Protocol of the Healthy Brain Study: An accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context

Healthy Brain Study consortium; Esther Aarts; Agnes Akkerman; Mareike Altgassen; Ronald Bartels; Debby Beckers; Kirsten Bevelander; Erik Bijleveld; Esmeralda Blaney Davidson; Annemarie Boleij; Janita Bralten; Toon Cillessen; Jurgen Claassen; Roshan Cools; Ineke Cornelissen; Martin Dresler; Thijs Eijsvogels; Myrthe Faber; Guillén Fernández; Bernd Figner; Matthias Fritsche; Sascha Füllbrunn; Surya Gayet; Marleen M. H. J. van Gelder; Marcel van Gerven; Sabine Geurts; Corina U. Greven; Martine Groefsema; Koen Haak; Peter Hagoort; Yvonne Hartman; Beatrice van der Heijden; Erno Hermans; Vivian Heuvelmans; Florian Hintz; Janet den Hollander; Anneloes M. Hulsman; Sebastian Idesis; Martin Jaeger; Esther Janse; Joost Janzing; Roy P. C. Kessels; Johan C. Karremans; Willemien de Kleijn; Marieke Klein; Floris Klumpers; Nils Kohn; Hubert Korzilius; Bas Krahmer; Floris de Lange; Judith van Leeuwen; Huaiyu Liu; Maartje Luijten; Peggy Manders; Katerina Manevska; José P. Marques; Jon Matthews; James M. McQueen; Pieter Medendorp; René Melis; Antje Meyer; Joukje Oosterman; Lucy Overbeek; Marius Peelen; Jean Popma; Geert Postma; Karin Roelofs; Yvonne G. T. van Rossenberg; Gabi Schaap; Paul Scheepers; Luc Selen; Marianne Starren; Dorine W. Swinkels; Indira Tendolkar; Dick Thijssen; Hans Timmerman; Rayyan Tutunji; Anil Tuladhar; Harm Veling; Maaike Verhagen; Jasper Verkroost; Jacqueline Vink; Vivian Vriezekolk; Janna Vrijsen; Jana Vyrastekova; Selina van der Wal; Roel Willems; Arthur Willemsen

doi:10.1371/journal.pone.0260952

Peer Review History

Original SubmissionMay 12, 2021
23 Jun 2021 Decision Letter - Amir-Homayoun Javadi, Editor PONE-D-21-15454 Protocol of the Healthy Brain Study: an accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context PLOS ONE Dear Dr. Fernández, 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. While your manuscript is judged favouribly, there are a few points raised by the reviewer that can help to improve the manuscript. Please submit your revised manuscript by Aug 07 2021 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: http://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, Amir-Homayoun Javadi, PhD Academic Editor PLOS ONE Journal Requirements: 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. 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. We note that you have indicated that data from this study are available upon request. 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. In your revised cover letter, 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 sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). 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 as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. 3. Please amend your authorship list in your manuscript file to include author Lucy Overbeek. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This Study Protocol describes the ongoing Healthy Brain Study (HBS). I found the description comprehensive and I think the resulting database will be a much used resource. The access procedure is well described and reasonable. I have some comments that the authors may consider in a revision, listed in order of appearance in the ms: * I agree that a reductionist approach is common, but several longitudinal studies surely include a broad range of variables and a holistic approach; this is not unique for HBS. * Life events are highlighted. Such events have been explored in several other past studies, and a question is whether the authors in the quite short period of 1 year expect a sufficient number of significant events to substantiate analyses? Here, the timing with the pandemic is very interesting and it is a strength of the study to capture this major event. * The protocol has an elegant assessment of factors such as physical activity, stress, and sleep that go beyond past studies. However, to be fair, also past studies meant to target real world events (even if with scales and questionnaires). * I applaud the stress on population-based cohorts and the risk with selection bias in convenience samples. Here, it could also be mentioned that studies like the Swedish Betula project (e.g., Nyberg, et al, 2020 Ageing Res Rev) have used such an approach. In HBS, some comment is warranted on the exclusion criteria in relation to representativeness (such as taking antidepressants or having a disease that hinders physical exercise). Relatedly, the strategies to recruit participants could influence the final representativeness of the sample. For example, the involvement of employers can bias the sample to people who have a work. Have the authors any plans of assessing how representative for the general population their final sample actually will be? * Opting out from a study and later dropping out from a study are important variables. So far, after a quite short period of time, as many as 13% withdrew (typically after the 1st assessment). I lacked information on whether the researchers will replace those who drop out at such an early stage, and also how they plan to deal with drop-out analyses. ******** 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 [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. https://doi.org/10.1371/journal.pone.0260952.r001
