-->PONE-D-26-20582-->-->Transmission dynamics and risk factor analysis of Opisthorchis viverrini infection after selective praziquantel treatment: evidence from a urine antigen assay and fecal examination in an endemic community in Northeast Thailand-->-->PLOS One

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Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: No

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-->5. Review Comments to the Author

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Reviewer #1: The manuscript presents a strong and well-designed epidemiological study investigating the transmission dynamics of Opisthorchis viverrini infection in an endemic region of Northeast Thailand. The prospective cohort design, the analysis of both incidence and reinfection, and the integration of urine antigen detection together provide important and highly interesting findings with clear public health relevance. In particular, the application of urinary antigen ELISA for monitoring transmission dynamics represents an important contribution to the field and highlights the potential advantages of non-invasive diagnostic approaches in opisthorchiasis surveillance. The manuscript is generally well written, scientifically sound, and supported by robust epidemiological data. The discussion is balanced and appropriately cautious. However, I would ask the authors to further discuss several important methodological and interpretational issues before publication.

1. FECT as an imperfect reference standard. This is probably the most important methodological issue of the manuscript. The diagnostic performance of the urine ELISA is evaluated against FECT, although FECT itself has relatively low sensitivity and cannot reliably distinguish O. viverrini eggs from minute intestinal flukes. Therefore, sensitivity, specificity, kappa values, and false-positive calculations may be distorted by the limitations of the reference standard itself. The authors partially acknowledge this issue; however, I recommend emphasizing this point more clearly in the Discussion section. In particular, the following statement or a similar interpretation should be considered: “Because FECT is an imperfect reference standard, the reported diagnostic performance metrics of urine ELISA should be interpreted cautiously.”

2. Interpretation of ELISA-positive cases: The manuscript would benefit from a more detailed discussion regarding the biological interpretation of urine antigen positivity. It is not entirely certain that every ELISA-positive individual represents an active egg-producing infection. Urinary antigen positivity may also reflect residual circulating antigens, delayed antigen clearance after treatment, or possibly very early-stage infection before detectable egg shedding. This important immunological and diagnostic aspect deserves further discussion.

3. Reinfection versus treatment failure: The manuscript interprets positivity at 24 weeks mainly as reinfection. However, it remains unclear whether all cases truly represent reinfection or whether some individuals may have experienced partial treatment failure, persistent low-level infection, or subcurative praziquantel response. I recommend that the authors discuss this distinction more thoroughly, as it may influence the interpretation of reinfection dynamics.

4. Increased risk associated with previous praziquantel treatment: The finding that prior praziquantel treatment is associated with higher infection risk is epidemiologically very interesting. However, this association may be strongly confounded. It is possible that individuals with repeated praziquantel treatments are simply those with the highest long-term exposure risk and most persistent behavioural risk factors. Therefore, previous praziquantel treatment history may function more as a marker of repeated exposure rather than an independent biological risk factor. This interpretation should be further elaborated in the Discussion.

5. Duration of follow-up and potential seasonal effects: The 6-month follow-up period is appropriate for evaluating short-term epidemiological dynamics; however, it may not fully capture seasonal transmission patterns. I would ask the authors to comment on whether the study period coincided with specific environmental or sociocultural factors in the region, such as: fishing seasons, rainy season-related ecological changes, national or local festivals involving traditional raw fish consumption. These factors could potentially influence transmission intensity and reinfection rates and would strengthen the epidemiological interpretation of the findings.

Overall, this is an important and valuable study with strong epidemiological content and highly relevant findings. After addressing the points above, I believe the manuscript would make a meaningful contribution to the field.

Reviewer #2: Dear authors. I've read this manuscript with interest. Congratulations. I was surprised to see that during the 24 w study period, the incidense was higher in those negative at baseline (hence not infected during the previous years) than the reinfection rate in those positive at baseline. But that is what the numbers show.

The manuscript is well written in fluent language.

Major:

*The main problem that I find is the relation between the two methods; urinary ELISA and FECT. Using the ELISA it is a 5-10-fold (!) increase in prevalence/incidense/reinfection rate. It is well known (as written in the manuscript) that FECT is an imperfect 'gold standard' with both false positives and especially false negatives. It is almost comparing apples and oranges and make the section The diagnostic accuracy difficult (and unnecessary??). In line 324 it states ELISA has sensitivity 61.9%, which is not so good when the number of positive ELISA is so much higher than FECT (due to false positive 'gold standard'/FECT?).

Table 4 mix just one technical test quantification (sensitivity) and one prevalencedependent diagnostic predictive value (NPV).

In line 328 it says: 'The positive urine ELISA results among fecal egg-negative individuals (i.e. false positives) ranged from 0.1% to 1.6%.' How do you calculate those numbers? There is a 5-10-fold higher number of of ELISA positives than FECT positives.

I suggest the diagnostic accuracy section is rewritten for clarity. As the study is not really designed to validate the test properties of the two diagnostic methods, you may alternativly consider if the section can be omitted and the difference in test properties be discussed in Discussion, based on findings from previous studies. Especially interesting is the assumed specificity of ELISA (many false positives?)

*Fig 2: At least in the reviewer version of the manuscript the background is all black. Was it supposed to be lines/arrows between the boxes?

Minor:

*Line 65; CCA should be written in full the first time i appears ( it is written in full in line 68).

*Line 427-429 (The outcome..) The sentence is difficult to understand, suggest rephrase.

