PONE-D-23-23141Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Ye,

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

Please submit your revised manuscript by Dec 11 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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

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

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

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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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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

Reviewer #2: No

Reviewer #3: Yes

Reviewer #4: Yes

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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

Reviewer #2: Yes

Reviewer #3: 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: Dear authors,

I have reviewed your work and appreciate your meticulous work on this subject. Overall, your protocol seems well designed and comprehensive. The literature review and data extraction methods appear to be comprehensive and robust, appropriate to the purpose of the study.

I suggest you take into consideration my suggestions below:

1-You can further expand the keywords used for the literature search. (For example: neurodegeneration,neurodegenerative disease, neurocognitive disorder, neuropsychiatric disorder) This will help researchers screen for all relevant studies.

2-You can make the information used for data extraction more detailed. Definition of cognitive impairment, Cognitive impairment measurements, etc.

3-You can define the variables to be used for dose-response analysis in more detail.

I wish you a successful completion of your work.

Reviewer #2: This protocol details the methodology to be followed for a systematic review and meta-analysis on hypoglycemic events and cognitive impairment in patients with type 2 diabetes mellitus. Ye et al. present an interesting protocol, well-structured and with a methodologic plan of interest. This type of study is needed in this population, so the protocol is relevant.

However, there are several comments that should be noted and addressed:

a. Eligibility criteria. Detail inclusion criteria for exposure, such as definition for hypoglycemic events or assessment methods. Furthermore, specify criteria for outcome (cognitive impairment), i.e., assessment methods, definition, etc.

b. Line 96. Specify the type of observational studies to be included.

c. Line 97. “Individuals with a diagnosis of T2DM will be incorporated”. Will only studies that report medical diagnosis be included or could they be self-reported? Please specify. Also, will the participants included be adults? Please specify and indicate age range.

d. Line 103. Please delete criterion 1. This is a repeated criterion that has already been established as an inclusion criterion.

e. Line 131.

f. Line 153. Will a minimum number of studies be considered for meta-analysis? Will different meta-analyses be performed depending on the study design? Please detail.

g. Line 157. Provide the interpretation of I2 according to the percentages of heterogeneity and its respective reference.

h. Line 165. Will a minimum of studies be considered for meta-regression analyses? Consider Cochrane recommendations.

i. For subgroup and meta-regression analyses consider BMI status and physical activity levels. Also, add these variables for data extraction.

j. Lines 171-172. Please provide more detail on the possible dose-response curve analysis to be performed.

k. Lines 174-175. Will a minimum of studies be considered for publication bias? Consider Sterne et al. (2011) recommendations. Moreover, for the linear regression approach, what will be the p-value considered significant?

l. Lines 177-178. Specify the characteristics of the levels of evidence. Detail the levels of evidence possible to be graded according to GRADE. What does high, medium, low and very low mean?

m. I think it would be useful for the authors to discuss the potential role of exercise, sleep, and other lifestyle behaviors in the association between hypoglycemic events and cognitive decline in patients with type 2 diabetes mellitus. In this sense, manuscripts with an integrative and translational character should be included in the discussion, such as doi: https://doi.org/10.1186/s12902-019-0402-3; doi: https://doi.org/10.1586/eem.10.78; doi: https://doi.org/10.4093/dmj.2022.0007; doi: https://doi.org/10.1136/bmj-2022-072691; and doi: http://dx.doi.org/10.1136/bjsports-2022-106355

Reviewer #3: Comments to the authors

Abstract

• “The connection that exists between hypoglycemic occurrences and the likelihood of cognitive impairment will be investigated through an organized review of multiple databases.” It is better to include a sentence summarising the inclusion criteria: "Studies that ........ were included".

• “Both Chinese and English literature…” Remove this from the summary.

Introduction

• “…normal individuals” Change from normal to healthy

• “By constructing a diabetic rat model, Seok Joon Won…”. Better: "In animal models, it has been observed that..."

• “This investigation seeks to update the systematic review and meta-analysis by including the latest relevant studies”. Better “This systematic review and meta-analyses aimed to…”

Methods and materials

• If it is a meta-analysis of observational studies, the MOOSE guideline should also be included.

• “All observational studies published in Chinese or English will be included”. Why not include other languages? Even if authors only know English and Chinese, there are translation tools that allow studies in other languages to be included.

