PONE-D-24-54764The UK Biobank Mental Health Enhancement 2022: Methods and ResultsPLOS ONE

Dear Dr. Davis,

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 2025 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 rebuttal 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 .

We look forward to receiving your revised manuscript.

Kind regards,

Sandar Tin Tin

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please note that PLOS ONE has specific guidelines on code sharing for submissions in which author-generated code underpins the findings in the manuscript. In these cases, we expect all author-generated code to be made available without restrictions upon publication of the work. Please review our guidelines at https://journals.plos.org/plosone/s/materials-and-software-sharing#loc-sharing-code and ensure that your code is shared in a way that follows best practice and facilitates reproducibility and reuse.

3. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript.

4. Thank you for stating the following in the Competing Interests section:

“I have read the journal's policy and the authors of this manuscript have the following competing interests: AJ received a fee to talk at the centenary of the Scottish Action for Mental Health (SAMH). The other authors declare no conflict of interest.”

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

5. We note that you have indicated that there are restrictions to data sharing for this study. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

Before we proceed with your manuscript, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., a Research Ethics Committee or Institutional Review Board, etc.). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of recommended repositories, please see

https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

We will update your Data Availability statement on your behalf to reflect the information you provide.

6. Please remove your figures from within your manuscript file, leaving only the individual TIFF/EPS image files, uploaded separately. These will be automatically included in the reviewers’ PDF.

7. 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.

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

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: No

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

**********

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: Summary of the work: This study reports findings from the UK Biobank’s second mental health questionnaire wave. First, they explain the question changes from MHQ1 to MHQ2. Then they evaluate many characteristics of MHQ2, including comparisons between MHQ1 and MHQ2. This work not only provides a useful understanding of the mental health progression of the UKB participants, but it also provides a useful test-retest evaluation of the lifetime prevalence measures of the UKB.

Overall thoughts: This study is an exciting contribution to the field that will allow many researchers to expand their investigation of mental health in the UK Biobank. Their explanation of the differences in questions, participant overlap, and demographics between MHQ1 and MHQ2 are clear and valuable to the field. The figures are nice and effectively convey the information they intend to. Their analytical evaluation of MHQ2 however could be improved by further methodological explanation and potentially increased statistical rigor. Some analyses are performed with minimal explanation and some comparison results have no stated statistical analyses where the authors may wish to include them. With that said, the comparisons they provided are useful and important for researchers of the field to see. Therefore, I excitedly endorse its acceptance at PLOS ONE after minor revisions.

Minor comments:

1. Methodological clarity would be improved if the sections in the Methods that explain the analyses/comparisons of results were more clearly linked. For example using 1, 2, 3/A, B, C/or identical headers to link the method and its associated result.

2. Many methods, particularly analyses, do not seem to be seem to be explained in detail anywhere in the paper or supplement. This not only often leaves the reader with confusion about what analysis was done but also how to evaluate the results. Relatedly, many tables seem to include statistical quantifications that are not explained in the paper or table legend.

a. For example, please elaborate on how relative risk for depression and anxiety, stated in line 376, were

calculated. The authors state that the relative risk for these disorders are approximately the same, was this

determined using statistical analysis?

b. For example, details of the evaluation of lifetime diagnosis between MHQ1 and MHQ2, and its associated Table

4, are unclear. Particularly, the line “after taking into account onsets after MHQ1 (including unknown onsets),

between 75% to 93% of the test-retest variation in direction ‘Met 2 not 1’ and all in direction ‘Met 1 not 2’

remains unexplained” should be improved for clarity. Please explain how unknown onsets are incorporated (I assume the authors included any unknown onset into ‘onsets after MHQ1’ which seems an odd choice because it is not clear why these unknown onsets would be more likely to occur after MHQ1 as opposed to before). Additionally, how is test-retest variation determined and what does 75%-93% variation mean for this finding? What indicates that this variation is unexplained? Table 4, which relates to this result, could also be improved by further elaboration. What does the “Agree (%)” column refer to? The column “New onset (% Met 2 not 1)” should also explicitly state in the legend that this is the percent of individuals in the Met 2 not 1 group that reported new onset since MHQ1. Please also explain how new onset was determined.

