PONE-D-20-01564

Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD.

PLOS ONE

Dear Dr. Kaalund-Brok,

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 address carefully all the extensive list of amendments and clarifications requested by the reviewers in the various sections of the manuscript. 

Please submit your revised manuscript by November 30th. 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,

Andrea Martinuzzi

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. One of the noted authors is a group or consortium [INDICES]. In addition to naming the author group and listing the individual authors and affiliations within this group in the acknowledgments section of your manuscript, please also indicate clearly a lead author for this group along with a contact email address.

4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

5. Please include a copy of Table 10 which you refer to in your text on page 20.

[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: Partly

**********

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

Reviewer #1: No

Reviewer #2: Yes

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: Yes

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: Yes

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 manuscript entitled ‘Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD’ with the aim to describe treatment responses and their predictors during the first 12 weeks of MPH treatment using repeated measurements of symptoms and adverse reactions (ARs) to treatment in 207 children recently diagnosed with ADHD.

The manuscript can be further improved based on the following comments.

Study Design

Page 6 the sentence ‘There was made a protocol (S11 and S12)’ to be revised.

Page 7, the statement ‘the study was not registered in a registry for clinical trials (see the ethics section)’ not clear. In the ethics section, it was written ‘The study was registered in ClinicalTrials.gov (NCT04366609)’

CGI-S, CGI-I, WFIRS-P, BSSERS-C language version and scoring method including classification of scores to be highlighted.

Page 11, for the statement ‘Ten percent missing data on items on WFIRS-P subscales were allowed and missing data on items were set as 0 (never or not at all)’ reason to be provided.

Description on the missing data to be provided. i.e percentages of missing data, pattern etc.

Page 11 symbol X² to be replaced with symbol 'Chi' square. Likewise with S9 Table footnote (italicize X to be replaced with 'Chi' symbol).

Page 12, the citation for SPSS including publisher name to be highlighted.

Results

Page 12 for ‘187 (90.3%) patients (mean age 9.6 (SD 1.5)’ the mean and SD are similar to mean, sd for 207 patients.

Figure 1, difficult to be visualized.

Page 13 Table 1, decimal points to be standardized. 9.88 (comma to be replaced with dot)

Page 16 Table 2, bp/m to be written as bpm. Effect size could be presented.

Page 15 for the statement ‘The mean percent reductions of scores on the clinician-rated ADHD-RS-C subscale from week 0 to 12 were 52.0% on Inattention and 56.0% on Hyperactivity-Impulsivity' 52.0 % and 56.0% to be revised as 51.7% and 53.0%.

Page 15, for the statement ‘ nd the mean percentage reductions on the parent-rated ADHD-RS-P subscales were 48.1% on Inattention, 45.0% on Hyperactivity-Impulsivity, and 50.7% on Conduct problems (S6 Table)’ the figures did not tally with the figures in S6Table.

Page 15, for ‘CI 95% 2.2 to 2.5’ & Page 17 ‘CI 95% 0.5 to 0.9), Page 19 & 21 text and Table 4 & 5' CI95% to be written as 95%CI.

Page 17, Adverse reactions, Table 2 to be cited for height and weight findings.

Page 18 Table 3, what estimate refers, to be clearly labelled/defined.

Page 18 Table 3, Page 20 Table 4, Page 21 Table 5, model fit/goodness of fit measures to be stated.

Page 21 Table 5, the estimate to be replaced with b. SD errors to be written as std error.

Page 21, for the statement 'Severely ill and most extremely ill rated patients (CGI-S 6-7) had a significantly higher risk of reduced appetite compared with patients rated not ill to moderately ill (CGI-S 1-5) in week 0 and throughout the whole treatment period (OR = 2.41, CI 95% 1.42 to 4.08).' the results to be displayed in the table.

Page 21, for the statement 'Higher CGI-S scores at week 0 predicted a higher end dose of IR-MPH. CGI-S at week 0 and age explained together 12.7% (p > 0.001) of the variance of the end-dose IR-MPH' indicate clearly R square and denoted in the table footnote. For p >0.001, to use < and representative p value.

S4 Table footnote, were all these confirmed missing data and not numbers after minus the missing data? Missing data: ¹ n = 147, ² n= 143, ³ n = 195, ⁴ n = 193; S5 Table footnote Missing data: ¹ n = 66, ² n = 48, ³ n = 59; S6 Table footnote Missing data: ¹ n = 174, ² n = 171, ³ n = 163, ⁴ n = 179, ⁵ n = 127, ⁶. Likewise please check S7 Table and S8 Table.

S4 Table, for 'Medium, higher education (15-14 years)' should be written as 15-16 years.

S4 Table, Cap for 'T'otal. Likewise for total in S7 Table.

S9 Table 9, symbol % to be highlighted in the table.

S5 Table, symbol % for individual figure to be omitted since the symbol was highlighted after the variable name. Likewise with S6 Table.

Limitation on sample size or power of study to be discussed if any.