• “The study has no restrictions on sex, race, duration of diabetes, or severity of diabetes among the participants” But is the severity of diabetes going to be controlled in some way?

• “…likelihood of cognitive dysfunction will be included”. Is there a way to determine if there is cognitive disorder? It is important to establish this a priori before the study.

• Inclusion criteria – “Studies not published in Chinese or English” and “Participants with gestational diabetes”. Exclusion criteria are not the opposite of inclusion criteria. Exclusion criteria are those that exclude participants or studies from inclusion even though they meet the inclusion criteria.

• Search strategy – I suggest this section be placed before the eligibility criteria.

• Data extraction – “the primary author” ¿first author? “period of publication” ¿year of publication? “type of diabetes mellitus” Isn't it just type 2 diabetes mellitus? “type of cognitive impairment” The type of cognitive dysfunction that can be included needs to be defined beforehand.

• “Evaluation of literature quality (publication bias)” – First, how many authors did the publication bias assessment? Secondly, I do not recommend putting publication bias. Publication bias generally refers to the Egger test and the funnel plot for meta-analysis.

• Data synthesis – First, the authors should rate the heterogeneity, for example, as not important, moderate, substantial, and considerable. Second, the p-value of heterogeneity should be assessed. Third, why did you choose the value of 30% or more to do a random-effects meta-analysis? Why not 50%? Or why not if p is < 0.05? I suggest doing the random effects meta-analysis, studies with some heterogeneity in the population and its characteristics will be included, and fixed effects meta-analyses usually give narrower confidence intervals, which can be misleading in some contexts.

• Publication bias – And what p-value is used as a threshold to consider that there is publication bias?

• Grading the quality of evidence – It is proposed to explain it a little more (not much, but a little more, yes)

Reviewer #4: Congratulations to the authors. This is a well-written and constructed manuscript. I enjoyed learning about the study. I believe it is worthy of publication.

Some minor changes:

1. Abstract

- I suggest including the specific study design (systematic review and meta-analysis protocol).

- I recommend including both that this protocol will be adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols and the meta-analysis will be guided by the Cochrane Collaboration Handbook recommendations.

- Line 28: I suggest specifying the way in which the inconsistences will be solved.

2. Introduction

- Great

- Objective: The objective of this manuscript is not to explore the cumulative effect of the frequency of hypoglycemia events on cognitive function, but to establish the methodological structure (protocol) in order to explore, through systematic review and meta-analysis, the cumulative effect of the frequency of hypoglycemia events on cognitive function. Reconsider.

3. Methods and materials

- Line 89. The systematic review should also be adhered to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement.

- Line 96. Could the author please state the reason for the exclusion of experimental studies?

- Line 156: It is suggested to indicate the range of heterogeneity based on I2 (not important, moderate, substantial, and considerable)

- Will the authors consider the corresponding p-value?

4. Discussion

- Line 190: The authors state that “This investigation seeks to explore the connection between hypoglycemic events and cognitive impairment”. However, they pretend to “clarify the precise association between hyperglycemia and different types of cognitive dysfunction”. Is this correct?

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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: Yes: Carlos Pascual-Morena; Irene Martínez-García

Reviewer #4: No

**********

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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-23-23141R1Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Yuan,

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

 Please submit your revised manuscript by Jan 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

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. 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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

Reviewer #2: Yes

Reviewer #3: 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 #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: 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: Dear authors

I have carefully considered your responses to my requests for revisions and am pleased to note that your changes have both broadened and deepened the study. The expansion of the keywords has made the literature search more comprehensive, while the elaboration of the data extraction information has significantly increased the transparency and credibility of the study. In addition, the more detailed definition of the variables to be used for the dose-response analysis strengthens the methodological integrity of the study and contributes to the interpretation of the results.

Thank you for your hard work and diligence in this process.

Reviewer #2: The authors adrressed satisfatorily all the commentts and the manuscript can now be accepted for publication

Reviewer #3: Comments to the authors

Most of the comments have been dealt with satisfactorily, but I still have a few issues that I feel should be addressed.

• “There will be four categories for heterogeneity: not important (0%-40%), moderate (30%-60%), substantial (50%-90%) and considerable (75%-90%). The fixed effect model will be applied for combined analysis if the I2 value is less than 50%. A random effect model will be applied when P < 0.1 or I2 > 50%[32, 33]. Subgroup analysis and other techniques will be used to investigate sources of clinical or methodological heterogeneity when I2 > 75%.” - I suggest that considerable is 75-100%. I also suggest including subgroup studies even if there is no detected statistically significant heterogeneity.

