PONE-D-24-01984Association of a Cleaner-burning Stove with Blood Pressure in Adults in Rural MalawiPLOS ONE

Dear Dr. Balmes,

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: No

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Reviewer #1: No

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: Bates and colleagues investigates the relationship of household air pollution with blood pressure (BP) in rural Malawi using two exposure metrics: (1) treatment group as a categorical proxy for duration of exposure to cleaner-burning cookstove use (earlier treated, later treated, and never treated), and (2) personal 24-48h PM2.5/CO exposures. Their data are from a previous RCT (CAPS) that investigated improved cookstove use with <5 child pneumonia, and a cohort study in adults in the RCT study area with measurements at three time points (baseline, Year 1, Year 2). Automated BP measurements were added in the last two years of the cohort study. Results from linear regression models, adjusted for sex, age, smoking status, and BMI, provided little evidence of exposure-response relationships of personal exposure to PM2.5/CO with BP, but a cross-sectional analysis of the mean difference in BP between RCT (ever received an improved cookstove) and cohort (never received an improved cookstove) participants revealed lower systolic BP in RCT participants. The authors suggest their results highlight improvements in BP due to a clean cookstove intervention.

Contributions and strengths of the paper:

1. Fills a knowledge gap on the relationships between HAP and BP in sub-Saharan Africa, which is an understudied region with a growing cardiovascular disease burden and persistent use of solid fuel for cooking.

2. Study benefits from variability in HAP exposure (stove type and 24h-48h personal exposure measurements) created by linking into the site of a randomized stove trial.

3. I appreciate the use of a DAG to clearly communicate assumed relationships between variables for the PM2.5/CO-BP analyses and justify the regression adjustment set.

Major comments:

1. The novelty of this study is rather overstated, and many important and relevant studies on HAP and blood pressure are not referenced or discussed. BP is one of the better researched health outcomes in relation to HAP, and there is a relatively strong literature indicating a harmful effect of HAP on subclinical cardiovascular outcomes including BP, albeit not well described in this manuscript. Some examples are below, including a systematic review, though this list is not inclusive and many other studies are relevant to this one but not referenced:

• Systematic review: Li L, Yang A, He X, Liu J, Ma Y, Niu J, Luo B. Indoor air pollution from solid fuels and hypertension: A systematic review and meta-analysis. Environ Pollut. 2020 Apr;259:113914. doi: 10.1016/j.envpol.2020.113914. Epub 2020 Jan 7. Erratum in: Environ Pollut. 2020 Nov;266(Pt 1):115085. PMID: 31935611.

• Giorgini P, Di Giosia P, Grassi D, Rubenfire M, Brook RD, Ferri C. Air Pollution Exposure and Blood Pressure: An Updated Review of the Literature. Curr Pharm Des. 2016;22(1):28-51. doi: 10.2174/1381612822666151109111712. PMID: 26548310.

• Baumgartner, J., Carter, E., Schauer, J.J., Ezzati, M., Daskalopoulou, S.S., Valois, M.F., Shan, M. and Yang, X. Household air pollution and measures of blood pressure, arterial stiffness and central haemodynamics. Heart. 2018. doi:10.1136/

heartjnl-2017-312595

• Young BN, Clark ML, Rajkumar S, Benka-Coker ML, Bachand A, Brook RD, Nelson TL, Volckens J, Reynolds SJ, L'Orange C, Good N, Koehler K, Africano S, Osorto Pinel AB, Peel JL. Exposure to household air pollution from biomass cookstoves and blood pressure among women in rural Honduras: A cross-sectional study. Indoor Air. 2019 Jan;29(1):130-142. doi: 10.1111/ina.12507. Epub 2018 Oct 15. PMID: 30195255; PMCID: PMC6301093.

The paper’s main contribution is stated on line 72, “Specifically, studies of the association of exposure to HAP and blood pressure in sub-Saharan Africa are limited…” but the authors missed the recent HAPIN trial, which included ~1,000 participants in Rwanda, and a quasi-experimental improved cookstove analysis in urban Rwanda (Jagger et al. 2019, doi: 10.1007/s10393-018-1391-9) that included studies of BP.

As shown by the studies mentioned above, this is not the (line 54) “first longitudinal study…” in sub-Saharan Africa, and although data were collected over multiple years, it’s unclear whether only one year or multiple years of data were included in the analysis.

