Review for 10.1186/s12876-025-04180-8 (2025)

Title: Association between gastrointestinal disorders and sleep-related problems: the mediating
effect of depression
Version: 3 Date: 03 Jun 2025
Reviewer's report:
The topic of the association between gastrointestinal disorders and sleep disorders is important,
particularly given increasing interest in the gut-brain axis. Below are detailed suggestions to
improve your manuscript:
Abstract:
1. It is unnecessary to include the URL link to the NHANES database in the abstract; this
information is better suited for the methods section or references.
2. The results section of the abstract would benefit from including more specific numerical
data, such as exact percentages, odds ratios with confidence intervals, and p-values, to provide
a clearer and more informative summary of the findings.
Introduction:
1. Although the concept of a relationship between GI health and sleep health is relatively
new, there is already a growing body of literature exploring this connection, particularly
through the lens of the gut-brain axis, inflammation, microbiome composition, and psychiatric
comorbidities. Therefore, it is important for the authors to clearly mention the novelty and unique
contribution of their study. Please clarify how this work adds to or differs from existing research.
Without a clearly stated research gap and rationale, the Introduction (background section) is
currently not complete. So, state 1. research gap in the field, and 2. your novel contribution to
the field.
2.  Mention specific study objectives or hypotheses, preferably in the final paragraph of the
introduction.
Methods:
1. The use of self-reported, single-item questions to define both gastrointestinal disease and sleep
disorders (“SP have stomach or intestinal illness?” and “Ever told doctor had trouble sleeping?”)
is a major limitation. These questions are vague, non-specific, and do not differentiate between
types, duration, or severity of conditions. If more specific items or validated instruments
(for example, GI symptom scales, sleep quality questionnaires like PSQI) are available in
NHANES, they should be used. Otherwise, these limitations must be clearly acknowledged in
the Discussion and Limitations sections.
2. The authors include a broad range of covariates, which is great. However, the rationale
for choosing each covariate should be more clearly explained, especially why cardiovascular
comorbidities and depression were included but not others, like anxiety or chronic pain, which
may also confound the relationship between GI disorders and sleep. Some variables (e.g., “ever
told by a doctor you have CHD”) may raise recall bias or underreporting and could be discussed
as potential sources of misclassification.
3. The BMI cutoffs used (25.5–30.59 kg/m² for overweight) are unconventional. Please clarify
why these specific thresholds were chosen instead of standard WHO cutoffs (25.0–29.9 kg/m²
for overweight, #30.0 kg/m² for obesity).
5. The application of three logistic regression models is appropriate. However, it is unclear
whether multicollinearity among covariates was assessed. Also, no information is provided
on how mediation analysis was performed, including what mediators were tested and what
statistical method was used.
6. Some parts of the text suffer from grammatical errors, unclear phrasing, and formatting issues.
For example, “If the answer is, then identified as gastrointestinal disease” should be revised as
“If the answer is yes, then identified as gastrointestinal disease.”
Results:
1. For the simple statistical tests, such as chi-square and t-tests (i.e., those not involving
regression, your Table 1), your outcome of interest is sleep disorder, and your main
exposure variable is gastrointestinal (GI) disorders. Therefore, instead of comparing baseline
characteristics (e.g., gender, age, smoking, etc.) between participants with and without sleep
disorders, it would be more appropriate to compare these characteristics between those with and
without GI disorders.
The goal here is not to assess whether variables like gender are associated with sleep disorders,
which has been well established for more than a decade, but rather to determine whether the
prevalence of sleep disorders differs between participants with and without GI disorders. At the
same time, comparing variables like gender distribution or mean age between the GI and non-GI
groups will help you assess whether any observed difference in sleep disorder prevalence may
be confounded by differences in these baseline characteristics (e.g., if one group has a higher
proportion of females or older individuals).
This approach would more directly support your study’s aim and help provide context for
interpreting the observed association between GI disorders and sleep disorders.
