-->PONE-D-25-66438-->-->Prevalence and risk factors for colorectal neoplasia in asymptomatic Vietnamese undergoing screening colonoscopy-->-->PLOS One

Dear Dr. Quach,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Apr 05 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Chih-Wei Tseng

Academic Editor

PLOS One

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3. Please upload a copy of Supporting Information S1 Fig, S2 Fig, S1 Table, S2 Table, S3 Table, S1 File. STROBE Checklist which you refer to in your text on page 24.

4. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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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: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

-->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.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->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: Yes

Reviewer #2: 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: Section-by-Section Appraisal & Suggestions:

Title, Abstract, and Keywords:

Excellent. Clear, concise, and accurately reflect the study.

Introduction:

Well-structured. Establishes the global/regional burden of CRC, the problem of early-onset cancer, and the specific lack of data/policy in Vietnam. Clearly states the study's aim.

Suggestion: Consider adding a sentence explicitly mentioning the lack of data in asymptomatic Vietnamese individuals to further justify the study's focus.

Materials and Methods:

Generally excellent. Ethics, participant recruitment, definitions, and procedures are well-described.

Minor Issues:

Line 105-110 (Definitions): The definition for "Non-alcohol consumption" is slightly awkward ("never drinking or drinking alcohol once per month or less"). Consider rephrasing to "Alcohol consumption was defined as drinking more than once per month."

Line 127-128: "...analysed. The participating endoscopists directly evaluated..." Consider combining: "...recorded and analyzed by the participating endoscopists using standardized data collection sheets."

Line 156: "SPSS (version 23; SPSS Inc, Chicago, IL)" - It's more standard to use "IBM SPSS Statistics for Windows, Version 23.0."

Results:

Clear presentation of participant flow, demographics, and prevalence data.

Critical Error in Table 1: There is a significant formatting/presentation error in the BMI rows. The numbers under "No colorectal neoplasia" and "Colorectal neoplasia" columns for BMI ≥23 and <23 do not align correctly with the headers and total N. The percentages (55.4%, 44.6%, 70.3%, 29.7%) seem to be swapped between the "No CRN" and "CRN" groups or are miscalculated. This must be corrected. The p-value (0.021) suggests a difference, but the displayed numbers are confusing.

Table 1 Footnote: The footnote says p-values for age groups represent comparisons with the reference group (< 40 years). This is typically indicated in the table with superscripts (e.g., a, b, c). Add these superscripts to the p-value column for clarity.

Lines 203-205: The rationale for using age ≥40 as a binary cut-off is very good and should be kept. It strengthens the analysis.

Discussion:

Overall, strong. Effectively compares findings to regional studies, explains potential reasons for higher prevalence, and discusses each risk factor in depth.

Lines 236-240: The paragraph comparing findings to a study on IBS patients is slightly confusing. It states the high proportion of advanced CRN "may be attributed to the inclusion of symptomatic patients," which contrasts with your study's focus on asymptomatic individuals. This comparison may not be the most relevant. Consider focusing more on comparisons with other asymptomatic screening studies.

Lines 272-279: The handling of the conflicting Vietnamese case-control study is excellent – pointing out key methodological differences (asymptomatic vs. unspecified, control group without colonoscopy).

Limitations Section (Lines 294-300): Acknowledges key limitations appropriately. Consider adding that the single-center design, while a limitation, also ensured standardized, high-quality colonoscopy procedures, which is a strength for internal validity.

Conclusion:

Accurate and concise. Appropriately summarizes key findings.

References & Supporting Information:

References appear comprehensive and relevant.

Check Formatting: Ensure all references conform strictly to PLOS ONE's citation style (e.g., journal abbreviations, author lists, etc.).

Supporting information (checklist, figures, tables) is appropriate.

Reviewer #2: Prevalence and risk factors for colorectal neoplasia in asymptomatic Vietnamese undergoing screening colonoscopy .