3. The results include many comparisons between quantitative measures, but do not state a statistical difference. For example, starting on line 343, “those with lifetime eating disorders are more likely to have a degree qualification (eating disorder 53%; depression 46%; no mental disorder 44%)” compares the degree qualification of these 3 groups but not does indicate if these groups are statistically different. I recognize that this work is intended more as a descriptor for the new MHQ2, but I would refrain from drawing conclusions about these comparisons without statistical analysis. I recommend either including this statistical analysis or dampening claims about such comparisons throughout the paper.

4. For the methodological explanation starting at line 256, “Age at MHQ2…”, why was age of participants who did not complete MHQ2 included in the average age calculated for MHQ2? I assume that this age calculation is used in the demographics comparison table, which seems problematic as this does not accurately reflect the age of the MHQ2 participants to my mind. Though perhaps I misunderstand the explanation of this methodology, in which case I recommend improving the clarity of writing for this section.

5. I recognized that criteria for lifetime status is unchanged from MHQ1, but it may be of value to restate these criteria in this work.

6. I assume “dx” in Table 3 is short for diagnosis. Please include this abbreviation in the table legend.

Reviewer #2: This manuscript describes the procedure and content of the UK Biobank (UKB) MHQ2 questionnaire, provides a general cohort description, and presents overall comparisons between the two mental health data collections in UKB. The authors report a significant enhancement to the UKB resource by conducting a second mental health data collection in 169,253 individuals, bringing the total number of UKB participants with mental health data from at least one time point to 215,252, and those with data from two time points to 111,275. This represents a major advancement for the UKB mental health phenotypes and is an important contribution to the research field.

The manuscript clearly outlines the rationale and procedural decisions made during the design phase. The authors describe the characteristics of participants across the two waves and the broader UKB cohort, as well as across symptom-based criteria for lifetime disorders. They also examine changes in mental health using ‘current’ assessments and assess the consistency of measures using ‘lifetime’ assessments.

Comments and suggestions

1. It appears that the authors defined participants based on completion of all questionnaire modules. Given the difference between the number of individuals who started (175,266) and those who completed (169,252), 6,014 individuals did not finish the questionnaire. Inability to complete the full questionnaire may be linked to more severe mental health conditions, such as difficulties with concentration, fatigue, or other relevant health issues. The responses provided by these individuals before discontinuation could still be valuable for analyzing MHQ2 data. It would be helpful if the authors could clarify their decision to exclude these individuals in this context.

2. If data on completion times are available, it would be informative to include basic descriptive statistics on the time required to complete the full questionnaire. This would help estimate the time investment expected from participants.

3. Is it possible to determine whether the worst episodes described in detail in MHQ1 and MHQ2 refers to the same episode or two different episodes? This distinction would be useful both for assessing changes in symptoms across different episodes and for evaluating recall inconsistency for symptoms of the same episode. As the questionnaire does not seem to ask about the age at which the worst episode occurred, making this distinction may be challenging. Clarification on this point would be valuable.

4. It is unclear why psychotic experiences were omitted from MHQ2. While balancing questionnaire length and topic coverage is important, multiple assessments of psychotic symptoms could be highly relevant for investigating their links to, for example, cannabis use, medication use, or changes over the second half of the lifespan. Related to this, the wording in lines 502–504 of the Conclusions section may unintentionally suggest that psychotic experiences were included in this data collection. Rewording this sentence for clarity is recommended.

5. There appears to be a minor inconsistency in the reported sample size. The abstract and Tables 2 and 3 state that the number of respondents was 169,253, while the Results section (line 276) and Figure 2 state 169,252. It would be helpful to double-check and ensure consistency across the manuscript.

**********

6. 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: No

**********

[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.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/ . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org . Please note that Supporting Information files do not need this step.

The UK Biobank mental health enhancement 2022: methods and results

PONE-D-24-54764R1

Dear Dr. Davis,

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.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

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,

Sandar Tin Tin

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 #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: Yes

**********

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

Reviewer #1: 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

**********

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

**********

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: (No Response)

**********

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

**********