PONE-D-19-32237

A modelling approach to estimate the prevalence of treatment-resistant schizophrenia in the United States

PLOS ONE

Dear Mr. Mørup,

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 Mar 28 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,

Giuseppe Carrà, MD, PhD

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 http://www.plosone.org/attachments/PLOSOne_formatting_sample_main_body.pdf and http://www.plosone.org/attachments/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please ensure that you include a title page within your main document. We do appreciate that you have a title page document uploaded as a separate file, however, as per our author guidelines (http://journals.plos.org/plosone/s/submission-guidelines#loc-title-page) we do require this to be part of the manuscript file itself and not uploaded separately.

Could you therefore please include the title page into the beginning of your manuscript file itself, listing all authors and affiliations.

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."

1. Please provide an amended Funding Statement that declares *all* the funding or sources of support received during this specific study (whether external or internal to your organization) as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now.  
2. Please state what role the funders took in the study.  If any authors received a salary from any of your funders, please state which authors and which funder. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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

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

"All authors are employees of H. Lundbeck A/S"

We note that one or more of the authors are employed by a commercial company: H. Lundbeck A/S.

1. Please provide an amended Funding Statement declaring this commercial affiliation, as well as a statement regarding the Role of Funders in your study. If the funding organization did not play a role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript and only provided financial support in the form of authors' salaries and/or research materials, please review your statements relating to the author contributions, and ensure you have specifically and accurately indicated the role(s) that these authors had in your study. You can update author roles in the Author Contributions section of the online submission form.

Please also include the following statement within your amended Funding Statement.

“The funder provided support in the form of salaries for authors [insert relevant initials], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.”

If your commercial affiliation did play a role in your study, please state and explain this role within your updated Funding Statement.

2. Please also provide an updated Competing Interests Statement declaring this commercial affiliation along with any other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products, etc. 

Within your Competing Interests Statement, please confirm that this commercial affiliation 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 this adherence statement is not accurate and  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 both an updated Funding Statement and Competing Interests Statement in your cover letter. We will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

5. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

6. Please include a caption for figure 1.

[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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: I was unable to find the 'Supporting Information' files that the authors promised to provide, unless the intent was to consider the manuscript text itself as a 'Supporting Information' file.

In addition, the authors did not provide the spreadsheet or other software used to implement the Markov model.

These omissions actually make it difficult to make a full evaluation of this contribution, and some details required to confirm rigor and reproducibility of the estimates are missing.

That being said, if we make an assumption that the authors have acted and performed the research task with integrity and in a fashion that is acceptable from the standpoint of rigor and reproducibility, it should be noted that this contribution has a focus on the construct of 'Treatment-Resistant Schizophrenia,' often conceptualized as a categorical phenomenon or as one end of a spectrum of treatment responsiveness, and the size of the TRS caseload is of interest in pharmacoeconomics and pharmacoepidemiology as might be seen when pharmaceutical industry research and development decisions are made about investments in new medications for schizophrenia. Further, the results of the Markov modeling appear to be sound and logic supports descriptive statements provided by the authors, who offer several simulations, each based on reasonably plausible assumptions (e.g., concerning SMR to the extent that excess mortality might be shortening the lives of people who suffer from treatment-resistant schizophrenia. Further, there is a clearly stated set of limitations and assumptions, which should be helpful as a guide to future modeling work along these lines.

It is of interest that the authors adopted a deterministic approach and did not use simulation approaches that might provide interval estimates to complement the point estimates. (One might say that the three 'proxy' approaches lay out a set of alternative estimates that might be used in place of credible intervals or confidence intervals.)

A few minor comments:

The authors mention 'true prevalence' and this echoes some prior literature in the field, but indeed what we have are estimates and it might be argued that the construct of 'true prevalence' should have been abandoned long ago. The authors provide reasons for rejecting this notion, and they offer a range of estimates, each based on plausible assumptions about deterministic values in the Markov modeling simulations.

In general the paper is well-written and many PLOSONE readers should find it relatively easy to read and without a great deal of technical jargon. One exception involves a number of instances in which the subject of the sentence is a singular or a plural noun and the other parts of the sentence (e.g., verb form; subject complement) are the opposite. This situation can be remedied with some careful copyediting.

Reviewer #2: This study performs a Markov cohort simulation to model prevalence of treatment resistant schizophrenia. It uses data from public health databases as well as estimates from published estimates from systematic reviews.