Major issues with the various subsections

Title, Abstract, Keywords

1)Title

•Scope mismatch / definitional ambiguity ("colorectal neoplasia): The title refers to the lesions that involve the spectrum of CRC on a broad scale, and the manuscript has defined CRN as including adenomas/SSL/CRC and subsequently has reported the advanced CRN separately. There needs to be more specific information (e.g., adenoma/serrated lesions and cancer) or an unequivocated definition in the title/abstract. This is important as it can mislead readers and indexers (to think that the results are cancer or precancer) thereby affecting interpretability and comparability.

•"Asymptomatic" not operationalized in title: Title claims asymptomatic screening population, but "asymptomatic" is defined by absence of lower GI + alarm symptoms and includes self-paid voluntary checkups (selection)."This also implies that this is an average risk screening population; most especially if it's a self-selected cohort, external validity is limited.

•The short title repeats the long title with little shortening. short titles should enhance discoverability and clarity on the layout of journal pages/metadata.

2) Abstract

•Study design & sampling frame not sufficiently explicit: Abstract says "cross-sectional" and "voluntary screening colonoscopy," but does not flag this is a single-center, self-paid, self-selected cohort. This information matters because selection bias can lead to overestimating prevalence and cause distortions in the estimation of risk factors; and readers need this upfront.

•The choices of predictors in the risk factor model are not sufficiently transparent: The abstract refers to age (approximately 40), BMI (approximately 23), and family history as the independent predictors, but does not state the covariates that were considered, as well as the approaches to control the potential confounding factors (e.g., sex, smoking, alcohol consumption).

•Definitions of outcomes not mentioned: CRN and advanced CRN prevalence are provided, but there is no abstract summary of their definition (adenoma/SSL/CRC; advanced criteria). Outcome definition propels prevalence magnitude and cross study comparisons.

3) Keywords

•Keywords are too generic and do not include important indexing terms: Current list does not include "screening colonoscopy," "adenoma," "advanced neoplasia," "serrated lesions," "asymptomatic," and "cross-sectional." Discoverability and appropriate indexing in the databases will be minimized, reducing reach and the chances of citation.

Introduction

•Rationale and knowledge gap are not well specified- Gap is stated ("limited data in asymptomatic") but not sharpened into a testable, novel contribution: The intro repeats that Vietnam lacks screening infrastructure and that asymptomatic data are limited, but does not specify what is uniquely unknown (e.g., age-stratified prevalence including <40, advanced CRN proportion, or risk-factor performance in a self-paid cohort). It is important for the question to be well defined so the reader can assess whether or not the methods and results actually address the question.

•Important construct ("asymptomatic") is not introduced with sufficient precision- The intro presents CRC as "largely asymptomatic until advanced" and calls for screening "even in asymptomatic individuals", but fails to preview the manuscript's operational definition of asymptomatic (no lower GI + no alarm symptoms) and the implications of voluntary/self-paid selection. This is important because the significance of "asymptomatic" has a strong influence on generalizability and risk interpretation.

•Internal logic for the age threshold is not consistent. The introduction claims that there is an increase in early-onset colorectal cancer (CRC) and cites age groups (40, 45, 50); however, no explanation is given in the introduction for including individuals aged 18 and older until the Methods section. Without an explicit a priori rationale, inclusion of very young adults can appear to be a post hoc inclusion and may serve to dilute screening-relevant inference.

Methods --

•Study design & setting Selection bias not handled/mitigated- The research is introduced as a prospective cross-sectional research on voluntary, self-paid screening colonoscopy participants in one private clinic. This is a recruitment frame with a high likelihood of selection bias (health-seeking, greater SES, risk-aware people), and which has the potential to overstate prevalence estimates and mislead risk factor associations unless carefully mitigated.

•"Asymptomatic" definition & ascertainment are under specified. “Asymptomatic” is characterized by the lack of distinctive lower intestinal symptoms and alarm symptoms but Methods fails to indicate how symptoms/anemia/weight loss were evaluated (structured questionnaire vs chart review vs labs), by whom, and at what time in relation to colonoscopy.This is significant because misclassification, especially marginally symptomatic or inadequately screened people, can distort prevalence and relationships.

