Title: Association between fibrosis-4 index (FIB-4) and gallstones: An analysis of the NHANES
2017-2020 cross-sectional study
Version: 0 Date: 22 Feb 2025
Reviewer:  Wan-Zhe Liao
Reviewer's report:
This cross-sectional study investigates the association between FIB-4 and gallstone prevalence
in U.S. adults using NHANES 2017-2020 data. The topic is novel, as the relationship between
FIB-4 and gallstones remains underexplored. The manuscript is well-structured, and the use
of a nationally representative dataset is a strength. However, several methodological and
interpretational issues require clarification and improvement to strengthen validity and impact.
Major Comments:
1. The abstract and results describe a "positive association" between FIB-4 and gallstones, yet
Table 2 reports an OR=0.58 (95% CI: 0.42–0.82) for the highest FIB-4 quartile in the fully
adjusted model, suggesting a reduced risk. This contradicts the stated direction of association.
Clarify whether this reflects a protective effect or if there is an error in terminology (e.g., "inverse
association").
2. The trend test across quartiles (P<0.0001) implies increasing risk with higher FIB-4, but
the quartile-specific ORs do not align linearly (e.g., Q3 OR=0.56 vs. Q4 OR=0.58). Re-
examine model specifications (e.g., residual confounding, collinearity) and ensure consistency
in reporting.
3. Gallstones were self-reported via questionnaire, which may introduce recall bias. Imaging
confirmation (ultrasound) is the gold standard for gallstone diagnosis; reliance on self-report is
a significant limitation. Acknowledge this and discuss potential misclassification bias.
4. Key confounders like diet, physical activity, and lipid profiles (e.g., cholesterol levels) are
omitted. These factors influence both FIB-4 and gallstone risk. Justify their exclusion or discuss
how their absence might bias results.
5. Subgroup analyses (Figure 3) identify interactions with age, sex, and metabolic conditions.
However, no adjustment for multiple testing (e.g., Bonferroni correction) is mentioned,
increasing the risk of Type I errors. Address this limitation and interpret subgroup findings
cautiously.
Minor Comments:
1. Justify the exclusion of participants aged <20 years. Gallstones are rare in this group, but
explicit reasoning is needed.
3. Provide FIB-4 quartile cutoffs in Table 1 or the Methods section to enhance reproducibility.
4. Standardize reference formatting (e.g., inconsistent spacing in citations like "[1]" vs. "[2-4]").
5. Ensure figures (e.g., RCS plot in Figure 2) are legible and axis labels are clearly described in
the caption. In Table 1, clarify whether percentages are weighted to reflect NHANES sampling
design.
Title: Association between fibrosis-4 index (FIB-4) and gallstones: An analysis of the NHANES
2017-2020 cross-sectional study
Version: 0 Date: 22 Feb 2025
Reviewer:  Wan-Zhe Liao
Reviewer's report:
This cross-sectional study investigates the association between FIB-4 and gallstone prevalence
in U.S. adults using NHANES 2017-2020 data. The topic is novel, as the relationship between
FIB-4 and gallstones remains underexplored. The manuscript is well-structured, and the use
of a nationally representative dataset is a strength. However, several methodological and
interpretational issues require clarification and improvement to strengthen validity and impact.
Major Comments:
1. The abstract and results describe a "positive association" between FIB-4 and gallstones, yet
Table 2 reports an OR=0.58 (95% CI: 0.42–0.82) for the highest FIB-4 quartile in the fully
adjusted model, suggesting a reduced risk. This contradicts the stated direction of association.
Clarify whether this reflects a protective effect or if there is an error in terminology (e.g., "inverse
association").
2. The trend test across quartiles (P<0.0001) implies increasing risk with higher FIB-4, but
the quartile-specific ORs do not align linearly (e.g., Q3 OR=0.56 vs. Q4 OR=0.58). Re-
examine model specifications (e.g., residual confounding, collinearity) and ensure consistency
in reporting.
