Title: Dynamic Changes in Liver Stiffness Measurement by 2D Shear-wave Elastography
Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B and Well-controlled
Viremia: A Retrospective Study
Version: 4 Date: 26 Jun 2025
Reviewer's report:
Thank you for your effort .
1. MAJOR UNADDRESSED ISSUES
1.1 Fundamental Statistical Methodology Concerns
Issue: Data-derived threshold and circular reasoning
• The 8.2 kPa cutoff was derived post hoc from the same dataset, creating circular reasoning
and potential overfitting
• Author Response: Authors provided justification and tested alternative cutoffs but failed to
address the fundamental methodological flaw
• Implementation Status: NOT ADEQUATELY ADDRESSED
• Critical Gap: The authors did not implement the reviewer’s key recommendation to use an a
priori threshold from literature or perform proper cross-validation. Testing alternative cutoffs
from the same dataset does not resolve the circular reasoning issue.
1.2 Statistical Power and Model Stability
Issue: Overfitting concerns with limited events
• Only 27 HCC events with multiple predictors evaluated, risking model instability
• Author Response: Authors provided sensitivity analyses but did not address the fundamental
statistical power issue
• Implementation Status: PARTIALLY ADDRESSED
• Critical Gap: No consideration of penalized regression methods or other approaches to
handle the events-per-variable constraint. The sensitivity analyses do not resolve the underlying
statistical power limitations.
2. METHODOLOGICAL ISSUES INADEQUATELY ADDRESSED
2.1 “Unstable” Group Heterogeneity
Issue: Lack of analysis of trajectory patterns within unstable group
• The “unstable” group is heterogeneous, mixing increasing and decreasing trends
• Author Response: Authors stated it was difficult to analyze due to variable timing but did not
attempt alternative approaches
• Implementation Status: NOT ADDRESSED
• Critical Gap: No effort was made to explore simpler categorizations (e.g., predominantly
increasing vs. decreasing) or to acknowledge this as a significant limitation affecting
interpretation.
2.2 Follow-up Definition Justification
Issue: Unclear rationale for excluding final LSM in non-HCC patients
•  Using second-to-last LSM for non-HCC patients is unusual and needs justification
• Author Response: Authors provided rationale but the explanation is methodologically
questionable
• Implementation Status: INADEQUATELY ADDRESSED
• Critical Gap: The authors’ justification for prediction purposes is weak, as this approach may
introduce bias and is not standard practice in survival analysis.
3. IMPLEMENTATION VERIFICATION ISSUES
3.1 Claimed Statistical Analysis Modifications
Issue: Authors claimed to add statements about stepwise regression process
• Author Claim: “We have added relevant statements in statistical analysis section (Page 8, lines
177–179)”
• Critical Gap: Without clear evidence of implementation, the claimed improvements remain
unverified. May be I missed where it implemented.
3.2 Limitation Section Additions
Issue: Authors claimed to add multiple limitation statements
• Author Claims: Multiple statements about adding limitations regarding external validation,
heterogeneous unstable group, and cirrhosis diagnosis
• Verification Status: The specific additions mentioned are not clearly identifiable in the
available manuscript text
4. CONCEPTUAL ISSUES REMAINING UNRESOLVED
4.1 Clinical Applicability Concerns
Issue: Equipment and population specificity not adequately addressed
• The 8.2 kPa threshold may be specific to the SuperSonic Imagine equipment and study
population
• Author Response: Authors acknowledged this but provided no solution or mitigation strategy
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No discussion of how clinicians should apply these findings with different
equipment or in different populations.
4.2 Model Generalizability
Issue: Limited discussion of model limitations in clinical practice
•  The model needs prospective validation and calibration in other cohorts
• Author Response: Authors acknowledged this as a limitation
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No roadmap provided for future validation or interim clinical application
guidelines.