•Eligibility/exclusion choices may cause systematic changes in prevalence estimates- Excluding patients with inadequate bowel prep (Boston score thresholds), incomplete colonoscopy, and withdrawal time <6 minutes appropriate for quality control but Methods don't say if the excluded patients were different from the included patients (no comparison table) and how many were excluded because of what reason (some of this appears later in Results) Exclusions associated with patient factors (age/comorbidity/constipation) can introduce bias in the estimates of prevalence/risk factors.

•Exposure (risk factor) measurement is too gross and incomplete - Smoking is defined as “currently smoking or ever smoked,” and alcohol as “never/≤1× per month” vs others, with no quantity/duration, no pack-years, no standard-drink metric, and no dietary/physical activity/diabetes/dyslipidemia capture (acknowledged only in Discussion, not planned in Methods). This matters because crude exposure measurement increases residual confounding and can wash out true associations or create spurious ones.

•Outcomes are defined, but key procedural/ histology safeguards missing- CRN/advanced CRN definitions are clear, however, Methods do not state if pathologists were blinded to clinical risk factors/endoscopic impression, whether there was dual reading or how disagreements were resolved. Lack of blinding/standardization can cause classification bias especially for serrated lesion/dysplasia calls.

Results

•Prevalence reporting is not contextual in terms of uncertainty and age standard- The Results reflect CRN and an advanced CRN prevalence of 26.2% and 9.0%, respectively, without the reporting of 95% confidence intervals or age-standardised estimates, despite a significantly age-skewed sample (88.4% aged 40 years and above), In the absence of standardisation and certainty, the reported prevalence may be deceptive, and difficult to compare between different populations.

•Endoscopic characterization vs pathology discordance is flagged but not resolved- The manuscript points out a discrepancy between 15.3% of lesions that were NICE type 1 but "all were histologically confirmed as CRN." This suggests a possible problem of misclassification or quality of documentation, which can lead to lack of confidence in endoscopic evaluation and characterisation of the lesion.

•Results occasionally include interpretation that belongs in Discussion- The Results section speculates on reasons for null associations (e.g. "limited number" and "biological differences"). Results should be descriptive; interpretation here can look like narrative steering too and weakens objectivity.

Discussion

•The generalizability is exaggerated with regard to self-selected, self-paid cohort- Discussion interprets prevalence and risk factors to be informative of wider screening prioritization and national level context although its sample is limited to one private clinic and to individuals who had voluntarily paid to undergo colonoscopy. This is very significant as selection bias can materially change the prevalence and predictor strength. overgeneralizing to mislead policy/clinical implications.

•"Asymptomatic" framing runs a risk of conflating screening populations- The Discussion repeatedly uses "asymptomatic individuals" as if this is synonymous with average-risk screening, however inclusion criteria and recruitment likely represent a health-seeking, risk-aware subset (and ascertainment of symptoms is not completely standardized). if "asymptomatic" is misinterpreted, the conclusions on when/whom to screen may be incorrectly applied.

•Causal or directive language extends beyond the limitations imposed on cross-sectional data - Assertions that certain criteria detected "ought to be considered to prioritise subjects" go beyond association and approach prescriptive screening recommendations. PLOS ONE expects conclusions to equal design limits; cross sectional associations do not make case for causality, or optimal triage rules.

•Limitations are enumerated, important ones underemphasized- The paper has listed some limitations (single center; exclusions; missing risk factors), but failed to anticipate the most serious threats: self-paid volunteer sampling, possible inaccurate classification of symptoms, and instability of models in the case of advanced CRN (wide CIs). Framing Incomplete limitation may cause conclusions to seem stronger than they should be, leading to high rejection or revision risk.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #1: No

Reviewer #2: Yes:  PROF ANYANWU G EMEKA

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

<div>PONE-D-25-66438R1-->-->Prevalence and risk factors for colorectal neoplasia in asymptomatic Vietnamese undergoing self-funded screening colonoscopy-->-->PLOS One

Dear Dr. Quach,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 04 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Chih-Wei Tseng

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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 #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

-->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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: 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.-->

Reviewer #1: Yes

Reviewer #2: Yes

**********

-->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 #1: Yes

Reviewer #2: 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 #1: Generalizability and the "Screening-Attending" Population:

The authors have commendably re-framed their population as "screening-attending" or "self-funded screening" throughout the manuscript and have strengthened the limitations section to explicitly address selection bias. This is a major improvement.

