PONE-D-21-12914

Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in Ethiopia

PLOS ONE

Dear Dr. Zewude,

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

Please can you address the following comments I have as Academic Editor:

Overall the English language is good but the manuscript needs a final copy-edit before publication. E.g. 2.4 million (not millions) in the abstract. Line 36 should read ‘may have *more* similar’. There are other small errors.

Introduction: Please update the malaria burden numbers from 2018 to more recent data (e.g. using the latest World Malaria Report)

Table 1. Please briefly explain in the legend the difference between the 3 models. The table should be broadly understandable to the reader without referring to the main text.

The abstract is rather hard to follow for a generalist reader. Please consider rewriting this sentence: “The main objective of this study was to quantify the variance component of cluster effects and cluster characteristics on individual malaria rapid diagnostic tests (RDT) outcome.”   Perhaps you could say something like ‘to quantify the extent of clustering of malaria infection as assessed by RDT’.

 Similarly the results section of the abstract is hard to read. Can you name some of the most important variables for explaining the clustering, which you found?

I suggest moving the final paragraph which discusses malaria climate further up in the discussion, since this is a key point. Please reference other studies which have sought to explain malaria prevalence by both climate variables as well as MIS variables. For example the Malaria Atlas Project is a major group which has been working on this problem for many year. E.g. see the map tab on the Malaria Atlas Project forecasts of malaria prevalence for Ethiopia https://malariaatlas.org/trends/country/ETH  What are the differences in the variables used for analysis in this study or other similar geospatial models compared to yours?

I suggest removing the phrase ‘best alternative’ for analysis on line 398, since there are many other sophisticated methods which seek to do this, e.g. geospatial modelling as referenced above.

Please submit your revised manuscript by Aug 28 2021 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,

Lucy C. Okell

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. 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: Yes

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

Reviewer #1: Yes

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3. 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: Yes

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4. 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

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5. 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: Review for "Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in Ethiopia"

PLOS one

PONE-D-21-12914

Overview

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This manuscript analysis a good sized data of malaria prevalence in Ethiopia (MIS data).

The stated main aim of the analysis is to estimate the variances of random effects terms that describe variation between clusters that is unexplained by covariates.

As malaria is of course an important public health problem, analyses that can inform policy makers are always useful.

The analysis is well conducted and care is taken to account for some of the important diffulties present in this type of data.

Overall I think the analysis is a useful contribution to the literature.

I have some minor points that I have detailed below.

I have also included a fairly large number of language edits.

Minor points

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My main problem with the manuscript in it's current state is that the policy importance of the main aim of the analysis is not well explained and is not trivially obvious.

What policy implications does a large (or small) between-cluster variance component have?

I can imagine some.

Maybe it suggests that we are still missing covariates important for predicting malaria.

If so, what might those covariates be and what are the barriers to collecting that data?

Is it that nonlinear models and interaction terms are needed?

Or is it that there are cluster level drivers that we will never be able to measure?

What does this mean for policy, that we an never make excellent predictions of malaria or that the only way to guide resource distribution is to measure malaria prevalence in ever cluster in a country?

Relatedly, while you cite some references that use random effects models, you don't cite any estimates of between-cluster variance from any other study.

While I recognise that these estimates might be difficult to find in many papers, if this is the main aim of the analysis, any previous attempts at estimating this value should be mentioned, if nothing else to help us set our expectations.

Have previous estimates found that between-cluster variation is very high or very low?

I'm not sure if this point is relevant but in some senses, the cross-validation error in models of malaria prevalence are a measure of the same quantity.

It is the amount of malaria prevalence that cannot be predicted with the covariates in the model.

The paragraph in lines 80-84 seems very unecessary to me. The structure of the paper is totally standard.

Lines 243-245. I'm not sure what this line means. Are you saying that you needed to seperately calculate the weights and tell PROC GLIMMIX to use them? Or that you have provided the weights in an attached dataset? Or something else.

The section in lines 251-257 that explain how variable selection was performed should be in the methods somewhere.

Lines 367-395. Given that this section is the main result (according to the aims of the analysis stated in the abstract and intro) I think it should go near the beginning of the results section. Unless I have misunderstood, the hypothesis tests in line 276 are part of the same result (is the variance component zero, if not how big is the variance component). So bringing these two sections together would improve the structure.

