Acupuncture for treating attention deficit hyperactivity disorder in children: A protocol for systematic review and meta-analysis.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) patients often use complementary and alternative medicine to treat symptoms, and acupuncture is one option. This systematic review aims to assess whether acupuncture is an effective treatment for attention deficit hyperactivity disorder (ADHD).
METHODS: We will search nine databases from their inception: PubMed, AMED, CINAHL, EMBASE, the Cochrane Central Register of Controlled Trials, RISS, KoreaMed, KISS, and the China National Knowledge Infrastructure database. Two investigators will independently review the selected studies, extract the data, and analyze them. The Cochrane Risk of Bias Assessment Tool will be used to assess the risk of bias. DISCUSSION: Because this is a systematic review, no ethical approval is needed. The systematic review will be published in a peer-reviewed journal and disseminated both electronically and in print. The review will be updated to support health policy and practice. TRIAL REGISTRATION NUMBER: Reviewregistry1345.

Introduction

Attention deficit hyperactivity disorder (ADHD) is a disorder with symptoms of inattention, hyperactivity, and impulsivity. The estimated prevalence of ADHD is 7.2% in children and adolescents worldwide [1]. The prevalence of ADHD in children is 7.8%–9.5% in the United States [2] and 6.27% in China [3]. The drug treatment for children with ADHD includes stimulant medication, atomoxetine, and antidepressants in combination with behavioral therapies [4]. However, these therapies are not free of side effects, including abdominal pain, headache, cardiovascular risk, irritability, and insomnia [5].

The reported use of complementary and alternative medicine for ADHD ranges from 12% to 64% [6]. Nutritional interventions, herbal preparations, massage, mind–body medicine, and acupuncture are most commonly used [6]. Acupuncture involves inserting needles for therapeutic or preventive purposes into the skin tissue and underlying tissues at specific points on the body, called acupuncture points [7]. These points can also be stimulated with electricity, lasers, pressure, heat, and ultrasonic waves [7]. Acupuncture is widely used in Asia for managing a variety of conditions, including cardiovascular diseases, infertility, pain and mental health [8-11]. In the cerebral cortex, acupuncture can stimulate the growth and development of nerve fibers, neural nerve regeneration and brain connectivity [12-14]. It has been hypothesized that acupuncture can improve attention, especially active attention, in children with ADHD [15, 16]. To date, the use of acupuncture for ADHD has been investigated in three systematic reviews (SRs) in English [17-19]. One of these three were Cochrane reviews, but they found no eligible studies [19]. The other two reviews indicated limited evidence that acupuncture may be beneficial for the treatment of ADHD [17, 18]. Further, the authors combined the studies regardless of control treatments and ignored clinical heterogeneities, resulting in potentially biased or inaccurate conclusions [17]. They are also outdated and may miss several newly published studies [17, 18]. Therefore, this systematic review will aim to provide and up-to-date evaluation on the effects of acupuncture on children with ADHD.

Methods

Study registration

The protocol is registered at reviewregistry1345 (https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/625ffb6ceccdb1001efe3598/) [20].

Criteria for considering studies in this review

Types of studies

We will include prospective randomized controlled trials (RCTs). Observational, cohort, qualitative, uncontrolled, laboratory, and case-control studies and case series will be excluded. Language restrictions will not apply.

Types of participants

Children with ADHD will be included regardless of sex or nationality.

Types of interventions and controls

We will include studies that investigated invasive acupuncture with or without electrical stimulation on body, ear and head. Other methods of stimulating acupuncture points without needle insertion (acupressure, pressure buttons, laser stimulation, etc.) will be excluded. Treatments that may be used as control interventions include general conventional treatments (medications), sham treatments (interventions that mimic acupuncture/real treatment in some aspects but differ in others, such as skin penetration or point location), and waiting lists. The acceptance of sham acupuncture as a valid control is highly controversial [21-23], and we will analyze the results using subgroup and sensitivity analyzes. In addition to acupuncture and another active treatment, we will also include studies that compared the active treatment with acupuncture, as well as studies that combined the active treatment with acupuncture. We will exclude RCTs comparing two different forms of acupuncture or using other types of alternative therapies including cupping, herbal medicines, exercise and etc.

Type of outcome measures

Primary outcomes. Improvement in ADHD symptoms [24]: DSM-IV-based scales (Conners’ Rating Scales (Parent and teacher), Disruptive Behavior Rating Scale, ADHD-RS (Parent, Teacher, and Investigator)) or Global assessment scales (Clinical Global Impression-Improvement or Severity scale, Children’s and Parent’s Global Assessment Scales).