Remaining Concern: While the term "screening-attending" is more accurate, the Discussion and Conclusion could still be misconstrued by a casual reader. The findings are highly valuable for describing this specific cohort and for generating hypotheses, but they should not be interpreted as directly applicable to the "average-risk Vietnamese population" at large. The authors have done a good job of inserting cautionary language, but the final conclusion could be sharpened to reinforce this point. The statement "CRN was prevalent among asymptomatic Vietnamese adults undergoing self-funded screening colonoscopy" is precise and should be the central takeaway.

Inference on Screening Age Threshold:

The authors have correctly softened their language around the optimal screening age, moving from directive statements to hypothesis-generating ones ("raise the hypothesis," "warrants further investigation"). This is appropriate and responsible.

Remaining Concern: The discussion of the age threshold (lines 276-281) is well-balanced. However, it is important to reiterate that the finding of a significant risk at age ≥40 in this cohort does not, by itself, provide evidence for the efficacy or cost-effectiveness of starting screening at that age in the general population. The authors acknowledge the need for population-based studies, which is sufficient. No further action is needed, as the current phrasing is appropriate.

Handling of the NICE Type I Discordance:

The authors' response to the discordance between endoscopic NICE I classification and histological CRN is reasonable, citing the challenge of small lesions. The addition of the reference [27] supports this.

Remaining Concern: While the explanation is plausible, the manuscript could briefly mention that this discordance, while not affecting the final pathology-based diagnosis, highlights a limitation of real-time optical diagnosis in this setting. The current text in the Discussion (lines 259-264) adequately frames this as a known challenge.

Minor Comments

Abstract - Conclusions: The abstract conclusion ("Advanced age, overweight, and family history of colorectal cancer were independent factors associated with CRN.") is accurate and well-stated. It avoids overgeneralization.

Introduction (Lines 89-95): The rationale for including adults aged ≥18 years is now much clearer and well-justified by the opportunistic screening context in Vietnam. This effectively addresses the previous concern about a post-hoc inclusion.

Methods - Exposure Measurement (Lines 336-344): The authors have significantly strengthened the limitations section by explicitly acknowledging the crude categorization of smoking and alcohol and the lack of data on diet, physical activity, and metabolic factors. This transparency is excellent and crucial for interpreting the risk estimates.

Results - Table 1: The corrected Table 1 is now accurate. The use of superscripts (a, b, c, d) for age group p-values is a clear and helpful addition.

Discussion - Advanced CRN Associations (Lines 318-324): The authors provide a balanced discussion on why BMI and family history were not significant for advanced CRN, citing both statistical power and potential biological differences. This is a fair and nuanced interpretation.

Use of AI: The declaration of AI use for language editing is transparent and follows best practices.

Reviewer #2: Most areas of concern from the title, abstract, introduction, method, result and discussion have been addressed, and others were presented as limitations.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review?  For information about this choice, including consent withdrawal, please see our Privacy Policy.-->

Reviewer #1: No

Reviewer #2: Yes:  PROF ANYANWU GODSON EMEKA

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

To ensure your figures meet our technical requirements, please review our figure guidelines: https://journals.plos.org/plosone/s/figures

You may also use PLOS’s free figure tool, NAAS, to help you prepare publication quality figures: https://journals.plos.org/plosone/s/figures#loc-tools-for-figure-preparation.

NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

-->PONE-D-25-66438R2-->-->Prevalence and risk factors for colorectal neoplasia in asymptomatic Vietnamese undergoing self-funded screening colonoscopy-->-->PLOS One

Dear Dr. Quach,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jun 15 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

As the corresponding author, your ORCID iD is verified in the submission system and will appear in the published article. PLOS supports the use of ORCID, and we encourage all coauthors to register for an ORCID iD and use it as well. Please encourage your coauthors to verify their ORCID iD within the submission system before final acceptance, as unverified ORCID iDs will not appear in the published article. Only  the individual author can complete the verification step; PLOS staff cannot  verify ORCID iDs on behalf of authors.