Revision 1
3 Sep 2021 Author Response Journal requirements 1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have applied the PLOS ONE style templates. 2) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. Sharing the full Healthy Brain Study (HBS) resource does not comply with the EU General Data Protection Regulation, because the HBS resource contains a substantial amount of sensitive personal data. Applications for data access can be sent to hbs-data@radboudumc.nl. Then, the HBS scientific board reviews the application. Our governance policy ensures that all use of data is within the limits of the original purpose as described in the information brochure for participants and that only those data are shared that are relevant for answering the proposed research question. 3) Please amend your authorship list in your manuscript file to include author Lucy Overbeek. We would like to propose that the Healthy Brain Study consortium is the only author and omit the names of the project leader Guillén Fernández and project manager Lucy Overbeek. In our view, mentioning the consortium as the only author would perfectly reflect the nature of the team-science based cross-faculty initiative from the Radboud campus in Nijmegen. We consider our roles as supportive and required for managing the project rather than as principal investigators. We understand that a corresponding author is required. Guillén Fernández fulfills the role of the corresponding author on behalf of the consortium. As stated, all members of the consortium contributed to the design of the study, edited the manuscript, and approved the final version. Response to reviewer * I agree that a reductionist approach is common, but several longitudinal studies surely include a broad range of variables and a holistic approach; this is not unique for HBS. We fully agree with the reviewer that several longitudinal studies include a broad range of variables and a holistic approach. In lines 35-38 we mention that “we think that current brain research suffers from at least five key limitations and we set up the Healthy Brain Study (HBS) to tackle these five limitations together”. Thus, we consider the uniqueness of the HBS that it combines the following five strengths 1) a broad range of variables, 2) repeated assessments across one year, 3) single subject inferences, 4) real-world assessments, and 5) a population-based sample. We propose stressing that tackling these five limitations together is the uniqueness of the HBS by adapting the sentence starting in line 94 into “In conclusion, the unique feature of the HBS is that it combines the five above-mentioned strength resulting in in-depth phenotyping of a large range of cognitive, affective, behavioral, and social dimensions with a biological sampling of brain and body-related processes.”. However, there are other studies (e.g., Betula project) that have another focus on a longitudinal design with a very long-term perspective of more than 25 years (https://www.umu.se/en/research/projects/betula---aging-memory-and-dementia/). * Life events are highlighted. Such events have been explored in several other past studies, and a question is whether the authors in the quite short period of 1 year expect a sufficient number of significant events to substantiate analyses? Here, the timing with the pandemic is very interesting and it is a strength of the study to capture this major event. When designing the study, we hoped for some major national events around for example governmental elections or sports. A pandemic was of course not expected, but is indeed very interesting and offers additional opportunities. We agree with the reviewer that one year is a rather a short period for capturing life events, but we chose the age range of 30-39 because it is a socially challenging age range that is characterized by a relatively high number of rather impactful life events (e.g., family planning, career-related changes, buying a house etc.). To assess life events, participants give responses to twenty types of life events (Brugha & Cragg, 1990). In addition, to assess the subjective impact of life events, we ask participants to rate the subjective impact the event had on their lives on a scale from 0 (no impact at all) to 10 (major impact, fundamental change). Preliminary data showed that 130 out of 298 (44%) of the HBS participants that completed the life event questionnaire at T1 experienced one or more life events in the year before participating and 78 out of 175 (45%) and 46 out of 100 (46%) of HBS participants that completed the life event questionnaire at T2 respectively T3 experienced one or more life events. As this is a protocol paper, we do not want to report any preliminary data and propose not to include the above-mentioned data on life events in the manuscript. Reference: Brugha, T. S. & Cragg, D. The list of threatening experiences: the reliability and validity of a brief life events questionnaire. Acta Psychiatr Scand 82, 77-81 (1990). * The protocol has an elegant assessment of factors such as physical activity, stress, and sleep that go beyond past studies. However, to be fair, also past studies meant to target real world events (even if with scales and questionnaires). We agree with the reviewer that many past and ongoing