Title: Dynamic Changes in Liver Stiffness Measurement by 2D Shear-wave Elastography
Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B and Well-controlled
Viremia: A Retrospective Study
Version: 4 Date: 26 Jun 2025
Reviewer's report:
Thank you for your effort .
1. MAJOR UNADDRESSED ISSUES
1.1 Fundamental Statistical Methodology Concerns
Issue: Data-derived threshold and circular reasoning
• The 8.2 kPa cutoff was derived post hoc from the same dataset, creating circular reasoning
and potential overfitting
• Author Response: Authors provided justification and tested alternative cutoffs but failed to
address the fundamental methodological flaw
• Implementation Status: NOT ADEQUATELY ADDRESSED
• Critical Gap: The authors did not implement the reviewer’s key recommendation to use an a
priori threshold from literature or perform proper cross-validation. Testing alternative cutoffs
from the same dataset does not resolve the circular reasoning issue.
1.2 Statistical Power and Model Stability
Issue: Overfitting concerns with limited events
• Only 27 HCC events with multiple predictors evaluated, risking model instability
• Author Response: Authors provided sensitivity analyses but did not address the fundamental
statistical power issue
• Implementation Status: PARTIALLY ADDRESSED
• Critical Gap: No consideration of penalized regression methods or other approaches to
handle the events-per-variable constraint. The sensitivity analyses do not resolve the underlying
statistical power limitations.
2. METHODOLOGICAL ISSUES INADEQUATELY ADDRESSED
2.1 “Unstable” Group Heterogeneity
Issue: Lack of analysis of trajectory patterns within unstable group
• The “unstable” group is heterogeneous, mixing increasing and decreasing trends
• Author Response: Authors stated it was difficult to analyze due to variable timing but did not
attempt alternative approaches
• Implementation Status: NOT ADDRESSED
• Critical Gap: No effort was made to explore simpler categorizations (e.g., predominantly
increasing vs. decreasing) or to acknowledge this as a significant limitation affecting
interpretation.
2.2 Follow-up Definition Justification
Issue: Unclear rationale for excluding final LSM in non-HCC patients
•  Using second-to-last LSM for non-HCC patients is unusual and needs justification
• Author Response: Authors provided rationale but the explanation is methodologically
questionable
• Implementation Status: INADEQUATELY ADDRESSED
• Critical Gap: The authors’ justification for prediction purposes is weak, as this approach may
introduce bias and is not standard practice in survival analysis.
3. IMPLEMENTATION VERIFICATION ISSUES
3.1 Claimed Statistical Analysis Modifications
Issue: Authors claimed to add statements about stepwise regression process
• Author Claim: “We have added relevant statements in statistical analysis section (Page 8, lines
177–179)”
• Critical Gap: Without clear evidence of implementation, the claimed improvements remain
unverified. May be I missed where it implemented.
3.2 Limitation Section Additions
Issue: Authors claimed to add multiple limitation statements
• Author Claims: Multiple statements about adding limitations regarding external validation,
heterogeneous unstable group, and cirrhosis diagnosis
• Verification Status: The specific additions mentioned are not clearly identifiable in the
available manuscript text
4. CONCEPTUAL ISSUES REMAINING UNRESOLVED
4.1 Clinical Applicability Concerns
Issue: Equipment and population specificity not adequately addressed
• The 8.2 kPa threshold may be specific to the SuperSonic Imagine equipment and study
population
• Author Response: Authors acknowledged this but provided no solution or mitigation strategy
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No discussion of how clinicians should apply these findings with different
equipment or in different populations.
4.2 Model Generalizability
Issue: Limited discussion of model limitations in clinical practice
•  The model needs prospective validation and calibration in other cohorts
• Author Response: Authors acknowledged this as a limitation
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No roadmap provided for future validation or interim clinical application
guidelines.