2. Revise the following:
Original:” Multivariate logistic regression analysis showed that there was
a significant risk difference between gastrointestinal diseases and sleep
disorders#OR#95%CI#2.02 (1.75#2.33##P<0.001##especially in age#gender#race#marital
status#smoking#diabetes#CHF#CHD#stroke and other aspects.(Table 2)”
Revised version: “Multivariate logistic regression analysis showed that individuals with
gastrointestinal diseases had 2.02 times the odds of having sleep disorders (95% CI: 1.75–2.33,
P < 0.001). Other factors such as age, gender, race, marital status, smoking, diabetes, congestive
CHF, CHD, stroke, and additional variables were also significant risk factors for sleep disorders
(Table 2). “
3. The following sentence is unclear and factually inaccurate based on the data presented in the
table. Please revise it as follows
Original: ”Among participants with gastrointestinal disorders, the incidence of sleep
disorders#11.3%#589 cases/4961 cases#were higher than those without sleep disorders#5.9%#
992 cases/14495 cases”
Revised version: “The prevalence of gastrointestinal disease was higher among participants with
sleep disorders compared to those without (11.3% vs. 5.9%, P < 0.001).”
4. The following sentence is confusing and incorrect:
Original: “...the incidence of sleep problems in the unadjusted model increased by 98% for each
additional unit of gastrointestinal disease.”
Revised:  “...participants with gastrointestinal diseases had a 98% higher odds of having sleep
disorders compared to those without gastrointestinal diseases in the unadjusted model.”
Similarly update interpretations for Model 1 and Model 2: "higher odds" is correct, not "increase
per unit."
5. Adjusting for so many variables (e.g., PIR as continuous and categorical, BMI the same way)
could risk overfitting or collinearity. Mention in the Methods or Discussion whether you checked
variance inflation factors (VIFs) or other diagnostics.
6. The following is a bit vague. Consider rephrasing for clarity:
Original: “...indicating that the positive correlation was not significantly affected by these factors
(Pint>0.05)”
Revised: “...suggesting that the association between gastrointestinal diseases and sleep disorders
remained consistent across these subgroups.”
7. For your mediation analysis section, the current phrasing is confusing, particularly in the use
of "indirect mediating effect: OR" and "total effect coefficient: OR." These terms mix concepts
from linear regression (e.g., "coefficient") with odds ratios (from logistic regression), which
may mislead readers. It would be more accurate to specify that indirect and total effects were
estimated on the log-odds scale and exponentiated for interpretation as ORs, if that’s the case.
Discussion and limitations:
1. There is no mention of the odds ratios from the main multivariable regression (e.g., OR 2.02),
which is essential in interpreting the study’s main findings. I suggest that state the main odds
ratio for sleep disorder in those with vs. without GI disease, and clarify that mediation was
partial, with depression explaining about 30% of the association.
2. Check for unusual casual language in your discussion section for example:
Phrases like “gastrointestinal disorders mediated by depression have direct…” imply a causal
mechanism, which is not supported by the cross-sectional data. I recommend adding a clear
disclaimer about the exploratory nature of the mediation analysis and the inability to confirm
causality due to the study design.
2. There appears to be an inconsistency between your discussion and results sections. In the
discussion, you state that occasional smokers were significantly more likely to experience poor
sleep quality, whereas in the results section (lines 277–279), you mention that non-smokers
were the ones with poorer sleep quality. Please clarify and ensure consistency between the two
sections.
3. It is recommended to acknowledge in the limitations section that, while the sample size
may be sufficient for traditional statistical analyses, it is relatively small for machine learning
applications.
Conclusion:
Your conclusion includes causal and clinical recommendations that overreach the limitations of
a cross-sectional observational study. Consider rewriting it.
Tables and figures:
Table 1:
1. See the first comment I mentioned in the Results section.
2. Include a note specifying that values are mean ± standard error for continuous variables (e.g.,
age, BMI).
3. Reorder the rows logically (e.g., demographics first, then lifestyle, then comorbidities).
4. Highlight in the footnote how statistical comparisons were performed (e.g., chi-square for
categorical, t-test for continuous).
Figure 2: Figure 2’s caption can be enhanced as “Figure 2. Forest plot showing the odds ratios for
the association between gastrointestinal diseases and sleep disorders across different subgroups."
Overall: The tables could be improved to be more self-explanatory, allowing readers to
understand the content without needing to refer back to the main text. Specifically, consider
defining all abbreviations directly under each table.
Writing:
There are several grammatical, typographical, and punctuation errors throughout the manuscript.
A thorough proofreading is recommended to correct such errors and improve the overall
readability.