2. The description of the study design, timeline of enrollment and measurements, sample sizes for different analyses, and even the type of study (longitudinal versus cross-sectional) is outright confusing. The manuscript would benefit from clarification of:

a. The relative timing of recruitment, measurements, and interventions in CAPS versus BOLD-Chikwawa participants.

b. The protocol for BP measurements (i.e., were they collected at home, did participants quietly rest for 5-mins prior to measurements, etc.).

c. The number of participants with specific measurements and that are included in each analysis (ex. How many/how were personal exposure participants selected?).

d. Justifications for study design and analytical decisions (ex. dropping all observations >200 ug/m3, excluding participants with SBP/DBP < 80/50 mmHg).

e. Whether BP measurements in the pollutant-BP analysis were from Year 2 only, or from Years 1 and 2.

3. Although the discussion attempts to address potential biases, key confounders and possible sources of selection and information biases were not examined.

a. Other potential common causes of exposure to HAP and BP include temperature, day of the week, time of day, outdoor air pollution, participant’s occupation.

b. Selection wasn’t discussed with respect to the lack of follow-up in 25% and 30% of participants in Years 1 and 2, respectively, 49% study participation rate in the BOLD-Chikwawa study, or personal exposure measurements in a subsample of the study population.

c. No discussion of how an information bias would (line 260) ‘obscure’ a true association. What direction, and what is the likely magnitude?

d. Given the possible biases not discussed and reported differences between CAPS and non-CAPS participants, I’m not sure that exposure misclassification (paragraph stating line 297) entirely explains the lack of a relationship between pollutants and BP, or that the finding of lower BPs in CAPS participants is not confounded by other factors.

4. This paper needs to be more explicit about the type of study conducted and whether it is a causal versus descriptive analysis. The use of ‘association’ rather than ‘effect’ throughout the manuscript, cross-sectional analyses while emphasizing the strength of longitudinal data, and use of DAGs/the discussion of adjustment send mixed messages. Adjustments to language, interpreting results within the limits of the data/models, and being explicit about the specification for statistical models would help to refine the manuscript and interpretation of results.

See a discussion on the use of causal language in observational studies:

• Haber NA, Wieten SE, Rohrer JM, et al. Causal and Associational Language in Observational Health Research: A Systematic Evaluation. American Journal of Epidemiology. Volume 191, Issue 12, December 2022, Pages 2084–2097, https://doi.org/10.1093/aje/kwac137

• Hernán MA. The C-Word: Scientific Euphemisms Do Not Improve Causal Inference From Observational Data. Am J Public Health. 2018 May;108(5):616-619. doi: 10.2105/AJPH.2018.304337. Epub 2018 Mar 22. PMID: 29565659; PMCID: PMC5888052.

Minor comments:

· Please provide confidence intervals rather than p-values in the results section, as is recommended by most epideimology journals.

· Reporting geometric mean/SD in Supplementary Table 1 may provide a better summary of central tendencies that are less influenced by extreme values, especially given the report of right-skewed pollutant distributions.

· Information presented in results tables could be more clearly labelled and should have accurate units.

· The Mortimer et al. study (2017) of CAPS trial results reports on cookstove malfunction/breakage and sustained use post-intervention. Perhaps results in this paper could support discussion in the paragraph starting on line 266.

Mortimer K, Ndamala CB, Naunje AW, Malava J, Katundu C, Weston W, Havens D, Pope D, Bruce NG, Nyirenda M, Wang D, Crampin A, Grigg J, Balmes J, Gordon SB. A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial. Lancet. 2017 Jan 14;389(10065):167-175. doi: 10.1016/S0140-6736(16)32507-7. Epub 2016 Dec 7. PMID: 27939058; PMCID: PMC5783287.

· Line 281 reports impacts to ‘risk ratios,’ but risk ratios were not estimated in this manuscript.

Reviewer #2: The authors present interesting results from an analysis of associations between household air pollution and blood pressure in a cohort in rural Malawi. The study includes participants from a rural Malawi cohort, some of which were enrolled in clean cookstove intervention. Participants enrolled in the cookstove study (CAPS) had lower systolic blood pressure, but there was no association with pollutant concentrations based on personal exposure monitoring. The authors do a good job of describing their results and inherent limitations of this study. The authors appropriately describe limitations of the study design and limitations (alongside the strengths of) the 48-hour personal exposure monitoring conducted in this study. However, I do have several concerns about the results, including caveated results that still may be overstated. Major and minor comments are outlined below:

Major Comments:

1. Overall, my major concern is overstating findings describing differences between those in the CAPS study and the non-CAPS group. I do not think there is enough evidence to support the claim in the conclusion that the evidence “supports an association between improved stove types and reduced systolic blood pressure” (lines 344-345). Notably the non-CAPS population appears distinct, including an older population with fewer normal weight individuals. These are both factors that drive hypertension and are challenging to account for with adjustments. As the authors indicate, a population that was interested in a cook stove intervention study may be unique. Additionally, there was no significant associations between pollutant concentrations, CAPS stove type subgroup, or blood pressure outcome. There was also no difference in the CAPS population in diastolic pressure. Additionally, there was confirmation of use of the clean cookstove use at follow-up. Based on these factors, I think the evidence primarily supports that participants who decided to enroll in CAPS were more likely to have lower systolic blood pressure at follow-up, not that there was a difference by stove type.

2. I believe the statistical analysis plan should be better clarified. While the study is described as longitudinal, the analysis itself appears to be a cross sectional analysis of data using the second visit in a longitudinal cohort study.

a. I was additionally unsure about the analysis of associations between pollutant concentrations and blood pressure. Were repeated measures utilized for this and if not why were only associations between pollutants and blood pressure analyzed at visit 2? I felt the analysis would have improved with a longitudinal model that accounted for repeated measures of HAP concentrations and blood pressure at years 1 and 2 visits.

3. I was looking for clarity on whether other covariates were considered but not included in the final model for the analysis of stove use/type and blood pressure. For example, I would have expected obesity or BMI to be considered, as there were fewer “Normal” weight individuals in the Non-CAPS group, which could influence blood pressure estimates.

Minor Comments.

1. I would recommend citing the following article from the HAPIN trial as a more comprehensive review of prior research, which notably showed higher gestational blood pressure among the LPG stove intervention group.

Ye W, Steenland K, Quinn A, et al. Effects of a Liquefied Petroleum Gas Stove Intervention on Gestational Blood Pressure: Intention-to-Treat and Exposure-Response Findings From the HAPIN Trial. Hypertension. 2022;79(8):1887-1898. doi:10.1161/HYPERTENSIONAHA.122.19362

2. 1033 participants presented to follow-up 2 but 910 were included in the final analysis. It would be helpful to understand the reason for exclusion as this represents ~10% of the population, which is already significantly decreased from those assessed at baseline.

3. The article list adjustment by “gender” , while “sex” may be more appropriate in this case.

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Reviewer #2: No

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PONE-D-24-01984R1Association of a Cleaner-burning Stove with Blood Pressure in Adults in Rural MalawiPLOS ONE

Dear Dr. Balmes,

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.

The reviewers have suggested minor revision of your revised manuscript. Please refer to their comments below.

Please submit your revised manuscript by Oct 30 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.

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We look forward to receiving your revised manuscript.

Kind regards,

Anindita Dutta, Ph.D.

Academic Editor

PLOS ONE

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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.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Partly

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

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

Reviewer #1: (No Response)

Reviewer #2: No

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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

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for the opportunity to review the revised manuscript. I appreciate the additional details and analyses provided by the authors. In particular, the introduction better communicates the existing literature and the paper’s main contributions, and the study design and timing of measurements is clearer. However, there are several major points that remain in the revised manuscript, and I would like to see these addressed before this paper is published:

The cited literature to justify the exclusion of SBP/DBP < 80/50 mmHg describes values for “low blood pressure” which may be different from “implausible” BP values. Are the excluded BP values so low that they are “implausible”? How many values were excluded, and does including these low BP values change the results? Also, the NIHLBI low blood pressure citation should be included in the manuscript.

The revised draft includes additional language to expand the discussion of potential biases, but there should be more explicit discussion of how these biases may affect results (magnitude and/or direction of bias, as per STROBE guidelines).

Selection bias

Less than half (49%) of the eligible participants agreed to participate and, of these, only 60% contributed measurements. Starting on line 277 of the revised manuscript, the authors state that, “…individuals concerned about either their health or exposure to cooking emissions could have been the most likely to agree to participate in the study,” but that, “it is not obvious how [possible selection] would easily have affected associations based on objective measurements of both blood pressure and air pollution/stove distribution”.

The authors should evaluate (and discuss) possible selection bias by comparing their socio-demographic and health/exposure features of participants who contributed to this analysis with (1) those invited to participate from the parent study (n=3000) and (2) those who agreed to participate (n=1470).

Confounding

In response to our previous comment on other potential confounders, the authors asked for clarification on how temperature and day of the week could confound stove use- and/or HAP-BP relationships.

