-->PONE-D-25-56488-->-->The Association between Novel Anthropometric Indices and Cognitive Function in Iranian Older Adults: Bushehr Elderly Health (BEH) Program-->-->PLOS ONE

Dear Dr. Pejman Sani,

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Additional Editor Comments:

Dear Authors

This manuscript has several strengths, most notably its large sample size and standardized measurement approach. However, it requires significant revision to meet the journal's publication standards. Major concerns center on statistical methods—specifically the use of stepwise regression and unclear model diagnostics—as well as the justification for the cognitive impairment definition and adherence to the mandatory open-data policy. We encourage the authors to carefully revise the manuscript to fully address the reviewers' detailed comments.

Best Regards

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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-->3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

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-->4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: 1. Some sentences are long and could be broken into shorter sentences for readability.

2. References to prevalence in Iran could include more recent statistics if available.

3. Consider emphasizing why these indices are practical alternatives to HOMA-IR (cost and accessibility) a bit earlier to strengthen the rationale.

4. Consider summarizing borderline associations separately from statistically significant results to improve clarity.

5. Some sentences are repetitive (e.g., noting no association for TyG and LAP in multiple places). Consolidating these points could improve readability.

6. Clarify whether quartile-based analyses were adjusted for multiple comparisons.

Reviewer #2: •The study design is cross-sectional, yet several statements imply causality (e.g., “interplay between metabolic indices and cognitive function”). These should be rephrased to reflect association, not cause–effect.

•Some methodological details are insufficient: the phrase “phase 2 of baseline measurements” is ambiguous; it should clearly indicate whether this was a second wave of data collection or a subsample of a longitudinal cohort.

•Definitions of cognitive impairment (based on impairment in ≥1 of 3 tests) may overestimate prevalence; justification or sensitivity analysis using stricter criteria is needed.

•Despite reporting significant associations, the biological and clinical relevance of observed odds ratios (close to 1.0) is minimal and should be interpreted cautiously.

•The manuscript states that covariates were selected using backward stepwise regression, which can lead to unstable models and overfitting. Covariate inclusion should be theory-driven or justified by prior evidence.

•The paper does not describe how missing data were handled. State whether listwise deletion, imputation, or other methods were used.

•No mention of multicollinearity testing, goodness-of-fit (e.g., Hosmer–Lemeshow test), or sensitivity analyses is provided.

•Effect sizes and confidence intervals are reported but should be discussed in terms of practical importance.

•The decision to stratify by sex is reasonable, but the rationale for doing so should be stated explicitly and, ideally, supported by a statistical test for interaction.

•The manuscript is understandable, but several sentences are long, redundant, or grammatically inconsistent.

•Minor typographical errors occur (“demantia,” “measuremnts”).

•Paragraphs in the Discussion are overly descriptive; the narrative should be condensed and more analytical.

•Ensure consistent formatting of tables, units (mmol/L vs mg/dL), and reference style.

A professional English-language edit is recommended before resubmission.

1.Clarify the study design and population. Clearly describe what “phase 2 of baseline” refers to and specify inclusion/exclusion criteria.

2.Refine the definition of cognitive impairment. Provide justification for your threshold (impairment in ≥1 test) and test an alternative stricter definition in sensitivity analysis.

3.Re-examine model specification. Replace stepwise regression with theory-driven models or demonstrate that results are robust to different covariate sets.

4.Address data handling. Explain how missing values were treated and whether multicollinearity was assessed.

5.Add regression diagnostics. Include measures such as pseudo-R² and goodness-of-fit statistics.

6.Report and interpret effect sizes more cautiously. ORs near 1.0 may be statistically significant but clinically negligible.

7.Revise discussion and conclusion. Avoid causal language; discuss mechanisms and confounders (sex hormones, fat distribution, inflammation).

8.Ensure open data compliance. Deposit anonymized dataset in a public repository and update the Data Availability Statement.

9.Language and formatting. Shorten repetitive sections, standardize tables and figures, and fix minor English errors.

Lines 1–3:

“The Association between Novel Anthropometric Indices and Cognitive Function in Iranian Older Adults…”

Comment: The title accurately reflects the topic but is lengthy. A concise version such as “Novel Anthropometric Indices and Cognitive Function among Iranian Older Adults” would improve clarity and alignment with PLOS ONE’s concise title policy.

Lines 4–22:

Comment: Multiple affiliations are clearly presented; however, ensure consistent formatting of institutional units (e.g., use “Tehran University of Medical Sciences, Tehran, Iran” uniformly).

Abstract (Lines 36–64)

Lines 38–41:

The background succinctly introduces TyG, VAI, and LAP, but it would benefit from a stronger rationale explaining why these indices might predict cognitive impairment (e.g., connection to insulin resistance mechanisms).

