Dear Dr Wright,

Thank you for submitting your manuscript entitled "The Association Between Cognitive Ability and Body Mass Index: A Sibling-Comparison Analysis in Four Longitudinal Studies" for consideration by PLOS Medicine.

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Kind regards,

Beryne Odeny

Senior Editor

PLOS Medicine

Dear Dr. Wright,

Thank you very much for submitting your manuscript "The Association Between Cognitive Ability and Body Mass Index: A Sibling-Comparison Analysis in Four Longitudinal Studies" (PMEDICINE-D-22-02815R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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We hope to receive your revised manuscript by Nov 30 2022 11:59PM. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

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

We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

Please use the following link to submit the revised manuscript:

https://www.editorialmanager.com/pmedicine/

Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Callam Davidson,

PLOS Medicine

plosmedicine.org

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Comments from the reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

The paper by Wright, Davies, and Bann considers the association between adolescent cognitive ability, and later adult BMI. They demonstrate that these associations are visible only in between-family analyses, and not within-family, suggesting that these associations are probably due to shared confounders within families. This review considers the statistical aspects of the paper.

The authors use a mixed effects model of continuous BMI, and a quantile regression method, suitable for the family data structure. They use multiple cohorts, and consider the sensitivity of the results to each cohort used. My comments are relatively minor.

In the REWB models, the association is reported as the difference in adult BMI between the extremes of the cognitive ability distribution. This is an unnecessarily large difference - for me it would make more sense to report the difference between the 75th and 25th percentiles, i.e. the middle of the upper and lower halves of the distribution.

The abstract uses "points" when "kg/m2" would be more accurate.

In the statistical methods section, age is reported as one of the adjustment variables. I assume this is age as an adult, when BMI is measured? This could be clearer. Also, maternal age and birth order are included in the models. Are these correlated? Within families, these must be quite strongly linked. Is that OK for these models?

I disagree slightly with the interpretation of the quantile regression results. In the between-family analysis, it looks to me as though there is no (or very little) evidence of an association between adolescent cognitive ability and the location of the 10th percentile of the adult BMI distribution, whereas there does seem to be an association with higher percentiles of BMI. I have seen this before. The lower end of the BMI distribution is fairly fixed, but the risk factor (lower adolescent cognitive ability) is associated with a "stretching" of the BMI distribution in adulthood. Not required for this paper, but I wonder if this can be seen in the variance of adult BMI in relation to adolescent cognitive ability?

Reviewer #2: This is a very nicely written sibling analysis of cognitive ability and BMI. The association between higher cognitive ability and lower BMI does not hold when comparing siblings, which suggest family confounding. The data comes from 4 cohort studies, which provides sufficient evidence base. The methods and results are clearly described, and the results are interpreted appropriately. I didn't find anything to improve in the manuscript.

Reviewer #3: This important paper reports large-scale within-family analysis of associations between cognitive test performance in adolescence and body mass index (BMI) in adulthood using data from about 5000 families in the United States. The key findings is that the association between cognitive performance and BMI is substantially attenuated when comparisons are made between siblings within a family. This attenuation is nearly complete (effect sizes are quite close to zero in the within-family analysis) and much greater than in models that use statistical methods to adjust for socioeconomic differences between families.

Cognitive test performance and body mass index are negatively correlated. In neurology, this association has been explored as suggesting potential brain-damaging effects of obesity. In life-course epidemiology, the same association has been explored as suggesting effects of cognitive abilities on obesity risk. Overall, there is more evidence to support the latter of these interpretations; in longitudinal studies, differences in cognitive performance tend to precede differences in body mass index. However, the mechanism through which an association between cognitive performance and obesity comes about is unclear. In this article the authors show convincing evidence that differences between the families of high- and low- cognitive performance individuals account for the gradient.

The sibling comparison design used in this study is a powerful method to separate effects that arise from an individual's own cognitive characteristics from those that arise from family-level factors correlated with those characteristics, including parents' education and income, health behaviors, values, etc.