Ambient temperature could affect 24-h mean personal exposure through its effect on behavior related to stove use or pollutant formation, and temperature is a well-established predictor of BP. If there is no temperature fluctuation during the study period (which seems unlikely given that data collection occurred over the entire year), this would limit concern about temperature as a confounder, but this should be explicitly mentioned.

BP and 24-h personal exposure measurements could vary by day of week if activity patterns also tend to vary by day of week (e.g., greater rest during the weekends, greater activity during weekdays, market days, etc).

If ambient temperature and day of week were measured, sensitivity analyses that additionally adjust for these variables may be helpful to assess the stability of results.

Additionally,

If the authors agree that outdoor PM could be a confounder and it was not measured, the lack of adjustment for outdoor PM might be considered a limitation of the work and mentioned in the discussion.

I agree that time of day may not be related to a 24-h mean personal exposure measurement. Thank you for this clarification. However, it is still relevant for BP, as BP varies diurnally, and could be included to improve precision (assuming it’s not on the causal pathway).

If occupation is constant across study participants, I agree that the potential for confounding by this factor is limited. This should be mentioned in the discussion.

Information bias

Line 306 mentions the possibility of personal exposure monitor failure. Did this occur during data collection? Do you expect that this contributed to exposure misclassification and attenuation of results?

Line 310 states: “It is likely, however, that at the second follow-up at least some of the stoves would already have experienced technical failures and some families would have discontinued their use, for potentially many reasons.” How would this have affected results?

(Line 328-330) “The fact that [the provision of improved stoves] was not associated with decreased BP could potentially be due to HAP exposures not actually being causal for BP…”

I generally agree that this is a possibility. Though the statement gives a lot of weight to the exposure difference between stove groups, which by my read is either ~1 ug/m3 or 0.16 ug/m3? (see comment below about confusion in presentation of this result). The range of PM2.5 is not presented but the arithmetic mean is 1,317 ug/m3 and the geo mean is 119 ug/m3, indicating a very wide exposure range. Given the exposure range and log-linear exposure-response for PM and BP and other cardiovascular outcomes rather consistently observed in the ambient and household air pollution literature, is there any reason to expect a measurable BP benefit from stove that resulted in a 0.16 or 1 ug/m3 difference in PM2.5?

Line 233 – if the mean difference is still on the log scale, then it should be presented as log(ug/m3) rather than ug/m3.

Reviewer #2: The authors have made significant improvements to the manuscript and responded adequately to most of my comments.

I have additional minor comments.

1. I feel the causal language, though improved from the initial draft, is still overstated, including “causal association” in the abstract. I believe it is more appropriate to state that this single site cross-sectional study shows an association between stove type and blood pressure.

2. Figure 1 appears lower resolution and the figure is hard to read. Recommend uploading a higher resolution version of the figure if possible

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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

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Association of a Cleaner-burning Stove with Blood Pressure in Adults in Rural Malawi

PONE-D-24-01984R2

Dear Dr. Balmes,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Please edit your manuscript as per the minor comments of Reviewer 1 as mentioned in "6. Review Comments to the Author" to make it print ready. Though it will not got to the reviewers again, you will still need to address those minor comments before it may be published.

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Anindita Dutta, Ph.D.

Academic Editor

PLOS ONE

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Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

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

Reviewer #1: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed concerns from the previous review. I appreciate their further discussion and analyses on covariates, selection bias, and inclusion/exclusion criteria. The study design is clearer, and the manuscript reads more smoothly.

I am happy for this manuscript to move forward to publication with the following minor edits addressed. I do not need to review this paper again.

Minor comments:

1. Lines 60-61: “In the latest Global Burden of Disease comparative risk factor analysis, high systolic blood pressure (SBP) is the leading risk factor, accounting annually for approximately 10 million deaths and 200 million disability-adjusted life years.”

The following modification would improve the clarity of this sentence: “…is the leading risk factor for the disease burden globally, accounting for…”

2. The introduction paragraph from line 60-89 could use a concluding sentence to summarize what the cited studies, together, say about clean cooking interventions in sub-Saharan Africa.

3. Lines 319-320: “We think misclassification of blood pressure, although certainly possible, is a less likely explanation.”

It would be helpful to provide the reader with a brief explanation of why not.

4. The paragraph from line 375-392 provides a nice summary of previous work, but it would be helpful to add text that situates your results within this literature.

5. Lines 203-204: “The threshold values were selected based on maximization of the linear correlation of PM2.5 and CO level concentrations…”

Please add the PM-CO correlation with all the data in the SI.

Reviewer #2: The manuscript is improved in this revision and the authors have adequately addressed my concerns.

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Reviewer #1: No

Reviewer #2: No

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