Please review this paper.
user
Title: Dynamic Changes in Liver Stiffness Measurement by 2D Shear-wave Elastography
Predict Hepatocellular Carcinoma in Patients with Chronic Hepatitis B and Well-controlled
Viremia: A Retrospective Study
Version: 4 Date: 26 Jun 2025
Reviewer's report:
Thank you for your effort .
1. MAJOR UNADDRESSED ISSUES
1.1 Fundamental Statistical Methodology Concerns
Issue: Data-derived threshold and circular reasoning
• The 8.2 kPa cutoff was derived post hoc from the same dataset, creating circular reasoning
and potential overfitting
• Author Response: Authors provided justification and tested alternative cutoffs but failed to
address the fundamental methodological flaw
• Implementation Status: NOT ADEQUATELY ADDRESSED
• Critical Gap: The authors did not implement the reviewer’s key recommendation to use an a
priori threshold from literature or perform proper cross-validation. Testing alternative cutoffs
from the same dataset does not resolve the circular reasoning issue.
1.2 Statistical Power and Model Stability
Issue: Overfitting concerns with limited events
• Only 27 HCC events with multiple predictors evaluated, risking model instability
• Author Response: Authors provided sensitivity analyses but did not address the fundamental
statistical power issue
• Implementation Status: PARTIALLY ADDRESSED
• Critical Gap: No consideration of penalized regression methods or other approaches to
handle the events-per-variable constraint. The sensitivity analyses do not resolve the underlying
statistical power limitations.
2. METHODOLOGICAL ISSUES INADEQUATELY ADDRESSED
2.1 “Unstable” Group Heterogeneity
Issue: Lack of analysis of trajectory patterns within unstable group
• The “unstable” group is heterogeneous, mixing increasing and decreasing trends
• Author Response: Authors stated it was difficult to analyze due to variable timing but did not
attempt alternative approaches
• Implementation Status: NOT ADDRESSED
• Critical Gap: No effort was made to explore simpler categorizations (e.g., predominantly
increasing vs. decreasing) or to acknowledge this as a significant limitation affecting
interpretation.
2.2 Follow-up Definition Justification
Issue: Unclear rationale for excluding final LSM in non-HCC patients
•  Using second-to-last LSM for non-HCC patients is unusual and needs justification
• Author Response: Authors provided rationale but the explanation is methodologically
questionable
• Implementation Status: INADEQUATELY ADDRESSED
• Critical Gap: The authors’ justification for prediction purposes is weak, as this approach may
introduce bias and is not standard practice in survival analysis.
3. IMPLEMENTATION VERIFICATION ISSUES
3.1 Claimed Statistical Analysis Modifications
Issue: Authors claimed to add statements about stepwise regression process
• Author Claim: “We have added relevant statements in statistical analysis section (Page 8, lines
177–179)”
• Critical Gap: Without clear evidence of implementation, the claimed improvements remain
unverified. May be I missed where it implemented.
3.2 Limitation Section Additions
Issue: Authors claimed to add multiple limitation statements
• Author Claims: Multiple statements about adding limitations regarding external validation,
heterogeneous unstable group, and cirrhosis diagnosis
• Verification Status: The specific additions mentioned are not clearly identifiable in the
available manuscript text
4. CONCEPTUAL ISSUES REMAINING UNRESOLVED
4.1 Clinical Applicability Concerns
Issue: Equipment and population specificity not adequately addressed
• The 8.2 kPa threshold may be specific to the SuperSonic Imagine equipment and study
population
• Author Response: Authors acknowledged this but provided no solution or mitigation strategy
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No discussion of how clinicians should apply these findings with different
equipment or in different populations.
4.2 Model Generalizability
Issue: Limited discussion of model limitations in clinical practice
•  The model needs prospective validation and calibration in other cohorts
• Author Response: Authors acknowledged this as a limitation
• Implementation Status: ACKNOWLEDGED BUT NOT ADDRESSED
• Critical Gap: No roadmap provided for future validation or interim clinical application
guidelines.
assistant