3. Gallstones were self-reported via questionnaire, which may introduce recall bias. Imaging
confirmation (ultrasound) is the gold standard for gallstone diagnosis; reliance on self-report is
a significant limitation. Acknowledge this and discuss potential misclassification bias.
4. Key confounders like diet, physical activity, and lipid profiles (e.g., cholesterol levels) are
omitted. These factors influence both FIB-4 and gallstone risk. Justify their exclusion or discuss
how their absence might bias results.
5. Subgroup analyses (Figure 3) identify interactions with age, sex, and metabolic conditions.
However, no adjustment for multiple testing (e.g., Bonferroni correction) is mentioned,
increasing the risk of Type I errors. Address this limitation and interpret subgroup findings
cautiously.
Minor Comments:
1. Justify the exclusion of participants aged <20 years. Gallstones are rare in this group, but
explicit reasoning is needed.
3. Provide FIB-4 quartile cutoffs in Table 1 or the Methods section to enhance reproducibility.
4. Standardize reference formatting (e.g., inconsistent spacing in citations like "[1]" vs. "[2-4]").
5. Ensure figures (e.g., RCS plot in Figure 2) are legible and axis labels are clearly described in
the caption. In Table 1, clarify whether percentages are weighted to reflect NHANES sampling
design.
Please review this paper.
user
Title: Association between fibrosis-4 index (FIB-4) and gallstones: An analysis of the NHANES
2017-2020 cross-sectional study
Version: 0 Date: 22 Feb 2025
Reviewer:  Wan-Zhe Liao
Reviewer's report:
This cross-sectional study investigates the association between FIB-4 and gallstone prevalence
in U.S. adults using NHANES 2017-2020 data. The topic is novel, as the relationship between
FIB-4 and gallstones remains underexplored. The manuscript is well-structured, and the use
of a nationally representative dataset is a strength. However, several methodological and
interpretational issues require clarification and improvement to strengthen validity and impact.
Major Comments:
1. The abstract and results describe a "positive association" between FIB-4 and gallstones, yet
Table 2 reports an OR=0.58 (95% CI: 0.42–0.82) for the highest FIB-4 quartile in the fully
adjusted model, suggesting a reduced risk. This contradicts the stated direction of association.
Clarify whether this reflects a protective effect or if there is an error in terminology (e.g., "inverse
association").
2. The trend test across quartiles (P<0.0001) implies increasing risk with higher FIB-4, but
the quartile-specific ORs do not align linearly (e.g., Q3 OR=0.56 vs. Q4 OR=0.58). Re-
examine model specifications (e.g., residual confounding, collinearity) and ensure consistency
in reporting.
3. Gallstones were self-reported via questionnaire, which may introduce recall bias. Imaging
confirmation (ultrasound) is the gold standard for gallstone diagnosis; reliance on self-report is
a significant limitation. Acknowledge this and discuss potential misclassification bias.
4. Key confounders like diet, physical activity, and lipid profiles (e.g., cholesterol levels) are
omitted. These factors influence both FIB-4 and gallstone risk. Justify their exclusion or discuss
how their absence might bias results.
5. Subgroup analyses (Figure 3) identify interactions with age, sex, and metabolic conditions.
However, no adjustment for multiple testing (e.g., Bonferroni correction) is mentioned,
increasing the risk of Type I errors. Address this limitation and interpret subgroup findings
cautiously.
Minor Comments:
1. Justify the exclusion of participants aged <20 years. Gallstones are rare in this group, but
explicit reasoning is needed.
3. Provide FIB-4 quartile cutoffs in Table 1 or the Methods section to enhance reproducibility.
4. Standardize reference formatting (e.g., inconsistent spacing in citations like "[1]" vs. "[2-4]").
5. Ensure figures (e.g., RCS plot in Figure 2) are legible and axis labels are clearly described in
the caption. In Table 1, clarify whether percentages are weighted to reflect NHANES sampling
design.
assistant