it is unclear whether deaths are related to liver disease progression,
critical illness, or unrelated comorbid conditions. The primary endpoint (365-day mortality) may
be influenced by post-discharge factors and outpatient management, which are not accounted
for in the analysis. Furthermore, follow-up details and censoring strategies are not explicitly
described.
4. Covariate Selection and Confounding
Multivariable Cox regression models are used with progressive adjustment (Model 1 unadjusted,
Model 2 adjusted for age and sex, and Model 3 including clinical and laboratory covariates).
However, no established ICU severity indices (e.g., SOFA, APACHE II) are incorporated.
These are strong predictors of ICU mortality and their absence limits the ability to contextualize
RAR’s independent prognostic value. In addition, potential treatment confounders—such as
albumin administration, transfusions, mechanical ventilation, or vasopressors—are not included
or discussed.
5. Statistical Analysis
Kaplan-Meier curves demonstrate clear separation between RAR quartiles, with significant
log-rank tests. Cox models show increasing hazard ratios across quartiles, particularly for Q4.
Restricted cubic spline analysis reveals a nonlinear relationship between RAR and long-term
mortality, supporting the choice of categorization. However, the performance metrics of RAR
are modest. The AUC for 28- and 365-day mortality prediction using RAR alone is 0.625–0.629,
indicating poor discriminative ability. Even the combined AUC with TBiL and Scr remains
moderate (0.742), with limited specificity and sensitivity.
6. Nomogram and Predictive Tool Development
A nomogram is presented using RAR, TBiL, and Scr for mortality prediction. It is derived
solely from the current dataset without external or internal validation (e.g., bootstrapping or
split-sample). Calibration, net reclassification improvement, or decision curve analysis are not
performed. As a result, the clinical utility of the nomogram remains theoretical.
7. Interpretation of Findings
The manuscript presents RAR as a robust, independent predictor of mortality in ICU patients
with NAFLD. However, the interpretation does not adequately consider the context-specific
variability of RDW and albumin. The potential for reverse causation or residual confounding is
not addressed. There is a tendency to overstate the predictive value of RAR despite the relatively
low AUC and the absence of ICU-specific risk scores in the models.
8. Discussion of Mechanisms and Pathophysiology
The discussion broadly attributes the prognostic role of RAR to inflammation, oxidative
stress, and nutritional status. While references are provided linking RDW and albumin to
systemic disease processes, the manuscript does not offer direct mechanistic insights specific to
NAFLD or critical illness. The potential impact of acute hepatic decompensation, hemodynamic
instability, or treatment interventions on RAR is not examined.
Minor Points of Evaluation
• The manuscript alternates between the terms NAFLD and MAFLD, though patients were
included using NAFLD coding. No effort is made to retrospectively define MAFLD or
differentiate between the two concepts.
• Sample size inconsistencies exist. The methods mention 661 patients initially, but the analysis
is conducted on 616. This discrepancy is not explained.
• The imputation method for missing data is mentioned only briefly, without specification of the
statistical approach or the proportion of imputed variables.
• Table 1 contains numerous variables and is overly dense. The clinical relevance of many
comparisons (e.g., SpO#, temperature) is unclear.
Limitations Identified in the Study
• Retrospective single-center design without prospective validation.
• Diagnosis of NAFLD based on administrative coding without imaging or histological
verification.
• Lack of ICU-specific severity scores to contextualize mortality risk.
• No information on treatment-related confounding (e.g., use of albumin or transfusion).
• Moderate predictive performance of RAR as an isolated biomarker.
• Nomogram lacks validation and clinical implementation pathway.
• Cause of death not recorded—mortality may not be directly attributable to liver-related
pathology.
Title: Prognostic Significance of Red Cell Distribution Width to Albumin Ratio in ICU Patients
with NAFLD: A Retrospective Analysis
Version: 1 Date: 29 Mar 2025
Reviewer's report:
This retrospective cohort study evaluates the association between the red cell distribution
width to albumin ratio (RAR) and mortality in patients with non-alcoholic fatty liver disease
(NAFLD) admitted to the intensive care unit (ICU), utilizing the MIMIC-IV database. The
primary and secondary outcomes were 365-day and 28-day all-cause mortality, respectively.
RAR was analyzed both as a continuous variable and across quartiles. The study demonstrates
that elevated RAR levels are significantly associated with increased short- and long-term
mortality, even after multivariable adjustment. Additional analyses included Kaplan-Meier
curves, Cox proportional hazards models, restricted cubic spline (RCS) analysis, ROC analysis,
and nomogram development.
Major Points of Evaluation
1. Study Design and Cohort Definition
The study is retrospective in design and relies entirely on secondary data from MIMIC-IV.
The use of ICD-9/10 codes for the identification of NAFLD introduces the possibility of
misclassification bias, particularly in an ICU population where NAFLD may not be accurately
coded. The manuscript does not provide confirmatory laboratory, imaging, or histologic criteria
for NAFLD, which limits diagnostic precision. Moreover, since this is a single-center dataset,
derived from a tertiary academic center in the US, external validity is inherently limited.
