Review for 10.1186/s12876-025-04158-6 (2025)

Title: CTI as a Biomarker for Diarrhea in U.S. Adults: Insights from NHANES 2005–2010
Version: 3 Date: 23 Jun 2025
Reviewer:  Amira A. A. Othman
Reviewer's report:
First of all
I want to congratulate the authors on their work, "A retrospective cohort analysis of C-reactive
protein-triglyceride-glucose index (CTI) with chronic constipation and diarrhea: data from
NHANES 2005–2010." In this study, Yang et al. aimed to investigate the association between the
C-reactive protein-triglyceride-glucose index (CTI), a novel biomarker combining inflammation
and insulin resistance, and chronic bowel dysfunction, specifically diarrhea and constipation.
Using NHANES data, the authors aim to fill a critical gap in understanding how metabolic and
inflammatory pathways synergistically impact gastrointestinal health. Their findings could offer
a practical tool for identifying individuals at higher risk of chronic diarrhea, potentially guiding
early interventions.
The authors tried to contribute to this field of research with new findings; nevertheless, there is
an observation for which sufficient justification must be obtained.
In general:
1. The language is generally clear, but some minor grammatical errors and awkward phrasings
could be improved.
- e.g., "wwere" in Methods, inconsistent hyphenation in "C-reactive protein-triglyceride-
glucose".
- Consider having the manuscript proofread by a native English speaker or a professional editing
service.
2. Abbreviations must be fully written at their first appearance.
In Title:
1. The title should indicate the age and locality of the study population at which the National
Health and Nutrition Examination Survey (NHANES) was performed. The title is informative,
but could be more concise. I suggest “ CTI as a Biomarker for Chronic Diarrhea in U.S. Adults:
Insights from NHANES 2005–2010”.
In the Abstract section
2. The background subsection in the abstract :
-  Should be the shortest part of the abstract. It should briefly outline the following information:
What is already known about the subject, related to the paper in question. What is not known
about the subject, and hence what the study intended to examine (or what the paper seeks to
present)? Please reconstruct it properly.
- Briefly mention the clinical significance of CTI’s dual role (inflammation + IR) earlier.
3. In the method subsection in the abstract :
-  The type of study: a population-based study.
- Nothing was mentioned about the participant's age, sex, ethnicity, etc.
- It would help if you described the aim of your statistical analysis.
- Clarify study design and analysis techniques: “This cross-sectional study analyzed NHANES
data (2005–2010) using …….. analysis.”
4. In the results subsection in the abstract :
-   Clarify the contradictory Model 3 result (OR=1.28, p>0.05) to avoid confusion. Was the trend
clinically meaningful despite statistical insignificance?.
5. In the conclusion subsection in the abstract :
- Emphasize the novelty of CTI’s specificity for diarrhea (not constipation) and its potential
clinical utility.
In the Introduction section:
6. Try to provide a summarized description of the National Health and Nutrition Examination
Survey (NHANES) in the background section. You may use the following: “NHANES
(www.cdc.gov/nchs/nhanes) is designed to assess the health and nutritional status of adults
and children in the United States. The survey is distinctive in that it incorporates both
physical examinations and interviews. Several cross-sectional, nationally representative health
examination surveys are part of the NHANES program. Questions about demographics,
health insurance status, dietary habits, acute and chronic medical issues, mental health, and
prescription drug use are all included in the health interview. Exam components can change
between survey cycles but typically include blood pressure, dental exams, vision, hearing,
dermatology, fitness, balance and strength testing, respiratory testing, taste and smell, and
body measurements (weight, height, skin folds, body composition scans). Hematology, organ
and endocrine function (e.g., thyroid, kidney), environmental exposure, dietary biomarkers,
metabolic and cardiovascular health, and infectious disease are a few examples of laboratory
components.
7. Strengthen the rationale for studying CTI by citing more evidence on its predictive value
beyond oncology (currently limited to Refs 24–25).
8. Clearly state the hypothesis (e.g., "We hypothesized CTI would correlate more strongly with
diarrhea due to shared inflammatory pathways").
In the Methods section:
9. Please move the sentences defining the NHANES to the introduction section rather than the
methodology section.
10. The study utilized the 2005-2010 NHANES survey cycle. why did you choose the study
survey cycle? The survey includes study cycles from 2001 to 2023.
11. Please provide the participants' sociodemographic data.
12. How the sample size was calculated.
13. Mention ethical approval earlier in the methodology to emphasize compliance.
14. Justify the exclusion criteria more transparently. For example, why were participants with
incomplete CBC data (n=26) excluded?
15. Clarify if the formula (0.412 × Ln(CRP) + TyG) was validated in gastrointestinal cohorts
or adapted from prior work.
16.  Consider adding dietary fiber intake, a known modifier of bowel dysfunction, to covariates.
In the Results section:
17. In all tables, please explain the abbreviations under the tables.
18. Ensure that table captions succinctly describe the content for standalone clarity.
19. In subgroup analysis, address the wide confidence intervals in non-hypertensive/low-BMI
subgroups. Could this reflect insufficient power?
20. In Mediation Analysis, the modest effects (e.g., waist circumference) warrant discussion—
are they biologically plausible or artifacts of adjustment?.
In the Discussion section:
21. The discussion section is one of the final parts of a research paper, in which an author
describes, analyzes, and interprets their findings. They explain the significance of those results
and tie everything back to the research question(s). In this manuscript, there is confusion
between what should be written in the introduction and discussion sections. Please reconstruct
the discussion section.
22. Contrast the null constipation finding with existing literature linking obesity to constipation
(Ref 20). Is CTI insensitive to motility-related mechanisms?
23. Expand on metformin’s protective role: Could AMPK activation explain the attenuated CTI-
diarrhea link in users?
24. Acknowledge limitations more prominently (e.g., self-reported stool frequency/Bristol scale
may misclassify outcomes).
This manuscript addresses an important question with robust NHANES data and thoughtful
analyses. Strengthening the clinical context, clarifying methodological choices, and discussing
contradictory results would enhance its impact. The specificity of CTI for diarrhea is a
compelling finding that merits further longitudinal validation. With minor refinements to clarity,
focus, and visual presentation, it could better highlight its contributions to both science and
clinical practice.