We look forward to receiving your revised manuscript.

Kind regards,

Chih-Wei Tseng

Academic Editor

PLOS One

Journal Requirements:

1. If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

2. Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

[Note: HTML markup is below. Please do not edit.]

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 #1: All comments have been addressed

**********

-->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 #1: Partly

**********

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

Reviewer #1: No

**********

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

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Reviewer #1: Yes

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Reviewer #1: Yes

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-->6. Review Comments to the Author

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Reviewer #1: 2. Severe selection bias undermines generalizability (unchanged from prior review)

The study recruits from a single private polyclinic in Ho Chi Minh City, where participants pay out-of-pocket for colonoscopy. These individuals are likely wealthier, more health-conscious, and have different risk profiles than the general Vietnamese population. The authors have added cautionary language to the conclusion, but this does not fix the fundamental design limitation. For a high-impact journal, a single-center, self-selected cohort cannot support meaningful prevalence estimates for the broader population – even as a “hypothesis-generating” study, the bias is too large.

3. Post-hoc age dichotomization is a serious methodological flaw

The authors dichotomized age at ≥40 years for multivariable analysis without pre-specification, then used the data to justify this cutoff. This is a classic example of data-driven dichotomization that inflates Type I error and yields unstable estimates. The correct approach would have been to model age flexibly (splines, fractional polynomials) or use clinically justified cutoffs from external literature. The authors’ stated reason – avoiding collinearity and preserving power – does not excuse the post-hoc decision.

4. Inadequate control for confounding

The multivariable model adjusts for only 6 variables (age, sex, BMI, family history, smoking, alcohol). Numerous known CRN risk factors are omitted: diabetes, physical inactivity, red/processed meat intake, NSAID use, dietary fiber, and socioeconomic status. Given the self-selected nature of the cohort, residual confounding is likely substantial. The authors do not provide any sensitivity analyses (e.g., E-values, propensity score approaches) to assess robustness.

5. Underpowered analysis for advanced CRN

Only 64 participants had advanced CRN. The multivariable model for this outcome includes 6 predictors, yielding an events-per-variable ratio of ~10.7 – at the absolute minimum acceptable threshold. The resulting confidence intervals are very wide (e.g., age OR 5.20, 95% CI 1.22–22.11), and the null findings for BMI and family history should not be interpreted as evidence of no association. The authors acknowledge this limitation, but the analysis remains exploratory and should not be presented as definitive.

6. Unvalidated definition of “asymptomatic”

Asymptomatic status was determined by unstructured clinical interviews, not by validated instruments (e.g., Rome criteria). No information is provided on inter-rater reliability or the specific questions asked. Recall bias is likely, and some participants may have had mild or intermittent symptoms that were not captured. The prevalence estimate could be meaningfully affected by misclassification.

7. NICE type I discordance highlights quality issue

The authors note that 15.3% of lesions were endoscopically classified as NICE type I (suggesting hyperplastic) but were histologically confirmed as neoplasia. This discordance rate is higher than reported in high-quality optical diagnosis studies. It raises questions about the endoscopists’ real-time diagnostic accuracy and whether all participants received equivalent quality examination. The authors add a sentence acknowledging this as a limitation, but the high discordance should have triggered a more thorough quality control review.

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Reviewer #1: No

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-->PONE-D-25-66438R3-->-->Prevalence and risk factors for colorectal neoplasia in asymptomatic Vietnamese undergoing self-funded screening colonoscopy-->-->PLOS One

Dear Dr. Quach,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS One

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Reviewer #1: All comments have been addressed

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

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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-->6. Review Comments to the Author

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Reviewer #1: 1. Severe Selection Bias – Findings Not Generalizable

The study recruits from a single private polyclinic in Ho Chi Minh City where participants pay out-of-pocket for colonoscopy. These individuals are inherently wealthier, more health-conscious, and likely have different risk profiles (e.g., lower smoking rates, higher health literacy, different dietary patterns) than the general Vietnamese population. The authors acknowledge this limitation but continue to frame the findings as relevant to "asymptomatic Vietnamese adults" – which is misleading.

