Cohort Profile: Health Effects Monitoring Programme in Ndilǫ

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from

PEER REVIEW HISTORY

BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS

TITLE (PROVISIONAL) Cohort Profile: Health Effects Monitoring Program in Ndilǫ, Dettah, and Yellowknife (YKHEMP) AUTHORS Chan, Laurie; Hu, Xue Feng; Cheung, Janet; Parajuli, R. P.; Rosol, Renata; Yumvihoze, Emmanuel; Williams, Linna; Mohapatra, Asish

VERSION 1 – REVIEW

REVIEWER Catherine Bulka University of North Carolina REVIEW RETURNED 25-Mar-2020

GENERAL COMMENTS This manuscript profiles a very unique cohort of Canadians exposed to arsenic and other contaminants as a result of living near Giant Mine. The cohort is moderately sized (n=2,037) and includes both children and adults. Participants completed questionnaires and provided biospecimens (urine, saliva, and toenail clippings) for various testing. Participants will be followed- up in the future – within 2 years for children and within 7 years for adults – and have consented for their past medical records to be

reviewed. I enjoyed reading this manuscript, and think it should be http://bmjopen.bmj.com/ accepted for publication. It is clear that the investigators designed this study in a most comprehensive manner. I do, however, have a few minor comments.

Introduction The Introduction provides a very nice comprehensive overview of the history Giant Mine and its legacy within the City of Yellowknife. With regard to the project objectives of the YKHEMP cohort, I am wondering if the investigators may want to be a little more specific on September 27, 2021 by guest. Protected copyright. in terms of which health outcomes are of particular interest. For instance, what health parameters are being measured using the biospecimens collected at baseline? What diseases can the questionnaire data be used to ascertain? If the investigators wish to examine how contaminant exposures influence disease risk, they will be limited to the diseases for which they have collected data.

Cohort Profile There appear to be some differences between randomly-selected and voluntary participants. Notably, volunteers were more likely to have worked at Giant Mine. There also appear to be demographic and lifestyle (including dietary) dietary differences between the participant groups. Will these groups be pooled together for analyses, or treated separately in some way?

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Page 10, Line 10: how will participants be contacted (mail, telephone)? If investigators have lost contact with participants, will efforts be made to trace them? How much attrition is expected? Please explain the random selection of additional participants to make up for participant attrition…Since these new participants will not have baseline measurements collected, it is unclear to me how useful their recruitment will be…

Page 11, Line 10: Medical histories were used to ascertain disease status for chronic conditions that have been associated with contaminant exposure (e.g., hypertension). However, these diseases mostly affect adults. Were any child-specific conditions evaluated for children participants?

Page 12, Line 6: Please specify all chemicals analyses performed and the laboratory assays used…I am assuming ICP-MS but the investigators should specify. There should also be some mention of limits of detection and how non-detects were treated.

Table 2 is very nice and I appreciate how the authors summarized this information. Could they also provide which medical conditions were identified from the free text in the medical records?

Findings to Date I appreciate how the efforts to more intensively follow-up participants with elevated contaminant levels. The investigators obviously gave much thought to the design of this study.

Minor Comments and Questions There are many non-standard acronyms throughout the manuscript. I wonder if the authors might be able to provide a table listing these for readers to reference.

I am wondering more about the children enrolled in the study. http://bmjopen.bmj.com/ Some of the children in this study were as young as 3 years old…Were their medical records linked to their mothers? Did their parents complete the questionnaires on their behalf? Were there any unique challenges to collecting biospecimens from children this young? I think the answers to these questions would be of interest to the scientific community.

REVIEWER Nathalie Saint-Jacques on September 27, 2021 by guest. Protected copyright. Nova Scotia Health Authority Cancer Care Program; Dalhousie University, Department of Medicine Canada REVIEW RETURNED 08-Apr-2020

GENERAL COMMENTS General comment

This manuscript provides a description of a study program, the Health Effects Monitoring Program in Ndliq, Dettah, and Yellowknife (YKHEMP) established to examine the relationship of exposure to arsenic and other chemicals of potential concern (COPCs) such as antimony, cadmium, lead, manganese, and vanadium and health outcomes. The creation of such program is a very important step towards measuring the impact of environmental contaminations

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from upon the health of communities living in proximity to the Giant Mine, one of the most contaminated sites in Canada.

However, this manuscript is not ready for publication. Overall, the manuscript lacks structure and clarity. The health outcomes have not been clearly defined and there has been no attempt to interpret any of the preliminary findings and relate these to the existing body of literature. In addition, much of the dialogue is focused on arsenic with no attempt to explain to the reader what could be the potential health effects resulting from exposure to other COPCs of interest. The authors have made no references to latency between exposure and disease development – and what are those diseases of interest? This is not clear. Will there be sufficient statistical power? Are the methodologies used to collect biological samples for the YKHEMP and CHMS comparable? And what are CHMS? Is the population sampled in CHMS a good comparative to YKHEMP? There are many unanswered questions. Has this research received Ethics Approval?