• Publication bias – Why is p < 0.10 not used to assume publication bias? It is the most commonly used value.

Reviewer #4: Congratulations to the authors. This is a well-written and constructed manuscript. I enjoyed learning about the study. I believe it is worthy of publication.

Some minor changes:

- Line 85: I propose to rephrase the objective. I suggest the following: "This manuscript aims to establish a methodological structure (protocol) to explore the cumulative effect of frequency of hypoglycemic events on cognitive function and further explore the dose-response relationship through systematic review and meta-analysis, which aims to update the association between hypoglycemia and cognitive impairment by including the latest relevant studies."

- Could the authors please cite the MOOSE statement?

**********

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: Yes: Carlos Pascual-Morena; Irene Martínez-García

Reviewer #4: 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.

PONE-D-23-23141R2Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysisPLOS ONE

Dear Dr. Yuan,

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.

1) The researcher can disagree with the comment given by reviewer.

For example, Reviewer stated that "2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the

most commonly used value.

Ans: We appreciate you informing us that two types of publication bias P-values are

currently in use: 0.05 and 0.1. Since 0.1 is more rigorous and widely used, we have

adjusted the P-value to 0.1 per your recommendation. For more information, see lines

206-207.

As an editor, suggest it to keep statistical significance in scientific research is p < 0.05. I have given my details below. Moreover, Please explain in detail the Publication bias. The current has no justification and explanation.

The commonly used threshold for statistical significance in scientific research is p < 0.05, which means that the observed results are unlikely to have occurred by chance alone. However, the use of p < 0.10 to assume publication bias is not a standard practice. The threshold of p < 0.05 is widely accepted in the scientific community and is considered a standard level of significance.

The rationale behind using a stricter threshold for publication bias assessment is to reduce the risk of false positives or Type I errors. Setting a more lenient threshold, such as p < 0.10, increases the likelihood of incorrectly concluding that there is publication bias when it may not actually be present.

When assessing publication bias, researchers often use various statistical tests and graphical methods, such as funnel plots, Egger's test, and Begg's test. These tools help evaluate whether there is a systematic relationship between study precision and effect size, which could indicate the presence of publication bias. 

2) Please Revisit the exclusion criteria. I am giving some suggestion. It is not mandatory to include all suggestion. yet your study exclusion criteria is important

Study Design:

Exclude studies that are not primary research articles (e.g., reviews, editorials, commentaries).

Exclude observational studies lacking a clear dose-response relationship or studies not reporting relevant data for a dose-response analysis.

Exclude studies with insufficient methodological detail or poor quality (e.g., high risk of bias, inadequate statistical analysis).

Population:

Exclude studies that focus exclusively on populations other than patients with type 2 diabetes mellitus.

Exclude studies with mixed populations where data on patients with type 2 diabetes cannot be extracted separately.

Exclude studies with comorbid conditions that could independently affect cognitive function (e.g., neurodegenerative diseases other than diabetes-related cognitive impairment).

Intervention/Exposure:

Exclude studies that do not report hypoglycemic events or provide insufficient information on the exposure.

Exclude studies where the dose or severity of hypoglycemic events is not clearly defined.

Exclude studies where the exposure assessment does not align with the objectives of the dose-response meta-analysis.

Outcome:

Exclude studies that do not report cognitive impairment as an outcome.

Exclude studies that use different definitions or measurements of cognitive impairment.

Exclude studies with insufficient data for the dose-response relationship or studies not reporting relevant effect measures.

Publication Characteristics:

Exclude studies published in languages other than those your team can review.

Exclude studies with incomplete or inaccessible data, and those without sufficient details to conduct a dose-response analysis.

Duration and Follow-up:

Exclude studies with a duration that is too short to capture meaningful cognitive changes.

Exclude studies with inadequate follow-up periods or those not reporting relevant follow-up data.

Publication Date:

Consider excluding older studies if there have been significant advancements in the understanding of diabetes-related cognitive impairment over time.

Intervention Heterogeneity:

Exclude studies with significant heterogeneity in interventions or treatment protocols that may impact the ability to conduct a meaningful dose-response analysis.

