PONE-D-20-38159

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

PLOS ONE

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Academic Editor

PLOS ONE

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Editor: The manuscript performed a GWAS analysis to show possible COVID-19 associated SNPs. However, the significance of the results was substantially undermined due to (1) the very limited confirmed positive cases of COVID-19 in the study (n=168), and (2) the low sensitivity of Mennis COVID-19 prediction model. Based on the current available data of COVID-19 cases, a substantial increase in confirmed COVID-19 cases in the study will help provide a more reliable conclusion.

Reviewer #1: The manuscript describes mainly negative results from a prediction model based on the symptoms to a GWAS analysis. The study makes almost no suggestive conclusions but is important to publish these results nonetheless. Most of my comments would rather focus on the "what I wish were done" rather than requirements for publication since given the methodology and results and the absence of any strong conclusions, the statements made are not unreasonable.

- I found the number of cases in this study too small. This is a limitation of the data, however, I think there could me more work done to increase the cohort given the widespread access to COVID-19 patient data.

- The racial diversity is quite lacking in the data to consider the effort done in GWAS analysis of high value.

- I do not understand why a conversion into binary variables was required for each of the variables in preprocessing. A trainable model is capable of dealing with ordinal variables without any conversion. Is it due to the heterogeneity between symptom reporting in different data sets?

The following comments are requirements for clarification of the methodology

- Logistic regression models are ML models, which means that there is a training phase. A complete description of the model hyperparameters and training procedures (training/test splits) is required to assess the validity of the model.

- There are multiple mathematical/statistical notions that need to be properly typed (italic p for p-value... etc.)

PONE-D-20-38159R1

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

PLOS ONE

Dear Dr. van Blokland,

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 submit your revised manuscript by Jul 18 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.

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'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Wenbin Tan

Academic Editor

PLOS ONE

Journal Requirements:

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.

Review Comments to the Author

Reviewer #2: This manuscript reports symptom-based predictive phenotypes as proxies for COVID-19 to understand genetic susceptibility to COVID-19. The strategy is well thought out and there are no problems. However, it is not clear whether or not differences due to the genetic background of the population have been taken into account. Are the eight genome-wide significantly different variants for viral infections selected from the NHGRI-EBI GWAS Catalog from a valid population for this comparison? Are GWAS meta-analyses of cohorts containing different genetic backgrounds valid? Should the current findings be considered valid only for specific populations? For example, rs5798227 associated with COVID-19 seems to be present in most Asians. It would be better if there was mention of the differences in genetic background among populations and how this affects the prediction model.

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility

PONE-D-20-38159R2

Dear Dr. van Blokland,

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.

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Kind regards,

Wenbin Tan

Academic Editor

PLOS ONE