In the abstract in the results (word limit allowing), I think it would be useful to state the result that 55% of the variability in malaria outcomes could be attributed to the differences betwen SEAs. This to me is the most useful statement of the results.

Line 418: I am glad that you spend some time to discuss the surprising result that mosquito net use predicts increased malaria prevalence. However I think you have perhaps missed a likely cause of this estimate. I would guess that the positive relationship is because nets are delivered to areas with high malaria burden and people are more likely to use the nets if they feel malaria is a big risk to them. This argument does however raise the problem that the causality might be reversed here (malaria causes nets).

Line 197: You have written the sigma2b is an estimate of what *could* be explained. Quite subject but I would think of it as what *needed to be* explained. The random effect could explain everything if you removed everything.

Language issues

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Abstract, methods. A sample of 9272 individuals were *used* in this

Abstract, conclusions. The methods used in this study have allowed *us* to make

Line 28: the survey design organizes the.

Line 29: *They* then select. Or something like that.

Line 36: or enumeration area, may have more similar.

Line 44: This model also does not allow us to study the association

Line 46: The intra-cluster correlation can *give* useful. Or something.

Line 54: regression models allow *analysts* to take into

Line 59: within-cluster.

Throughout, check whether within-cluster and between-cluster have hyphens.

Line 65: as a set of control variables, *the analysis* may provide information *on* how

Line 70: Also, it does not allow *analysts* to examine *the* influence of

Equation 2 and 3: I think the squared term in the denominators should come after the i|j. {w_{i|j}}^2 if you use latex.

Line 186: The *results from the* weighted analyses across

Line 187: and variance *parameters* of the

Line 188: results obtained *were* slightly

Line without a number after equation 5: identical for all the SEAs and bj *quantifies*

Line without a number beforeequation 6: The third model *was* defined

Just after line 233: The VPC measures *the* proportion

Line 315: to *have* had malaria than

Line 332: their interpretations *are* natural

Line 426: This *implies* that

Line 446: explanatory variables *were* introduced

Line 447: Hence, there is still a large

Line 456: have allowed *us* to make

Line 461: Such *an* approach yield*s*

Line 483: environment *are* interrelated, interpretation

Ref 29. The first author is Rabe‐Hesketh S I believe.

Ref 35 Type in neighbourhood.

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PONE-D-21-12914R1Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in EthiopiaPLOS ONE

Dear Dr. Zewude,

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.

There has been a reassignment of editor since the last version. The previous reviewer has kindly accepted to review again, noting still a concern with the policy interpretation. The new editor has checked the previous editorial assessment both for the previous version of this manuscript and the earlier version, while also looking in detail at the present manuscript. It is felt there is enough information to make a decision, although the editor has been unable to revise the supplementary material that should be provided in a more accessible format such as pdf.

There are currently a number of issues that have to be addressed. In a general manner, PLOS ONE strongly suggests the use of the STROBE or similar checklists to ensure that reporting is complete (https://www.strobe-statement.org/download/strobe-checklist-cross-sectional-studies-pdf). You can include in the revision the checklist specifying the line numbers where each aspect is addressed. I see things missing, starting with the rationale, the population of interest, who was tested for malaria, everybody in the household? A sample?

