Title: Association between C-reactive protein to lymphocyte ratio and gallstones: A cross-
sectional study
Version: 0 Date: 23 Mar 2025
Reviewer's report:
Dear authors,
Please address the following:
Weaknesses
1.Cross-Sectional Design: Limits causal inference. Elevated CLR may result from gallstone-
induced inflammation rather than precede it.
2. Self-Reported Gallstones: Introduces potential misclassification bias. Imaging confirmation
would improve diagnostic accuracy.
3. Residual Confounding: Unmeasured factors (e.g., diet, physical activity, genetic
predisposition) may influence results.
4. **Multiple Testing in Subgroups**: No adjustment for multiple comparisons increases Type
I error risk (e.g., BMI interaction *P*=0.0446).
5. Modest Effect Sizes: Fully adjusted ORs (e.g., 1.08 for ln CLR) raise questions about clinical
significance.
6. Handling of Missing Data: Exclusion of participants with missing data (#65% of initial
sample) may introduce selection bias. Imputation methods could strengthen robustness.
Key Concerns
1. BMI Interaction Interpretation:
- While the interaction term for BMI is significant (*P*=0.0446), only the BMI #30 subgroup
shows a clear association (OR=1.14). The authors should clarify whether this reflects a true
biological interaction or residual confounding.
2. CLR vs. Other Inflammatory Markers: The incremental value of CLR over CRP alone or
other ratios (e.g., NLR, MLR) is not discussed.
3. Data Presentation
- Table 1 contains a typo under PIR for stone formers ("156. 5.26)").
- Table 3 alignment issues may hinder readability.
Recommendations
1. Address Design Limitations:  Acknowledge reverse causality explicitly and propose
longitudinal studies to establish temporality.
2. Strengthen Diagnostic Validity: Discuss plans for imaging-confirmed gallstone diagnosis in
future work.
3. Refine Statistical Analysis:
- Apply Bonferroni correction or false discovery rate control for subgroup analyses.
- Consider multiple imputation for missing data.
4. Enhance Clinical Context: Compare effect sizes of CLR with established gallstone risk factors
(e.g., obesity, diabetes).
5. Clarify Mechanisms : Elaborate on how obesity modifies the CLR-gallstone relationship (e.g.,
metabolic dysfunction, chronic inflammation).
6. Revise Tables:  Correct formatting errors and ensure consistency in decimal places and
notation.
---
Title: Association between C-reactive protein to lymphocyte ratio and gallstones: A cross-
sectional study
Version: 0 Date: 23 Mar 2025
Reviewer's report:
Dear authors,
Please address the following:
Weaknesses
1.Cross-Sectional Design: Limits causal inference. Elevated CLR may result from gallstone-
induced inflammation rather than precede it.
2. Self-Reported Gallstones: Introduces potential misclassification bias. Imaging confirmation
would improve diagnostic accuracy.
3. Residual Confounding: Unmeasured factors (e.g., diet, physical activity, genetic
predisposition) may influence results.
4. **Multiple Testing in Subgroups**: No adjustment for multiple comparisons increases Type
I error risk (e.g., BMI interaction *P*=0.0446).
5. Modest Effect Sizes: Fully adjusted ORs (e.g., 1.08 for ln CLR) raise questions about clinical
significance.
6. Handling of Missing Data: Exclusion of participants with missing data (#65% of initial
sample) may introduce selection bias. Imputation methods could strengthen robustness.
Key Concerns
1. BMI Interaction Interpretation:
- While the interaction term for BMI is significant (*P*=0.0446), only the BMI #30 subgroup
shows a clear association (OR=1.14). The authors should clarify whether this reflects a true
biological interaction or residual confounding.
2. CLR vs. Other Inflammatory Markers: The incremental value of CLR over CRP alone or
other ratios (e.g., NLR, MLR) is not discussed.
3. Data Presentation
- Table 1 contains a typo under PIR for stone formers ("156. 5.26)").
- Table 3 alignment issues may hinder readability.
Recommendations
1. Address Design Limitations:  Acknowledge reverse causality explicitly and propose
longitudinal studies to establish temporality.
2. Strengthen Diagnostic Validity: Discuss plans for imaging-confirmed gallstone diagnosis in
future work.
3. Refine Statistical Analysis:
- Apply Bonferroni correction or false discovery rate control for subgroup analyses.
- Consider multiple imputation for missing data.
4. Enhance Clinical Context: Compare effect sizes of CLR with established gallstone risk factors
(e.g., obesity, diabetes).
5. Clarify Mechanisms : Elaborate on how obesity modifies the CLR-gallstone relationship (e.g.,
metabolic dysfunction, chronic inflammation).
6. Revise Tables:  Correct formatting errors and ensure consistency in decimal places and
notation.
---
Please review this paper.
user
Title: Association between C-reactive protein to lymphocyte ratio and gallstones: A cross-
sectional study
Version: 0 Date: 23 Mar 2025
Reviewer's report:
Dear authors,
Please address the following:
Weaknesses
1.Cross-Sectional Design: Limits causal inference. Elevated CLR may result from gallstone-
induced inflammation rather than precede it.
2. Self-Reported Gallstones: Introduces potential misclassification bias. Imaging confirmation
would improve diagnostic accuracy.
3. Residual Confounding: Unmeasured factors (e.g., diet, physical activity, genetic
predisposition) may influence results.
4. **Multiple Testing in Subgroups**: No adjustment for multiple comparisons increases Type
I error risk (e.g., BMI interaction *P*=0.0446).
5. Modest Effect Sizes: Fully adjusted ORs (e.g., 1.08 for ln CLR) raise questions about clinical
significance.
6. Handling of Missing Data: Exclusion of participants with missing data (#65% of initial
sample) may introduce selection bias. Imputation methods could strengthen robustness.
Key Concerns
1. BMI Interaction Interpretation:
- While the interaction term for BMI is significant (*P*=0.0446), only the BMI #30 subgroup
shows a clear association (OR=1.14). The authors should clarify whether this reflects a true
biological interaction or residual confounding.
2. CLR vs. Other Inflammatory Markers: The incremental value of CLR over CRP alone or
other ratios (e.g., NLR, MLR) is not discussed.
3. Data Presentation
- Table 1 contains a typo under PIR for stone formers ("156. 5.26)").
- Table 3 alignment issues may hinder readability.
Recommendations
1. Address Design Limitations:  Acknowledge reverse causality explicitly and propose
longitudinal studies to establish temporality.
2. Strengthen Diagnostic Validity: Discuss plans for imaging-confirmed gallstone diagnosis in
future work.
3. Refine Statistical Analysis:
- Apply Bonferroni correction or false discovery rate control for subgroup analyses.
- Consider multiple imputation for missing data.
4. Enhance Clinical Context: Compare effect sizes of CLR with established gallstone risk factors
(e.g., obesity, diabetes).
5. Clarify Mechanisms : Elaborate on how obesity modifies the CLR-gallstone relationship (e.g.,
metabolic dysfunction, chronic inflammation).
6. Revise Tables:  Correct formatting errors and ensure consistency in decimal places and
notation.
---
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