Most references listed in the Reference section have not been referred to in the main body of the manuscript.

I invite the authors to look at previous ‘Cohort profile” manuscripts published by BMJ Open and use these as a starting point to layout the structure of the paper. I also recommend reading the following manuscript: https://academic.oup.com/ije/article/46/6/1762/4093155.

Please find below a list of minor, major and discretionary revisions http://bmjopen.bmj.com/ which could be used to strengthen this publication.

Minor Revisions

1. Abstract word count exceeds the 300 word requirement, please review. on September 27, 2021 by guest. Protected copyright. 2. Page 3 Line 17: Please replace ‘2037’ by ‘2036’ (based on Table 1). 3. Page 3 Lines 22-29: The number of participants listed do not match numbers appearing in Table 1. For example, the authors state “In Yellowknife, there were 890 (673 adults, 217 children), …” According to Table 1, it should state: “In Yellowknife, there were 891 (675 adults, 216 children), …”. 4. Page 3 Lines 43-45: “Findings to date: This cohort profile report presents the descriptive statistics of the COPC concentrations in urine and toenail samples.” Please replace with Key findings of the study (i.e. provide numbers etc.). 5. Page 3 Lines 46-46: “Concentrations in the urine were compared to the population data based on the Canadian Health Measures Survey.” Please remove – this is not a “Finding to date – i.e. results, this is methodology. 6. Page 3 Lines 253-55: “ Investigators interested in learning more about how to obtain YKHEMP data can contact

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[email protected].” . Does not belong to abstract, please remove. 7. Sections “Future plans” and “Strengths and limitations” should be removed from abstract. The abstract should include a section reporting on ‘Results’ and ‘Conclusion’. I invite the authors to look at the general structure of abstracts published in BMJ Open and use this as template. 8. Page 5 Lines 3-22: Please move ‘Strengths and limitations to ‘Discussion’. 9. Page 6 Lines 14-18: “As a result, there are currently 237,000 tonnes of arsenic trioxide dust present at the site, contained in 15 underground chambers, and 4 large tailings ponds.” Please provide reference. 10. Page 6 Line 18 : “…is within approved limits” . Please detail what are those limits. 11. Page 6 Lines 23-25: “ … an estimated 20,000 tonnes of arsenic trioxide dust was released into the environment every year”. Would you please review this information, the cited reference appears to state “20,000 tonnes per day. 12. Page 6 Lines 41-43: “Investigate any associations between COPC concentrations, particularly arsenic, within the population and observed or reported health outcomes within that same population.” How about” : Measure associations between COPC concentrations and observed/reported health outcomes in YKHEMP participants”? Based on your ‘Finding to date” section. You also want to “Compare body-burden COPC concentrations in YKHEMP participants to those reported in CHMS” ?? 13. Page 6 Lines 46-48: “b) Explore results sharing with other related studies to understand sources of contaminant exposure and their relationships with health outcomes.”

Please clarify?? http://bmjopen.bmj.com/ 14. Page 8 Lines 18-20: “The two-wave approach was designed to account for any potential seasonal effect on exposure.” I would clarify this. I think you are referring to “levels of COPC in biological samples” rather than ‘exposure’. 15. Page 8 Line 31: “A sample of dwellings was selected from the list”. How was this done? (i.e. criteria for dwelling selection).

16. Page 8 Lines 38-40: “Population aged 6 and above were on September 27, 2021 by guest. Protected copyright. invited to participate during wave 1, and the population aged 3 and above were included in wave 2. “ Current data shown in tables show age 3, please change to age 6. Also, I suggest keeping consistent terminology throughout the manuscript. Please use either ‘wave’ or ‘phase’. 17. Page 89 Lines 9-11: Please review number of participants to match count appearing in Table 1. 18. TABLE 1 title: I suggest replacing ‘Demographic and socioeconomic characteristics’ with ‘Sociodemographic characteristics’. Also please refer to the following paper for example on how to structure your table: https://academic.oup.com/ije/article/46/6/1762/4093155. 19. Page 12 Lines 3-5: “The retrospective phase of YKHEMP collected the medical history of all participants for the past 5”. Please explain why ‘5 years’ - how can this be possible in those aged less than 5 years? And why Table 2 only reports