Secondary outcomes

Total treatment efficacy

Quality of life

Adverse events (AEs)

Search method for identifying studies

Electronic searches

The electronic database searches will be conducted in PubMed, AMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), three Korean databases—KoreaMed, the Research Information Service System (RISS), the Korean Studies Information Service System (KISS), and the China National Knowledge Infrastructure (CNKI) database. We will use English for the search terms of all eight databases. In addition, we will use Korean for RISS and KISS and Chinese for CNKI.

Additional studies will be identified by searching the reference lists of the selected studies. We will also search the World Health Organization’s International Clinical Trial Registration Platform (ICTRP) (http://apps.who.int/trialsearch), ClinicalTrials.gov (http://clinicaltrials.gov/), and The Clinical Research Information Service (CRIS) (https://cris.nih.go.kr/cris/index/index.do). In addition to the studies located in the database searches, we will include relevant SRs and articles by searching the reference lists of these studies. In addition, dissertations and abstracts will be included in the search.

Search strategy

The search strategy will use the following terms: (acupuncture OR acup* OR electroacupuncture OR ear acupuncture) AND (attention deficit OR attention OR hyperactivity* or ADHD).

Data collection, extraction, and analysis

Selection of studies

Two reviewers (JTK, KK) will independently evaluate the titles and abstracts of the studies identified in the searches and select appropriate studies based on the predefined criteria. Disagreements in study selection will be resolved by another reviewer (MSL). A Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant flowchart will be used to document and summarize the study selection [25, 26].

Data extraction

The selected articles will be reviewed by two independent reviewers (JTK and LA), who will extract data from the articles based on the predefined criteria. The extracted data will include the acupuncture intervention, the control intervention, the main outcomes, and adverse effects, as well as the author(s) name, year of publication, country, sample size, age, and sex of the study participants. We will tabulate the extracted data for further analysis. GRADE software will be used to assess the strength of evidence based on the Cochrane Handbook for Systematic Reviews of Interventions, and a table summarizing the results will be produced.

Based on the revised Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) [27], details of the acupuncture method and control interventions will be extracted. In cases where studies do not meet standards (lack of STRICTA protocol, insufficient information), we will email or call the authors for additional information and note the results in the final publication. We will also report the case where it is not possible to contact the PI of the study and obtain the full information. While all studies that meet the search criteria will be included, those that do not meet the proposed standards will be listed separately and the reason for exclusion is noted. Only those studies that meet the inclusion criteria and none of the exclusion criteria will be included in the results tables.

Assessment of risk of bias

We will assess the risk of bias based on the Risk of Bias Assessment Tool (RoB 2.0) developed by the Cochrane Collaboration [28]. Five aspects will be examined: randomization, deviations from planned interventions, missing outcome data, measurement of outcomes, and selection of reported outcomes. Risk of bias will be graded as "low risk of bias," "some concern," or "high risk of bias" for each area of each study. Disagreements will be resolved by involving a third reviewer when necessary.

Data analysis

The data analysis will be carried out using the Cochrane Collaboration’s Review Manager (RevMan) software, version 5.4 for Windows (Nordic Cochrane Center, Copenhagen, Denmark). Comparisons of the intervention and control groups will be performed. The assessment of clinical effectiveness will be based on the risk ratio for the categorical data and the mean difference (MD) for the continuous data. Efficacy values will accompany categorical and continuous variables with 95% confidence intervals. We will use the standardized MD rather than the weighted MD for variables with different scales. When heterogeneity was detected by chi-square or Higgins I2 tests, we will perform subgroup analyses to determine the cause of clinical heterogeneity. Due to the variety of interventions, study designs, and other factors involved in the included studies, a random-effects model will be used to assess the combined effect sizes of the efficacy variables. The Egger regression method and funnel plots will be used to assess publication bias. We will contact the investigators of the original study if we discover missing or incomplete data.

A subgroup analysis will be conducted according to different control interventions (acupuncture vs. sham acupuncture, acupuncture vs. conventional intervention, acupuncture combined with conventional intervention vs. conventional intervention) and stimulation type (manual vs. electrical). The meta-analysis results will be subjected to sensitivity analyses, where appropriate, to determine their robustness.

We will provide all data underlying the results of this study in the article and supplementary materials.

Ethics and dissemination

The protocol for this systematic review does not require ethical approval. In addition to peer-reviewed publications and conference presentations, the results of this review will be widely disseminated.

