-->PONE-D-25-68814-->-->Diagnostic Performance of Abbreviated Non-contrast Liver MRI for Detecting Synchronous Colorectal Liver Metastases-->-->PLOS One

Dear Dr. Charoenchue,

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-->-->The manuscript has been reviewed by two experts in the area. Both thought the work was both well conducted and well described, but they came to quite different conclusions. The proposed reject was based on the availability of several other and similar work in the field. Thus you will have to argue stronger as why this work adds additional value to the collected scientific knowledge. For that reason I decided on a major revision, and I think you will find the detailed comments provided by the reviewers very helpful, should you decide to revise.-->-->

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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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Reviewer #1: No

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: General Assessment:

Well-conducted and clinically relevant study addressing the diagnostic performance of abbreviated non-contrast liver MRI for detection of colorectal metastases (CRLM). The results are strong and generally well presented. Overall, the manuscript would benefit from minor to moderate revisions focused on wording and structure as well as providing some select extra data.

Comments:

1. Statistical Analysis (Section 2.4, lines 190–193)

The reviewer understands the authors’ intention; however, the current wording is misleading and difficult to follow. A clearer explanation of the statistical approach would improve readability.

What the authors appear to have done:

A ROC analysis was performed using the 4-point diagnostic confidence score (0–3) as an ordinal test variable to discriminate between metastasis and non-metastasis. This appropriately reflects the clinically relevant binary decision in routine practice, where confidence scores of 2–3 are typically considered positive and 0–1 negative for presence of CRLM.

Hence:

The AUROC represents the overall discriminatory ability of abbreviated MRI to distinguish patients with and without metastases.

Sensitivity and specificity calculated at the predefined threshold describe test performance at this specific operating point.

Rewriting this passage to explicitly reflect this logic would greatly improve clarity and reduce the risk of misinterpretation.

2. This is along the same vein: Diagnostic performance (lines 231 - 232)

Strong results that clearly are of clinical interest. However, wording should be adjusted, as AUROC does NOT indicated "diagnostic accuracy" but measures discriminatory performance. These two are not identical. Tests with identical AUROC can differ in accuracy (think : total area under the curve is identical, but the shape can differ substantially).

The wording should be adjusted to avoid conceptual imprecision.

3. Interobserver Agreement (lines 234 - 240)

No major criticism, just a suggestion - the authors have used an ordinal scale (0 - 3). Under these circumstances, a weighted kappa (that penalizes disagreements at the levels of 0 and 3 more than on the levels 1 and 2) could be considered rather than an unweighted kappa.

4. False-Positives and False-Negative Findings

These are only mentioned in narrative form, as far as this reviewer can see. To make the paper STARD-compliant, please provide some extra information, preferably in table form , elaborating on absolute number of false positives and negatives (per reader) as well as the classification of these findings (pathology or imaging based) - e.g. hemangioma, FNH, focal fat, etc. This information, summarized in a table should be provided, not necessarily in the main text, but certainly as supplemental information.

5. Discussion on AI / Radiomics

"Future radiomics / AI may improve specificity". This is vague and generic. No AI or Radiomics approach has been implemented in this study. The authors, if they want to include this point, as AI and Radiomics are popular right now, they may at least elaborate no HOW AI and radiomics may address the specific issues described (e.g. DWI-related signal abnormalities and artefacts) or alternatively de-emphasize this point if it only stands as an isolated placative sentence.

However, without grasping for AI or Radiomics, there are other things one could (at least additionally) address to the DWI-related issues: A more immediate and practical message would be to emphasize protocol optimization and quality assurance, especially for DWI, that are crucial in a shortened protocol. With fewer sequences in an abbreviated protocol, there is less redundancy to compensate for artefacts poor image quality. Protocol optimization would be a crucial first step to address these issues without invoking AI solutions and should be emphasized more strongly.

6. DWI speculations (Line 303).

For this clinically oriented paper it is unnecessary to speculate on why certain metastatic lesion exhibit less diffusion restriction. It is sufficient to state this as an observed fact rather than speculate on the underlying mechanisms, that are more complex and numerous than only relatively reduced cellular density.

7. Line 306 - 311

Conceptually reasonable and correct. But there are possible predictors mentioned by the authors without linking them to their own data (there is no analysis on which of their FN patients ad which risk factors). So, the authors could either present and exploratory thesis ("... in our cohort, false negatives occurred in patients), or, if this is purely speculative based on external literature (entirely valid to do so), just state that this is a conceivable hypothesis based on external data in the text.

8. Terminology: "Diagnostic Accuracy" , this time in the discussion

The reviewer is entirely aware that "diagnostic accuracy" is often used as an umbrella term in radiology, encompassing both AUROC and threshold-specific metrics. However, greater conceptual clarity would be preferable. The study evaluated the discriminatory performance of an abbreviated MRI liver for CRLM and demonstrated high sensitivity, specificity and accuracy at the predefined thresholds (e.g. optimal cutoff selected by using Youden's index).

9. Prevalence and Performance Metrics (lines 265 - 266)

The sentence :

“Nevertheless, the sensitivity, specificity, accuracy, and area under the AUROC remain clinically relevant for patients, even in scenarios of lower prevalence.”

should be reworked.

The preceding paragraph correctly explains the higher prevalence of CRLM in the study cohort. Sensitivity, specificity, and AUROC are independent of prevalence, while accuracy is strongly prevalence-dependent.

With lower prevalence (as expected in real-world, non-selected cohorts), the proportion of true negatives increases, and with unchanged specificity, overall accuracy would be expected to increase rather than decrease. Given their results, the authors could argue that accuracy may be even higher in real-world cohorts. The current phrasing undersells the findings.