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on ‘Medical questionnaire for YKDFN’ if ALL participants were given the questionnaire? 20. Page 12 Lines 17-19: “were extracted through keyword searching in the participants’ medical records from the Wolf EMR electronic medical record system, Northwest Territories Health Authority.” Would you please clarify when this system was implemented and whether it allows searches to go back 5 years? 21. Page 12 Line 22: “All participants who provided consent were invited to complete a Lifestyle Questionnaire”. Please indicate the percentage of participants providing consent? Were there variations by participant groups? 22. Page 12 Line 26-28: “Participants were also asked to complete a short Food Frequency Questionnaire (FFQ) on the types and amounts of fish consumed.” Why fish? Please explain. Also as there has been much information published on the association between shellfish consumption and arsenic body burden, would you please explain why the questionnaire was restricted to fish? 23. Page 12 Line 49: “Participants were instructed to abstain from eating seafood 3 days before …” Based on this statement information regarding seafood consumption was collected. Please include this information in Table 2. 24. Page 12 Line 45: “Urine, toenail, and saliva samples were collected, and COPCs were analyzed for participants”. Please provide a brief justification as to why you have chosen these types of biological markers etc.. what are the evidences of their performances based on literature? 25. Page 15 Line 5-10: “We are at the very early stage of analyzing the YKHEMP baseline data. Here, the descriptive statistics of the concentrations of COPCs measured in urine and toenail samples of participants are presented.” Remove. 26. Page 15 Line 10-14: “Currently, the key question addressed http://bmjopen.bmj.com/ was whether the residents of Ndilǫ, Dettah, and Yellowknife had elevated exposure to arsenic and selected COPCs in relation to the genera Canadian population.” This does not belong to the results section. Please move to end of introduction. 27. Page 15 Lines 28-33: “Urinary inorganic arsenic concentration was calculated as the total concentration of

arsenite As(III), arsenate As(V), monomethylarsonic acid on September 27, 2021 by guest. Protected copyright. (MMA), adimethylarsinic acid (DMA).” Somewhere in the text, it should be explained why this is important. What are knowns effects of these various arsenic species/forms on human health? 28. Page 15 Line 40: Please define “CHMS.” 29. Page 15 Lines 14-54 and Page 16 Lines 7-15. All this information belongs to the Methodological section, not findings/results – please move in appropriate section. 30. Page 16 Lines 17: This is where your ‘Findings/Result section begins. 31. Table 3: Somewhere in the methodology section you should explain clearly that you are going to compare the data collected in YKHEMP groups to those reported by CHMS surveys. In doing so I would also suggest to highlight how the methodologies, survey questionnaires etc.. compare. Also the statement “The differences between adults and children for the four participation groups in YKHEMP were also tested”

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appearing at bottom of table should be presented as a footnote. Right now it is not connected to anything. Also, why not presenting those results as well? 32. Table 4: Footnotes should have distinct superscripts to avoid confusion. Also, why do you use ‘n’ for the YHKEMP random sample and ‘N” for the CHMS to indicate the number of participants falling in each age strata? Consider reviewing title. 33. Table 4: footnote is running into main text, please fix. 34. Page 20 Line 3: “There was a total of 225 participants whose…” Please indicates what proportion this represents overall. 35. Page 20 Line 3-20: This is a process which should be detailed in the Methodology section. 36. Page 20 Line 22: Good place to start a discussion. 37. Page 20 Lines 42-47: Again, this information does not belong to a discussion. Also, please list explain what you mean by ‘major health outcomes’. 38. Page 21 Lines 26-31: “By comparing the arsenic exposure levels in the randomly selected sample and the volunteers, we will be able to see if any individual or group with high exposure might be ignored by systematic sampling. “ In addition, it will help identifying possible participation bias. … 39. Page 21 Lines 36-40: Please note that biological samples offers a window on exposure whereas, medical records offers a window on ’ health outcomes’ – there are not complementary. They are collected for different reasons. 40. Page 21 Lines 52-54: “ … in cases when participants had elevated levels of urinary lead, they were asked to have their blood lead concentrations measured to confirm the lead exposure”. Again, this is important information belonging to the Methodology section, not the Discussion.

http://bmjopen.bmj.com/ Major Revisions

1. Page 3 Line 38-40:“…have their medical records reviewed by the research team for the past 5 years to allow for the investigation between exposure and health outcomes …”. Please explain how this timeline was determined?

2. Page 6 Lines 42-44: "Arsenic exposure is of particular on September 27, 2021 by guest. Protected copyright. concern because of its known toxic effects including increased risk of skin cancer and other health conditions.[4–9]”. Please also speak to the effects of other COPCs on human health and provide references. 3. Page 12 Lines 10-12: “The medical history included diagnosed diseases, e.g., hypertension, diabetes, cancer and common clinical symptoms associated with contaminant exposure.” A succinct list of health outcomes, including clinical symptoms, should be provided. The selection of these health outcomes should be evidenced- based. As the purpose of this program is to examine the relationships between exposure to COPCs and health outcomes, these health outcomes should be clearly defined ‘a priori’ and largely selected based on evidences from the literature. In addition, as comparisons will be made against data from CHMS, it would be important for the reader to know what CHMS has been collected.