Reviewer #2: This is a timely and well conducted study. The rationale is presented in a very clear way and the authors make good points in the need for more echologic valid studies as well as the lack of a standard definition of "response" in the field. the methods are appropriate and the reporting good.. I only have a few suggestions:

“Attention deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterised by pervasive and impairing symptoms of inattention and/or hyperactivity and impulsivity with onset of symptoms before age 7 years (International Classification of Diseases and Related Health Problems, ICD-10)[1]” is per se not correct as ICD -10 does not include ADHGD; rather, it includes Hyperkinetic syndrome, which is roughly equivalent to the ADHD combined presentation of the DSM-5. So the authors may rephrase as follows (or similar): “Attention deficit/hyperactivity disorder (ADHD) as defined in the DSMS is a heterogeneous neurodevelopmental disorder characterised by pervasive and impairing symptoms of inattention and/or hyperactivity and impulsivity with onset of symptoms before age 12 or 7 when considering the definition of Hyperkinetic syndrome (International Classification of Diseases and Related Health Problems, ICD-10)[1], roughly equivalent to the combined presentation of ADHD as per the DSM”

The focus of the paper ins on the pharmacological treatment … but the author may want to remind the reader that non pharmacological treatments, in particular parent traingin behaviors, offer complementary interventions (eg, for opposition behaviors) (eg: https://pubmed.ncbi.nlm.nih.gov/29083042/ )

“Several meta-analyses of the short-term efficacy of immediate release MPH (IR-MPH) in randomized placebo-controlled trials have reported large effect sizes (range from 0.54 to 1.83) on ADHD core symptoms, when effects are measured as differences in endpoint or change in scores of parent-rated and teacher-rated ADHD symptoms and behaviour”: please provide references

Methods

“There was made a protocol (S11 and S12)” is a bit odd; I would suggest. Study protocol is available (S11 and S12)

Results

I wonder whether the normalisation, in addition to /borderline normalisation results could be also presented (including in the abstract)

Discussion

The lack of blinding should also be discussed among the limitations

Reviewer #3: The paper focuses on one of the most common psychiatric diseases in childhood and adolescence. This fact makes it particularly interesting and current. The drug therapy of ADHD and the risk / benefit relationship between therapy and adverse reactions are a permanent topic of discussion in the scientific community. Therefore this paper addresses the two most controversial points: the therapeutic efficacy of methylphenidate and its safety.

Clinicians, statisticians and epidemiologists consider time to be one of the main variables in observational and experimental studies. From this point of view, the choice to make an ecological study of only 12 weeks creates some perplexity. One of the critical points of ADHD drug therapy is maintaining efficacy over time. In the MTA study, also cited by the authors of this paper, a decrease in the therapeutic response was observed between the second and third year of treatment. The safety evaluation of a drug also takes a long time, especially for the observation of rare adverse events.

The study design and methodology used are very good and the statistical analysis is of a remarkable level. The choice of predictors of the therapeutic response is accurate. The sample size is adequate for the objectives of the study.

**********

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: Yes: Pietro Panei

[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.

PONE-D-20-01564R1

Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD.

PLOS ONE

Dear Dr. Kaalund-Brok,

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 address the few remaining concerns of reviewer 2.

Please submit your revised manuscript by April 30th. 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,

Andrea Martinuzzi

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. 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: (No Response)

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: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

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: No

Reviewer #2: Yes

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: (No Response)

Reviewer #2: I would suggest only a couple of points to improve the quality of the paper:

" Several meta-analyses of the short-term efficacy of immediate release MPH (IR-MPH) in randomized placebo-controlled trials

have reported large effect sizes (range from 0.54 to 1.78) on ADHD core symptoms, when effects are measured as differences

in endpoint or change in scores of parent-rated and teacher-rated ADHD symptoms and behaviours[14,15].: Network meta-analyses (eg, https://pubmed.ncbi.nlm.nih.gov/30097390/ and https://pubmed.ncbi.nlm.nih.gov/28700715/ ) should also be mentioned as their estimates are more precise than those form pairwise meta-analyses

in the discussion, the authors may refer to effects of MPH on important outcomes not generally include din RCTs, such as physical injuries (https://pubmed.ncbi.nlm.nih.gov/31302218/), suicides, etc...a summary is reported in https://pubmed.ncbi.nlm.nih.gov/32905677/

Reviewer #3: Dear authors,

Congratulations on the great deal of work you have done. Your paper is original and interesting. Furthermore, the fact that there is no control group does not represent a limitation since an observational field study. Observational studies designed well and conducted according to the protocol can give the same information as experimental clinical trials. If anything, a short follow-up is unusual (12 weeks) for this type of study. Having available the administrative and clinical data of the observed cohort would be interesting to observe it for a longer period. The method used to define the predictors of the methods of treatment with methylphenidate is elegant, appropriate and very sophisticated. It is not clear the reason for choosing numerous primary objectives also since it is a multifactorial syndrome. It would be better to identify one or two main outcomes of pharmacological treatment and analyzing data in relation to these primary outcomes. In particular it is important to know the relationship between cost and benefit of treatment with methylphenidate even if there are numerous studies on this matter. Furthermore, predicters analysis is easily applicable to clinical practice? Does it allow you to change the natural history of the syndrome? In the future it would be useful to conduct a deepening also in this field. The figures and tables are clear and help in reading the paper, especially the flowchart allows you to immediately understand the design of the study.

Overall you have done a good work of a high level of statistical and a study of the factors involved in the ADHD useful for understanding the multifatorial mechanisms that are at the origin of the syndrome.

This paper does not violate the ethics code of scientific publications.

**********

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.

Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naïve children with ADHD.

PONE-D-20-01564R2

Dear Dr. Kaalund-Brok,

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,

Andrea Martinuzzi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: