Title: Nonlinear Association between AST/ALT Ratio and 28-Day All-Cause Mortality
Following ICU Admission in Critically Ill Cirrhotic Patients: A Retrospective Cohort Study
Version: 1 Date: 31 Mar 2025
Reviewer's report:
Dear Editor,
Thank you for inviting me to review the manuscript entitled "Nonlinear Association Between
AST/ALT Ratio and 28-Day Mortality in Critically Ill Cirrhotic Patients: A Retrospective
Cohort Study."
General Overview
This manuscript explores the association between the aspartate aminotransferase-to-alanine
aminotransferase (AST/ALT) ratio and 28-day mortality in critically ill cirrhotic patients
admitted to the intensive care unit (ICU). Using data from the MIMIC-IV database, the authors
analyzed a cohort of 2,090 cirrhotic patients and identified a nonlinear association between AST/
ALT ratio and mortality, with a critical threshold of 3.6. Below this threshold, the association
was pronounced, while beyond it, the relationship plateaued. The findings offer valuable insights
into prognostic markers in ICU settings for cirrhotic patients, emphasizing the importance of
AST/ALT ratio as an independent predictor of mortality.
The manuscript is methodologically sound, and the statistical analysis is comprehensive.
However, further refinements in the interpretation of findings, mechanistic underpinnings, and
sensitivity analyses are necessary to enhance clinical relevance and statistical robustness.
Clinical Comments
Discuss the Implications of Saturation Effect and Threshold
The nonlinear relationship and saturation effect at a threshold of 3.6 are novel findings. However,
the clinical implications of this threshold are not fully addressed. Does this threshold suggest an
optimal range for prognostic utility? Could interventions aimed at lowering AST/ALT below this
level improve outcomes? A discussion on how this information might refine risk stratification
or therapeutic monitoring would be helpful.
Clarify Prognostic Relevance of AST/ALT in Advanced Cirrhosis
The study suggests that higher AST/ALT ratios correlate with higher mortality, yet the plateau
beyond 3.6 implies diminishing prognostic relevance in severely decompensated states. This
phenomenon may reflect the dominance of other pathophysiological factors (e.g., multiorgan
dysfunction) at advanced disease stages. A brief discussion on whether AST/ALT remains a
reliable prognostic marker in late-stage cirrhosis would strengthen clinical interpretation.
Consider Gender-Specific Differences in AST/ALT Prognostic Value
The authors mention subgroup analysis indicating stronger associations in male patients. Given
sex-based differences in hepatic metabolism and inflammation, discussing whether sex-specific
cutoffs for AST/ALT should be explored would be an important addition.
Statistical Comments
Assess and Report Model Calibration
Although the manuscript presents robust AUC values, calibration metrics such as the Brier score
or calibration plots should be reported to assess the model’s performance in predicting actual
mortality risk. Model calibration is essential for determining whether predictions align with
observed outcomes.
Perform Sensitivity Analyses for Inflection Point Variability
The threshold of 3.6 was derived through exploratory analysis using piecewise linear models.
Sensitivity analyses varying the inflection point and comparing models with different thresholds
should be conducted to ensure robustness of the saturation effect findings.
Title: Nonlinear Association between AST/ALT Ratio and 28-Day All-Cause Mortality
Following ICU Admission in Critically Ill Cirrhotic Patients: A Retrospective Cohort Study
Version: 1 Date: 31 Mar 2025
Reviewer's report:
Dear Editor,
Thank you for inviting me to review the manuscript entitled "Nonlinear Association Between
AST/ALT Ratio and 28-Day Mortality in Critically Ill Cirrhotic Patients: A Retrospective
Cohort Study."
General Overview
This manuscript explores the association between the aspartate aminotransferase-to-alanine
aminotransferase (AST/ALT) ratio and 28-day mortality in critically ill cirrhotic patients
admitted to the intensive care unit (ICU). Using data from the MIMIC-IV database, the authors
analyzed a cohort of 2,090 cirrhotic patients and identified a nonlinear association between AST/
ALT ratio and mortality, with a critical threshold of 3.6. Below this threshold, the association
was pronounced, while beyond it, the relationship plateaued. The findings offer valuable insights
into prognostic markers in ICU settings for cirrhotic patients, emphasizing the importance of
AST/ALT ratio as an independent predictor of mortality.
The manuscript is methodologically sound, and the statistical analysis is comprehensive.
However, further refinements in the interpretation of findings, mechanistic underpinnings, and
sensitivity analyses are necessary to enhance clinical relevance and statistical robustness.
