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| Name | Class |
|---|---|
| Thomas Jefferson University | OTHER |
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We propose the novel integration of two echocardiographic technologies - three-dimensional echocardiography using semi-automated right ventricular analysis coupled with the administration of ultrasound enhancing agents - to improve the inter-rater reliability and accuracy of various measures of right ventricular size and function, compared with cardiac MRI.
Patients with repaired congenital heart disease with residual pulmonary insufficiency represent a challenging group of patients with congenital heart disease as they develop progressive right ventricular dilation and failure, increasing the risk for sudden cardiac death and often necessitating pulmonary valve replacement. These patients require close follow-up with serial cardiac imaging; however, the complex three-dimensional structure of these dilated right ventricles renders them difficult to adequately image with traditional two-dimensional echocardiography. Due to these difficulties, cardiac MRI is the current gold standard for assessing right ventricular size and function in these patients. However, cardiac MRI is costly and less accessible for patients than echocardiography. Although initial studies comparing 3D echocardiography with MRI showed that 3D echocardiography underestimates right ventricular size, recent advances in three-dimensional imaging technologies which utilize automated ultrasound "speckle-tracking" and artificial intelligence technology are lessening this inherent bias. Furthermore, the use of commercially-available ultrasound enhancing agents made of lipid microspheres has improved left ventricular endocardial border detection, inter-rater reliability and correlation of 3D echocardiography obtained estimates of left ventricular size and function compared with Cardiac Magnetic Resonance (CMR). However, their use has yet to be applied to the three-dimensional echocardiographic assessment of the right ventricle in congenital heart disease despite their ability to improve right ventricular endocardial border detection with three-dimensional echocardiography in adults. The investigators propose the novel integration of two echocardiographic technologies - three-dimensional echocardiography using semi-automated right ventricular analysis coupled with the administration of ultrasound enhancing agents - to change the paradigm of how clinicians assess the right ventricles of patients with repaired congenital heart disease with residual pulmonary insufficiency. The investigators hypothesize that ultrasound enhancing agents will improve the inter-rater reliability and accuracy of various measures of right ventricular size and function, compared with cardiac MRI, thereby filling an important gap in existing methods for assessing right ventricular function. Lastly, because of the current limitations in assessing right ventricular function in this population, as a secondary aim, the investigators will also assess three-dimensional right ventricular strain -- a novel quantitative surrogate of right ventricular function.
Overall Objectives: To shift the paradigm in the assessment of right ventricular size and function by developing a protocol to assess the right ventricles in patients with repaired congenital heart disease with residual pulmonary insufficiency by integrating the use of three-dimensional echocardiography with semi-automated right ventricular analysis software with the intravenous administration of ultrasound enhancing agents.
Specific Aim 1. To compare the accuracy and inter-rater reliability of 3D echocardiography-based measurements of right ventricular end-diastolic volume, end-systolic volume, and ejection fraction, with and without contrast, with MRI derived values in patients with repaired congenital heart disease with residual pulmonary insufficiency.