Discussion

Clinicians may be able to utilize the results of this systematic review and meta-analysis on the evidence related to the safety and effectiveness of acupuncture for treating ADHD in children.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist.

(DOC)

Click here for additional data file.

STandards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) checklist (https://stricta.info/checklist/).

(PDF)

Click here for additional data file.

4 Jul 2022

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,

Christine Nardini

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

Additional Editor Comments:

The protocol is very interesting and highly needed, in particular for the absence of language limitations, and for the request of RCT with no constraints on blindeness. However, the presentation of this study requires to be polished, please read below:

“Nowadays, acupuncture is widely

accepted as a treatment method for a variety of conditions, including pain condition and

mental health [8].” This is in fact true with limited geographical application, please rephrase, give context and add citations

“In the cerebral cortex, acupuncture can stimulate the growth and

development of nerve fibers and increase the number and quality of synaptic connections” lacks of reference

“Several studies have hypothesized that acupuncture can improve attention, especially active

attention, in children with ADHD [9].” One citation one study, please rephrase and/or add appropriate citations

“Therefore, the aim of this systematic review and meta-analysis is to provide up-to-date information on the effects of acupuncture on children

with ADHD and to critically evaluate the evidence obtained from randomized trials.” Please state clearly the hypothesis you are testing

“Of these three Cochrane

reviews, one contained no applicable studies [12].” The meaning of this sentence is not clear, what does “applicable studies” mean? Also the authors state that the studies are outdated for this reason only the new work is proposed, discussion is missing as to the limits/outcome of these older meta analyses to justify this proposed work

Acceptance of sham acupuncture as a valid control is highly controversial, and the authors do not discuss this point. Results with and without these studies should probably be provided

“reviewregistry1345” I could not access this study protocol, please add a link or other means to access

2.2.4.1. how will improvement be assessed? Please state criteria

2.3.2 it is not clear why this is separated from 2.3.1, and why not all databases are listed right away.

SR acronym is never explained

Also the authors state that in case of missing (STRICTA) or ambiguous data they will contact the principal investigators, but how will it be possible to recover details on the acupuncture procedure sometimes after years that the study is finished? This should be discussed and clarified and alternatives should also be given (If for instance the PI cannot be reached, or too long a time has passed etc.)

In addition to the PRISMA I would also suggest to add the STRICTA guidelines in the supplementary data

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

Reviewers' comments:

[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.

5 Jul 2022

Comment 1) 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

Revised> We have now edited the manuscript according to guideline.

The protocol is very interesting and highly needed, in particular for the absence of language limitations, and for the request of RCT with no constraints on blindeness. However, the presentation of this study requires to be polished, please read below:

Comment 2) “Nowadays, acupuncture is widely accepted as a treatment method for a variety of conditions, including pain condition and mental health [8].” This is in fact true with limited geographical application, please rephrase, give context and add citations

Revised> We have now revised the sentence according to comments as follow (page 3, lines 14-16).

Acupuncture is mainly widely used in Asia for managing a variety of conditions, including cardiovascular diseases, infertility, pain and mental health [8-11].

Comment 3) “In the cerebral cortex, acupuncture can stimulate the growth and development of nerve fibers and increase the number and quality of synaptic connections” lacks of reference

Revised> We have now rewritten the sentence and added the references as follow (page 3, lines 7-9 from the bottom).

In the cerebral cortex, acupuncture can stimulate the growth and development of nerve fibers, neural nerve regeneration and brain connectivity [12-14].

Comment 4) “Several studies have hypothesized that acupuncture can improve attention, especially active attention, in children with ADHD [9].” One citation one study, please rephrase and/or add appropriate citations

Revised> We have now rewritten the sentence and added the references as follow (page 3, lines 6-7 from the bottom).

It has been hypothesized that acupuncture can improve attention, especially active attention, in children with ADHD [15, 16].

Comment 5) “Therefore, the aim of this systematic review and meta-analysis is to provide up-to-date information on the effects of acupuncture on children with ADHD and to critically evaluate the evidence obtained from randomized trials.” Please state clearly the hypothesis you are testing.

Revised> We have now rewritten the sentence as suggested (page 4, lines 1-2).

Therefore, this systematic review will aim to evaluate the effects of acupuncture on children with ADHD.

Comment 6) “Of these three Cochrane reviews, one contained no applicable studies [12].” The meaning of this sentence is not clear, what does “applicable studies” mean?