1. Rationale: The authors do not provide the rationale for studying MIS2011 when a more recent MIS2015, https://www.malariasurveys.org/documents/Ethiopia_MIS_2015.pdf , is available. They should discuss the rationale why this might be still interesting. They mention the survey as ref [6] but they do not say why they have not used MIS 2015. They should also explicitly mention the trends. They mention the trend from 2015-2019. What happened from 2011 to 2015? That should come first since this is precisely after this study.
2. The literature revision does not include multilevel studies using MIS. They exist, should be mentioned and acknowledged and compared in the discussion. There is in particular a study using Ethiopia MIS 2015, https://doi.org/10.1186/s12889-020-09560-1 . See also https://doi.org/10.1016/j.ijid.2020.12.062 . Also the authors should not oversell the novelty of the study. Using multilevel modelling is standard in many fields and using sample weights with complex survey structure is a requirement in order to get results representative at the National level. It is not a plus to use them. It is just wrong if you do not use them here. It might be right if a different sampling strategy is used. Overall the introduction can be shortened considerably
3. There is a need to edit the language. Please make a thorough language check. Example of sentences that can be improved: “The results also show that the individuals vulnerability to malaria infection decreases significantly with increase in age”. Maybe “increasing age” or “for older, maybe separate sentences
4. Your main result on cluster-level variance should refer to the best model. And that is the model with covariates. However the abstract states “About 55% of the variability in malaria RDT outcomes of individuals could be attributed to the difference between clusters. However, when accounting for the individual / household- and cluster-level characteristics, part of the variability which is relevant at the cluster-level became lower.”. Please provide only the figure for the best overall model according to AIC or BIC (say explicitly which criteria you are using) mentioning that the percentage variability is “after controlling for ….”. On the other hand, you might report M1 instead of M2 since M2 precisely aims at explaining what is behind the cluster variation (with no change in the individual level controls).
5. Make clear in the abstract the population you are analyzing: Eg: “A sample of 9272 individuals” [representative of the National population? The adult population? This is never very clear]. Also: why are you focusing only on three states? How are these states compared to the National average?
6. The referee is concerned with the lack of policy feedback gained from the multilevel analysis. While it is true that more recent data being available, this has less of an impact, the policy consequence of finding that a large proportion of variance remains at the cluster level is that policy should focus on those hotspots of malaria. In order for the analysis to be useful what would be interesting is to know where these malaria hotspots are located. You should provide a map showing the cluster random effects to guide action and comment on them (do they move along regional lines, are they very local, …).
7. In the introduction you mention two levels of effects, the cluster and the household. However, the methods section only has random effects at the cluster level. This should be listed as a limitation since there are obvious correlation among malaria status at the household level. Why are you not including this? That would strengthen the paper since part of the currently described as cluster variance must be household-level variance and you can potentially separate one from the other?
8. I have been unable to look at the supplementary material and it is fundamental to see whether PLOS ONE statistical guidelines are being followed since there are many missing elements in the main text. Please provide it in an edited format, eg. Pdf. Not tex.
9. In table 1 provide fit statistics for model 0.
10. The names of the models are different in table 1 and 2. Is model 2 model 1 and model 3 model 2?

A more comprehensive assessment needs to wait to see the supplementary material. Just make sure that all the issues raised in the strobe statement and PLOS guidelines for statistical reporting in (https://journals.plos.org/plosone/s/submission-guidelines).

Please submit your revised manuscript by Mar 19 2022 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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If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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We look forward to receiving your revised manuscript.

Kind regards,

José Antonio Ortega, Ph.D.

Academic Editor

PLOS ONE

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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)

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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: Yes

**********

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

Reviewer #1: Yes

**********

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: 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: 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: Rereeview for "Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in Ethiopia"

PLOS one

PONE-D-21-12914

Review

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The authors have made a number of language edits in line with the editors comments and my own. These are all fine.

None of my comments in my original review were very important. However, the comment that I thought was most important related to setting the study into it's policy context. Some of the results, such as estimating which factors (age, temperature etc.) are related to high malaria, have obvious policy implications, but are also the same thing that people have been estimating for years. The big novelty in this study that I could see was the focus on estimating the between cluster variance after accounting for covariates (this is stated as such in line 456). However, the policy importance of the between cluster variance wasn't clear to me; how does a Ministry of Health use this information to guide malaria control for example?

In response the authors have added "The variation could be due to bio-ecological or human factors or other covariates that are important for predicting malaria prevalence but not included in the study. These factors may help to guide malaria control interventions and improve their efficiency and effectiveness, and hence may lead to more effective public health strategies and could have important policy implications for health promotion."

This states that the results are important for policy but still don't say how or why they are important. Again, what specific actions might a ministry take that they wouldn't have had taken without this information?

I'm afraid this isn't a particularly good or helpful rereview. I'm just saying the same thing I said last time. But I don't believe the authors have really fixed the issue.

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Reviewer #1: No

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PONE-D-21-12914R2Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in EthiopiaPLOS ONE

Dear Dr. Zewude,

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.