Specific Aim 2. To compare the accuracy and inter-rater reliability of 3D echocardiography measurement of right ventricular strain with MRI derived right ventricular (RV) strain in patients with repaired congenital heart disease with residual pulmonary insufficiency.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| diagnostic arm | Experimental | Contrast enhanced 3D echo (Lumason) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sulfur Hexafluoride Lipid Type A Microspheres 25 MG Injection Powder for Suspension [LUMASON] | Drug | The patient will receive the weight-based dose of Lumason of 0.03 mL/kg per injection, not to exceed 2.4 mL per injection per the FDA and manufacturer recommendations. |
| Measure | Description | Time Frame |
|---|---|---|
| Accuracy of 3D Echocardiography Based Measurements of Right Ventricular Size Compared to MRI Derived Values. | Echocardiography derived measurements of right ventricular end-diastolic volume, end-systolic volume, with and without contrast, and MRI derived values in patients with repaired congenital heart disease | All images were obtained on the same day of the study. MRI analysis performed by clinical reading attending. Echo analysis performed offline after completing of imaging. |
| Accuracy of 3D Echocardiography Based Measurements of Right Ventricular Function Compared to MRI Derived Values. | Echocardiography derived measurements of right ventricular ejection fraction, with and without contrast, and MRI derived values in patients with repaired congenital heart disease | All images were obtained on the same day of the study. MRI analysis performed by clinical reading attending. Echo analysis performed offline after completing of imaging. |
| Inter-rater Reliability of 3D Echocardiography Based Measurements of Right Ventricular Size and Function With and Without Contrast | The agreement of echocardiography derived measurements of right ventricular end-diastolic volume, end-systolic volume, and ejection fraction, with and without contrast, will be compared between the two readers using the intraclass correlation coefficient. | All echocardiographic images obtained on the day of the study participation. Analysis done offline. |
| Measure | Description | Time Frame |
|---|---|---|
| Comparing Echocardiographic and MRI Derived Right Ventricular Strain Measurement. | 3D echocardiography measurement of right ventricular strain will be compared with MRI derived RV strain in patients with repaired congenital heart disease using an intraclass correlation coefficient. | Echocardiography and MRI images obtained on the day of study participation. Analysis done after image acquisition complete |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Nemours Childrens Hospital | Wilmington | Delaware | 19803 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25156915 | Background | Weinberg CR, McElhinney DB. Pulmonary valve replacement in tetralogy of Fallot. Circulation. 2014 Aug 26;130(9):795-8. doi: 10.1161/CIRCULATIONAHA.114.005551. No abstract available. | |
| 21251297 | Background | Geva T. Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support. J Cardiovasc Magn Reson. 2011 Jan 20;13(1):9. doi: 10.1186/1532-429X-13-9. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Diagnostic Arm | The echocardiography team will perform baseline echocardiographic views of the right ventricle without contrast. The patient will receive the weight-based dose of Lumason of 0.03 mL/kg per injection, not to exceed 2.4 mL per injection per the FDA and manufacturer recommendations. Dosages and timing of administration as well as patient size and transducer type will be recorded for each patient. The total cumulative dose of Lumason from the clinical study and the research study will not exceed the maximum recommended dose by the manufacturer, 4.8 mL. A single injection will not exceed the maximal FDA-recommended dose of 2.4 mL per single injection. These echocardiographic views of the right ventricle with ultrasound enhancing agent will be compared to the measurements made without the use of ultrasound enhancing agents, and the measurements made in MRI. Sulfur Hexafluoride Lipid Type A Microspheres 25 MG Injection Powder for Suspension [LUMASON]: The patient will receive the weight-based dose of Lumason of 0.03 mL/kg per injection, not to exceed 2.4 mL per injection per the FDA and manufacturer recommendations. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 6, 2022 |