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4. Table 2: Information collected in Table 2 should be tabulated by participant groups and included in this manuscript. If not compiles, I suggest waiting for this information to be tabulated prior to re-submitting for publication. 5. Discussion should start around Page 20 Line 22. It should expand on the importance of geological formation and diet as predictors of arsenic body burden. It should also compare how current findings compare to what has been published to date. Find a comparative study … For example, you state : “The relationships between the diet and lifestyle variables, the genetic information, and the concentrations of metals in urine and the arsenic concentrations in the toenail will also be conducted”. This in itself is a statement speaking to specific study objectives. In the discussion, you need to explain how diet, lifestyle variables and genetic information are expected to influence the concentrations of metals in urine, toenail etc.. which in turn will influence health. 6. Page 20 Lines 52-54: “Project progresses, which may also apply to remediation processes at 7. other mining sites worldwide.” This is an important point. Please capitalize on this idea. In Canada alone, how many communities have been impacted (and continue to be) impacted by contaminations due to gold mining activities ? Nova Scotia is certainly a good place to start. Much work has been published to that effect – contamination of drinking well water by arsenic related to geological formation and mining activities etc.. 8. Page 21 Lines 3-5: “Indigenous people (YKDFN and NSMA) who were more vulnerable to environmental contamination …” Another important point to develop … how do you connect this assumption to the results

presented? http://bmjopen.bmj.com/ 9. Page 22 Lines 17-53: This section describe what is referred to as “Integrated Knowledge Translation Approach”. I suggest this information to be included in the Methodology. 10. The overall structure of the manuscript should be revised and the use of subheadings is recommended. Below are my suggestions but these are simple general guidelines to ensure that methods are no longer mixed with results etc. on September 27, 2021 by guest. Protected copyright. ABSTRACT Background Methods and Analyses Preliminary results Conclusion

MAIN DOCUMENT Background - Description of the problem - Description of the program - Objectives o Overall o Specific t Methods and Analyses - Cohort description - Study design

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- Baseline survey component o Lifestyle questionnaire o Food frequency questionnaire o Physical examination and medical questionnaire o Biological samples (i.e. urine, toenails etc.) o Genotyping o Medical records - Data analyses

Preliminary results Discussion Strengths and limitations Conclusion and future work

Discretionary Revisions

1. Page 15 Line 3: Consider replacing “Findings to date’ WITH ‘Preliminary results” 2. Tables 3-5: Consider presenting the following information as a footnote at the bottom of tables: “Values presented in the parentheses are the 95% confidence interval. *Significantly different from CHMS.”

VERSION 1 – AUTHOR RESPONSE

Reviewer(s)' Comments to Author: http://bmjopen.bmj.com/ Reviewer: 1

This manuscript profiles a very unique cohort of Canadians exposed to arsenic and other contaminants as a result of living near Giant Mine. The cohort is moderately sized (n=2,037) and includes both children and adults. Participants completed questionnaires and provided biospecimens (urine, saliva, and toenail clippings) for various testing. Participants will be followed-up in the future – within 2 years for children and within 7 years for adults – and have consented for their past medical on September 27, 2021 by guest. Protected copyright. records to be reviewed. I enjoyed reading this manuscript, and think it should be accepted for publication. It is clear that the investigators designed this study in a most comprehensive manner. I do, however, have a few minor comments.

Introduction The Introduction provides a very nice comprehensive overview of the history Giant Mine and its legacy within the City of Yellowknife. With regard to the project objectives of the YKHEMP cohort, I am wondering if the investigators may want to be a little more specific in terms of which health outcomes are of particular interest. For instance, what health parameters are being measured using the biospecimens collected at baseline? What diseases can the questionnaire data be used to ascertain? If the investigators wish to examine how contaminant exposures influence disease risk, they will be limited to the diseases for which they have collected data.

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We have now provided more details in the description of health outcomes measured. The information on the health outcomes of the participants were collected only from the medical history questionnaire or the electronic health records search. The list was developed primarily based on ATSDR (2007) and the reference is now added. We have included the medical history questionnaire and the list of medical code including search words in the Supplementary Material. For children, we have measured CC16 and KIM-1 in urine as two candidate biomarkers of effect for arsenic. CC16, a secretory protein in the lung, and KIM-1, a molecule upregulated in the kidneys. The rationale and methods are now described with added references. We have also summarized the diseases and symptoms that were included in the medical history questionnaire and medical record search in Table 2.

Yes. The volunteers may likely participate because of their perceived higher risk such as having worked at the mine or consuming more local harvest. We have treated the two groups separately and presented all the results separately as well. Data of the two groups will be pooled together if bigger sample size is needed for certain future analyses, and only when no difference was found in the exposure or the association between exposure and health outcomes. We will report and discuss if any differences were identified.