Reviewer #3: The manuscript entitled "Transmission dynamics and risk factor analysis of Opisthorchis viverrini infection after selective praziquantel treatment: evidence from a urine antigen assay and fecal examination in an endemic community in Northeast Thailand" reports the results of a longitudinal study assessing O. viverrini infection status using urine antigen ELISA and FECT in a rural endemic area of Thailand at baseline, 4 weeks post-treatment, and 24 weeks post-treatment. Overall, there are relatively few publications addressing this topic, and the study could contribute valuable information to the field. However, several major issues need to be addressed before the manuscript can be considered for publication.

Major comments

1. Use of the term "transmission dynamics"

The title and framing of the manuscript emphasize "transmission dynamics." However, with only baseline and 24-week follow-up measurements, the study design is not sufficient to characterize transmission dynamics in the strict epidemiologic sense. The data allow assessment of longitudinal change, cumulative incidence, reinfection, or infection acquisition over time, but not detailed transmission dynamics. The title and objectives should therefore be revised to better reflect the actual study design and analytical scope.

2. Unclear description of study population, sampling and grouping strategy

The Methods and Results sections do not clearly explain the study population and diagnostic group definitions. In particular, the definitions of the study groups appear inconsistent and overlapping. For example:

• Group 1 is described as "participants who were O. viverrini antigen negative and/or O. viverrini eggs positive"

• The other group is described as "participants who were O. viverrini antigen negative and/or O. viverrini eggs negative"

These definitions are confusing and potentially overlapping due to the use of "and/or." The grouping criteria should be clearly and consistently defined throughout the manuscript and figures.

In addition, Line111 states “A random household sample of the sub-district population aged 15 years or older was contacted and invited to participate”. However, the sampling methodology is insufficiently described. The authors should clearly specify the sampling frame (e.g., census list, household registry, village roster) and the sampling strategy used (e.g., simple random sampling, cluster sampling, multistage sampling, or systematic sampling) to allow readers to assess the representativeness of the study population and potential selection bias.

3. Inconsistency regarding reinfection period

The manuscript refers to reinfection occurring over 24 weeks; however, based on the study design, reinfection appears to have occurred during the 20-week interval between the 4-week post-treatment assessment and the 24-week follow-up. For example:

• Table 5 title states: "(combined incidence and/or reinfection) over a period of 24 weeks of the study"

• Similar wording appears in Line 374.

This should be corrected for accuracy. In general, the description of the study timeline and participant flow requires clearer presentation.

4. Statistical terminology not defined

The abbreviation "aRR" (adjusted relative risk) is used but not defined in the manuscript. Statistical terms and measures should be clearly introduced when first mentioned.

5. Mismatch between stated objectives and presented analyses

The manuscript does not consistently focus on the stated aims of transmission dynamics and risk factor analysis. For example, Table 4 mainly presents diagnostic accuracy of urinary antigen ELISA compared with fecal examination at baseline and 24 weeks post-treatment. While potentially useful, this analysis does not directly address the stated primary objectives and appears disconnected from the main narrative. The authors should either better integrate these analyses into the study aims or reconsider the organization and focus of the manuscript.

Given the concerns above, particularly regarding conceptual framing, study description, and consistency of reporting, I do not currently recommend acceptance of this manuscript in its present form.

Minor comments

1. Line 65: "CCA" should be written out in full at first mention.

2. Typographical error in Supplementary Figure S1: the word "infection" is misspelled.

3. Line 220: "48 weeks post-treatment" is mentioned, but no such follow-up time point is described in Figure 2 or elsewhere.

4. Line 263: "Among the antigen-positive participants (group 1, n = 244)" is inconsistent with Figure 2, where Group 1 appears to include participants who were antigen-positive and/or stool-positive.

5. Figures 3, 4, and 5 are of poor resolution and should be improved for publication quality.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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-->PONE-D-26-20582R1-->-->Longitudinal changes and risk factors of Opisthorchis viverrini infection after selective praziquantel treatment: evidence from urine antigen assay and fecal examination in an endemic community in Northeast Thailand-->-->PLOS One

Dear Dr. Kopolrat,

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 Jul 25 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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-->

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We look forward to receiving your revised manuscript.

Kind regards,

Petr Heneberg

Academic Editor

PLOS One

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Additional Editor Comments:

Before we proceed, please address the following two points:

First, please verify the source and license of the underlying geospatial data used in Fig. 1. The response indicates that the figure was created in QGIS, but QGIS is the software used to prepare the map and does not by itself establish that the underlying map layers, boundaries, or other geospatial data are compatible with publication under the CC BY 4.0 license. Please add the actual data source(s) for the map layers to the figure caption and confirm that these data can be redistributed under the journal’s license.

Second, please harmonize the ethics and consent wording between the manuscript and the submission form. The submission ethics statement indicates that only participants who provided written informed consent were included, whereas the manuscript states that adults provided written informed consent and that parents or legal guardians provided verbal consent for participants aged 15–17 years. Please ensure that the wording is consistent and that the reported form of consent for minors matches the ethics approval.

Once these technical issues are corrected, no further scientific revision appears necessary.

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Longitudinal changes and risk factors of Opisthorchis viverrini infection after selective praziquantel treatment: evidence from urine antigen assay and fecal examination in an endemic community in Northeast Thailand

PONE-D-26-20582R2

Dear Dr. Kopolrat,

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,

Petr Heneberg

Academic Editor

PLOS One

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