Revised> We have now changed the words to “eligible studies” (page 3, line 4 from the bottom).

Comment 7) Also the authors state that the studies are outdated for this reason only the new work is proposed, discussion is missing as to the limits/outcome of these older meta analyses to justify this proposed work.

Revised> We have now rewritten the sentence as follows (page 3,lines 1-2 from the bottom and page 4, line 1).

However, the authors combined the studies regardless of control treatments and ignored clinical heterogeneities. They concluded biased or exaggerated conclusions [17]. They are also outdated and may miss several newly published studies [17, 18].

Comment 8) Acceptance of sham acupuncture as a valid control is highly controversial, and the authors do not discuss this point. Results with and without these studies should probably be provided.

Revised> Thank you very much for your valuable. We have now added the sentences with references as follows (page 5, lines 2-4).

The acceptance of sham acupuncture as a valid control is highly controversial [21-23], and we will analyze the results using subgroup and sensitivity analyzes.

Comment 9) “reviewregistry1345” I could not access this study protocol, please add a link or other means to access

Revised> There was a link as reference [20] in the original submission. We have now added the link in the text (page 4, lines 6-7).

(https://www.researchregistry.com/browse-the-registry#registryofsystematicreviewsmeta-analyses/registryofsystematicreviewsmeta-analysesdetails/625ffb6ceccdb1001efe3598/)

Comment 10) 2.2.4.1. how will improvement be assessed? Please state criteria.

Revised> We have now added the core-outcomes related to measuring improvement (core-outcomes) with references as follow (lines 11-14).

Improvement in ADHD symptoms [24]: DSM-IV-based scales (Conners’ Rating Scales (Parent and teacher), Disruptive Behavior Rating Scale, ADHD-RS (Parent, Teacher, and Investigator)) or Global assessment scales (Clinical Global Impression-Improvement or Severity scale, Children’s and Parent’s Global Assessment Scales)

Comment 11) 2.3.2 it is not clear why this is separated from 2.3.1, and why not all databases are listed right away.

Revised> We have now combined two sections as one and added the details as follow (page 5, lines 6-7).

The Clinical Research Information Service (CRIS) (https://cris.nih.go.kr/cris/index/index.do).

Comment 12) SR acronym is never explained.

Reply> It is already spelled out in the page 3, line 4 from the bottom.

Comment 13) Also the authors state that in case of missing (STRICTA) or ambiguous data they will contact the principal investigators, but how will it be possible to recover details on the acupuncture procedure sometimes after years that the study is finished? This should be discussed and clarified and alternatives should also be given (If for instance the PI cannot be reached, or too long a time has passed etc.)

Revised> Thank you for your comments. We have now added the sentence for the commented cases (page 7, lines 8-9).

If the principal investigators cannot be reached or too much time has elapsed, we will note this in the full review reports.

Comment 14) In addition to the PRISMA I would also suggest to add the STRICTA guidelines in the supplementary data

Reply> We have now added it as supplementary file.

2 Aug 2022

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,

Christine Nardini

Academic Editor

PLOS ONE

Additional Editor Comments:

It is essential that you clarify how you will handle cases where studies do not comply to standards (lack of STRICTA protocol, lack of sufficient information, impossibility to contact the PI of the study, etc) and in which cases you will discard the study for lack of quality

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

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

Reviewer #1: 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 #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Page 3 - "Acupuncture is mainly widely used" - 'mainly widely' does not read well. Suggest rephase to "Acupuncture is widely used in Asia"

Page 3 - five lines from the bottom "one contained no eligible studies". I do not understand what the authors mean here. If no studies were eligible, does it mean that the review showed that there are zero studies that asses the use of acupuncture in children with ADHD? Eligible in what sense?

Page 3 - last line "They concluded biased or exaggerated conclusions". This almost seems like a contradiction to the previous comment that these studies indicted limited evidence. If the evidence is limited and exaggerated, this implies that there is in fact no evidence. I would suggest "Further, the authors combined the studies regardless of control treatments and ignored clinical heterogeneities, resulting in potentially biased or inaccurate conclusions"

Page 4 - line 2. Rephase "...systematic review will aim to provide and up-to-date evaluation on the effects...."

Page 4 - Under types of studies. Specify which languages will be used for the searches.

Page 4 to 5 - In types of interventions and controls, how will studies that include alternative therapies alongside acupuncture (eg cupping, exercise) be handled?