Participants will be contacted by email and mail. About 1,100 participants provided an email address, http://bmjopen.bmj.com/ they will be sent an invitation letter by email. For the others who did not provide an email address, we will send a letter to the address we have for them on file. We will make extra effort to contact them by advertisements on the local radio and on social media about the study restarting. We expect some of them may reach out to us after hearing about the study looking to sample past participants. Yellowknife is a fairly transient city, and we expect that a number of these individuals may no longer reside at the address provided. Therefore, we expect an attrition rate for the Yellowknife general population to be 20% for children and 40% for adults. The attrition rate of the YKDFN will be lower at on September 27, 2021 by guest. Protected copyright. 10% and 20% respectively.

A random selection will be done to make up for attrition of participants over this 5 year period. This new sample will be designed with the updated demographic information for the Yellowknife population and the updated sample requirements for the project. In the 2022-2023 questionnaire, a question will be asked to decide if the child was part of the population of 2017-2018, i.e. was the child between 3 to 17 years old in 2017-2018 and had the child been living in Yellowknife for one year prior to 2017- 2018. If yes, we will be able to retrieve their medical records. Also, some of them might have participated in our baseline survey as volunteers.

We agree that the additional randomly selected participants will not help to decrease the attrition bias. However, we want to make sure the next sampling frame will include enough sample to represent the Yellowknife population and enough statistical power to detect any difference in arsenic and other chemical body burdens between Yellowknife population and the national biomonitoring survey- CHMS.

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We mainly focus on health conditions associated with chronic arsenic exposure among adults. We have added the details of measuring two urinary biomarkers for lung and kidney functions for children specifically.

Revised as suggested.

Table 2 is very nice and I appreciate how the authors summarized this information. Could they also provide which medical conditions were identified from the free text in the medical records?

Revised as suggested. We have added the description with a reference and also included the medical history questionnaire and key words for medical file search in the Supplementary Materials.

Findings to Date I appreciate how the efforts to more intensively follow-up participants with elevated contaminant levels. The investigators obviously gave much thought to the design of this study.

Thank you.

Minor Comments and Questions There are many non-standard acronyms throughout the manuscript. I wonder if the authors might be http://bmjopen.bmj.com/ able to provide a table listing these for readers to reference.

List of abbreviations added.

I am wondering more about the children enrolled in the study. Some of the children in this study were as young as 3 years old…Were their medical records linked to their mothers? Did their parents

complete the questionnaires on their behalf? Were there any unique challenges to collecting on September 27, 2021 by guest. Protected copyright. biospecimens from children this young? I think the answers to these questions would be of interest to the scientific community.

Medical records start at birth but not linked to mothers. Parents completed the questionnaires on their child’s behalf for any children from 3-12 years of age. However starting from age 13, the youth was able to answer the questionnaire for themselves. It was indeed challenging to collect urine for some children to pee into a cup. We used Toilet Hats for children. All this new information is now added in the revised manuscript.

Reviewer: 2

General comment

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Most references listed in the Reference section have not been referred to in the main body of the manuscript. I invite the authors to look at previous ‘Cohort profile” manuscripts published by BMJ Open and use these as a starting point to layout the structure of the paper. I also recommend reading the following manuscript: https://academic.oup.com/ije/article/46/6/1762/4093155. Please find below a list of minor, major and discretionary revisions which could be used to strengthen this publication.

Minor Revisions

1. Abstract word count exceeds the 300 word requirement, please review.

Revised

2. Page 3 Line 17: Please replace ‘2037’ by ‘2036’ (based on Table 1).

The total sample size is 2037. The participant number by sex add up to 2036 due to one participants self-identified as “other”. We put a note to table 1. http://bmjopen.bmj.com/

3. Page 3 Lines 22-29: The number of participants listed do not match numbers appearing in Table 1. For example, the authors state “In Yellowknife, there were 890 (673 adults, 217 children), …” According to Table 1, it should state: “In Yellowknife, there were 891 (675 adults, 216 children),…”.

Revised

4. Page 3 Lines 43-45: “Findings to date: This cohort profile report presents the descriptive statistics on September 27, 2021 by guest. Protected copyright. of the COPC concentrations in urine and toenail samples.” Please replace with Key findings of the study (i.e. provide numbers etc.).

Revised

5. Page 3 Lines 46-46: “Concentrations in the urine were compared to the population data based on the Canadian Health Measures Survey.” Please remove – this is not a “Finding to date – i.e. results, this is methodology.

Removed as suggested.

6. Page 3 Lines 253-55: “ Investigators interested in learning more about how to obtain YKHEMP data can contact [email protected].” . Does not belong to abstract, please remove.