studies assess real-world events (even if with scales and questionnaires). We consider our approach innovative, because for two reasons. First, we believe that assessing real-world events with wearable devices is more objective than scales and questionnaires. When we designed the study in 2017, hardly any longitudinal study included wearable devices. As the field of wearable technology has developed rapidly, in the meantime, several longitudinal studies have added wearable devices to their data collection methods. For example, subsets of UK Biobank participants and Rotterdam Study participants wore an accelerometer (Doherty et al., 2017; Koolhaas et al., 2017). Furthermore, in line with our response to the first comment of the reviewer, we would like to stress that including real-world assessments is one of the five strengths of the HBS, so it is not unique by itself. In particular, the HBS includes repeated assessments with wearable devices in three different seasons over one year starting at varying time points within a year. When we designed the study, to our knowledge, this was unique for HBS. In the meantime, a subset of UK Biobank participants is performing seasonal repeats with a wearable device (https://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=1008). Second, the HBS combines physiological recordings with wearable devices with ecological momentary assessments using a smartphone application. We consider the additional collection of momentary assessments of mood and behavior and context information innovative. We added this explanation to the discussion section when reflecting on the HBS study design (line 393). References: Doherty A. et al. Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study. PLoS One 12(2), e0169649 (2017). Koolhaas C.M. et al. Objective Measures of Activity in the Elderly: Distribution and Associations With Demographic and Health Factors. Journal of the American Medical Directors Association 18 (10), 838-847 (2017). * I applaud the stress on population-based cohorts and the risk with selection bias in convenience samples. Here, it could also be mentioned that studies like the Swedish Betula project (e.g., Nyberg, et al, 2020 Ageing Res Rev) have used such an approach. In HBS, some comment is warranted on the exclusion criteria in relation to representativeness (such as taking antidepressants or having a disease that hinders physical exercise). Relatedly, the strategies to recruit participants could influence the final representativeness of the sample. For example, the involvement of employers can bias the sample to people who have a work. Have the authors any plans of assessing how representative for the general population their final sample actually will be? We defined a population-based sample as 1,000 HBS participants (500 men and 500 women) from the Nijmegen region (≤ 15 km) of whom 220 have a low, 340 a middle, and 430 a high level of education. We perform continuous monitoring of sex and level of education for enrollment and drop-out rates. For example, when we observed that our first wave of participants consisted of mainly higher educated people, we adapted the campaign by displaying pictures and stories of real, middle educated participants in promotion materials and focused on employers with low and middle educated staff. Concerning recruiting unemployed people, we reach them by their municipalities, our social media campaign and local influencers. * Opting out from a study and later dropping out from a study are important variables. So far, after a quite short period of time, as many as 13% withdrew (typically after the 1st assessment). I lacked information on whether the researchers will replace those who drop out at such an early stage, and also how they plan to deal with drop-out analyses. We aim to acquire full longitudinal datasets of 1,000 participants. We expect a withdrawal rate of 15%, and will therefore recruit 1,150 individuals to participate in the study. This information was lacking in the manuscript and has now been added to the recruitment paragraph in lines 138-139: “We aim to acquire full longitudinal datasets of 1,000 participants. We expect a withdrawal rate of 15%, and will therefore recruit 1,150 individuals to participate in the study.”. How to deal with drop-out analyses is up to the researchers who will use the data. Partial datasets of withdrawn participants will be included in the data release, along with documentation of what parts of the data are available for each subject and information about the reasoning for withdrawal. Attachments Attachment Submitted filename: HBS Consortium_Rebuttal letter_PLOS ONE.pdf https://doi.org/10.1371/journal.pone.0260952.r002
