PONE-D-23-13392Most bothersome symptom in migraine and probable migraine: a population-based studyPLOS ONE

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: 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.

Reviewer #1: Yes

Reviewer #2: Yes

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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: 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: Kim SJ et al. investigated what the common bothersome symptom (MBS) of Korean migraineurs are. Nausea was most common followed by phonophobia, vomiting and photophobia. I found the manuscript very well written with rigid data and appropriate citations providing another important information about Asians migraineurs which are different from Western population.

I only have few minor comments.

1. Association of BMI and photophobia reported by Winter AC et al. was interesting to know. Could you explain the pathophysiology (if not well known, your speculation) why high BMI may lead to higher percentage of photophobia?

2. Authors mentioned the response to acute treatment and its association with MBS. It is important for readers to know that the use of triptan was very low in the current cohort (noted in Supplementary table). I suggest mentioning the percentage of triptan users (around 0.3%?) in the main text.

3. I thought alternative way of showing % of Table 3, Table 4 and Sup Table 1 would be using number of patients in each category shown on the first row for denominators. I am not 100% sure which one would be more appropriate. You can leave it as current form if you think the current way is better, but please consider.

4. Sup Table 2: I was amazed that all probable migraine patients had at least one of the associated symptoms. By ICHD-3, if a patient meets category A, B, C and E, and not D (associated symptoms), he/she can be diagnosed as probable migraine (if not meeting definite TTH diagnosis). Could you explain why there was no patient without associated symptoms in probable migraine group (i.e. were patients without associated symptoms excluded)?

Reviewer #2: Ever since the US FDA proposed "most bothersome symptoms" (MBS) as a co-primary endpoint, in addition to clinical trial results, several large-scaled research studies have been published from both Eastern and Western countries. The concept of this paper aims to explore the differences between migraine and probable migraine (PM), which indeed represents the current scientific gap. The research findings also provide conclusive evidence of variations in MBS between Eastern and Western populations. The following are some issues for the authors to address:

1. In the Methods Section, the subjects' headache diagnoses were derived from the migraine diagnostic module, without further confirmation from headache specialists. As mentioned in the text, the migraine diagnostic module is not entirely accurate in diagnosing migraine and PM. If there are misdiagnoses, the association between MBS and headache could be affected. How does this impact the conclusions of the study?

2. In the Methods section, nausea and vomiting were treated as two distinct entities. However, according to ICHD-3, the criteria for recognizing migraine-associated symptoms are "at least one of the following: nausea and/or vomiting, photophobia and phonophobia." Therefore, nausea and vomiting can actually be considered as one item in the ICHD-3. In fact, these two symptoms often have a sequential relationship in many patients: if nausea persists without improvement, it can progress to vomiting. The authors are suggested to explain why they separated these two symptoms during analysis.

3. In the Results section, no association between visual aura and photophobia as an MBS, as shown in Tables 3 and 4, regardless of whether it was migraine or PM. However, Taiwanese study mentioned a higher frequency of photophobia as MBS in migraine with aura compared to migraine without aura and chronic migraine. As both studies focus on Asian populations, why is there such a difference?

4. In the Discussion section, it is mentioned that one possible explanation for the differences in MBS between Eastern and Western populations could be the varying prevalence of photophobia. However, differences in the prevalence of photophobia do not necessarily indicate the level of bothersomeness. If you hypothesize that "a symptom with lower prevalence is less likely to be chosen as MBS," it contradicts the findings of your study, where the majority of participants with migraine still selected nausea as MBS rather than phonophobia or photophobia, despite the proportions of these symptoms in the migraine population being ranked as phonophobia (80.6%) > photophobia (73.5%) > nausea (70.6%). This discrepancy may challenge your hypothesis.

5. In the Discussion section, you mentioned that your results demonstrated the suitability of MBS as a co-primary endpoint. However, the treatment response in this study was assessed using mTOQ-6, which solely focuses on headaches and not MBS [Headache. 2015 Apr;55(4):502-18.]. Consequently, using mTOQ-6 as the sole indicator for treatment response in this study does not allow for a determination of whether MBS is suitable or not as a co-primary endpoint. Hence, the concluding statement in the abstract and the 7th paragraph of the discussion may be an overinterpretation of the results.

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Reviewer #1: No

Reviewer #2: No

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Most bothersome symptom in migraine and probable migraine: a population-based study

PONE-D-23-13392R1

Dear Dr. Chu,

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,

Keisuke Suzuki, MD, PhD

Academic Editor

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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 #1: All comments have been addressed

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

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

Reviewer #1: I Don't Know

Reviewer #2: Yes

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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

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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

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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: I have no further comments on this manuscript, and I think it is acceptable. Thank you very much for your hard work.

Reviewer #2: The authors have addressed my comments adequately in the revised manuscipt. I do not have further comments.

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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: No

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