My one comment about the paper regards how the authors interpret their data. To my mind, the authors lean too heavily on family socioeconomic differences as the confounder driving cognitive performance associations with BMI. Covariate adjustment for measures of family SES do not account for large fractions of the association between cognitive performance and BMI. I fully agree with the authors that measurement error may lead to incomplete control for SES in the covariate-adjusted between-family models. But the much larger attenuation seen in the within-family analyses suggests that there may be more to the family-level confounding of cognitive performance-BMI associations than socioeconomic status. It would enhance the article to include some discussion of what these other family level factors might be.

Importantly, the authors note that public health messaging around diet and exercise seem to have limited impact on adults' obesity risk. One interpretation of the data reported in this paper is that such messaging may nevertheless impact the way parents raise their children.

Reviewer #4: This is an interesting study testing between- and within-family associations between adolescent / young adult cognitive ability and BMI measured between ages 20 and 60 years. The study takes advantage of four different cohorts resulting in 2,250 siblings from 5,602 households. The study found in a between-family comparison that higher cognitive ability was associated with lower BMI, and family socioeconomic position attenuated this association slightly. However, in a within-sibling comparison cognitive ability and BMI were not associated, suggesting that the associations are explained by unmeasured familial (shared environmental or genetic) factors.

The authors have used recently developed state of the art statistical analyses to address the study questions. While this is a well-written manuscript, which conveys an important message, there are, however, a few concerns.

Most important one relates to self-reported height and weight. While the authors have discussed this briefly as a study limitation, they have not addressed - in their analyses or discussion - that, according to some studies self-reports of weight and height carry a gender/sex bias, women more often underreport their weight and overreport their hight compared with men.

This may to some extent bias the sibling-comparisons - in sibling pairs discordant for sex. While the models have covaried for sex, I would suggest carrying out stratified sub-group analyses with sex-concordant and sex-discordant sibling pairs. This at least would reduce some of the reporting bias.

Table 1 is very difficult to comprehend, what do below average and above average refer to? The numbers M(SD), N(%) do not make much sense. This needs further clarification. Alternatively, you may want to consider just showing characteristics of your cohorts and total study population without reference to below and above average, would make more sense to me, and would allow more straightforward comparison to other studies.

Please update your literature review. For instance, your literature on statistics of obesity and overweight prevalence and their disease burden is outdated (e.g. 10.1371/journal.pmed.1003198).

Please attenuate your conclusion about family SEP, as it is on the same pathway than cognitive ability; hence, an alternative interpretation of the attenuated associations between cognitive ability and BMI in analyses including SEP is that SEP is a mediator?

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr. Wright,

Thank you very much for re-submitting your manuscript "The Association Between Cognitive Ability and Body Mass Index: A Sibling-Comparison Analysis in Four Longitudinal Studies" (PMEDICINE-D-22-02815R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

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Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

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If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.  

We look forward to receiving the revised manuscript by Feb 17 2023 11:59PM.   

Sincerely,

Callam Davidson,

Associate Editor 

PLOS Medicine

plosmedicine.org

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

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Comments from Reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

I thank the authors for their consideration of my original points. I am happy with their responses, and have no further comments to make.

Reviewer #4: The authors have done a good job in answering the concerns that this reviewer had. However, regarding Table 1, which has been clarified, I continue having difficulties in understanding the rows related to households, and why the Ns are constant across total, below average and above average. Perhaps you could add a footnote, which would clarify this detail.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Dear Dr Wright, 

On behalf of my colleagues and the Academic Editor, Dr Sanjay Basu, I am pleased to inform you that we have agreed to publish your manuscript "The Association Between Cognitive Ability and Body Mass Index: A Sibling-Comparison Analysis in Four Longitudinal Studies" (PMEDICINE-D-22-02815R3) in PLOS Medicine.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper. 

Sincerely, 

Callam Davidson 

Associate Editor 

PLOS Medicine