Page 5 lines 5 to 6, I find this sentence clumsy. Rephrase the sentence to clarify that combined treatments will be considered eg. "we will also include studies that compared the active treatment with acupuncture, as well as studies that combined the active treatment with acupuncture"

Page 6 - "searching reference lists of the selected studies" is written 3 times on this page.

Page 6 search strategy. Is it worth adding "ADHD" to the search?

Page 7 Assessment of risk bias. This paragraph has been written in the past tense. I think it should be written in future tense, assuming it is relevant to the proposed analyses.

Data: Given that the authors propose performing subgroup analyses, data from studies included in the review will need to be obtained / downloaded. These data should be made available and how this will be done should be discussed within the text.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

2 Aug 2022

Dear Editor

On the behalf of my co-author, I would like to thank you for arranging peer-review of our manuscript and for your invitation to submit a revised version. We have highlighted the revised points according to valuable comments. We appreciate the effort of the reviewers and believe that their constructive suggestions have resulted in a stronger manuscript for the PLoS One’s readers.

Yours faithfully,

Myeong Soo Lee, PhD on the behalf of co author

Additional Editor Comments:

Comment 1) It is essential that you clarify how you will handle cases where studies do not comply to standards (lack of STRICTA protocol, lack of sufficient information, impossibility to contact the PI of the study, etc) and in which cases you will discard the study for lack of quality

Revised> Thank you very much for your valuable comments. We have now changed the original sentences as following sentences (P. 7, Data extraction, 2nd paragraph).

“In cases where studies do not meet standards (lack of STRICTA protocol, insufficient information), we will email or call the authors for additional information and note the results in the final publication. We will also report the case where it is not possible to contact the PI of the study and obtain the full information. We will include all eligible studies, regardless of missing information and poor quality, to obtain complete evidence.”

Reviewers' comments:

Comment 1): Page 3 - "Acupuncture is mainly widely used" - 'mainly widely' does not read well. Suggest rephase to "Acupuncture is widely used in Asia"

Revised> We have now changed it as commented (P. 3, 2nd paragraph, line 6).

Comment 2) Page 3 - five lines from the bottom "one contained no eligible studies". I do not understand what the authors mean here. If no studies were eligible, does it mean that the review showed that there are zero studies that asses the use of acupuncture in children with ADHD? Eligible in what sense?

Revised> Thank you so much for your valuable comment. We have now clarified this as followings (P.3, lines 4-5 from the bottoms).

“One of these three were Cochrane reviews, but they found no eligible studies [19].”

Comment 3) Page 3 - last line "They concluded biased or exaggerated conclusions". This almost seems like a contradiction to the previous comment that these studies indicted limited evidence. If the evidence is limited and exaggerated, this implies that there is in fact no evidence. I would suggest "Further, the authors combined the studies regardless of control treatments and ignored clinical heterogeneities, resulting in potentially biased or inaccurate conclusions"

Revised> We have now changed it according to your valuable comments (P 3, lines 1-2 from the bottoms).

Comment 4) Page 4 - line 2. Rephase "...systematic review will aim to provide and up-to-date evaluation on the effects...."

Revised> We have now changed it according to your valuable comments (P. 4, line 2).

Comment 5) Page 4 - Under types of studies. Specify which languages will be used for the searches.

Revised> Thank you so much for your valuable comment. We have now added this under the Electric searches as followings (P. 6, lines 5-6).

“We will use English for the search terms of all eight databases. In addition, we will use Korean for RISS and KISS and Chinese for CNKI.”

Comment 6) Page 4 to 5 - In types of interventions and controls, how will studies that include alternative therapies alongside acupuncture (eg cupping, exercise) be handled?

Revised> Thank you so much for your valuable comment. We have now added this as followings (P. 5, lines 8-9).

“We will exclude RCTs comparing two different forms of acupuncture or using other types of alternative therapies including cupping, herbal medicines, exercise and etc.”

Comment 7) Page 5 lines 5 to 6, I find this sentence clumsy. Rephrase the sentence to clarify that combined treatments will be considered eg. "we will also include studies that compared the active treatment with acupuncture, as well as studies that combined the active treatment with acupuncture"

Revised> We have now changed it according to your suggestion (P. 5, lines 6-8).

Comment 8) Page 6 - "searching reference lists of the selected studies" is written 3 times on this page.

Revised> We have now corrected them according to your valuable comments (P. 6, 2nd paragraph, lines 5-7).

Comment 9) Page 6 search strategy. Is it worth adding "ADHD" to the search?

Revised> We have now added it according to your valuable comments (P. 6, Search strategies, line 3).