Critical issue: The prevalence estimates (26.2% overall CRN, 9.0% advanced CRN) cannot be extrapolated to the general population. The authors correctly note that the study was "not designed to provide population-level prevalence estimates," yet the abstract, results, and discussion repeatedly imply broader relevance. For a high-impact journal, a single-center, self-selected cohort cannot support meaningful prevalence estimates – even as a “hypothesis-generating” study, the bias is too large to justify any conclusion about the Vietnamese population.

Required action:

Revise the title and abstract to explicitly state that findings are from a self-selected screening-attending cohort in a private clinical setting, not representative of asymptomatic Vietnamese adults.

Remove or substantially tone down statements implying generalizability (e.g., "CRN was prevalent in asymptomatic Vietnamese adults" should become "CRN was prevalent in this self-selected screening cohort").

Add a dedicated paragraph in the Discussion quantifying the expected direction and magnitude of selection bias.

2. Post-hoc Age Dichotomization – Methodologically Flawed

The authors dichotomized age at ≥40 years for multivariable analysis, then used the data to support this cutoff. This is data-driven dichotomization that inflates Type I error, reduces statistical power, and yields unstable estimates. The authors claim the cutoff was "informed by prior evidence," but the references cited (Quach 2012, Saito 2021, Park 2009) do not provide a validated threshold of 40 years for screening in Vietnam. Moreover, the authors did not pre-specify this cutoff in a protocol; they derived it from their own data (note that 88.4% of participants were ≥40 years, making the comparison highly unbalanced).

The correct approach would have been to model age as a continuous variable (using restricted cubic splines or fractional polynomials) or to use clinically justified cutoffs from external guidelines (e.g., 45 or 50 years). The authors' justification – "avoiding collinearity and preserving power" – is not acceptable.

Required action:

Re-analyze the data with age as a continuous variable (e.g., per 10-year increment) and report adjusted odds ratios.

If dichotomization is retained, provide a pre-specified analysis plan or external validation of the 40-year cutoff from an independent dataset.

Alternatively, present both continuous and dichotomized models in supplemental materials and clearly state that the dichotomized analysis is exploratory.

3. Inadequate Control for Confounding – Residual Bias Likely

The multivariable model adjusts for only six variables (age, sex, BMI, family history, smoking, alcohol). Numerous established CRN risk factors are omitted:

Diabetes mellitus / insulin resistance

Physical inactivity

Red/processed meat intake

Dietary fiber consumption

NSAID/aspirin use

Socioeconomic status (critical given the self-selected, wealthy cohort)

Previous screening history

The authors acknowledge this limitation but provide no sensitivity analyses (e.g., E-values, propensity score calibration, or negative control outcomes) to assess robustness to unmeasured confounding. Given the observational design and the self-selected nature of the cohort, residual confounding is likely substantial.

Required action:

Calculate E-values for the main findings (age, BMI, family history) to quantify the minimum strength of association that an unmeasured confounder would need to have with both exposure and outcome to explain away the observed effects.

Explicitly state that causal inferences cannot be drawn and that the reported associations may be confounded.

4. Underpowered Analysis for Advanced CRN – Findings Should Not Be Presented as Definitive

Only 64 participants had advanced CRN. The multivariable model includes 6 predictors, yielding an events-per-variable ratio of ~10.7 – at the absolute minimum acceptable threshold (some methodologists recommend ≥15-20). The resulting confidence intervals are extremely wide (e.g., age OR 5.20, 95% CI 1.22–22.11), and the null findings for BMI (OR 1.62, 95% CI 0.91–2.88) and family history (OR 2.01, 95% CI 0.92–4.40) should not be interpreted as evidence of no association. The authors acknowledge the limited statistical power, yet they present these results in Table 3 alongside the primary analysis without sufficient warning.

Required action:

Move the advanced CRN analysis to supplemental materials with a clear disclaimer that it is exploratory and underpowered.

Remove statements in the abstract and results that suggest any conclusion about advanced CRN beyond "age may be associated, but estimates are imprecise."

5. Unvalidated Definition of "Asymptomatic" – Risk of Misclassification

Asymptomatic status was determined by unstructured clinical interviews, not validated instruments (e.g., Rome IV criteria, structured symptom questionnaires). No information is provided on inter-rater reliability, the specific questions asked, or whether symptom assessment was blinded to colonoscopy findings. Recall bias is likely. Some participants may have had mild or intermittent symptoms (e.g., occasional abdominal discomfort) that were not captured, potentially misclassifying symptomatic individuals as asymptomatic and biasing prevalence estimates upward.

Required action:

Provide the actual symptom questionnaire or structured interview form as a supplemental file.

Report the proportion of participants who endorsed any symptom (even if considered minor) and compare their CRN prevalence to truly asymptomatic participants as a sensitivity analysis.

Acknowledge that the lack of a validated instrument is a major limitation.

6. NICE Type I Discordance Raises Quality Concerns – Inadequately Addressed

The authors report that 15.3% of lesions were endoscopically classified as NICE type I (suggesting hyperplastic) but histologically confirmed as neoplasia. This discordance rate is substantially higher than reported in high-quality optical diagnosis studies (where negative predictive value for adenoma is typically >90% for NICE type I). The authors attribute this to "known limitations of optical diagnosis" and note that endoscopists had ADRs >30%. However, an ADR >30% does not guarantee accurate optical characterization. The high discordance raises legitimate concerns about:

Real-time diagnostic accuracy of the participating endoscopists

Whether all lesions were adequately examined (e.g., adequate bowel preparation, withdrawal time, imaging quality)

Potential selection bias in which lesions were resected

Required action:

Provide a stratified analysis of NICE type I discordance by lesion size (≤5 mm vs. >5 mm) and location.

Report the inter-endoscopist variation in NICE classification accuracy.

Discuss whether any lesions classified as NICE type I were left in situ (i.e., not resected) – if so, the true prevalence of CRN may be underestimated.

7. Single-Center Design with 5 Endoscopists – Lack of External Validity

All colonoscopies were performed by 5 endoscopists at a single private facility. The results may reflect local practice patterns, lesion recognition skills, and patient demographics that are not representative of other regions in Vietnam (e.g., rural areas, public hospitals). The authors acknowledge this, but the discussion still overgeneralizes.

Required action:

Add a clear statement that external validation in multi-center, population-based samples is required before any screening policy recommendations can be derived from these data.

**********

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Reviewer #1: No

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-->

Prevalence and risk factors for colorectal neoplasia in a self-selected Vietnamese screening cohort undergoing self-funded colonoscopy

PONE-D-25-66438R4

Dear Dr. Quach,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Chih-Wei Tseng

Academic Editor

PLOS One

Additional Editor Comments (optional):

Although the authors have addressed all comments, the reviewer still has some concerns regarding the article. However, I believe that the authors have made their best efforts to improve the manuscript and have appropriately acknowledged the issues that could not be fully resolved as study limitations. Therefore, I suggest that acceptance of this article may be considered.

Reviewers' comments:

Reviewer's Responses to Questions

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Reviewer #1: All comments have been addressed

**********

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Reviewer #1: Partly

**********

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

Reviewer #1: No

**********

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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.-->

Reviewer #1: Yes

**********

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

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Reviewer #1: 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 #1: 1. Selection bias is fatal to generalizability (unresolvable)

The problem: Self-selected, self-funded, single-center cohort from a private clinic. Participants were "likely more health-conscious and had better healthcare access" – the authors admit this but cannot quantify or correct for it.

Why this matters for high-impact journals:

Prevalence estimates (26.2% CRN, 9.0% advanced CRN) cannot inform screening policy or population risk

The authors' own E-values (1.98-2.49) show that moderate unmeasured confounding could explain all associations

The Vietnam population census standardization (age-standardized prevalence 21.3%) is statistically correct but clinically meaningless when the source cohort is non-representative

What the authors did: Added caveats and a limitations paragraph. This is insufficient for high-impact publication where actionable conclusions are expected.