Lines 43–49 – Methods:

Specify that logistic regression was sex-stratified a priori to justify separate male/female analyses. Also indicate that confounders were selected via backward stepwise regression.

Lines 50–56 – Results:

Results are clearly stated but slightly overloaded with numeric detail. Report only the key significant results with directionality; move others to the Results section. Include the total cognitive impairment prevalence (63.9%) only once.

Lines 57–60 – Conclusion:

Avoid causal language (“highlight the interplay”) and rephrase to reflect association: “These results suggest complex, sex-specific associations between metabolic indices and cognition.”

**Add the study design (“cross-sectional”) explicitly in the first sentence of the Abstract.

Introduction (Lines 65–99)

Lines 69–71:

Strong epidemiological framing. Add a recent Iranian study (within the last 3 years) to justify local context.

Lines 75–92:

Excellent description of insulin resistance and novel indices. However, several sentences could be condensed to reduce redundancy (e.g., references 11–17 repeat the mechanistic explanation).

Lines 93–97:

The final paragraph should explicitly define the gap in prior literature—few studies examining TyG, VAI, and LAP together in non-diabetic older adults—and restate the novelty more assertively.

Study Design (101–118):

•Clarify timeline: The manuscript says “phase 2 of baseline ”measurements”—this phrasing is confusing. Specify if this is the second data collection wave.

•Mention ethical approval and consent here briefly, then expand later.

•State explicitly that the analysis was conducted in 2025 and that no identifiable data were accessed.

Data Collection (119–133):

•Sentence structure unclear (“Data collection included age, sex, income, and level of education, which were gathered…”). Revise for grammatical accuracy.

•Define how income was categorized.

•The PCA-based socio-economic index is mentioned but without variance explained; report the percentage of variance accounted for by the first principal component.

Lifestyle and Physical Activity (128–133):

•Include the name of the validated questionnaire used (e.g., Global Physical Activity Questionnaire, IPAQ, etc.).

•The MET categories differ from WHO thresholds—justify the classification system or cite a local validation.

Cognitive Tests (134–152):

•Excellent that three instruments were used. However, the combination rule (“impairment in one or more tests”) could inflate prevalence; justify this decision.

•Report Cronbach’s α, or internal reliability, for each translated test in the current sample.

•Replace “demantia” (typo, line 140) with “dementia.”

Physical and Laboratory Measures (153–172):

•Add the year of calibration or QA/QC procedure for lab assays.

•Minor typographical error: “measuremnts” → “measurements.”

•Define units consistently (e.g., mmol/L or mg/dL, but not both in formulae).

Novel Anthropometric Indices (173–184):

•Formulas are accurate. For transparency, provide conversion factors between mg/dL and mmol/L where applicable.

•Clarify whether lipid and glucose measures were log-transformed before inclusion in models.

Statistical Analysis (185–197):

•Excellent inclusion of regression modeling. However:

oAdd model diagnostics (e.g., Hosmer–Lemeshow test, multicollinearity check).

oReport how missing data were handled (listwise deletion, imputation?).

oAvoid “backward stepwise”; instead, use theoretical or evidence-based selection to avoid model overfitting.

oState the statistical power or effect size detectable given N=2,426.

Table 1 (225–226):

•Formatting issue: inconsistent column spacing and misaligned p-values.

•Many p-values are reported without correction for multiple testing; consider FDR adjustment.

•Provide units in table headers (e.g., “BMI (kg/m²)”).

•The table is overcrowded; consider splitting demographic and biochemical variables.

Lines 213–219:

The text correctly describes significant group differences but overuses repetition. Condense to highlight major findings (e.g., higher prevalence of impairment in females, p < 0.001).

Lines 228–246:

•Report model goodness-of-fit or pseudo-R² for logistic regressions.

•Use consistent precision (two decimals for OR, two for CI limits).

•Clarify whether sex-stratified analyses were exploratory or planned.

Tables 2–4 (Lines 247–252):

•Tables are detailed but overly complex; emphasize key associations in text rather than reproducing all.

•Clearly label adjusted covariates in each legend.

•Highlight significant findings (e.g., p < 0.05) using bold or footnotes rather than asterisks scattered inconsistently.

•Verify that confidence intervals match p-values; some do not align (e.g., p=0.4 but CI excludes 1).

Discussion (Lines 253–313)

Lines 253–258 – Summary:

Concise and appropriate; however, avoid restating numeric results. Instead, emphasize direction and magnitude.

Lines 259–278 – TyG:

Well contextualized. Consider including a physiological rationale for lack of association (e.g., TyG reflects peripheral IR, not central nervous system IR). Current explanation is accurate but could be tightened.

Lines 279–292 – VAI:

Balanced, but the section mixes discussion of literature with results. Suggest splitting into “Comparison with prior studies” and “Potential mechanisms.”

