Though cardiac transplantation is a lifesaving intervention, cardiac allograft rejection (CAR) remains a relatively common and serious complication that confers an increased risk of acute graft failure and adverse patient outcomes. For three decades, endomyocardial biopsy (EMB) with histological grading, as recommended by the International Society of Heart and Lung Transplantation (ISHLT) has been the broadly applied standard for CAR diagnosis. However, it is widely appreciated that the ISHLT rejection grading standard lacks diagnostic accuracy and has limited ability to discern the mechanism of rejection. These limitations expose patients to risks of both over-treatment and under-treatment, and highlight the unmet need for more accurate and informative approaches to histopathologic analysis of EMB samples. Our team is a leader in computational pathology image analysis with over 200 papers and >30 issued patents in this area. We have already developed and evaluated a computer assisted histopathology grading evaluation (CACHE) scheme which (1) in N=205 patients, had an area under the receiver operating characteristic curve (AUC)=0.95 compared to two cardiac pathologists (mean AUC=0.74) in distinguishing normal from failing hearts and (2) could distinguish low and high ISHLT rejection grades in N=1109 patients with a performance that exceeds that of trained cardiac pathologists. Recognizing the frequent discordance between ISHLT rejection grade and the clinical trajectory of a rejection event, we will further develop and optimize CACHE to identify new ?grade agnostic? morphologic biomarkers of clinically serious CAR. Our scientific premise is that morphologic biomarkers prioritized based on their correlation to patients? clinical trajectories and underlying immunological disease mechanisms will generate an accurate, consistent and informative classifier for diagnosing allograft rejection. In service of this hypothesis, the proposed research will address three specific aims.
In Aim 1, we will utilize computational image analysis to discover the morphologic biomarkers of rejection-related injury which are needed to develop a classifier capable of assessing the clinical trajectory of CAR.
In Aim 2, we will provide mechanistic annotation of biomarkers identified in Aim 1 through correlation with in-situ immunologic markers using custom multi-parameter immunofluorescence panels.
In Aim 3, we employ a multicenter, prospective cohort to validate the diagnostic and mechanistic accuracy of the new rejection classifier developed in Aims 1 and 2. Ultimately, development of a more accurate and mechanistically informative tool for morphologic diagnosis of CAR will improve patient outcomes by reducing over- and under- treatment and inspire applications in other organ transplants. Interestingly, development of a superior histologic diagnostic tool will empower development of alternative, biopsy-free diagnostic approaches that have been handicapped by the necessity of comparison with the flawed ISHLT rejection grade as a reference standard.

Public Health Relevance

For heart transplant recipients, allograft rejection remains a relatively common and serious complication associated with adverse patient outcomes. Shortcomings of the current rejection grading standard for heart biopsies leads to both over- and under-treatment, accordingly, this proposal will develop and validate a computer assisted rejection grading classifier that is more accurate, consistent and informative for diagnosing heart allograft rejection. Improved diagnostic accuracy will improve patient outcomes, inspire similar applications in other organ transplants and empower development of additional technologies that have been constrained by the current flawed rejection standard.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Luo, James
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code