Overall the study is interesting and contributes to the literature. The methods are appropriate to address the question, and it is written clearly and is readable for non-specialists. However, the report is also very brief and includes only one analysis using previously published data. Some recommendations are:

1) Various typos or other problems that should be corrected:

a. In the first paragraph of the introduction, line 5: ‘Some patients diagnosed with schizophrenia do only…’ Remove ‘do’.

b. Last sentence of the first paragraph of the introduction: ‘Additionally, half of the patients with TRS is…’ Remove ‘the’ and change ‘is’ to ‘are’.

c. Last sentence of the introduction: ‘United Stated’.

d. In the last paragraph of the Data section of the Methods (p.4, line 21): ‘TRS mortality was therefore adjusted proportionally adjusted…’ Repeated use of the word ‘adjusted’.

e. In the second paragraph of the Statistical Analysis section of the Methods (p.4, line 32): ‘The analysis were performed…’ Change ‘were’ to ‘was’.

f. The second sentence of the Discussion (‘The three different proxy definitions of TRS…’) is confusing. It would be helpful to reword it.

g. The last sentence of the first paragraph of the Discussion (‘albeit consistently higher estimates of TRS…’): United States is not capitalised properly.

h. First sentence of the second paragraph of the Discussion (‘Despite the one-way sensitivity analyses’): the sentence is confusing. Perhaps ‘revealed’ should be changed to ‘revealing’.

i. The last sentence of the third paragraph of the Discussion (‘the plausible ranges well coincide’) is clumsily worded. Perhaps ‘the plausible ranges coincide well’?

j. The last sentence of the Conclusion (‘The estimates are highly dependent of…’) is confusing. Perhaps ‘…are highly dependent on the proxy used…’?

2) If feasible to do so, it would be useful for the reader to include descriptives/summary statistics in the Results section about the data used for the analyses, although I am conscious that a number of data sets were used and that they were previously published elsewhere. At the moment it is unclear what the characteristics of the sample(s) used to estimate TMR prevalence were or how representative they were of the wider population.

3) In the Methods section, there are multiple assumptions described that were made for the model. For example, it is stated that the SMRs for TRS mortality was adjusted proportionally for proxy 1, but not for proxy 2 or 3. While I think that the rationale for these assumptions is reasonable, it would be helpful to add a discussion of these assumptions and how they may have impacted the results of the analysis to the limitations section in the Discussion.

Reviewer #3: I can congratulate the authors on their conceptualization of an interesting schizophrenia research question -- namely, how often treatment-resistant schizophrenia might be occurring in the United States. They appropriately identify a crucial issue- namely, how TRS case definitions are actualized.

The data they have pulled together seems quite appropriate, but it is possible that they have neglected some sources of data that are pertinent, and this topic deserves coverage in a revised limitations section of the paper.

Of special note might be the continuing uncertainty about whether any of the US databases now encompass the entire study population of cases of schizophrenia, within which the treatment-resistant case subset might be found.

Leaving aside issues of the completeness of the data and coverage of the US schizophrenia population, there are some uncertainties about the statistical modeling approach. Taking a step backward one might look for simulations that are more advanced (e.g., with Gibbs sampling), and here again, it is a topic for coverage in the Discussion section but not necessarily a serious impediment in relation to publication of this paper's estimates.

I remain unconvinced that the 22% estimate offered by the authors is that much different from the 30% estimate in the literature of the past. In addition, the description of the statistical approach does not mention how the 30% estimate might be used as a Bayesian prior, with the new evidence used to update that prior.

I'd be especially appreciative of a statistical approach that takes the 30% estimate as a Bayesian prior, and then evaluates that prior in relation to the new data now available.

Finally, I'd invite the authors to talk more about external generalizability, and here there is an important literature that might not be fully appreciated by PLOS readers and that stretches back to the US-UK diagnostic studies and the Sartorius-Wing group's work on the IPSS schizophrenia research. Some 38 citations are included, but I'm not seeing the important seminal work completed in that clearly pertinent study with samples from multiple countries.

Reviewer #4: This is an interesting paper based on simulations underpinned by epidemiological data to inform IPM models about the prevalence of TRS. The incidence data come from reliable sources, and the methodology appears sound, notwithstanding the points below which can mostly be easily addressed. I have a concern about the birth cohorts that were used for this exercise, and no method of validation of the model is reported in the methods, another major limitation.