2. Exposure Definition and Biomarker Calculation
RAR is calculated as the ratio of red cell distribution width (RDW) to serum albumin (g/
dL). Both RDW and albumin are nonspecific laboratory parameters influenced by acute and
chronic conditions. In ICU settings, albumin is frequently affected by capillary leakage, fluid
resuscitation, sepsis, and liver dysfunction. RDW may reflect systemic inflammation, nutritional
deficiencies, or hematologic stress. Therefore, the RAR value in this context may not reflect a
stable biomarker but rather a dynamic response to critical illness. This complex interplay is not
deeply explored in the manuscript.
3. Outcome Definition and Endpoint Integrity
The study focuses on all-cause mortality at 28 and 365 days. Cause-specific mortality is not
available in the dataset. Thus, it is unclear whether deaths are related to liver disease progression,
critical illness, or unrelated comorbid conditions. The primary endpoint (365-day mortality) may
be influenced by post-discharge factors and outpatient management, which are not accounted
for in the analysis. Furthermore, follow-up details and censoring strategies are not explicitly
described.
4. Covariate Selection and Confounding
Multivariable Cox regression models are used with progressive adjustment (Model 1 unadjusted,
Model 2 adjusted for age and sex, and Model 3 including clinical and laboratory covariates).
However, no established ICU severity indices (e.g., SOFA, APACHE II) are incorporated.
These are strong predictors of ICU mortality and their absence limits the ability to contextualize
RAR’s independent prognostic value. In addition, potential treatment confounders—such as
albumin administration, transfusions, mechanical ventilation, or vasopressors—are not included
or discussed.
5. Statistical Analysis
Kaplan-Meier curves demonstrate clear separation between RAR quartiles, with significant
log-rank tests. Cox models show increasing hazard ratios across quartiles, particularly for Q4.
Restricted cubic spline analysis reveals a nonlinear relationship between RAR and long-term
mortality, supporting the choice of categorization. However, the performance metrics of RAR
are modest. The AUC for 28- and 365-day mortality prediction using RAR alone is 0.625–0.629,
indicating poor discriminative ability. Even the combined AUC with TBiL and Scr remains
moderate (0.742), with limited specificity and sensitivity.
6. Nomogram and Predictive Tool Development
A nomogram is presented using RAR, TBiL, and Scr for mortality prediction. It is derived
solely from the current dataset without external or internal validation (e.g., bootstrapping or
split-sample). Calibration, net reclassification improvement, or decision curve analysis are not
performed. As a result, the clinical utility of the nomogram remains theoretical.
7. Interpretation of Findings
The manuscript presents RAR as a robust, independent predictor of mortality in ICU patients
with NAFLD. However, the interpretation does not adequately consider the context-specific
variability of RDW and albumin. The potential for reverse causation or residual confounding is
not addressed. There is a tendency to overstate the predictive value of RAR despite the relatively
low AUC and the absence of ICU-specific risk scores in the models.
8. Discussion of Mechanisms and Pathophysiology
The discussion broadly attributes the prognostic role of RAR to inflammation, oxidative
stress, and nutritional status. While references are provided linking RDW and albumin to
systemic disease processes, the manuscript does not offer direct mechanistic insights specific to
NAFLD or critical illness. The potential impact of acute hepatic decompensation, hemodynamic
instability, or treatment interventions on RAR is not examined.
Minor Points of Evaluation
• The manuscript alternates between the terms NAFLD and MAFLD, though patients were
included using NAFLD coding. No effort is made to retrospectively define MAFLD or
differentiate between the two concepts.
• Sample size inconsistencies exist. The methods mention 661 patients initially, but the analysis
is conducted on 616. This discrepancy is not explained.
• The imputation method for missing data is mentioned only briefly, without specification of the
statistical approach or the proportion of imputed variables.
• Table 1 contains numerous variables and is overly dense. The clinical relevance of many
comparisons (e.g., SpO#, temperature) is unclear.
Limitations Identified in the Study
• Retrospective single-center design without prospective validation.
• Diagnosis of NAFLD based on administrative coding without imaging or histological
verification.
• Lack of ICU-specific severity scores to contextualize mortality risk.
• No information on treatment-related confounding (e.g., use of albumin or transfusion).
• Moderate predictive performance of RAR as an isolated biomarker.
• Nomogram lacks validation and clinical implementation pathway.
• Cause of death not recorded—mortality may not be directly attributable to liver-related
pathology.
Please review this paper.
user
Title: Prognostic Significance of Red Cell Distribution Width to Albumin Ratio in ICU Patients
with NAFLD: A Retrospective Analysis
Version: 1 Date: 29 Mar 2025
Reviewer's report:
This retrospective cohort study evaluates the association between the red cell distribution
width to albumin ratio (RAR) and mortality in patients with non-alcoholic fatty liver disease
(NAFLD) admitted to the intensive care unit (ICU), utilizing the MIMIC-IV database. The
primary and secondary outcomes were 365-day and 28-day all-cause mortality, respectively.
RAR was analyzed both as a continuous variable and across quartiles. The study demonstrates
that elevated RAR levels are significantly associated with increased short- and long-term
mortality, even after multivariable adjustment. Additional analyses included Kaplan-Meier
curves, Cox proportional hazards models, restricted cubic spline (RCS) analysis, ROC analysis,
and nomogram development.