What would be needed: A population-based sampling frame. Without it, this remains a hypothesis-generating descriptive study of a niche cohort.

2. The "asymptomatic" definition is unvalidated and potentially circular

The problem: No validated instrument was used. Asymptomatic status was determined by "structured clinical assessment" – but the authors admit "no formal standardized questionnaire was used" and "no structured symptom questionnaire is available."

Critical gap: The authors could not perform the requested sensitivity analysis comparing "truly asymptomatic" to "mildly symptomatic" because they did not collect granular symptom data. This means we cannot rule out that some participants had subtle symptoms that prompted testing – a classic indication bias.

What the authors did: Acknowledged the limitation. This is honest but does not fix the problem.

High-impact standard: Symptom assessment requires validated instruments (e.g., Rome criteria, GSRS) with inter-rater reliability data.

3. Advanced CRN analysis is underpowered despite being moved to supplements

The problem: Only 64 advanced CRN cases. The authors moved this analysis to supplements with disclaimers, but the abstract still reports 9.0% advanced CRN prevalence as a primary finding.

The inconsistency: If the analysis is too underpowered for meaningful inference, why is the prevalence still featured prominently? The abstract should state clearly that advanced CRN estimates are imprecise (95% CI: 7.0%-11.3% is wide but not enormous – the real issue is the risk factor analysis, not the prevalence estimate itself).

What the authors did: Moved multivariable analysis for advanced CRN to supplements. This is appropriate, but the prevalence itself is still presented as a key finding.

What remains problematic: The exploratory age ≥40 years OR for advanced CRN is 5.20 with CI 1.22-22.11 – this is statistically significant but based on very few events. The authors appropriately call this "hypothesis-generating," but high-impact journals typically require larger event numbers for such claims.

4. The 40-year age threshold remains post-hoc and exploratory (appropriately labeled, but still problematic)

The problem: No pre-specified analysis plan. The authors now correctly label this as "exploratory secondary analysis," but the Introduction and Discussion still heavily imply clinical relevance of the 40-year threshold, citing Japanese screening guidelines starting at age 40.

The logical leap: Japan has population-based data supporting age 40 screening. Vietnam does not. The authors are using their exploratory finding to suggest "a potential burden of CRC in younger adults" – but without a representative sample, this is speculative.

What the authors did: Moved the dichotomized analysis to supplements, labeled it exploratory, and modeled age continuously in the primary analysis. This is methodologically correct.

What remains: The Discussion (lines 304-312) states: "these data suggest a potential burden of CRC in younger adults within screening-attending populations" – but the data only show this in their specific self-selected cohort. The leap to "younger adults" generally is unsupported.

Minor but Notable Issues

5. NICE classification discordance analysis is post-hoc and underpowered for inter-endoscopist variation

The authors added a stratified analysis showing discordance was higher in lesions ≤5 mm (25.0% vs. 4.9%). However, they state "no significant inter-endoscopist variation in NICE classification accuracy was observed" – but no statistical test or data are provided to support this claim. How many endoscopists? What were their individual discordance rates? Was there a formal kappa statistic?

6. Alcohol consumption definition is overly broad

"Drinking more than once per month" is a very low threshold that likely captures many very light drinkers. This may dilute the true effect of moderate/heavy drinking. The authors acknowledge this limitation.

7. Family history definition lacks specificity

"At least one affected first-degree relative at any age" – no distinction by number of relatives, age of onset, or whether the relative actually had screening-detected vs. symptomatic CRC. This is a common limitation but worth noting.

8. E-value interpretation is over-optimistic

The authors state unmeasured confounding "of at least moderate magnitude would be required" to explain away associations. However, E-values of ~2.0 mean that an unmeasured confounder associated with both the exposure and outcome by OR of ~2.0 could fully explain the effect. In observational epidemiology, such confounders are common (e.g., socioeconomic status, health-seeking behavior, diet). The authors do not discuss this adequately.

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

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