Removed as suggested.

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7. Sections “Future plans” and “Strengths and limitations” should be removed from abstract. The abstract should include a section reporting on ‘Results’ and ‘Conclusion’. I invite the authors to look at the general structure of abstracts published in BMJ Open and use this as template.

We have followed the BMJ Open template for “Cohort profile”. “Cohort profile” has a slightly different abstract structure as the other regular research papers. “Future plans” is a required section. “Findings to date” is equivalent to “Results” and typically no “Conclusion” section since the data are yet to be analysed and interpreted.

8. Page 5 Lines 3-22: Please move ‘Strengths and limitations to ‘Discussion’.

“Strength and limitations” is required by BMJ Open Cohort Profile as bullet points following the Abstract. We have elaborated each point in the discussion section as well.

9. Page 6 Lines 14-18: “As a result, there are currently 237,000 tonnes of arsenic trioxide dust present at the site, contained in 15 underground chambers, and 4 large tailings ponds.” Please provide reference.

Reference provided.

10. Page 6 Line 18 : “…is within approved limits” . Please detail what are those limits.

We removed this sentence to avoid confusion.

11. Page 6 Lines 23-25: “ … an estimated 20,000 tonnes of arsenic trioxide dust was released into the environment every year”. Would you please review this information, the cited reference appears to state “20,000 tonnes per day.

Thanks for pointing it out. We revisited the original reference and revised accordingly.

12. Page 6 Lines 41-43: “Investigate any associations between COPC concentrations, particularly arsenic, within the population and observed or reported health outcomes within that same population.” How about” : Measure associations between COPC concentrations and observed/reported health outcomes in YKHEMP participants”? Based on your ‘Finding to date” section. You also want to “Compare body-burden COPC concentrations in YKHEMP participants to http://bmjopen.bmj.com/ those reported in CHMS” ??

Revised as suggested.

13. Page 6 Lines 46-48: “b) Explore results sharing with other related studies to understand sources of contaminant exposure and their relationships with health outcomes.” Please clarify??

Revised. on September 27, 2021 by guest. Protected copyright.

14. Page 8 Lines 18-20: “The two-wave approach was designed to account for any potential seasonal effect on exposure.” I would clarify this. I think you are referring to “levels of COPC in biological samples” rather than ‘exposure’.

We have clarified as suggested. The two-wave approach was designed to account for any potential seasonal effect on levels of COPC in biological samples and risk factors for exposure such as water recreation activities, fishing, children playing outdoor with bare foot.

15. Page 8 Line 31: “A sample of dwellings was selected from the list”. How was this done? (i.e. criteria for dwelling selection).

Details of sampling method is now provided in the revised manuscript.

16. Page 8 Lines 38-40: “Population aged 6 and above were invited to participate during wave 1, and the population aged 3 and above were included in wave 2. “ Current data shown in tables show age 3,

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from please change to age 6. Also, I suggest keeping consistent terminology throughout the manuscript. Please use either ‘wave’ or ‘phase’.

Thanks for your suggestion. • We used wave 1 and wave 2 to refer to the participant recruitment period during baseline survey, September 2017 to December 2017 (wave 1) and April 2018 to June 2018 (wave 2). • We used phase 1 to refer to the baseline survey described in the manuscript, phase 2 to refer to first follow-up of children in 2022, and phase 3 to refer to follow-up of adult and children in 2027.

17. Page 89 Lines 9-11: Please review number of participants to match count appearing in Table 1.

Double-checked and revised.

18. TABLE 1 title: I suggest replacing ‘Demographic and socioeconomic characteristics’ with ‘Sociodemographic characteristics’. Also please refer to the following paper for example on how to structure your table: https://academic.oup.com/ije/article/46/6/1762/4093155.

Revised as suggested.

19. Page 12 Lines 3-5: “The retrospective phase of YKHEMP collected the medical history of all participants for the past 5”. Please explain why ‘5 years’ - how can this be possible in those aged less than 5 years? And why Table 2 only reports on ‘Medical questionnaire for YKDFN’ if ALL participants were given the questionnaire?

• The electronic medical record system was launched in 2014 and that is why we were only able to trace back participants’ health record for up to 5 years. The record starts at birth. • All participants were given a lifestyle questionnaire, which does not include medical questionnaire. A detailed medical questionnaire was given the YKDFN only. We rely on the medical records for the YK general populations. We have clarified these in the text.

20. Page 12 Lines 17-19: “were extracted through keyword searching in the participants’ medical records from the Wolf EMR electronic medical record system, Northwest Territories Health Authority.” http://bmjopen.bmj.com/ Would you please clarify when this system was implemented and whether it allows searches to go back 5 years?

Please refer to our response to point 19.

