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PONE-D-23-05111Molecular signature to predict quality of life and survival with glioblastoma using Multiview omics modelPLOS ONE

Dear Dr. Alrfaei,

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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: Partly

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: I Don't Know

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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: No

Reviewer #2: 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

Reviewer #2: 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: In this study, the authors proposed a bioinformatics analysis to predict quality of life and survival with glioblastoma using multi-omics model. Although the performance seems promising, some major points should be addressed as follows:

1. All analyses were conducted on TCGA public data without any validation.

2. At least mutations in the driver genes should be investigated.

3. It is unclear why iRF has been used as a feature selection method rather than the others. This step even can be done using traditional approaches i.e., univariate, statistical tests, etc. Thus, the authors should describe this part clearly or have a baseline comparison on it.

4. The authors reported ROC AUC and PRC but they did not show ROC curves, PR curves.

5. More references on bioinformatics workflow i.e., PMID: 35851932, PMID: 34572330 should be added to attract a broader readership.

6. Literature review is insufficient; the authors may improve it using some related works on bioinformatics-based glioblastoma.

7. Quality of figures should be improved.

Reviewer #2: The authors have applied the iRF algorithm to differentiate between short and long-term GBM survival and KPS and then computationally validated their findings. The overall material presented in this paper has integrated quality of life metrics into the study of quantitative cancer analysis, which is not often done in the field. Following is the list of questions and suggested areas of improvement for the authors:

1. The materials and methods section of this paper needs to be presented much before the results sections of the paper as it makes it difficult to interpret the results without understanding the mechanics of all the algorithms involved. The description of methods in the results section is breif and vague and leaves the readers with lots of questions regarding the methods. I would suggest the authors to explain their analysis pipeline well in the introduction section, if they are unable to move the methods section prior to the results. Keeping the diverse background of the PLOS ONE readership in mind, it is important to note that not all readers will be aware of methods used in this paper, prior to reading the methods section.

2. The abstract and introduction introduces the topic of integrative omics, the authors need to clarify the meaning of this term very lucidly in these early sections of the paper. For example, they can state that it integrates omics data with patient-level clinical data to identify biomarkers or molecular signatures.

3.The authors to explain the KPS scale in detail in the introduction section. For example what does it mean to say QOL >= 80 KPS.

4. Please explain why iRF method was used, how it is relevant to your dataset, and what other methods did you consider.

5.In the result sections , page 10, paragraph 1: The authors should explicitly mention that they are using iRF to classify between long and short term GBM survival, if not please provide more clarification of the objective here.

6.In the results sections the authors have presented AUPR scores with confidence intervals multiple times, they need to provide some qualitative explanation or significance of the results to the readers here. Also the authors need to clarify the parameters K=5 and Ba =10, and how these values were determined.

7. The authors state that "Additionally, we used iRF to recover the important interactions between these features." Can they explain what is the meaning of the term "important interactions", what is the process involved here in determining these interactions ? Is this a pairwise score between features or is a feature importance metric ?

8.Please explain the meaning of stability scores for example in the line "Recovered interactions are shown in Figure 2, which include stability scores for both OS ≥ 2years (Fig. 2a) and QOL ≥ 80 KPS (Fig. 2b)."

9.In the functional annotation and interaction analysis section, are any of the pathways the author found previously implicated in GBM or other cancers increased survival and positive clinical outcomes , i.e. OS>=2 and QOL >= 80 KPS ? Or are they new to the GBM literature ?

10. The authors need to clarify how the elastic net penalties were calculated or assigned for CPH regression model.

11. Please explain if the PCA validation was done on the entire dataset or on a specific hold out or test data set ? This needs to be clearly explained as validation must be carried out on a dataset on which the models were not trained.

12.Please cite the R Studio, here is a link on how to do it: https://psyteachr.github.io/quant-fun-v2/citing-r-rstudio.html

13.Figure 1 has only labels 'a' and 'b', the other labels mentioned in the figure caption are missing.

14. The overall english language should be reviewed thoroughly, there are typos in the manuscript, the gene names should be italicized, and figure resolutions need improvement.

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Reviewer #1: No

Reviewer #2: No

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Molecular signature to predict quality of life and survival with glioblastoma using Multiview omics model

PONE-D-23-05111R1

Dear Dr. Alrfaei,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Aniruddha Datta

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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: All comments have been addressed

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: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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

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: 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: My previous comments have been addressed well. Thus, I suggest it for publication on the current form.

Reviewer #2: I commend the authors for making the changes and substantially improving the quality of this article. This will be an important contribution to the area and interesting paper for the scientist in the community to read. Good luck and well done !!

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7. 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

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