10. Imaging Protocol Description (lines 280 - 292 and in the Abstract).

Factually correct, but a bit verbose and unclear. It should be more clearly stated that T2 fat-suppressed sequences were used (not T2 non-fat suppressed ). This clarification is important for reproducibility and implementation by other groups.

Overall, it would likely suffice to to note that

T2 fat-suppressed sequences increase lesion conspicuity in CRLM

and

DWI further enhances lesion detectability through exploiting increased diffusion restriction in metastatic lesions.

A detailed discussion of the underlying causes of increased diffusion is unnecessary and rather increases the risk of oversimplifying complex biological causes.

Condensing and focusing this section would improve overall clarity.

11. Limitations section

The limitations section is generally strong, but should be expanded or clarified further:

a) Retrospective Design

The limitations introduced by the retrospective design are not limited to prevalence issues but also introduce other problems such as potential selection-bias and inconsistencies in protocol and timing of examinations.

b) Post Hoc Design of the Abbreviated protocol.

The abbreviated protocol is a post hoc design - it is retroactively extracted from a larger, complete protocol. This is absolutely fine and completely in keeping with study design, but it should be acknowledged that this post hoc design represents also a significant limitation.

A real world optimized abbreviated protocol, as opposed to a post-hoc one, would potentially differ in slice thickness, coverage, b-values, acquisition planes due to different optimizations for time and quality efficiency. There could be different trade offs for SNR, spatial resolution and acquisition time that would be different in a purely A Priori designed Abbreviated protocol. The necessity of likely higher needs of reliability and quality in an abbreviated protocol have been pointed out earlier in these comments.

c) Scanner and Vendor Heterogeneity

Scanners from multiple vendors were used, as well as different field strengths. Potentially there were even differences in software versions between the scanners. This introduces heterogeneity due to e.g. differences in coil-configuration, gradient performance, fat-suppression methods, EPI train lengths, b-value implementation, artefact burden, etc.

This should be acknowledged in the paper as a limitation affecting internal validity. However, at the same time, it should be pointed out that this can function simultaneously as a strength, at this heterogeneity not only increases external validity but also more closely reflects clinical reality.

Nonetheless, this should be mentioned.

11. Conclusion

a) Wording and scope, lines 327 - 333

"High diagnostic performance" could be tempered a bit - yes, it was sufficiently powered, but a sample size of n=87 is still not enormous, especially in an enriched high-prevalence cohort. Maybe "good to excellent diagnostic performance" or, "high diagnostic performance in this selected cohort" would be alternatives.

b) The statement that "non-contrast MRI may serve as a viable alternative" is correct and acceptable, but should be qualified (e.g. "for many patients" or "for selected staging scenarios"), given the observed false negatives and false positives.

c) This reviewers main problem with the discussion stems from a single sentence. The reviewer is certain that usage was unintentional, but strongly believes wording should be changed.

line 333: "particularly when contrast administration is contraindicated or impractical."

The first part : "contraindicated" is entirely correct and appropriate. Circumstances such as renal failure, prior severe reaction to contrast, pregnancy or severe allergy are all good reasons to avoid giving contrast.

However, "impractical" is not only vague but is bordering on the inappropriate. In a cancer staging context, when exactly is giving contrast "impractical"? Busy list? Limited contrast budget? Patient late in the day?

The reviewer is convinced that any of the above mentioned reasons are absolutely not what the authors intended to express. Given the stakes in an oncological context (resectability, survivability), "impractical" sounds like cutting corners rather than a medically justified choice.

Should the authors want to name a second category beyond "contraindicated", clearly clinical considerations should be considered as an alternative, such as for example "resource-limited settings were contrast is unavailable" or similar reasonings.

Otherwise a good and contructive discussion.

Reviewer #2: This is a relatively well performed and presented work on a clinically particularly relevant topic, namely the use of non-contrast MRI for the detection of liver metastases in patients with colorectal cancer.

However, I do struggle to find the novelty in this work compared to the other published studies in the same topic (e.g. ref 16, 18 and 19). It would be of great value if the authors could explain in Introduction (and Discussion) section(s) their motivation to undertake this study when there are already numerous studies in the literature on the same topic.

Other points to consider:

-Were there any patients with mucinous colorectal cancers and if yes, how could the authors differentiate metastatic depositions in the liver from cysts and/or hemangiomas?

- Abstract, line 38: “This study evaluates” should be reworded to an “Aim” and ideally it should be identical to the one in the last paragraph in the Introduction section

- Abstract, Materials and Methods: The years of performing the study should be mentioned

- Introduction, line 72: “Kidney issues”, what is the difference with the next sentence in lines 73-74?

- Introduction, lines 93-95: Hypothesis should be moved higher up and also has to be expanded to include hypothesis regarding the secondary objective. The Aims should be positioned in the last paragraph of the Introduction

- Table 1: there is no meaning having statistical comparisons (and thus p-values) in Patient Characteristics. There was no hypothesis testing here.

- In general, the authors should try to round up numbers when it is of minor importance to have decimals (i.e., mean age 65.03 makes no sense; similarly 58.6% is similar to 59%)

- Results, line 235-236: what was the reason for presenting “other reliability metrics” when the Cohen’s kappa was already evaluated?

- Fig 3: the arrow in C is misplaced.

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Reviewer #1: No

Reviewer #2: No

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Diagnostic Performance of Abbreviated Non-contrast Liver MRI for Detecting Synchronous Colorectal Liver Metastases

PONE-D-25-68814R1

Dear Dr. Charoenchue,

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