-->PCOMPBIOL-D-25-01551

MIAAIM: Multi-Omics Image Integration with Dimensional Reduction for Tissue State Mapping

PLOS Computational Biology

Dear Dr. Reeves,

Thank you for submitting your manuscript to PLOS Computational Biology and apologies for the delay. After careful consideration, we feel that your manuscript has significant merit but does not fully meet PLOS Computational Biology'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.  In particular, please address the concerns of the reviewers concerning quantitative benchmarking of your algorithm and provide better support for your use of a multi-modal analysis on experimental data.

Please submit your revised manuscript within 60 days Jan 31 2026 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter

We look forward to receiving your revised manuscript.

Kind regards,

Joshua N. Milstein

Academic Editor

PLOS Computational Biology

Shayn Peirce-Cottler

Section Editor

PLOS Computational Biology

Additional Editor Comments (if provided):

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #1: The classification of prostate cancer Gleason scores is a powerful application of the MIAAIM framework. The manuscript already contains the critical data showing that the integrated multimodal model outperforms models based on single modalities. This result is a cornerstone of the paper's argument, as it provides direct evidence that multimodal integration yields a more complete and predictive representation of tissue states.

To make this method more impactful, it is suggested add an experiment to the presentation of these results: consider adding a summary table or a simple bar chart in the main text that directly compares the final classification accuracy (e.g., class-balanced accuracy) for models trained on:

1. IMC features only (including single-cell and neighborhood interaction scores).

2. MSI features only (including single-cell and neighborhood interaction scores).

3. The fully integrated IMC + MSI model.

While this information is mentioned in the text, a dedicated figure or table would provide a clear visualization of the performance gain achieved through multimodal integration.

Reviewer #2: Summary:

This paper describes MIAAIM, an open-source and modular computational framework for aligning and integrating multimodal, high-dimensional tissue imaging. By combining concepts such as UMAP and entropic-graph-based mutual information, MIAAIM can align data from disparate modalities. The authors focus on aligning data from imaging mass cytometry (IMC), mass spectrometry imaging (MSI), and histology. They apply the framework to a large diabetic foot ulcer (DFU) biopsy and to multi-core prostate cancer tissue microarrays (TMAs), demonstrating MIAAIM’s ability to extract biologically meaningful multimodal single-cell and spatial features.

Major Comments:

My main concern is the lack of quantitative benchmarking. The α–mutual information alignment method is conceptually elegant, but registration quality is reported primarily through qualitative visual inspection, which is a serious limitation. Commonly used quantitative metrics such as Dice coefficient, target registration error (TRE), or mutual information gain relative to baseline methods (e.g., Elastix) should be reported. I cannot foresee a path toward publication without explicit comparisons. These results are critical to clarify MIAAIM’s robustness and, more importantly, justify its novelty relative to existing registration tools. Lastly, a brief discussion of false discovery rates or validation strategies would strengthen the biological claims.

Minor Comments:

• Standardize reference formatting (several in-text citations have unmatched parentheses).

• Ensure all acronyms are defined at first mention.

• Clarify how manual landmarks were used in DFU alignment and whether this step introduces bias.

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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 #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

Figure resubmission:

While revising your submission, we strongly recommend that you use PLOS’s NAAS tool (https://ngplosjournals.pagemajik.ai/artanalysis) to test your figure files. NAAS can convert your figure files to the TIFF file type and meet basic requirements (such as print size, resolution), or provide you with a report on issues that do not meet our requirements and that NAAS cannot fix.-->-->

After uploading your figures to PLOS’s NAAS tool - https://ngplosjournals.pagemajik.ai/artanalysis, NAAS will process the files provided and display the results in the "Uploaded Files" section of the page as the processing is complete. If the uploaded figures meet our requirements (or NAAS is able to fix the files to meet our requirements), the figure will be marked as "fixed" above. If NAAS is unable to fix the files, a red "failed" label will appear above. When NAAS has confirmed that the figure files meet our requirements, please download the file via the download option, and include these NAAS processed figure files when submitting your revised manuscript.-->-->

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols-->

Dear Dr. Reeves,

We are pleased to inform you that your manuscript 'MIAAIM: Multi-Omics Image Integration with Dimensional Reduction for Tissue State Mapping' 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. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Joshua N. Milstein

Academic Editor

PLOS Computational Biology

Virginia Pitzer

Editor-in-Chief

PLOS Computational Biology

***********************************************************

Reviewer's Responses to Questions

Comments to the Authors:

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

Reviewer #2: I am satisfied with the changes to the manuscript and believe the paper is ready for publications. Congratulations to the author for the great work.

**********

Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

**********

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 #2: No