PONE-D-19-27969

Towards guidelines to harmonize textural features in PET:

Haralick textural features vary with image noise, but exposure-invariant domains enable comparable PET radiomics

PLOS ONE

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Additional Editor Comments (if provided):

Both reviewers are in agreement that the revised paper is much improved compared to the original submission. However, the first one is much more reserved, especially with respect to both the overall rationale and the clinical relevance of the work and estimates the most critical points of his first review were not adequatly adressed. The second reviewer has additional comments that will need to be taken into account in the second revision. However, it will require additional results and analyses in order to adequately respond to all initial and new comments of the first reviewer.

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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

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: 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: No

Reviewer #2: Yes

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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: I would like to thank the authors for their answers to my comments. However, their answers do not provide additional rational for the clinical relevance of this study. Although, the study is interesting in its theoretical merit the conclusions drawn are limited. The studied range of exposures is large an authors failed to address its clinical significance. Additionally, the limited set of studied texture features was not addressed. Perhaps other matrices are less prone to the exposure variation.

1. 'The use of a homogenous phantom is completely justified for several reasons, as now stated in the revision:

Line 171 “to quantify a true texture, one must first be able to identify truly homogeneous areas, where any

discerned texture is actually image noise”

We note that any heterogeneous phantom must be scale-invariant if it is to possess the same features over a range of different resolutions, as used in our work (c.f. Lines 137 - 145), and as is required to accommodate multicenter designs.'

Response: I do not agree that the phantom should be scale-invariant. In real life scenario tracer uptake in a tissue is not scale-invariant and thus the control for voxel size in the analysis is important.

2. 'Our result that Haralick feature values vary strongly with exposure, but that there are exposure domains with

stability, is important, and stand in contrast to previous literature. This seems to us more important than attempting

to quantify noise with textural features. In any event, we have incidentally quantified the image noise

thoroughly using nine first-order statistics (Fig. 2 and Table 2). In response to the reviews, we have shifted our

focus to the key point of exposure invariance, and we follow your suggested title change to read,'

Response: here remains the question if the instability is observed for the clinically used exposures, or is the result of wide range used for this study

3. 'Indeed, our main concern here is exposure within a VOI, which is the product of acquisition time and activity

concentration. Therefore, to arrive at comparable feature values between sites, the required exposures will

depend on the sensitivities of the PET/CT systems. These vary over several orders of magnitude depending

on the generation of the PET/CT systems. We used three hour acquisition times as limit to obtain the best

practicably achievable exposure, thus reflecting approaching a gold standard characterized by the smallest

possible noise. Similarly, the three seconds acquisitions represent an according worst case. The extremis

make sure, that clinically relevant exposures with strongly varying acquisition times and strongly varying sensitivity

of the devices fall inside the examined range. '

Response: I understand this reasoning and the differences in the scanner designs. However, could you give an example of a scanner that allows you for clinical image acquisition within 3s per bed position? My concern is that your range, even though it comprises all the clinically relevant times, is so wide that it actually shows the problem mostly in the range which is not clinically used

Reviewer #2: The authors provided a revised manuscript that investigates the dependence of grey level co-occurrence matrix features and several statistical features on exposure in a homogenous Ge-68 phantom. In my opinion, the manuscript improved considerably. Particularly the methods and the results section have been made easier to understand by focussing on one type of discretisation scheme.

I have the following comments:

1. The manuscript is quite long, which may discourage readers from reading it completely. Compare, for example, with Radiology, which allows for 3000 words in the main body, JNM (5000 words, incl. references), EJNMMI (6000 words, incl. references). I found the introduction particularly hard to digest. In the introduction the authors raise multiple points that are nonetheless relevant, but make it difficult for the reader to understand what this study is about. I would recommend to shorten the introduction considerably by summarising some of these points, and, if necessary, integrate some into the discussion.

2. The results contain subsections named “Grey-level co-occurrence matrices” and “Second order statistical features”. I found this somewhat confusing, as second order statistical features are GLCM features (in this work). I would recommend to change these section headers to be more descriptive, or aggregate them into a single section.

3. I would like to commend the authors for focussing on one resampling method only. However, it would be interesting to see what happens when a lower number of bins is selected. For example, Hatt et al. (10.2967/jnumed.114.144055; figure 2) show that some texture feature values (or their correlation with MATV) do depend on the number of bins. The number of bins chosen by the authors is at the high end of this range, which showed relatively few changes. A question that occurred to me was if features extracted from GLCMs with less columns/rows reach stable values earlier? This could be important to inform guidelines. I would recommend 8, 16, 32 bins in addition to the bin numbers already assessed. These values seem to be used more often, see, e.g. Leijenaar et al. (10.1038/srep11075).

4. Lines 103-105: PET/CT sites may be interpreted as anatomical sites instead of centres, which I think is the intended use.

5. Lines 137-139: I am not sure if the reference to nearest neighbourhood operations is necessary. I found it confusing, as it does not seem to bear on the current manuscript.

6. Lines 142-145 “Additionally, the highest …”: This seems to be more fitting for the discussion.

7. Lines 158-160 “The resulting exposures …”: This seems to be more fitting for the discussion. Moreover, what exposures are clinically relevant?

8. Lines 171-173 “(to quantify …”. This seems to be more fitting to the introduction.

9. Line 202: What is a multi-paradigm software?

10. Lines 217-219 “The large number …”: I did not understand the justification.

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Reviewer #1: No

Reviewer #2: No

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Towards guidelines to harmonize textural features in PET:

Haralick textural features vary with image noise, but exposure-invariant domains enable comparable PET radiomics

PONE-D-19-27969R1

Dear Dr. Prenosil,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Mathieu Hatt, MSc, PhD, HDR

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Both reviewers are now satisfied with the revised manuscript. Please take into account the few remaining remarks of reviewer #1 while preparing the final version.

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: (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

Reviewer #2: Yes

**********

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

**********

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

**********

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: (No Response)

Reviewer #2: The authors have adequately addressed my previous remarks.

The following comments are extremely minor:

1. The authors should not that not all references were parsed correctly, e.g. lines 100, 366, 422, 427.

2. Line 221-222: It would be better to explicitly define x-direction and y-direction in the context of a GLCM matrix, to avoid confusion with directions in the image grid.

3. Line 468-469: The sentence structure is not correct, particularly the “… extrema and, and as we have shown previously [47], and …” part.

4. Line 509: I would prefer d > 1 instead of d >> 1.

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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.

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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: Yes: Alex Zwanenburg