Clinical Comments
Discuss the Implications of Saturation Effect and Threshold
The nonlinear relationship and saturation effect at a threshold of 3.6 are novel findings. However,
the clinical implications of this threshold are not fully addressed. Does this threshold suggest an
optimal range for prognostic utility? Could interventions aimed at lowering AST/ALT below this
level improve outcomes? A discussion on how this information might refine risk stratification
or therapeutic monitoring would be helpful.
Clarify Prognostic Relevance of AST/ALT in Advanced Cirrhosis
The study suggests that higher AST/ALT ratios correlate with higher mortality, yet the plateau
beyond 3.6 implies diminishing prognostic relevance in severely decompensated states. This
phenomenon may reflect the dominance of other pathophysiological factors (e.g., multiorgan
dysfunction) at advanced disease stages. A brief discussion on whether AST/ALT remains a
reliable prognostic marker in late-stage cirrhosis would strengthen clinical interpretation.
Consider Gender-Specific Differences in AST/ALT Prognostic Value
The authors mention subgroup analysis indicating stronger associations in male patients. Given
sex-based differences in hepatic metabolism and inflammation, discussing whether sex-specific
cutoffs for AST/ALT should be explored would be an important addition.
Statistical Comments
Assess and Report Model Calibration
Although the manuscript presents robust AUC values, calibration metrics such as the Brier score
or calibration plots should be reported to assess the model’s performance in predicting actual
mortality risk. Model calibration is essential for determining whether predictions align with
observed outcomes.
Perform Sensitivity Analyses for Inflection Point Variability
The threshold of 3.6 was derived through exploratory analysis using piecewise linear models.
Sensitivity analyses varying the inflection point and comparing models with different thresholds
should be conducted to ensure robustness of the saturation effect findings.
Please review this paper.
user
Title: Nonlinear Association between AST/ALT Ratio and 28-Day All-Cause Mortality
Following ICU Admission in Critically Ill Cirrhotic Patients: A Retrospective Cohort Study
Version: 1 Date: 31 Mar 2025
Reviewer's report:
Dear Editor,
Thank you for inviting me to review the manuscript entitled "Nonlinear Association Between
AST/ALT Ratio and 28-Day Mortality in Critically Ill Cirrhotic Patients: A Retrospective
Cohort Study."
General Overview
This manuscript explores the association between the aspartate aminotransferase-to-alanine
aminotransferase (AST/ALT) ratio and 28-day mortality in critically ill cirrhotic patients
admitted to the intensive care unit (ICU). Using data from the MIMIC-IV database, the authors
analyzed a cohort of 2,090 cirrhotic patients and identified a nonlinear association between AST/
ALT ratio and mortality, with a critical threshold of 3.6. Below this threshold, the association
was pronounced, while beyond it, the relationship plateaued. The findings offer valuable insights
into prognostic markers in ICU settings for cirrhotic patients, emphasizing the importance of
AST/ALT ratio as an independent predictor of mortality.
The manuscript is methodologically sound, and the statistical analysis is comprehensive.
However, further refinements in the interpretation of findings, mechanistic underpinnings, and
sensitivity analyses are necessary to enhance clinical relevance and statistical robustness.
Clinical Comments
Discuss the Implications of Saturation Effect and Threshold
The nonlinear relationship and saturation effect at a threshold of 3.6 are novel findings. However,
the clinical implications of this threshold are not fully addressed. Does this threshold suggest an
optimal range for prognostic utility? Could interventions aimed at lowering AST/ALT below this
level improve outcomes? A discussion on how this information might refine risk stratification
or therapeutic monitoring would be helpful.
Clarify Prognostic Relevance of AST/ALT in Advanced Cirrhosis
The study suggests that higher AST/ALT ratios correlate with higher mortality, yet the plateau
beyond 3.6 implies diminishing prognostic relevance in severely decompensated states. This
phenomenon may reflect the dominance of other pathophysiological factors (e.g., multiorgan
dysfunction) at advanced disease stages. A brief discussion on whether AST/ALT remains a
reliable prognostic marker in late-stage cirrhosis would strengthen clinical interpretation.
Consider Gender-Specific Differences in AST/ALT Prognostic Value
The authors mention subgroup analysis indicating stronger associations in male patients. Given
sex-based differences in hepatic metabolism and inflammation, discussing whether sex-specific
cutoffs for AST/ALT should be explored would be an important addition.
Statistical Comments
Assess and Report Model Calibration
Although the manuscript presents robust AUC values, calibration metrics such as the Brier score
or calibration plots should be reported to assess the model’s performance in predicting actual
mortality risk. Model calibration is essential for determining whether predictions align with
observed outcomes.
Perform Sensitivity Analyses for Inflection Point Variability
The threshold of 3.6 was derived through exploratory analysis using piecewise linear models.
Sensitivity analyses varying the inflection point and comparing models with different thresholds
should be conducted to ensure robustness of the saturation effect findings.
assistant