Comment 10) Page 7 Assessment of risk bias. This paragraph has been written in the past tense. I think it should be written in future tense, assuming it is relevant to the proposed analyses.

Revised> We have now corrected them (P. 7, lines 2-3 from the bottoms, P. 8, lines 1-2).

"We will assess the risk of bias based on the Risk of Bias Assessment Tool (RoB 2.0) developed by the Cochrane Collaboration [28]. Five aspects will be examined: randomization, deviations from planned interventions, missing outcome data, measurement of outcomes, and selection of reported outcomes. Risk of bias will be graded as "low risk of bias," "some concern," or "high risk of bias" for each area of each study. Disagreements will be resolved by involving a third reviewer when necessary."

Comment 11) Data: Given that the authors propose performing subgroup analyses, data from studies included in the review will need to be obtained / downloaded. These data should be made available and how this will be done should be discussed within the text.

-----------------

Have the authors described where all data underlying the findings will be made available when the study is complete?

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

-------------

Revised> We have now added it as followings according to your valuable comments (P. 9, lines 1-2. P.10. Data availability).

P.9, Lines 1-2

“We will provide all data underlying the results of this study in the article and supplementary materials.”

Data availability

“The authors confirm that the data supporting the findings of this study will be fully available within the article and its supplementary materials. Further inquiries can be directed to the corresponding author.”

Submitted filename: Responses to reviewers comments.docx

Click here for additional data file.

8 Sep 2022

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,

Christine Nardini

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Authors,

as I noted earlier I again highlight the necessity to be crystal clear on the inclusion and exclusion criteria for the studies of the meta analysis.

This is the only, but crucial point that needs to be clearly addressed before the article can be published.

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

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

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

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for taking the time to make the proposed changes. I am satisfied that all previous comments have been considered. I have only one remaining concern regarding the following comment:

"We will include all eligible studies, regardless of missing information and poor quality, to obtain complete evidence."

I do not agree that poor quality studies should be included as this may lead to misuse and poor-quality results further down the line. If the authors wish to include these studies in their report, then I think that it should be explicitly stated that "whilst all studies that meet the search criteria will be considered, those that do not meet the proposed standards will be listed separately with the reason for exclusion noted". Reasons for exclusion should then be listed in a manner that it not ambiguous, eg "insufficient information" should state what was missing and how much was missing. Only those studies that meet the inclusion criteria and none of the exclusion criteria should be presented in the results tables.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

8 Sep 2022

Dear Reviewer,

On the behalf of my co-author, I would like to thank you for arranging peer-review of our manuscript and for your invitation to submit a revised version. We have highlighted the revised points according to valuable comments. We appreciate the effort of the reviewers and believe that their constructive suggestions have resulted in a stronger manuscript for the PLoS One’s readers.

Yours faithfully,

Myeong Soo Lee, PhD on the behalf of co author

Reviewers' comments:

Comment 1) Thank you for taking the time to make the proposed changes. I am satisfied that all previous comments have been considered. I have only one remaining concern regarding the following comment:

"We will include all eligible studies, regardless of missing information and poor quality, to obtain complete evidence."

I do not agree that poor quality studies should be included as this may lead to misuse and poor-quality results further down the line. If the authors wish to include these studies in their report, then I think that it should be explicitly stated that "whilst all studies that meet the search criteria will be considered, those that do not meet the proposed standards will be listed separately with the reason for exclusion noted". Reasons for exclusion should then be listed in a manner that it not ambiguous, eg "insufficient information" should state what was missing and how much was missing. Only those studies that meet the inclusion criteria and none of the exclusion criteria should be presented in the results tables.

Revised> We have now changed it as commented (P. 7, lines 2-5 from the bottoms).

“While all studies that meet the search criteria will be included, those that do not meet the proposed standards will be listed separately and the reason for exclusion is noted. Only those studies that meet the inclusion criteria and none of the exclusion criteria will be included in the results tables.”

Submitted filename: Responses to reviewers comments-PONE-D-22-17595R3.docx

Click here for additional data file.

19 Sep 2022

Acupuncture for treating attention deficit hyperactivity disorder in children: A protocol for systematic review and meta-analysis

PONE-D-22-17595R3

Dear Dr. Lee,

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,

Christine Nardini

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

30 Sep 2022

PONE-D-22-17595R3

Acupuncture for treating attention deficit hyperactivity disorder in children: A protocol for systematic review and meta-analysis

Dear Dr. Lee:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Christine Nardini

Academic Editor

PLOS ONE