15 Sep 2021 Decision Letter - Amir-Homayoun Javadi, Editor PONE-D-21-15454R1Protocol of the Healthy Brain Study: an accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social contextPLOS ONE Dear Dr. Fernández, Thank you for submitting your revision. I searched for the changes but couldn't find them. Please highlight them in the edited manuscript and mention page number (and even paragraph number) in your response letter. Please make sure to edit the manuscript based on the feedback and comments you have received. Please submit your revised manuscript by Oct 30 2021 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, Amir-Homayoun Javadi, PhD Academic Editor PLOS ONE Journal Requirements: 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. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: I thank the authors for their responses to my initial comments. I find many of their arguments valid. However, it was unclear to me what was actually changed in the manuscript. The authors mention one addition in the Discussion (not highlighted in my version of the revised ms), but other than that it was unclear from their response letter how they actually modified their manuscript. In particular, the issue of the uniqueness of their study relative to other existing ones and the difficult topic of drop-out should warrant not only sensible comments in a cover letter but also substantial changes in the ms. The same holds for life-events, even if I understand the point about not providing actual data in this particular report. ****** 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 [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. https://doi.org/10.1371/journal.pone.0260952.r003
Revision 2
15 Oct 2021 Author Response Dear Dr. Amir-Homayoun Javadi, Thank you for judging our manuscript entitled ‘Protocol of the Healthy Brain Study: an accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context’ favorably. Herewith we would like to respond to the reviewer. When we refer to line numbers in the following paragraphs, we refer to the line numbers in the revised manuscript with track changes. Journal requirements 1) Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. We have applied the PLOS ONE style templates. 2) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. Sharing the full Healthy Brain Study (HBS) resource does not comply with the EU General Data Protection Regulation, because the HBS resource contains a substantial amount of sensitive personal data. Applications for data access can be sent to hbs-data@radboudumc.nl. Then, the HBS scientific board reviews the application. Our governance policy ensures that all use of data is within the limits of the original purpose as described in the information brochure for participants and that only those data are shared that are relevant for answering the proposed research question. 3) Please amend your authorship list in your manuscript file to include author Lucy Overbeek. We would like to propose that the Healthy Brain Study consortium is the only author and omit the names of the project leader Guillén Fernández and project manager Lucy Overbeek. In our view, mentioning the consortium as the only author would perfectly reflect the nature of the team-science based cross-faculty initiative from the Radboud campus in Nijmegen. We consider our roles as supportive and required for managing the project rather than as principal investigators. We understand that a corresponding author is required. Guillén Fernández fulfills the role of the corresponding author on behalf of the consortium. As stated, all members of the consortium contributed to the design of the study, edited the manuscript, and approved the final version. Response to reviewer * I agree that a reductionist approach is common, but several longitudinal studies surely include a broad range of variables and a holistic approach; this is not unique for HBS. We fully agree with the reviewer that several longitudinal studies include a broad range of variables and a holistic approach. In lines 35-38 we mention that “we think that current brain research suffers from at least five key limitations and we set up the Healthy Brain Study (HBS) to tackle these five limitations together”. Thus, we consider the uniqueness of the HBS that it combines the following five strengths 1) a broad range of variables, 2) repeated assessments across one year, 3) single subject inferences, 4) real-world assessments, and 5) a population-based sample. We propose stressing that tackling these five limitations together is the uniqueness of the HBS by adapting the sentence starting in line 94 into “In conclusion, the unique feature of the HBS is that it combines the five above-mentioned strength resulting in in-depth phenotyping of a large range of cognitive, affective, behavioral, and social dimensions with a biological sampling of brain and body-related processes.”. However, there are other studies (e.g., Betula project) that have another focus on a longitudinal design with a very long-term perspective of more than 25 years (https://www.umu.se/en/research/projects/betula---aging-memory-and-dementia/). * Life events are highlighted. Such events have been explored in several other past studies, and a question is whether the authors in the quite short period of 1 year expect a sufficient number of significant events to substantiate analyses? Here, the timing with the pandemic is very interesting and it is a strength of the study to capture this major event. When designing the study, we hoped for some major national events around for example governmental elections or sports. A pandemic was of course not expected, but is indeed very interesting and offers additional opportunities. We agree with the reviewer that one year is a rather a short period for capturing life events, but we chose the age range of 30-39 because it is a socially challenging age range that is characterized