PONE-D-20-09338

Frailty and depression predict instrumental activities of daily living in older adults: a population-based longitudinal study using the CARE75+ cohort

PLOS ONE

Dear DR COVENTRY,

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.

We would appreciate receiving your revised manuscript by Jun 27 2020 11:59PM. When you are 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.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.

To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

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). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

We look forward to receiving your revised manuscript.

Kind regards,

Pasquale Abete

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 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 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 identifying or sensitive patient information) 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. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. 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. Thank you for stating the following financial disclosure:

"The funders had no role in study design, data collection and analysis, decision to

publish, or preparation of the manuscript."

At this time, please address the following queries:

a) Please clarify the sources of funding (financial or material support) for your study. List the grants or organizations that supported your study, including funding received from your institution.

b) State what role the funders took in the study. If the funders had no role in your study, please state: “The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

c) If any authors received a salary from any of your funders, please state which authors and which funders.

d) If you did not receive any funding for this study, please state: “The authors received no specific funding for this work.”

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. 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.

5. Your ethics statement must appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript.

Additional Editor Comments (if provided):

According to Reviewer's comments the manuscripts needs a major revision.

[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

Reviewer #2: Partly

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: 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: Yes

Reviewer #2: No

Reviewer #3: 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: No

Reviewer #2: Yes

Reviewer #3: 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: The authors evaluate if depression contributes, independently and/or in interaction with frailty, to loss of independence in instrumental activities of daily living (ADL) in older adults with frailty. They studied Longitudinal cohort study of people aged ≥75 years living in the community by usying multi-level linear regression model to quantify the relationship between depression (≥5 Geriatric Depression Scale) and frailty (electronic frailty index), and instrumental activities of daily living (Nottingham Extended Activities of Daily Living scale; range: 0-66; higher score implies greater independence). They included 553 participants at baseline; 53% were female with a mean age of 81 (5.0 SD) years. Depression and frailty (moderate and severe levels) were independently associated with reduced instrumental activities of daily living scores. Moreover, depression interacted with frailty to further reduce instrumental activities of daily living score in individuals with mild or moderate frailty. These relationships remained significant after adjusting for confounders.

The manuscript is interesting. However I have some concerns about the number of patients. What about the sample size and the power of the study? What about the comorbidities such as heart failure? Please see and discuss Liguori I et al. Depression and chronic heart failure in the elderly: an intriguing relationship. J Geriatr Cardiol. 2018 Jun;15(6):451-459.

Reviewer #2: The data has to be requested from the data controller's website. Technically the authors cannot make it fully available.

The authors used a subsample of participants in the CARE75+ cohort to examine the association between depression, frailty and instrumental activities of daily living (IADL) from baseline to 12 months of follow-up. The analytic approach is a linear mixed model with random intercept. The presentation and presentation of results can be improved. Answers to the following questions can improve a reader’s understanding of the validity of the results and conclusions.

1). Based on the flow chart, 106 participants were excluded from the study due to “delay between participant consent and baseline data being uploaded.” Were their baseline data available? If not, they probably would have been counted as “lost to study entry.” So my guess is their data were available. Then, what is the justification for this exclusion?

2). There was substantial amount of attrition (39% at 6 months and 60% at 6 months). It is known that linear mixed effects models are consistent under the assumption of missing at random. However, given this cohort’s age, it is unlikely the attrition was at random. The authors were not clear how many died, transitioned to a care home and was not followed, and was lost to follow-up due to other reasons. When attrition is not at random, the mixed effects model estimates are biased.

3). After estimating a linear mixed model, the authors presented marginal effects in Figure 2. Given that the analysis was done in Stata, I assume the authors used the margins statement after the linear mixed model for the marginal effects. However, the margins command after a mixed model in Stata only calculates the fixed effects part of the model, thus is not a real marginalization. Granted that if the missing at random assumption holds, the fixed part of the mixed model is equivalent to the population-averaged effects; however, given 2) this is unlikely to be true. The authors could take a look at the article by Rouanet et al. (2019) “Interpretation of mixed models and marginal models with cohort attrition due to death and drop-out” in Statistical Methods in Medical Research.

4). The authors speculated that “the absence of an effect in those with severe frailty stem from an underpowered analysis owing to smaller numbers.” However, the authors did not present the number of people with depression and severe frailty in each time period. A tabulate of sample size over time will be helpful.