Add a hypothesis why associations differ by sex (e.g., estrogenic modulation, body fat distribution).

Lines 293–299 – LAP:

Good synthesis, but a brief comment on potential multicollinearity between indices (VAI includes BMI and TG, which also feed into LAP) would enhance rigor.

Lines 300–305 – Integrative interpretation:

Excellent conceptual framing; could be improved by mentioning inflammation, oxidative stress, or adipokine dysregulation as shared mechanisms.

Lines 306–313 – Limitations:

Comprehensive. You may also add: “Residual confounding from unmeasured variables such as diet quality and APOE genotype cannot be excluded.”

Conclusion (Lines 314–320)

Sound and cautious, but slightly repetitive. Revise to two sentences:

“In this large cross-sectional study of Iranian older adults, novel anthropometric indices (TyG, LAP, VAI) were not consistently associated with cognitive impairment. Observed sex- and test-specific differences suggest the need for longitudinal studies to clarify causal pathways.”

References

•Ensure consistency in reference formatting.

•Add 3–4 recent studies (2023–2025) to strengthen currency.

https://doi.org/10.1007/s40200-024-01404-8

https://doi.org/10.1002/ncp.11273

https://doi.org/10.1016/j.puhe.2025.01.040

•Verify numbering sequence.

Reviewer #3: I have reviewed the manuscript entitled “The Association between Novel Anthropometric Indices and Cognitive Function in Iranian Older Adults: Bushehr Elderly Health (BEH) Program.” This study presents a cross-sectional analysis utilizing data collected from 2,426 participants aged 60 and older as part of the Bushehr Elderly Health program. Cognitive function was assessed through the Functional Assessment Staging Test (FAST), Mini-Cog, and Category Fluency Test (CFT) questionnaires. A key finding of this research is the gender-specific association between the Visceral Adiposity Index (VAI) and the results from the FAST, particularly in male participants.

The FAST primarily focuses on functional abilities rather than cognitive testing, evaluating various aspects of functioning from independence in basic activities of daily living to more advanced stages of dementia. However, it may not effectively detect mild cognitive impairment in the early stages of the disease process because of its emphasis on functional decline. Additionally, scoring can be subjective, reliant on the observer’s interpretation of an individual’s functioning, and it does not directly measure cognitive function, which may restrict its usefulness in diagnosing specific types of cognitive impairment. The Mini-Cog is a brief cognitive screening tool that assesses recall ability. It is quick and straightforward to administer and shows particular effectiveness in detecting dementia among older adults. The test requires minimal language skills, but its results may be influenced by cultural familiarity with time-telling devices and can lead to false negatives, particularly in the early stages of cognitive decline. The CFT evaluates verbal fluency and is often correlated with more comprehensive cognitive assessments, which enhances its utility in identifying cognitive impairment. However, the results can be affected by factors such as educational level, language proficiency, and cultural background, and performance may fluctuate based on the individual’s current state (e.g., fatigue or anxiety). Given the measurement limitations related to the primary outcomes and the inherent confounding factors associated with the cross-sectional design of this study, interpreting the results presents challenges. A cohort study design may be more appropriate for investigating the research topic at hand. I commend the authors for their significant efforts in conducting this study; however, several concerns and requests for clarification arise. Below are my observations and suggestions for further elaboration:

1. It is essential to provide a separate table that details the all basic characteristics and variables of participants, comparing men and women without subgrouping while reporting the P-values.

2. A thorough discussion of the advantages and limitations of the FAST, Mini-Cog, and CFT, as above mentioned, should be integrated into the discussion section. Additionally, consider addressing the potential influence of confounding factors, such as educational status, functional abilities, and physical health, which may differ by gender.

3. Although this study did not measure other non-insulin based indices of insulin resistance (IR) such as HOMA-IR and TG/HDL, explaining the results mainly through IR mechanisms, which are a vital component of the discussion section, indicates a strong need to revise the discussion section to focus more on the factual gender-specific differences in participant performance in tests that evaluate cognitive impairment.

4. I recommend including a recruitment flow chart that depicts the percentage of excluded participants at each stage, especially the proportion of missing laboratory values.

5. To enhance clarity, please rephrase “co-association” in line 304.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Shahin AbbaszadehShahin Abbaszadeh

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Novel Anthropometric Indices and Cognitive Function among Iranian Older Adults: Bushehr Elderly Health (BEH) Program

PONE-D-25-56488R1

Mahnaz Pejman Sani

Dear Dr. Mahnaz pejman Sani,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

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Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #3: All comments have been addressed

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-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #3: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #3: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #3: No

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #3: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #3: (No Response)

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Reviewer #3: Yes: Shahin AbbaszadehShahin Abbaszadeh

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