Some of the issues raised have been solved but there are still many issues pending revision in the abstract, the text, and the supplementary material. On a general remark, while PLOS ONE is a general interdisciplinary journal, this is an applied work not a methodological contribution. The substantive implications of the analysis need to be highlighted, and the goal cannot be just the application of a method (which is already standard in many areas).

1. Line numbers are missing in the manuscript with track changes. This makes it difficult to edit the manuscript. Please include them next time.
2. Abstract: I noted the rationale was missing and it is still missing. The background section cannot start as it does with “The 2011 Ethiopian National Malaria Indicator Surveys (EMIS) data used in this study have a multilevel structure where individuals in selected households are nested within cluster and this may result in dependent data”. You should start stating the purpose of your study and why is it relevant. The purpose also cannot be to apportion the variance by itself. It must be to apportion the variance of some measure of interest. You have reformulated the introduction but not the abstract.
3. You repeat twice “malaria rapid diagnostic test outcomes” in the background. Better use “prevalence of malaria”, or even in the first appearance “the prevalence of malaria
4. You declare twice in the abstract that you focus on three regions but you do not list them. Please do so. Note also the clumsy writing of the first mention on “Further, the study was also interested in assessing factors that affect the malaria rapid diagnostic test outcomes of household members in three major regions of Ethiopia.”. That cannot be “also” an interest. You are ONLY studying the prevalence of malaria in these 3 regions, not anywhere else. This is connected to the previous comment. The background section in the abstract has to be completely rewritten.
5. Note in the introduction you are also stating (p.3) similar things to the abstract. Please change also the introduction stating clearly the specific rationale at the beginning as it was suggested in the previous revision.
6. In the rest of the abstract you are not providing the concrete results or conclusions. Please state your MAIN results (maximum of 3 or 4) in a quantitative way.
7. Typos still present Eg: Supplemantary material is called, several times, “Supplementery Material”
8. The supplementary material needs to be thoroughly revised. It cannot be so verbose. What you are describing is the application of a backwards elimination algorithm. You do not need to describe each step in detail with all the estimates. Usually backwards elimination is carried out directly through some algorithmic procedure and you just need to report the variables you sequentially remove and their effect on the selection criteria (eg: AIC, BIC). It seems you are doing it by hand based on the p-value of a joint significance test. You could report the first step (the complete model), a table with the list of variables removed at each subsequent step together with the p-value of the type III test and the AIC or BIC after removing the variable, and the last step.
9. There is a need to copy-edit the manuscript. One more instance: “These three regions were considered due to the data sharing police of Ethiopian Public Health Institute that since we are not part of EMIS project team we had a limited access to the survey data for our research.” I’d suggest “The choice of these three regions was driven by the data-sharing limitations imposed by the Ethiopian Public Health Institute, the owner of the data”
10. The description of the target population and the sampling strategy needs to go in the data section, not in the response and explanatory variables section.
11. The policy implication in p.14 is unwarranted, “Therefore, the regional government should frequently provide IRS to households in malaria hot-spots areas and the population at risk, and further educate people about its advantage” given that you do not find a significant effect.
12. You are not commenting in the discussion the apparent contradictory result that those with mosquito nets are more likely to be infected. Why should that be so? Is this in line with the literature and with results from Ethiopia?
13. The paper is missing a table one with the proportions and mean values of variables, possibly by region, possibly according to the value of the dependent variable. Its absence makes interpretation very hard. Eg: Are mosquito nets very prevalent and its absence is telling us something about local conditions? Is spraying common… Please include it and use to it to inform the interpretation of results and the discussion.
14. Figure 1 has too small a type. It cannot be read.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
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José Antonio Ortega, Ph.D.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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Reviewer #1: No

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Reviewer #1: No

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Reviewer #1: Yes

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Reviewer #1: (No Response)

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Reviewer #1: Yes: Tim Lucas

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Multilevel Logistic Regression Modelling to Quantify

Variation in Malaria Prevalence in Ethiopia

PONE-D-21-12914R3

Dear Dr. Zewude,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

José Antonio Ortega, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

It is felt that the changes introduced have addressed the main concerns that prevented the paper from being acceptable for publication and the manuscript has gained in focus and relevance. The method section might still be too long, considering that the methods are standard, but it is OK to keep it as it is.

Reviewers' comments: