Dear Dr Rasmussen,

Thank you for submitting your manuscript entitled "Unlocking human capital: revealing relationships between early childhood experiences and adolescent and young adult health status in a resource-limited population" for consideration by PLOS Medicine.

Your manuscript has now been evaluated by the PLOS Medicine editorial staff and I am writing to let you know that we would like to send your submission out for external peer review.

However, before we can send your manuscript to reviewers, we need you to complete your submission by providing the metadata that is required for full assessment. To this end, please login to Editorial Manager where you will find the paper in the 'Submissions Needing Revisions' folder on your homepage. Please click 'Revise Submission' from the Action Links and complete all additional questions in the submission questionnaire.

Please re-submit your manuscript within two working days, i.e. by March 4, 2021.

Login to Editorial Manager here: https://www.editorialmanager.com/pmedicine

Once your full submission is complete, your paper will undergo a series of checks in preparation for peer review. Once your manuscript has passed all checks it will be sent out for review.

Feel free to email us at plosmedicine@plos.org if you have any queries relating to your submission.

Kind regards,

Beryne Odeny

Associate Editor

PLOS Medicine

Dear Dr. Rasmussen,

Thank you very much for submitting your manuscript "Unlocking human capital: revealing relationships between early childhood experiences and adolescent and young adult health status in a resource-limited population" (PMEDICINE-D-21-00948R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and 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.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the 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. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

We expect to receive your revised manuscript by May 31 2021 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,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

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

Requests from the editors:

Thank you for your submission. Before we proceed, please address the following editorial and reviewer comments.

1) Please revise your title according to PLOS Medicine's style. Your title must be nondeclarative and not a question. It should begin with main concept if possible. Please place the study design (e.g. "A prospective cohort study,") in the subtitle (i.e., after a colon).

2) Abstract summary - At this stage, we ask that you reformat your non-technical Author Summary. 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. The summary should be accessible to a wide audience that includes both scientists and non-scientists. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary.

3) In the abstract Methods and Findings:

a) Please ensure that all numbers presented in the abstract are present and identical to numbers presented in the main manuscript text.

b) Please quantify the main results with both 95% CIs and p values.

c) Please include the important dependent variables that are adjusted for in the analyses.

d) In the last sentence of the Abstract Methods and Findings section, please describe the main limitation(s) of the study's methodology.

4) Did your study have a prospective protocol or analysis plan? Please state this (either way) early in the Methods section.

a) If a prospective analysis plan (from your funding proposal, IRB or other ethics committee submission, study protocol, or other planning document written before analyzing the data) was used in designing the study, please include the relevant prospectively written document with your revised manuscript as a Supporting Information file to be published alongside your study, and cite it in the Methods section. A legend for this file should be included at the end of your manuscript.

b) If no such document exists, please make sure that the Methods section transparently describes when analyses were planned, and when/why any data-driven changes to analyses took place.

c) In either case, changes in the analysis-- including those made in response to peer review comments-- should be identified as such in the Methods section of the paper, with rationale.

5) Please add the following statement, or similar, to the Methods: "This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist)."

6) Please include the completed STROBE checklist as Supporting Information. When completing the checklist, please use section and paragraph numbers, rather than page numbers.

7) In the methods, please describe how the adolescent questionnaire was developed and verified. Please provide.

8) If you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information, or include a citation if it has been published previously.

9) In statistical methods, please refer to any post-hoc corrections to correct for multiple comparisons during your statistical analyses. If these were not performed please justify the reasons. Please refer to our statistical reporting guidelines for assistance (https://journals.plos.org/plosone/s/submission-guidelines.#loc-statistical-reporting)

10) In statistical methods, please discuss how you accounted for clustering of repeated measurements in this cohort.

11) Your study is observational and therefore causality cannot be inferred. Please remove language that implies causality, such as “greater influence on”, “have greatly increased”, or “investments in education have unlocked...” Refer to associations instead. Please temper the last sentence of your conclusion to avoid overreaching what can be concluded from the data. For example, refer to phrases such as “education has the potential to unlock…” and so forth.

12) In the Methods and Results section:

a) Please provide 95% CIs and p values for estimates in the main text and tables

b) When a p value is given, please specify the statistical test used to determine it.

13) Figures and tables:

a) Please indicate in the figure caption the meaning of the whiskers in Fig 4

b) Please define the following abbreviations in your tables. For example, IQR, SRCH, HAZ, BP, BMI

14) The terms gender and sex are not interchangeable (as discussed in http://www.who.int/gender/whatisgender/en/ ); please use the appropriate term.

15) Please use the "Vancouver" style for reference formatting and see our website for other reference guidelines https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references.

Comments from the reviewers:

Reviewer #1: See attachment

Michael Dewey

Reviewer #2: Rasmussen and colleagues use longitudinal data show that investments in education of females is associated with adult human capital in a Pakistani village decades later. Research of merit and has broad implications. A few points.

1.Secular trends - How was this addressed in this work. Many populations improve in health/well being over time(in fact from S1, your cohort got healthier between childhood and adolescence). I am curious of how was these shifts were addressed in your analyses and how if might impact your overall findings.

2.The role of undernutrition in early life it seems to me is under-emphasized by authors. We know growth, brain development and other systems can all impact outcomes later in life -- all need proper nutrition. Similar work in Guatemalan birth cohort, and other LMICs showed that nutritional investments in females had impact on adult human capital and intergenerational benefits, with regards to offspring birth size. Underweight children have been found to be associated with failing a school grade in early life. It would be good if these points are discussed in this work to improve its contributory value.

3. Measurements - What was done to ensure reliability of clinical measurements(WT, HT, BP, WC etc) ?

4. Raven score tests were not given to adolescents who had a phone interview. What proportion of the of your sample were these? How different were completers vs those who weren't interviewed?

Reviewer #3: The study tries to examine the role of early childhood experiences on health, cognition, and education outcomes of adolescents/young adults in Gilgit Baltistan, Pakistan. Childhood data collected was compared with data collected in adulthood to examine the relationship.

Strong introduction and methods sections. As the authors also highlight in line 64/65 that female empowerment and mental health variables were not available, yet the result section provides interesting insights.

If available, reference number 5 needs to be updated to a recent study/report.

Reference numbers for the ethics approval need to be reported in ethics approval section.

Although authors discuss bias in lines 423-424, some discussion on recall bias needs to be reported as a limitation for SRPH.

The manuscript has the potential to add to literature on examining the relationship of early and childhood health on adolescent/young adult health outcomes/status.

Reviewer #4: This well-structured manuscript describes an important study which investigated the non-verbal cognitive outcomes of a group of adolescents and young adults followed up following an early life cohort study of under-5 mortality and morbidity in Pakistan. This study leverages the value created by a large initial cohort study from the 1990's and spans of period of rapid socio-economic mobility due to increased accessibility of one of the poorest regions in Pakistan. While the high level results reported here of higher SES (in particular, maternal education), predicting better cognitive outcomes are not highly novel, they are nevertheless important given the region on which the study reports, the authors do include discussion on the context specific elements at a more granular level which are highly relevant and important in thinking about potential of such findings to inform policy.

The inclusion of measures of physical health (growth metrics, BMI, hypertension) as signals of potential risk for future NCD's is an additional strength. The methods and analysis approach is well described including specific reasons for children lost to follow up.

As noted in the abstract, measures on maternal mental health does seem like an important limitation and the potential role that this may have played deserves some discussion in the limitations section. Further discussion on the critical role this period of life represents in terms of being the crucible for intergenerational risk and resilience would add value.

No major revisions needed from my perspective, though suggest a formal statistical review and publication of analysis plan if possible

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

[LINK]

Attachments

Attachment

Submitted filename: rasmussen.pdf

Dear Dr. Rasmussen,

Thank you very much for re-submitting your manuscript "Examining the relationships between early childhood experiences and adolescent and young adult health status in a resource-limited population:  A prospective cohort study" (PMEDICINE-D-21-00948R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by three 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.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. 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. 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.

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

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.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

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 Jul 15 2021 11:59PM.   

Sincerely,

Beryne Odeny,

Associate Editor 

PLOS Medicine

plosmedicine.org

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

Requests from Editors:

1) Please remove the term “prospective” from the title as it is not clear that the research was prospectively planned, and there was no prespecified analysis plan.

2) Adolescent participants provided “written informed consent” - would assent and parental consent not be more usual? Either way, please clarify under which circumstances they offered assent or consent (e.g., married, or emancipated minors consented, while assent and/or parental consent was sought for younger adolescents?)

3) For references #3 & #10, please provide access dates for the referenced weblinks. Please ensure that all weblinks are accessible and access dates updated.

Comments from Reviewers:

Reviewer #1: The authors have addressed all my points.

Michael Dewey

Reviewer #2: No further comments

Reviewer #4: my comments have been adequately addressed by the authors

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

[LINK]

Dear Dr Rasmussen, 

On behalf of my colleagues and the Academic Editor, Dr. Kathryn Mary Yount, I am pleased to inform you that we have agreed to publish your manuscript "Examining the relationships between early childhood experiences and adolescent and young adult health status in a resource-limited population:  A cohort study" (PMEDICINE-D-21-00948R3) 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.

In the meantime, please log into Editorial Manager at http://www.editorialmanager.com/pmedicine/, click the "Update My Information" link at the top of the page, and update your user information to ensure an efficient production process. 

PRESS

We frequently collaborate with press offices. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximise its impact. If the press office is planning to promote your findings, we would be grateful if they could coordinate with medicinepress@plos.org. If you have not yet opted out of the early version process, we ask that you notify us immediately of any press plans so that we may do so on your behalf.

We also ask that you take this opportunity to read our Embargo Policy regarding the discussion, promotion and media coverage of work that is yet to be published by PLOS. As your manuscript is not yet published, it is bound by the conditions of our Embargo Policy. Please be aware that this policy is in place both to ensure that any press coverage of your article is fully substantiated and to provide a direct link between such coverage and the published work. For full details of our Embargo Policy, please visit http://www.plos.org/about/media-inquiries/embargo-policy/.

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, 

Beryne Odeny 

Associate Editor 

PLOS Medicine