-->PONE-D-25-69091-->-->Facilitating early diagnosis of chronic thromboembolic pulmonary hypertension with dynamic chest radiography: protocol for a multicenter, assessor-blinded, case-wise randomized superiority reader study (FIND-DCR)-->-->PLOS One

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Additional Editor Comments:

Please revise it based on the reviewers' feedback.

This multicenter, assessor-blinded reader study evaluates whether adding dynamic chest radiography (DCR) with pulmonary circulation analysis to the standard initial work-up for suspected pulmonary hypertension improves the diagnostic accuracy for chronic thromboembolic pulmonary hypertension (CTEPH).

A total of 108 cases will be randomized 1:1 to either standard work-up alone or standard work-up plus DCR. The primary endpoint is the accuracy of distinguishing CTEPH from non-CTEPH, using guideline-based final diagnoses as the reference standard. Secondary outcomes include sensitivity, specificity, predictive values, agreement with V/Q scintigraphy, and safety metrics. Recruitment runs from 2025 to 2027.

1. What specific mechanistic advantages does DCR-based pulmonary circulation analysis provide over the standard initial work-up in distinguishing CTEPH from non-CTEPH?

2. How does the study design control for reader-related biases, including inter-reader variability and potential learning or expectation effects when interpreting DCR-enhanced cases?

This question targets:

3. How will discordant findings between DCR and V/Q scintigraphy be analyzed, particularly in cases where DCR identifies perfusion defects not seen on V/Q or vice versa

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1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

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Reviewer #1: Yes

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-->2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

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Reviewer #1: Partly

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-->3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

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Reviewer #1: Yes

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Reviewer #1: Yes

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-->6. Review Comments to the Author

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Reviewer #1: MAJOR POINTS:

1. A key question is how well-established Dynamic chest radiography (DCR) is in Japan. Is it widely available?

2. Acute symptomatic pulmonary embolism on imaging within 3 months prior to enrolment is an exclusion. However, in Europe a recent PE is oftentimes the first evidence of CTEPH. In fact, a majority of CTEPH diagnoses in Europe emerge from an acute PE presentation (acute-on-chronic).

3. One disadvantage of a ‘high-probability of PH’ approach is that authors will be missing all CTEPH cases with normal RVs. Should be acknowledged.

4. I am unclear on whether chest CT is part of the ‘case package’ that is sent to the core lab. To leave out CTPA is a significant disadvantage for the patients and is not GL recommended. Modern CT delivers iodine maps and parenchymal imaging that is diagnostically relevant. Authors should describe precisely how CTPA participates in this study. If a reader receives a ‘case package’ the diagnosis may be evident without DCR. Please, explain.

MINOR POINTS:

5. PPS should be mentioned as an exclusion.

6. The title of the study should be DCR-FIND, and not FIND-DCR.

7. Replace V/Q scintigraphy with perfusion scintigraphy because that is what you are planning to do

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Reviewer #1: No

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Facilitating early diagnosis of chronic thromboembolic pulmonary hypertension with dynamic chest radiography: protocol for a multicenter, assessor-blinded, case-wise randomized superiority reader study (FIND-DCR)

PONE-D-25-69091R1

Dear Dr. Hosokawa,

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Kind regards,

Yoshiaki Taniyama, MD, PhD

Academic Editor

PLOS One

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