21. Page 12 Line 22: “All participants who provided consent were invited to complete a Lifestyle Questionnaire”. Please indicate the percentage of participants providing consent? Were there variations by participant groups? on September 27, 2021 by guest. Protected copyright. All participants provided consent. We have deleted the redundant “who provided consent” in the sentence.

22. Page 12 Line 26-28: “Participants were also asked to complete a short Food Frequency Questionnaire (FFQ) on the types and amounts of fish consumed.” Why fish? Please explain. Also as there has been much information published on the association between shellfish consumption and arsenic body burden, would you please explain why the questionnaire was restricted to fish?

We did not make it clear that this short FFQ focus on fish harvested from local lakes. Fish from local lakes is a key concern of the local stakeholders as main source of arsenic exposure. In response, we designed this short FFQ.

We are aware that shellfish is reported as contributor of arsenic body burden. We did ask the frequency of market shellfish consumption, as well as market fish consumption.

We have now clarified these points in the text and in Table 2.

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23. Page 12 Line 49: “Participants were instructed to abstain from eating seafood 3 days before …” Based on this statement information regarding seafood consumption was collected. Please include this information in Table 2.

This is an instruction for urine sample collection (to avoid potential short term exceed arsenic exposure) not for the food frequency question.

24. Page 12 Line 45: “Urine, toenail, and saliva samples were collected, and COPCs were analyzed for participants”. Please provide a brief justification as to why you have chosen these types of biological markers etc.. what are the evidences of their performances based on literature?

Reference added as suggested.

25. Page 15 Line 5-10: “We are at the very early stage of analyzing the YKHEMP baseline data. Here, the descriptive statistics of the concentrations of COPCs measured in urine and toenail samples of participants are presented.” Remove.

Removed as suggested.

26. Page 15 Line 10-14: “Currently, the key question addressed was whether the residents of Ndilǫ, Dettah, and Yellowknife had elevated exposure to arsenic and selected COPCs in relation to the genera Canadian population.” This does not belong to the results section. Please move to end of introduction.

Revised as suggested.

27. Page 15 Lines 28-33: “Urinary inorganic arsenic concentration was calculated as the total concentration of arsenite As(III), arsenate As(V), monomethylarsonic acid (MMA), adimethylarsinic acid (DMA).” Somewhere in the text, it should be explained why this is important. What are knowns effects of these various arsenic species/forms on human health?

Revised in the introduction section as suggested.

28. Page 15 Line 40: Please define “CHMS.” http://bmjopen.bmj.com/ CHMS was defined in the introduction section in the revised manuscript.

29. Page 15 Lines 14-54 and Page 16 Lines 7-15. All this information belongs to the Methodological section, not findings/results – please move in appropriate section.

Revised as suggested.

30. Page 16 Lines 17: This is where your ‘Findings/Result section begins. on September 27, 2021 by guest. Protected copyright.

Revised as suggested.

31. Table 3: Somewhere in the methodology section you should explain clearly that you are going to compare the data collected in YKHEMP groups to those reported by CHMS surveys. In doing so I would also suggest to highlight how the methodologies, survey questionnaires etc.. compare. Also the statement “The differences between adults and children for the four participation groups in YKHEMP were also tested” appearing at bottom of table should be presented as a footnote. Right now it is not connected to anything. Also, why not presenting those results as well?

References were added for the laboratory procedures of YKHEMP and CHMS. The statement of adult-children comparison was removed to avoid confusion.

32. Table 4: Footnotes should have distinct superscripts to avoid confusion. Also, why do you use ‘n’for the YHKEMP random sample and ‘N” for the CHMS to indicate the number of participants falling in each age strata? Consider reviewing title.

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from

Revised.

33. Table 4: footnote is running into main text, please fix.

Revised.

34. Page 20 Line 3: “There was a total of 225 participants whose…” Please indicates what proportion this represents overall.

We have deleted this paragraph all together as the results will need to be addressed in a risk assessment context that is beyond the scope of this cohort profile paper.

35. Page 20 Line 3-20: This is a process which should be detailed in the Methodology section.

Revised as suggested.

36. Page 20 Line 22: Good place to start a discussion.

Revised as suggested.

37. Page 20 Lines 42-47: Again, this information does not belong to a discussion. Also, please list explain what you mean by ‘major health outcomes’.

Removed as suggested.

38. Page 21 Lines 26-31: “By comparing the arsenic exposure levels in the randomly selected sample and the volunteers, we will be able to see if any individual or group with high exposure might be ignored by systematic sampling. “ In addition, it will help identifying possible participation bias.…

Revised as suggested.

39. Page 21 Lines 36-40: Please note that biological samples offers a window on exposure whereas, medical records offers a window on ’ health outcomes’ – there are not complementary. They are collected for different reasons. http://bmjopen.bmj.com/

Revised.

