PONE-D-25-14841The Healthy Brain 9 (HB9): A New Instrument to Characterize Subjective Cognitive Decline, and Detect Anosognosia in Mild Cognitive ImpairmentPLOS ONE

Dear Dr. Galvin,

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

Please submit your revised manuscript by Jun 19 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,

Carlos Tomaz, Ph.D.

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. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

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

Dr Galvin is the creator of the HB9 and the copyright is held by the University of Miami Miller School of Medicine. Dr Galvin is Chief Scientific Officer for Cognivue, Inc and receives consulting fees. The other authors have nothing to disclose. The authors take full responsibility for the data and have the right to publish all data.

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.

4. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

5. Please provide a complete Data Availability Statement in the submission form, ensuring you include all necessary access information or a reason for why you are unable to make your data freely accessible. If your research concerns only data provided within your submission, please write "All data are in the manuscript and/or supporting information files" as your Data Availability Statement.

6. Please remove all personal information, ensure that the data shared are in accordance with participant consent, and re-upload a fully anonymized data set.

Note: spreadsheet columns with personal information must be removed and not hidden as all hidden columns will appear in the published file.

Additional guidance on preparing raw data for publication can be found in our Data Policy (https://journals.plos.org/plosone/s/data-availability#loc-human-research-participant-data-and-other-sensitive-data) and in the following article: http://www.bmj.com/content/340/bmj.c181.long.

7. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

8. 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. 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

**********

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

Reviewer #1: No

**********

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

**********

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

**********

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: Thank you for the opportunity to review this manuscript. It tackles the important and clinically relevant areas of subjective cognitive decline (SCD) and anosognosia in mild cognitive impairment (MCI) by introducing the novel Healthy Brain 9 (HB9) instrument. This is certainly an original contribution, and the initial findings show promise. However, I believe significant revisions are needed to fully realize the potential of this work, particularly regarding the methodology and the interpretation of the results.

Looking at the Introduction, the research question is well-defined and addresses a clear gap in the field. The literature review is reasonably comprehensive and current. To make the manuscript's foundation even stronger, I'd suggest expanding the background discussion to more explicitly compare the HB9 with other existing, validated tools for SCD and anosognosia. Showing precisely how the HB9 overcomes limitations or fills specific niches left by current instruments would strengthen the rationale. Mentioning relevant reporting standards, like the COSMIN guidelines for patient-reported outcomes, early on might also help frame the psychometric approach more effectively.

Turning to the Methodology, the study utilizes a sample size and diversity that appear adequate for good external validity, and the documentation of recruitment and ethical procedures (IRB approval, consent) is thorough. The choice of statistical analyses like Cronbach's alpha, ROC curves, regression, and ANOVA is generally appropriate for the initial validation goals. However, a key limitation is the cross-sectional design. While suitable for a first look, it inherently prevents drawing conclusions about causality or the progression of SCD/anosognosia over time. This should be clearly acknowledged, perhaps with stronger recommendations for future longitudinal studies. Another point needing careful attention is the potential for recall bias due to the 5-year retrospective self-report period. While acknowledged, the manuscript could delve deeper into this limitation and ideally suggest concrete ways to mitigate it in future research, such as using ecological momentary assessment (EMA). There's also a critical discrepancy concerning the QDRS cut-off score – the text mentions ≥2, while Table 1 seems to use a mean of 1.6. This inconsistency needs immediate clarification and correction to ensure the methodology is reproducible and sound. Finally, while the statistical methods chosen are standard, the reported moderate sensitivity in the ROC analyses raises questions about the HB9's clinical utility for detecting subtle cognitive changes. It might be beneficial to explore more advanced machine learning techniques (like random forests or gradient boosting) with cross-validation, which could potentially improve diagnostic accuracy. Using specialized software like R (with packages such as "mirt" or "lavaan") or Python could also add a layer of analytical rigor and reproducibility.

In the Results section, the findings are generally presented clearly, and the tables are helpful for understanding the psychometric properties, group comparisons, and ROC analyses. However, the interpretation could go further by explicitly discussing the clinical significance of the findings, especially the implications of the moderate sensitivity observed in the ROC curves. What does this level of sensitivity mean practically for clinicians? The relatively weak correlations found between HB9 scores and objective cognitive tests or biomarkers also warrant more critical examination. What might this suggest about the construct the HB9 is measuring? Is it capturing subjective concerns distinct from objective performance? Furthermore, the influence of education seems somewhat underexplored. Simply noting a modest correlation isn't quite enough; conducting subgroup analyses or using methods like structural equation modeling (SEM) to probe how education moderates HB9 scores would provide valuable insights.

The Discussion does a good job of placing the findings within the context of existing literature and outlining potential clinical implications. The authors also effectively acknowledge limitations like the cross-sectional design and educational skew in the sample. However, the discussion would be strengthened by a deeper exploration of the potential impact of recall bias and the practical consequences of the moderate diagnostic sensitivity. When recommending future research, being more explicit about proposing longitudinal designs, EMA, advanced statistical methods, and perhaps psychometric refinements using Item Response Theory (IRT) or Confirmatory Factor Analysis (CFA) would provide a clearer roadmap. Referencing how the validation efforts align, or could better align, with standards like COSMIN would also add weight to the psychometric discussion.

Overall, the manuscript is logically structured, and the figures and tables are clear. Adherence to ethical standards seems good, although adding a specific statement about potential conflicts of interest or intellectual property related to the HB9 instrument itself would enhance transparency.

**********

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: Yes:  Danilo Assis Pereira

**********

[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.

Attachments

Attachment

Submitted filename: REVIEW_ A new measure of subjective cognitive complaints.pdf

The Healthy Brain 9 (HB9): A new instrument to characterize subjective cognitive decline, and detect anosognosia in mild cognitive impairment

PONE-D-25-14841R1

Dear Dr. James E. Galvin,

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,

Carlos Tomaz, Ph.D.

Academic Editor

PLOS ONE