Review for 10.1186/s12876-025-03809-y (2025)

Title: Association between fibrosis-4 index (FIB-4) and gallstones: An analysis of the NHANES
2017-2020 cross-sectional study
Version: 0 Date: 24 Feb 2025
Reviewer's report:
Dong, Zhang, and colleagues conducted a large-scale cross-sectional study to explore the
association between FIB-4 index levels and the prevalence of gallstones. Although the authors
reported a significantly reduced odds ratio (OR 0.58) of gallstone prevalence associated with
higher FIB-4 index quartiles, concerns remain regarding the methodology and interpretation of
the results. The authors repeatedly claim a positive association between FIB-4 and gallstones,
despite their findings suggesting the contrary.
Major Comments:
Page 5, Line 101: The exclusion of 1,388 patients from an initial cohort of 9,232 may introduce
potential selection bias. It is recommended that the authors compare the characteristics of the
excluded and included groups. If differences are observed, sensitivity analyses such as multiple
imputation or inverse probability of selection weights should be considered.
Page 7, Line 121: Age should not be included as a covariate in the model, as it is already used in
the calculation of the FIB-4 index. From Tables 1 and 2, age appears to be a major factor in the
association between FIB-4 and gallstones, which may explain the observed inverse association
between FIB-4 quartiles and gallstones.
Page 14, Line 221: The authors did not demonstrate a positive association between FIB-4 and
gallstones. Instead, conflicting results emerged depending on whether FIB-4 was treated as a
continuous or categorical variable. The discussion section should be revised to reflect these
findings. Additionally, the authors should address why crude (Model 1) and adjusted (Models
2 and 3) values yielded contradictory interpretations.
Page 17, Lines 257-259: This study is not only observational but also cross-sectional. For FIB-4
to be considered a prognostic tool for gallstones, it is essential that FIB-4 assessment precedes
the occurrence of gallstones. However, the study design, which relies on the question “Have
you ever been told you have gallstones?”, does not guarantee this temporal relationship. This
limitation should be addressed in the manuscript. Furthermore, the conclusion on Line 266 that
“Assessment by FIB-4 may be beneficial in the prevention and management of gallstones” is
overstated and should be rephrased to better reflect the study’s findings.
Minor Comments:
Causal Language: The term "relationship" should be replaced with "association" throughout the
manuscript, where appropriate, to avoid implying causality.
Page 7, Lines 126-128: There appears to be a typographical error that should be corrected.
Page 8, Lines 142-145: The authors state, “The study examined the relationship between FIB-4
and gallstone prevalence in the U.S. population using continuous variables (means) and 95%
CIs for continuous variables and percentages and CIs for categorical factors.” This sentence is
unclear and should be rephrased as: “The study examined the association between FIB-4 and
gallstone prevalence in the U.S. population, with FIB-4 assessed as both a continuous variable
and in quantiles. Odds ratios and 95% confidence intervals are presented for both analyses.”
Page 8, Line 148: The use of “stability” seems inappropriate here. “Heterogeneity” would be
a more suitable term.
Page 9, Lines 157-159: The sentence, “The prevalence of gallstones was lower in the highest
quartile of the FIB-4 compared to the lowest quartile of the FIB-4 but higher in the FIB-4,”
is grammatically incorrect. It appears the final part of this sentence belongs to the following
sentence and should be revised accordingly.
Page 11, Line 172: The "positive correlation" should be addressed alongside the non-
significance of the result.
Page 11, Line 175: The authors did not find a “positive connection.” Instead, they observed a
reduced odds of gallstone prevalence associated with higher FIB-4 quartiles.
Page 11, Line 178: The “progressive increase” was observed only in Model 1 and not in Models
2 or 3. This should be clarified.
Page 13, Lines 198-200: The statement that women and those under 50 had a lower odds of
gallstones associated with FIB-4 index should be corrected to: “a lower odds of gallstones
associated with FIB-4 index” rather than a "stronger positive correlation."
Page 13, Lines 202-204: The authors argue that BMI is a significant effect modifier in the
association between FIB-4 and gallstones. However, Figure 3 does not show any trend between
BMI levels and the odds ratio. The authors should verify whether BMI was properly included as
a categorical variable in the model for p-for-interaction calculation, rather than as a continuous
variable.
Page 15, Lines 227-228: The authors state, “For gender differences, the prevalence of gallstones
seems to be higher in women, and our study confirms this.” This statement is not valid, as the
authors did not report gallstone prevalence stratified by sex. It should be revised accordingly.
Page 17, Line 265: The association was not “independent.” The association was dependent on
other covariates and was not statistically significant after adjustment.