Major Points of Evaluation
1. Study Design and Cohort Definition
The study is retrospective in design and relies entirely on secondary data from MIMIC-IV.
The use of ICD-9/10 codes for the identification of NAFLD introduces the possibility of
misclassification bias, particularly in an ICU population where NAFLD may not be accurately
coded. The manuscript does not provide confirmatory laboratory, imaging, or histologic criteria
for NAFLD, which limits diagnostic precision. Moreover, since this is a single-center dataset,
derived from a tertiary academic center in the US, external validity is inherently limited.
2. Exposure Definition and Biomarker Calculation
RAR is calculated as the ratio of red cell distribution width (RDW) to serum albumin (g/
dL). Both RDW and albumin are nonspecific laboratory parameters influenced by acute and
chronic conditions. In ICU settings, albumin is frequently affected by capillary leakage, fluid
resuscitation, sepsis, and liver dysfunction. RDW may reflect systemic inflammation, nutritional
deficiencies, or hematologic stress. Therefore, the RAR value in this context may not reflect a
stable biomarker but rather a dynamic response to critical illness. This complex interplay is not
deeply explored in the manuscript.
3. Outcome Definition and Endpoint Integrity
The study focuses on all-cause mortality at 28 and 365 days. Cause-specific mortality is not
available in the dataset. Thus, it is unclear whether deaths are related to liver disease progression,
critical illness, or unrelated comorbid conditions. The primary endpoint (365-day mortality) may
be influenced by post-discharge factors and outpatient management, which are not accounted
for in the analysis. Furthermore, follow-up details and censoring strategies are not explicitly
described.
4. Covariate Selection and Confounding
Multivariable Cox regression models are used with progressive adjustment (Model 1 unadjusted,
Model 2 adjusted for age and sex, and Model 3 including clinical and laboratory covariates).
However, no established ICU severity indices (e.g., SOFA, APACHE II) are incorporated.
These are strong predictors of ICU mortality and their absence limits the ability to contextualize
RAR’s independent prognostic value. In addition, potential treatment confounders—such as
albumin administration, transfusions, mechanical ventilation, or vasopressors—are not included
or discussed.
5. Statistical Analysis
Kaplan-Meier curves demonstrate clear separation between RAR quartiles, with significant
log-rank tests. Cox models show increasing hazard ratios across quartiles, particularly for Q4.
Restricted cubic spline analysis reveals a nonlinear relationship between RAR and long-term
mortality, supporting the choice of categorization. However, the performance metrics of RAR
are modest. The AUC for 28- and 365-day mortality prediction using RAR alone is 0.625–0.629,
indicating poor discriminative ability. Even the combined AUC with TBiL and Scr remains
moderate (0.742), with limited specificity and sensitivity.
6. Nomogram and Predictive Tool Development
A nomogram is presented using RAR, TBiL, and Scr for mortality prediction. It is derived
solely from the current dataset without external or internal validation (e.g., bootstrapping or
split-sample). Calibration, net reclassification improvement, or decision curve analysis are not
performed. As a result, the clinical utility of the nomogram remains theoretical.
7. Interpretation of Findings
The manuscript presents RAR as a robust, independent predictor of mortality in ICU patients
with NAFLD. However, the interpretation does not adequately consider the context-specific
variability of RDW and albumin. The potential for reverse causation or residual confounding is
not addressed. There is a tendency to overstate the predictive value of RAR despite the relatively
low AUC and the absence of ICU-specific risk scores in the models.
8. Discussion of Mechanisms and Pathophysiology
The discussion broadly attributes the prognostic role of RAR to inflammation, oxidative
stress, and nutritional status. While references are provided linking RDW and albumin to
systemic disease processes, the manuscript does not offer direct mechanistic insights specific to
NAFLD or critical illness. The potential impact of acute hepatic decompensation, hemodynamic
instability, or treatment interventions on RAR is not examined.
Minor Points of Evaluation
• The manuscript alternates between the terms NAFLD and MAFLD, though patients were
included using NAFLD coding. No effort is made to retrospectively define MAFLD or
differentiate between the two concepts.
• Sample size inconsistencies exist. The methods mention 661 patients initially, but the analysis
is conducted on 616. This discrepancy is not explained.
• The imputation method for missing data is mentioned only briefly, without specification of the
statistical approach or the proportion of imputed variables.
• Table 1 contains numerous variables and is overly dense. The clinical relevance of many
comparisons (e.g., SpO#, temperature) is unclear.
Limitations Identified in the Study
• Retrospective single-center design without prospective validation.
• Diagnosis of NAFLD based on administrative coding without imaging or histological
verification.
• Lack of ICU-specific severity scores to contextualize mortality risk.
• No information on treatment-related confounding (e.g., use of albumin or transfusion).
• Moderate predictive performance of RAR as an isolated biomarker.
• Nomogram lacks validation and clinical implementation pathway.
• Cause of death not recorded—mortality may not be directly attributable to liver-related
pathology.
assistant