3) Please give two heading study strength and study limitation and explain in depth. 

4) The rational to use Grading the quality of evidence is not clear. Explain in depth. It is suggestion compare GRADE with AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), AHRQ (Agency for Healthcare Research and Quality) Methods Guide and ROBIS (Risk of Bias in Systematic Reviews) Tool.

Please submit your revised manuscript by Jan 19 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Muhammad Shahzad Aslam, Ph.D.,M.Phil., Pharm-D

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.

Additional Editor Comments:

1) The researcher can disagree with the comment given by reviewer.

For example, Reviewer stated that "2. Publication bias – Why is p < 0.10 not used to assume publication bias? It is the

most commonly used value.

Ans: We appreciate you informing us that two types of publication bias P-values are

currently in use: 0.05 and 0.1. Since 0.1 is more rigorous and widely used, we have

adjusted the P-value to 0.1 per your recommendation. For more information, see lines

206-207. 

As an editor, suggest it to keep statistical significance in scientific research is p < 0.05. I have given my details below. Moreover, Please explain in detail the Publication bias. The current has no justification and explanation.

The commonly used threshold for statistical significance in scientific research is p < 0.05, which means that the observed results are unlikely to have occurred by chance alone. However, the use of p < 0.10 to assume publication bias is not a standard practice. The threshold of p < 0.05 is widely accepted in the scientific community and is considered a standard level of significance.

The rationale behind using a stricter threshold for publication bias assessment is to reduce the risk of false positives or Type I errors. Setting a more lenient threshold, such as p < 0.10, increases the likelihood of incorrectly concluding that there is publication bias when it may not actually be present.

When assessing publication bias, researchers often use various statistical tests and graphical methods, such as funnel plots, Egger's test, and Begg's test. These tools help evaluate whether there is a systematic relationship between study precision and effect size, which could indicate the presence of publication bias.

2) Please Revisit the exclusion criteria. I am giving some suggestion. It is not mandatory to include all suggestion. yet your study exclusion criteria is important

Study Design:

Exclude studies that are not primary research articles (e.g., reviews, editorials, commentaries).

Exclude observational studies lacking a clear dose-response relationship or studies not reporting relevant data for a dose-response analysis.

Exclude studies with insufficient methodological detail or poor quality (e.g., high risk of bias, inadequate statistical analysis).

Population:

Exclude studies that focus exclusively on populations other than patients with type 2 diabetes mellitus.

Exclude studies with mixed populations where data on patients with type 2 diabetes cannot be extracted separately.

Exclude studies with comorbid conditions that could independently affect cognitive function (e.g., neurodegenerative diseases other than diabetes-related cognitive impairment).

Intervention/Exposure:

Exclude studies that do not report hypoglycemic events or provide insufficient information on the exposure.

Exclude studies where the dose or severity of hypoglycemic events is not clearly defined.

Exclude studies where the exposure assessment does not align with the objectives of the dose-response meta-analysis.

Outcome:

Exclude studies that do not report cognitive impairment as an outcome.

Exclude studies that use different definitions or measurements of cognitive impairment.

Exclude studies with insufficient data for the dose-response relationship or studies not reporting relevant effect measures.

Publication Characteristics:

Exclude studies published in languages other than those your team can review.

Exclude studies with incomplete or inaccessible data, and those without sufficient details to conduct a dose-response analysis.

Duration and Follow-up:

Exclude studies with a duration that is too short to capture meaningful cognitive changes.

Exclude studies with inadequate follow-up periods or those not reporting relevant follow-up data.

Publication Date:

Consider excluding older studies if there have been significant advancements in the understanding of diabetes-related cognitive impairment over time.

Intervention Heterogeneity:

Exclude studies with significant heterogeneity in interventions or treatment protocols that may impact the ability to conduct a meaningful dose-response analysis.

3) Please give two heading study strength and study limitation and explain in depth.

4) The rational to use Grading the quality of evidence is not clear. Explain in depth. It is suggestion compare GRADE with AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews), AHRQ (Agency for Healthcare Research and Quality) Methods Guide and ROBIS (Risk of Bias in Systematic Reviews) Tool.

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Association of hypoglycemic events with cognitive impairment in patients with type 2 diabetes mellitus: Protocol for a dose-response meta-analysis

PONE-D-23-23141R3

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