Dear Dr Mahony,

Thank you very much for submitting your revised manuscript 'Direct prediction of regulatory elements from partial data without imputation' for review by PLOS Computational Biology. Your manuscript has been fully evaluated by the three independent peer reviewers who had reviewed the first version of this manuscript when submitted to GLBIO.  While two of the reviewers are satisfied with the current version of the work, reviewer 2's comments still need some additional work. While your manuscript cannot be accepted in its present form, we are willing to consider a revised version in which the issues raised by reviewer 2 have been adequately addressed. 

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Your revisions should address the specific points made by each reviewer. Please return the revised version within the next 60 days. If you anticipate any delay in its return, we ask that you let us know the expected resubmission date by email at ploscompbiol@plos.org. Revised manuscripts received beyond 60 days may require evaluation and peer review similar to that applied to newly submitted manuscripts.

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(1) A detailed list of your responses to the review comments and the changes you have made in the manuscript. We require a file of this nature before your manuscript is passed back to the editors.

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- Figures uploaded separately as TIFF or EPS files (if you wish, your figures may remain in your main manuscript file in addition).

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We are sorry that we cannot be more positive about your manuscript at this stage, but if you have any concerns or questions, please do not hesitate to contact us.

Sincerely,

Sushmita Roy, Ph.D.

Associate Editor

PLOS Computational Biology

William Noble

Deputy Editor

PLOS Computational Biology

A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

[LINK]

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: My original review was positive and I do not have further comments.

Reviewer #2: The authors have address my concerns.

Reviewer #3: The addition of two different sections and some text to clarify limitations (I appreciate the truthful statement about the imputation part in the Discussion) have strengthened the manuscript. There are two points that are not fully addressed either because of time limitation or misunderstanding of my suggestions, which would be great to do so before publication.

- For my comment on using only previous iteration of IDEAS results as gold standard, for the completeness of this manuscript, that would be important to add a summary of the comparative results of IDEAS and other methods from the previous work. That would justify, to some extent, the use of IDEAS-only evaluation together with the added text.

- The comment on "why more states are better" was mainly referring to a controlled experiment where the number of states are set to an equal number for both the complete 5-mark segmentation and the incomplete 12-mark. The evaluations that are done would still be applicable but differences could then directly be attributed to using more marks including those that are complete rather than, say, more granular state assignments due to simply having more marks (i.e., 5 marks are not rich enough to have 42 meaningfully distinct states but 12 with imputation are).

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No: Supplementary tables need to be provided with segmentation information from each dataset for reproduction of at least each main figure.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Ferhat Ay

Dear Dr Mahony,

We are pleased to inform you that your manuscript 'Direct prediction of regulatory elements from partial data without imputation' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. Please be aware that it may take several days for you to receive this email; during this time no action is required by you. Once you have received these formatting requests, please note that your manuscript will not be scheduled for publication until you have made the required changes.

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Thank you again for supporting Open Access publishing. We look forward to publishing your paper in PLOS Computational Biology.

Sincerely,

Sushmita Roy, Ph.D.

Associate Editor

PLOS Computational Biology

William Noble

Deputy Editor

PLOS Computational Biology

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #3: All comments addressed.

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Have all data underlying the figures and results presented in the manuscript been provided?

Large-scale datasets should be made available via a public repository as described in the PLOS Computational Biology data availability policy, and numerical data that underlies graphs or summary statistics should be provided in spreadsheet form as supporting information.

Reviewer #3: Yes

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PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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 #3: Yes: FERHAT AY