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| 24468055 | Background | Valente AM, Cook S, Festa P, Ko HH, Krishnamurthy R, Taylor AM, Warnes CA, Kreutzer J, Geva T. Multimodality imaging guidelines for patients with repaired tetralogy of fallot: a report from the AmericanSsociety of Echocardiography: developed in collaboration with the Society for Cardiovascular Magnetic Resonance and the Society for Pediatric Radiology. J Am Soc Echocardiogr. 2014 Feb;27(2):111-41. doi: 10.1016/j.echo.2013.11.009. No abstract available. |
| 20797527 | Background | Shimada YJ, Shiota M, Siegel RJ, Shiota T. Accuracy of right ventricular volumes and function determined by three-dimensional echocardiography in comparison with magnetic resonance imaging: a meta-analysis study. J Am Soc Echocardiogr. 2010 Sep;23(9):943-53. doi: 10.1016/j.echo.2010.06.029. |
| 26647080 | Background | Muraru D, Spadotto V, Cecchetto A, Romeo G, Aruta P, Ermacora D, Jenei C, Cucchini U, Iliceto S, Badano LP. New speckle-tracking algorithm for right ventricular volume analysis from three-dimensional echocardiographic data sets: validation with cardiac magnetic resonance and comparison with the previous analysis tool. Eur Heart J Cardiovasc Imaging. 2016 Nov;17(11):1279-1289. doi: 10.1093/ehjci/jev309. Epub 2015 Dec 8. |
| 29908725 | Background | Laser KT, Karabiyik A, Korperich H, Horst JP, Barth P, Kececioglu D, Burchert W, DallaPozza R, Herberg U. Validation and Reference Values for Three-Dimensional Echocardiographic Right Ventricular Volumetry in Children: A Multicenter Study. J Am Soc Echocardiogr. 2018 Sep;31(9):1050-1063. doi: 10.1016/j.echo.2018.03.010. Epub 2018 Jun 19. |
| 26237996 | Background | Medvedofsky D, Addetia K, Patel AR, Sedlmeier A, Baumann R, Mor-Avi V, Lang RM. Novel Approach to Three-Dimensional Echocardiographic Quantification of Right Ventricular Volumes and Function from Focused Views. J Am Soc Echocardiogr. 2015 Oct;28(10):1222-31. doi: 10.1016/j.echo.2015.06.013. Epub 2015 Aug 1. |
| 30858745 | Background | Jenner J, Sorensson P, Pernow J, Caidahl K, Eriksson MJ. Contrast Enhancement and Image Quality Influence Two- and Three-dimensional Echocardiographic Determination of Left Ventricular Volumes: Comparison With Magnetic Resonance Imaging. Clin Med Insights Cardiol. 2019 Mar 5;13:1179546819831980. doi: 10.1177/1179546819831980. eCollection 2019. |
| 15036021 | Background | van den Bosch AE, Meijboom FJ, McGhie JS, Roos-Hesselink JW, Ten Cate FJ, Roelandt JR. Enhanced visualisation of the right ventricle by contrast echocardiography in congenital heart disease. Eur J Echocardiogr. 2004 Mar;5(2):104-10. doi: 10.1016/S1525-2167(03)00048-9. |
| 20513701 | Background | Mueller M, Rentzsch A, Hoetzer K, Raedle-Hurst T, Boettler P, Stiller B, Lemmer J, Sarikouch S, Beerbaum P, Peters B, Vogt M, Vogel M, Abdul-Khaliq H. Assessment of interventricular and right-intraventricular dyssynchrony in patients with surgically repaired tetralogy of Fallot by two-dimensional speckle tracking. Eur J Echocardiogr. 2010 Oct;11(9):786-92. doi: 10.1093/ejechocard/jeq067. Epub 2010 May 30. |
| 23537972 | Background | Friedberg MK, Fernandes FP, Roche SL, Slorach C, Grosse-Wortmann L, Manlhiot C, Fackoury C, McCrindle BW, Mertens L, Kantor PF. Relation of right ventricular mechanics to exercise tolerance in children after tetralogy of Fallot repair. Am Heart J. 2013 Apr;165(4):551-7. doi: 10.1016/j.ahj.2012.06.029. Epub 2013 Mar 5. |
| 12084585 | Background | Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002 Jun 19;39(12):1890-900. doi: 10.1016/s0735-1097(02)01886-7. |
| 30121240 | Background | Stout KK, Daniels CJ, Aboulhosn JA, Bozkurt B, Broberg CS, Colman JM, Crumb SR, Dearani JA, Fuller S, Gurvitz M, Khairy P, Landzberg MJ, Saidi A, Valente AM, Van Hare GF. 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Apr 2;73(12):1494-1563. doi: 10.1016/j.jacc.2018.08.1028. Epub 2018 Aug 16. No abstract available. |
| 29084778 | Background | Heng EL, Gatzoulis MA, Uebing A, Sethia B, Uemura H, Smith GC, Diller GP, McCarthy KP, Ho SY, Li W, Wright P, Spadotto V, Kilner PJ, Oldershaw P, Pennell DJ, Shore DF, Babu-Narayan SV. Immediate and Midterm Cardiac Remodeling After Surgical Pulmonary Valve Replacement in Adults With Repaired Tetralogy of Fallot: A Prospective Cardiovascular Magnetic Resonance and Clinical Study. Circulation. 2017 Oct 31;136(18):1703-1713. doi: 10.1161/CIRCULATIONAHA.117.027402. |
| 17620511 | Background | Oosterhof T, van Straten A, Vliegen HW, Meijboom FJ, van Dijk AP, Spijkerboer AM, Bouma BJ, Zwinderman AH, Hazekamp MG, de Roos A, Mulder BJ. Preoperative thresholds for pulmonary valve replacement in patients with corrected tetralogy of Fallot using cardiovascular magnetic resonance. Circulation. 2007 Jul 31;116(5):545-51. doi: 10.1161/CIRCULATIONAHA.106.659664. Epub 2007 Jul 9. |
| 29502588 | Background | Porter TR, Mulvagh SL, Abdelmoneim SS, Becher H, Belcik JT, Bierig M, Choy J, Gaibazzi N, Gillam LD, Janardhanan R, Kutty S, Leong-Poi H, Lindner JR, Main ML, Mathias W Jr, Park MM, Senior R, Villanueva F. Clinical Applications of Ultrasonic Enhancing Agents in Echocardiography: 2018 American Society of Echocardiography Guidelines Update. J Am Soc Echocardiogr. 2018 Mar;31(3):241-274. doi: 10.1016/j.echo.2017.11.013. No abstract available. |
| 27959665 | Background | Yusuf GT, Sellars ME, Deganello A, Cosgrove DO, Sidhu PS. Retrospective Analysis of the Safety and Cost Implications of Pediatric Contrast-Enhanced Ultrasound at a Single Center. AJR Am J Roentgenol. 2017 Feb;208(2):446-452. doi: 10.2214/AJR.16.16700. Epub 2016 Dec 13. |
| 16965977 | Background | Piscaglia F, Bolondi L; Italian Society for Ultrasound in Medicine and Biology (SIUMB) Study Group on Ultrasound Contrast Agents. The safety of Sonovue in abdominal applications: retrospective analysis of 23188 investigations. Ultrasound Med Biol. 2006 Sep;32(9):1369-75. doi: 10.1016/j.ultrasmedbio.2006.05.031. |
| 31038768 | Background | Kumar S, Purtell C, Peterson A, Gibbons P, Khan AM, Heitner SB. Safety profile of ultrasound enhancing agents in echocardiography. Echocardiography. 2019 Jun;36(6):1041-1044. doi: 10.1111/echo.14344. Epub 2019 Apr 30. |
| 11897214 | Background | Yong Y, Wu D, Fernandes V, Kopelen HA, Shimoni S, Nagueh SF, Callahan JD, Bruns DE, Shaw LJ, Quinones MA, Zoghbi WA. Diagnostic accuracy and cost-effectiveness of contrast echocardiography on evaluation of cardiac function in technically very difficult patients in the intensive care unit. Am J Cardiol. 2002 Mar 15;89(6):711-8. doi: 10.1016/s0002-9149(01)02344-x. |
| 29050828 | Background | Medvedofsky D, Mor-Avi V, Kruse E, Guile B, Ciszek B, Weinert L, Yamat M, Volpato V, Addetia K, Patel AR, Lang RM. Quantification of Right Ventricular Size and Function from Contrast-Enhanced Three-Dimensional Echocardiographic Images. J Am Soc Echocardiogr. 2017 Dec;30(12):1193-1202. doi: 10.1016/j.echo.2017.08.003. Epub 2017 Oct 17. |
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| ID | Title | Description |
|---|---|---|
| BG000 | Diagnostic Arm | Contrast enhanced 3D echo (Lumason) |
| Units | Counts |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||||
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| Diagnosis | Baseline Cardiac Diagnosis | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Accuracy of 3D Echocardiography Based Measurements of Right Ventricular Size Compared to MRI Derived Values. | Echocardiography derived measurements of right ventricular end-diastolic volume, end-systolic volume, with and without contrast, and MRI derived values in patients with repaired congenital heart disease | Two patients were unable to be analyzed for either the contrast or non-contrast group due to imaging quality and lack of complete 3D echo dataset | Posted | Mean | Standard Deviation | ml | All images were obtained on the same day of the study. MRI analysis performed by clinical reading attending. Echo analysis performed offline after completing of imaging. |
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| Primary | Accuracy of 3D Echocardiography Based Measurements of Right Ventricular Function Compared to MRI Derived Values. | Echocardiography derived measurements of right ventricular ejection fraction, with and without contrast, and MRI derived values in patients with repaired congenital heart disease | Two patients were unable to be analyzed for either the contrast or non-contrast group due to imaging quality and lack of complete 3D echo dataset | Posted | Mean | Standard Deviation | percentage | All images were obtained on the same day of the study. MRI analysis performed by clinical reading attending. Echo analysis performed offline after completing of imaging. |
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| Primary | Inter-rater Reliability of 3D Echocardiography Based Measurements of Right Ventricular Size and Function With and Without Contrast | The agreement of echocardiography derived measurements of right ventricular end-diastolic volume, end-systolic volume, and ejection fraction, with and without contrast, will be compared between the two readers using the intraclass correlation coefficient. | The initial second reader for the study was no longer available and no new second reader was able to be recruited for the study, therefore data was not collected for inter-rate reliability measures and data will never be analyzed in the future for this Outcome Measure given the timeframe for study completion. | Posted | All echocardiographic images obtained on the day of the study participation. Analysis done offline. |
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| Secondary | Comparing Echocardiographic and MRI Derived Right Ventricular Strain Measurement. | 3D echocardiography measurement of right ventricular strain will be compared with MRI derived RV strain in patients with repaired congenital heart disease using an intraclass correlation coefficient. | Images with sufficient quality were analyzed to obtain Global longitudinal strain values (expressed as a percentage) | Posted | Mean | Standard Deviation | percentage strain | Echocardiography and MRI images obtained on the day of study participation. Analysis done after image acquisition complete |
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Diagnostic Arm | Contrast enhanced 3D echo (Lumason) Sulfur Hexafluoride Lipid Type A Microspheres 25 MG Injection Powder for Suspension [LUMASON]: The patient will receive the weight-based dose of Lumason of 0.03 mL/kg per injection, not to exceed 2.4 mL per injection per the FDA and manufacturer recommendations. | 0 | 25 | 0 | 25 | 1 | 25 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| chest pain | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Participant reported pain which PI assessed as musculoskeletal. Resolved. |
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We acknowledge several limitations in our single-center study including the small sample size. Many patients had poor or suboptimal image quality which likely contributes to inaccuracies in calculation of RV size by echocardiography. The software used to analyze the RD echocardiography images was not designed for use with contrast enhanced echocardiograms potentially limiting the accuracy.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Shannon Nees, MD | Nemours Children's Hospital, Delaware | 302-651-6600 | shannon.nees@nemours.org |
| Apr 23, 2025 |
| Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D013771 | Tetralogy of Fallot |
| D012131 | Respiratory Insufficiency |
| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D013535 | Suspensions |
| ID | Term |
|---|---|
| D003102 | Colloids |
| D045424 | Complex Mixtures |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
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| Unknown or Not Reported |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Pulmonary stenosis |
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| Truncus arteriosus |
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| Other |
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Measurements of right ventricular end-diastolic volumes were compared between two groups using an intraclass coefficient
| Intraclass coefficient |
| 0.77 |
| 2-Sided |
Intraclass coefficient using a two-way mixed effects model |
| Other |
| Measurements of right ventricular end-systolic volumes were compared between two groups using an intraclass coefficient | Intraclass coefficient | 0.71 | 2-Sided | Intraclass coefficient using a two-way mixed effects model | Other |
| Measurements of right ventricular end-systolic volumes were compared between two groups using an intraclass coefficient | Intraclass coefficient | 0.685 | 2-Sided | Intraclass coefficient using a two-way mixed effects model | Other |
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