by a relatively high number of rather impactful life events (e.g., family planning, career-related changes, buying a house etc.). To assess life events, participants give responses to twenty types of life events (Brugha & Cragg, 1990). In addition, to assess the subjective impact of life events, we ask participants to rate the subjective impact the event had on their lives on a scale from 0 (no impact at all) to 10 (major impact, fundamental change). Preliminary data showed that 130 out of 298 (44%) of the HBS participants that completed the life event questionnaire at T1 experienced one or more life events in the year before participating and 78 out of 175 (45%) and 46 out of 100 (46%) of HBS participants that completed the life event questionnaire at T2 respectively T3 experienced one or more life events. As this is a protocol paper, we do not want to report any preliminary data and propose not to include the above-mentioned data on life events in the manuscript. Reference: Brugha, T. S. & Cragg, D. The list of threatening experiences: the reliability and validity of a brief life events questionnaire. Acta Psychiatr Scand 82, 77-81 (1990). * The protocol has an elegant assessment of factors such as physical activity, stress, and sleep that go beyond past studies. However, to be fair, also past studies meant to target real world events (even if with scales and questionnaires). We agree with the reviewer that many past and ongoing studies assess real-world events (even if with scales and questionnaires). We consider our approach innovative, because for two reasons. First, we believe that assessing real-world events with wearable devices is more objective than scales and questionnaires. When we designed the study in 2017, hardly any longitudinal study included wearable devices. As the field of wearable technology has developed rapidly, in the meantime, several longitudinal studies have added wearable devices to their data collection methods. For example, subsets of UK Biobank participants and Rotterdam Study participants wore an accelerometer (Doherty et al., 2017; Koolhaas et al., 2017). Furthermore, in line with our response to the first comment of the reviewer, we would like to stress that including real-world assessments is one of the five strengths of the HBS, so it is not unique by itself. In particular, the HBS includes repeated assessments with wearable devices in three different seasons over one year starting at varying time points within a year. When we designed the study, to our knowledge, this was unique for HBS. In the meantime, a subset of UK Biobank participants is performing seasonal repeats with a wearable device (https://biobank.ctsu.ox.ac.uk/crystal/label.cgi?id=1008). Second, the HBS combines physiological recordings with wearable devices with ecological momentary assessments using a smartphone application. We consider the additional collection of momentary assessments of mood and behavior and context information innovative. We added this explanation to the discussion section when reflecting on the HBS study design (line 393). References: Doherty A. et al. Large Scale Population Assessment of Physical Activity Using Wrist Worn Accelerometers: The UK Biobank Study. PLoS One 12(2), e0169649 (2017). Koolhaas C.M. et al. Objective Measures of Activity in the Elderly: Distribution and Associations With Demographic and Health Factors. Journal of the American Medical Directors Association 18 (10), 838-847 (2017). * I applaud the stress on population-based cohorts and the risk with selection bias in convenience samples. Here, it could also be mentioned that studies like the Swedish Betula project (e.g., Nyberg, et al, 2020 Ageing Res Rev) have used such an approach. In HBS, some comment is warranted on the exclusion criteria in relation to representativeness (such as taking antidepressants or having a disease that hinders physical exercise). Relatedly, the strategies to recruit participants could influence the final representativeness of the sample. For example, the involvement of employers can bias the sample to people who have a work. Have the authors any plans of assessing how representative for the general population their final sample actually will be? We defined a population-based sample as 1,000 HBS participants (500 men and 500 women) from the Nijmegen region (≤ 15 km) of whom 220 have a low, 340 a middle, and 430 a high level of education. We perform continuous monitoring of sex and level of education for enrollment and drop-out rates. For example, when we observed that our first wave of participants consisted of mainly higher educated people, we adapted the campaign by displaying pictures and stories of real, middle educated participants in promotion materials and focused on employers with low and middle educated staff. Concerning recruiting unemployed people, we reach them by their municipalities, our social media campaign and local influencers. * Opting out from a study and later dropping out from a study are important variables. So far, after a quite short period of time, as many as 13% withdrew (typically after the 1st assessment). I lacked information on whether the researchers will replace those who drop out at such an early stage, and also how they plan to deal with drop-out analyses. We aim to acquire full longitudinal datasets of 1,000 participants. We expect a withdrawal rate of 15%, and will therefore recruit 1,150 individuals to participate in the study. This information was lacking in the manuscript and has now been added to the recruitment paragraph in lines 138-139: “We aim to acquire full longitudinal datasets of 1,000 participants. We expect a withdrawal rate of 15%, and will therefore recruit 1,150 individuals to participate in the study.”