Reviewer #3: The authors in this study evaluate if depression contribute, independently and/or in interaction with frailty, to loss of independence in instrumental activities of daily living (IADL) in older adults with frailty in a longitudinal cohort study of people aged ≥75 years living in the community by using multi-level linear regression model. They included 553 participants at baseline. Depression and frailty (moderate and severe levels) were independently associated with reduced instrumental activities of daily living scores. Moreover, depression interacted with frailty to further reduce instrumental activities of daily living score in individuals with mild or moderate frailty. These relationships remained significant after adjusting for confounders.

The manuscript is very interesting. However I have some concerns about adjusting confounders: given that cognitive impairment is an independent factor for ADL and IADL loss and that depression and dementia are often overlapping in the elderly population, has cognitive impairment been evaluated in the sample? Furthermore, GDS is not a validated tool for the evaluation of depression in patients with cognitive impairment. Indeed I think that some clarifications are necessary about effects of depression symptoms on comorbidities, please see and discuss “Depressive symptoms predict mortality in elderly subjects with chronic heart failure. Testa G, Cacciatore F, Galizia G, Della-Morte D, Mazzella F, Gargiulo G, Langellotto A, Raucci C, Ferrara N, Rengo F, Abete P. Eur J Clin Invest. 2011 Dec;41(12):1310-7”.

**********

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

Reviewer #3: 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 to be viewed.]

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 us at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: Review PONE-D-20-09338.docx

PONE-D-20-09338R1

Frailty and depression predict instrumental activities of daily living in older adults: a population-based longitudinal study using the CARE75+ cohort

PLOS ONE

Dear Dr. COVENTRY,

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 Nov 07 2020 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

We look forward to receiving your revised manuscript.

Kind regards,

Pasquale Abete

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

According to Reviewer's comments the manuscript needs a major revision.

Sincerely,

P. Abete

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

Reviewer #3: 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

Reviewer #2: Partly

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: 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

Reviewer #2: No

Reviewer #3: 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

Reviewer #3: 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: All comments have been addressed. The manuscript presented in an intelligible fashion and written in standard English. No further comments.

Reviewer #2: The authors responded to my first question by changing the description of why the 106 patients were excluded.

The authors responded to my second question by saying “The study recorded a total of 14 deaths; half of these participants, i.e. 7/14, completed all three waves of the study (i.e. they died after the 12-month follow-up period).” In the main text this information should be given. In the follow chart and in the main text, the reason for loss to follow up (not death) should be given, at six months 214 (7 died) patients were not included ; and at 12 months 331 (7 died) patients were not included; what are the reason for the exclusions?

The model for 12-month loss to follow up should not be among only those patients with non-missing 6-month data, it should be among all 553 patients. The authors should show in their response letter the logistic regression for loss to follow up at 6 months with age and baseline frailty and depression as predictors, although I do not believe this necessarily mean anything because we still don’t know if other variables are related to loss to follow up. Descriptive statistics of all variables in Table 1 should be given for those with and those without loss to follow up, one table for 6-month; one table for 12-month. We can from the descriptive statistics get a glimpse of how different the two groups are.

The authors added Table 2 (cross-tabulation of depression and frailty at baseline, 6 months and 12 months) in response to my question about their speculation that “the absence of an effect in those with severe frailty stem from an underpowered analysis owing to smaller numbers”, we can see that there are only 2 patients with depression and no frailty in 12 months. This fact makes the models with interaction between depression and frailty very questionable. No descriptive data were given for the outcome NEAL at baseline, 6 months or 12 months. One cannot get a sense of how big the effects (coefficients) are relative to the distribution of the outcome.

Reviewer #3: All comments has been addressed. The manuscript is improved and is suitable for pubblication in present form

**********

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

Reviewer #3: 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.

Frailty and depression predict instrumental activities of daily living in older adults: a population-based longitudinal study using the CARE75+ cohort

PONE-D-20-09338R2

Dear Dr. COVENTRY,

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,

Pasquale Abete

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

No further comments.

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 #2: 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 #2: Yes

**********

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

Reviewer #2: 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 #2: No

**********

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 #2: 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 #2: (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 #2: No