1. Introduction: It’s unclear which reference the “30%” quote comes from. Is this based on a meta-analysis or similar?

2. Methods: Did you IPM model allow for the possibility of symptomatic or disease recovery / remission? If not, how could this have influenced your estimates?

3. Methods>Data: The model is restricted by other covariates over which incidence of schizophrenia varies, but which are not explicitly modelled. These would include ethnicity/migration status and cannabis use. Could the authors comment on how omitting these (and other) omitted variables could have affected TRS prevalence estimates?

4. Methods>Statistical Analysis: Please give more information about where you obtained the birth cohort data (1930-2014) from and how this was set up (i.e. stratified by sex?). How long were people simulated as at-risk of schizophrenia for? Typically this would be from ~16-64 years of age. I don’t understand the analysis fully here as you report the TRC prevalence for 2014. On this basis birth cohorts from 1998 onwards would not be relevant to your study, since they would be younger than 16 in 2014. The earliest lower age of onset I think you could go down to is 14 years, but 16 is more typical. This should be clarified. Equally, birth cohorts born in 1930 would be aged 84 in 2014, well passed the typical age of onset of psychosis. Very late onset psychosis has a distinct epidemiology, about which little is known with respect to TRS.

5. Methods>Statistical Analysis: How was the simulation model validated?

6. Table 1: Should there be corresponding confidence intervals around the prevalence of TRS and TRC proportion amongst people with schizophrenia?

7. Results: The text is unclear in places, for example “Comparing the one-way sensitivity analysis when changing the SMR rates…the model estimated an approximately 40% higher prevalence…” – it’s unclear to which line in Table 1 you are referring. Preference would be to report the TRS proportions specified in the Table, not the % change in TRS proportions. Similar argument for the “fivefold” increase.

Minor points:

8. Please remember to include page numbers which makes reviewing easier

9. Introduction: “…half of the patients with TRS is…” should be “…TRS are…”

10. Define acronyms on first usage, ICD, DSM etc

11. Table 1: You could indicate in the table, that Proxy 2 was the main definition to remind the reader at this point.

12. Discussion: Second sentence is unclear

13. Why did the authors chose the US population?

14. I did not have access to the full data in supplemental files, which were not provided to me. The authors may wish to check with PLoS One that open access to this data is available.

**********

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: James C. Anthony

Reviewer #2: No

Reviewer #3: No

Reviewer #4: Yes: James B. Kirkbride Ph.D.

[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.

PONE-D-19-32237R1

A modelling approach to estimate the prevalence of treatment-resistant schizophrenia in the United States

PLOS ONE

Dear Mr. Mørup,

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 22 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,

Giuseppe Carrà, PhD

Academic Editor

PLOS ONE

[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 #2: All comments have been addressed

Reviewer #4: (No Response)

**********

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: Partly

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #4: 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: Yes

Reviewer #4: 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 #2: Yes

Reviewer #4: 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: The authors have largely addressed the issues raised and the paper is improved for it. One final suggestion would be to add a limitation to the paper clearly acknowledging the potential issues with data accuracy and reliability in the datasets they have used.

Reviewer #4: Thank you for addressing my concerns, which are generally clear and have helped to improve the manuscript. One concern that I feels requires further detail and revision is over validation. The abstract of the paper states that the model was validated for the purpose of estimate the prevalence of TRS in the US. The author response to my earlier concern with this issue, however, noted that validity had been established by asking clinicians and statistical experts about the model and its methodological framework. This is not really internal validity but some measure of apparent or face validity. Internal validity would be more formally established using bootstrapping or some other cross-validation procedure applied to the available data. There is also no mention of any external validation (do the predictions from your model accurately predict TRS prevalence in the US in a representative sample?), which may not be possible in the absence of a reliable external dataset in which to test this. If so, external validation can simply be acknowledged as a limitation, but I would think there is more the authors could do to internally validate their models.

**********

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

Reviewer #4: Yes: James B. Kirkbride

[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.

A modelling approach to estimate the prevalence of treatment-resistant schizophrenia in the United States

PONE-D-19-32237R2

Dear Dr. Mørup,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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.

With kind regards,

Giuseppe Carrà, MD, PhD

PLOS ONE Academic Editor