. How to deal with drop-out analyses is up to the researchers who will use the data. Partial datasets of withdrawn participants will be included in the data release, along with documentation of what parts of the data are available for each subject and information about the reasoning for withdrawal. Other changes - Line 242, Table 1a: fertility treatment and breastfeeding are not part of the questionnaire. - Line 295: “At the end of December 2020, the HBS included 298 participants. Forty participants (13%) withdrew from the study so far, due to personal circumstances (e.g., pregnancy) or too much burden. Most participants withdrew after the first assessment. To date, participants performed 376 lab visits: 257 participants carried out the first assessment, 83 participants the second assessment, and 36 participants the third assessment completing the entire study protocol.” has been adapted into “At the end of June 2021, the HBS included 418 participants. Seventeen-one participants (17%) withdrew from the study so far, mostly because they experienced too much burden (n=41; 58%), got pregnant (n=11; 15%), or had been given a diagnosis or medication treatment (n=8; 11%). Most participants withdrew after the first assessment. To date, participants performed 755 lab visits: 380 participants carried out the first assessment, 237 participants the second assessment, and 138 participants the third assessment completing the entire study protocol.” - Table 1a is renamed to Table 1, Table 1b to Table 7, Table 7 to Table 8. - Reference list: references 27, 164, 165, 166 have been added. - Link for data access is adapted to https://www.healthybrainstudy.nl/en/data-and-methods/access in line 27 and 431. We hope we have satisfactorily responded to the comments and are looking forward to your decision about publishing our manuscript in PLOS ONE. On behalf of the Healthy Brain Study consortium, Guillén Fernández Lucy Overbeek Attachments Attachment Submitted filename: HBS Consortium_Rebuttal letter_PLOS ONE.docx https://doi.org/10.1371/journal.pone.0260952.r004
22 Nov 2021 Decision Letter - Fulvio D'Acquisto, Editor Protocol of the Healthy Brain Study: an accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context PONE-D-21-15454R2 Dear Dr. Fernández, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Fulvio D'Acquisto, PhD Academic Editor PLOS ONE Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors have responded well to my initial comments. I am fine with the ms in its current format and have no additional feedback to offer. Reviewer #2: This manuscript describes the ongoing protocols employed by the HBS in Nijmegen. The study is a large-scale representative data gathering study that seeks to provide a major community resource in the form of a database of brain activation, brain structure, and cognitive function measurements. Overall, the study has been extremely well designed and is well under way. The major weakness of the study has been, in my opinion, that people in the neuroscience community are not generally aware of it. The manuscript would therefore be of potentially high impact because it would bring awareness of the study to a much wider audience. The manuscript is clear and well-written, which should add to its impact. Comments I realize that the manuscript has been in revision, although this is the first time I have seen it. While I believe that the manuscript is appropriate for publication in its current form, I have two comments. First, I note that line 94 has a minor pluralization error. The word “strength,” should I believe, be “strengths.” The second is somewhat more serious and it may be late in the study process to address this point. One of the great challenges with databases of this kind is the problem of multiple comparisons. It hundreds of scholars each perform hypothesis tests on the database, it is unclear how to deal with the problem of multiple comparisons effectively. This may be particularly acute in research conducted by citizen scientists. If the opportunity arose, I think it would be a great addition to the manuscript to include a section of statistical practices and multiple comparisons. I’m sure that the study has procedures in place for this, but more discussion would be welcome and might help other studies as well. ****** 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: No https://doi.org/10.1371/journal.pone.0260952.r005
Formally Accepted
13 Dec 2021 Acceptance Letter - Fulvio D'Acquisto, Editor PONE-D-21-15454R2 Protocol of the Healthy Brain Study: an accessible resource for understanding the human brain and how it dynamically and individually operates in its bio-social context Dear Dr. Fernández: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Fulvio D'Acquisto Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0260952.r006

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