40. Page 21 Lines 52-54: “ … in cases when participants had elevated levels of urinary lead, they were asked to have their blood lead concentrations measured to confirm the lead exposure”. Again, this is important information belonging to the Methodology section, not the Discussion.

Major Revisions

Please refer to our response to minor revisions, point 19.

2. Page 6 Lines 42-44: "Arsenic exposure is of particular concern because of its known toxic effects including increased risk of skin cancer and other health conditions.[4–9]”. Please also speak to the effects of other COPCs on human health and provide references.

Reference added.

3. Page 12 Lines 10-12: “The medical history included diagnosed diseases, e.g., hypertension, diabetes, cancer and common clinical symptoms associated with contaminant exposure.” A

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from succinct list of health outcomes, including clinical symptoms, should be provided. The selection of these health outcomes should be evidenced-based. As the purpose of this program is to examine the relationships between exposure to COPCs and health outcomes, these health outcomes should be clearly defined ‘a priori’ and largely selected based on evidences from the literature. In addition, as comparisons will be made against data from CHMS, it would be important for the reader to know what CHMS has been collected.

A detailed list of diseases and conditions is now included in the Supplementary materials. We are comparing the urine chemical concentrations between YKHEMP and CHMS. We do not plan to compare the associations between urine chemical concentrations and health outcomes between our study and the CHMS as the two studies have different objectives and design. Different parameters are collected for the two studies and it will not be feasible to control for the same confounding factors. Our design to compare the associations between the different studied populations of this study. We also plan to compare the prevalence of the diseases to the Canadian general populations using data collected from the Canadian Chronic Disease Surveillance System (CCDSS).

Revised as suggested.

5. Discussion should start around Page 20 Line 22. It should expand on the importance of geological formation and diet as predictors of arsenic body burden. It should also compare how current findings compare to what has been published to date. Find a comparative study … For example, you state : “The relationships between the diet and lifestyle variables, the genetic information, and the concentrations of metals in urine and the arsenic concentrations in the toenail will also be conducted”. This in itself is a statement speaking to specific study objectives. In the discussion, you need to explain how diet, lifestyle variables and genetic information are expected to influence the concentrations of metals in urine, toenail etc.. which in turn will influence health.

Thanks for your suggestions. We removed these few statement as they are beyond the scope of this cohort profile paper. We will present those findings in subsequent manuscripts in the context of risk assessment. http://bmjopen.bmj.com/

6. Page 20 Lines 52-54: “Project progresses, which may also apply to remediation processes at . other mining sites worldwide.” This is an important point. Please capitalize on this idea. In Canada alone, how many communities have been impacted (and continue to be) impacted by contaminations due to gold mining activities ? Nova Scotia is certainly a good place to start. Much work has been published to that effect – contamination of drinking well water by arsenic related to geological formation and mining activities etc..

on September 27, 2021 by guest. Protected copyright. This is the reason that we think it is important to publish this cohort profile to share the design and preliminary with the scientific and public health community. It will be beyond the scope of this paper to review in details the number of relevant sites in Canada and worldwide.

8. Page 21 Lines 3-5: “Indigenous people (YKDFN and NSMA) who were more vulnerable to environmental contamination …” Another important point to develop … how do you connect this assumption to the results presented? As stated in the same paragraph, we did this by “The comparison of their arsenic exposure and health conditions to other YKHEMP participants, as well as to the Canadian population, may provide additional information on arsenic’s health effect.”

9. Page 22 Lines 17-53: This section describe what is referred to as “Integrated Knowledge Translation Approach”. I suggest this information to be included in the Methodology.

Revised as suggested.

10. The overall structure of the manuscript should be revised and the use of subheadings is

BMJ Open: first published as 10.1136/bmjopen-2020-038507 on 28 September 2020. Downloaded from recommended. Below are my suggestions but these are simple general guidelines to ensure that methods are no longer mixed with results etc.

Revised.

Discretionary Revisions

1. Page 15 Line 3: Consider replacing “Findings to date’ WITH ‘Preliminary results”

We checked recent published cohort profile on BMJ open and followed the same structure.

2. Tables 3-5: Consider presenting the following information as a footnote at the bottom of tables: “Values presented in the parentheses are the 95% confidence interval. *Significantly different from CHMS.”

Revised.

VERSION 2 – REVIEW

REVIEWER Catherine Bulka University of North Carolina, USA REVIEW RETURNED 28-Aug-2020

GENERAL COMMENTS I am very impressed by the authors revisions and by all of the careful thought and hard work that went into the initial study design. I believe the manuscript is ready for publication. One minor suggestion: the authors might want to include footnotes in Tables 3-5 that not all participants had urinary metal measurements available (only 1966 of the 2037 enrolled).