As a principal investigator in the proposed research, my role will be to apply HLA and ABO population genetics and informatics tools to immunogenetics datasets to develop an equitable ABO-compatible kidney allocation system policy, using my ABO-adjusted CPRA metric as a lever. We presented some of the preliminary data in an oral abstract talk at American Transplant Congress in June 2024. I have a longstanding enthusiastic interest in understanding the role of immune compatibility in access to transplantation and expect this project will further expand the impact of my work in kidney and stem cell transplantation. I have the expertise in HLA immunogenetics, informatics, and statistics necessary to complete this project.
My career path in immunogenetics began at the US bone marrow donor registry National Marrow Donor Program (NMDP) in the Bioinformatics Research department led by Martin Maiers. My research projects at NMDP translated directly into informatics systems that enabled rapid identification of HLA-matched registry donors. I received comprehensive training in statistical population genetics from Dr. Bill Klitz, an important mentor and collaborator from University of California-Berkeley. I pursued my PhD coursework at the University of Minnesota (UMN) while holding a full-time position at NMDP, enabling me to take new computer science and statistical methods straight from the classroom into my projects. As a senior researcher at NMDP, I hired several bioinformatics interns with many mentored research projects translating into publications. Though my industry position required me to focus primarily on building informatics tools and data to improve stem cell registry operations, our contributions had broader impacts across the field of immunogenetics.
My primary research focus at Tulane University School of Medicine is to adapt the HLA informatics technologies and registry datasets we developed in the stem cell transplant field towards new applications in solid organ transplantation and other immune-mediated diseases. An important project in solid organ transplant, improving the metric for HLA antibody sensitization (CPRA), was sponsored by United Network for Organ Sharing and successfully implemented in US national solid organ allocation system in 2023. Dr. Mankowski are PIs on an R01 project to integrate HLA molecular mismatch metrics into kidney organ allocation policy and have been begun publishing our data together (see MedRxiv preprint citation below). I am also co-investigator on two discovery-related NIAID projects in HLA/KIR genomics and HLA amino acid mismatching with NYU and UPenn. Tulane’s research environment is highly conducive to the clinical-translational aspects of my work. Towards this end I recently became a board-certified histocompatibility lab director and am surrounded by experienced investigators, clinicians, and educators. I have mentored three PhDs so far in my research lab who have each tackled diverse and impactful projects, and my lab currently has four PhD mentees, including a T32 trainee awardee. My strong track record of contributions in immunogenetics and transplant informatics demonstrates my capability to successfully perform the proposed research.
Ongoing and recently completed projects that I would like to highlight include:
NIDDK Research Project Grant R01DK139240 2024-03-01 to 2029-02-28 “Increasing Equity and Utility in Deceased Donor Kidney Allocation with HLA Molecular Matching”
The goal of this project is to design kidney allocation policy that would increase graft longevity with closer donor-recipient HLA matching. Historically HLA matching has been de-emphasized to address ethnic disparities in access, but our novel personalized immune compatibility likelihood (PICL) metric will enable increased emphasis on HLA matching without increasing disparity. We utilize high resolution HLA data for modeling HLA matching and apply evolutionary machine learning to identify optimal kidney allocation policy. Role: PI
NIAID Research Project Grant 2022-11-01 to 2027-10-31
“HLA Immunogenetics and Kidney Allograft Outcomes” [R01AI173095]
The goal of this project is to determine which categories of HLA amino acid mismatches best predict kidney graft failure and development of donor-specific HLA antibodies that cause graft rejection. My role on the project is development of HLA bioinformatics methods to extract and analyze HLA genotyping and antibody assay data for kidney transplant pairs at ten different participating centers and from the outcomes registry Scientific Registry for Transplant Recipients (SRTR) and interpret the findings in the context of HLA immunobiology.
Role: Co-investigator
HLA and KIR Region Genomics in Immune-Mediated Diseases 2020-07-01 to 2025-06-30 “MHC and KIR Sequencing and Association Analyses in the iGeneTRAiN Studies” [U01AI152960] The goal of this project is to identify MHC and KIR region genetic associations with solid organ transplant outcomes, integrating targeted HLA genotyping, genome-wide genotyping, and whole exome sequencing on multiple cohorts. My role on this project is to perform the association analysis for HLA amino acid motifs using the sequence feature variant type framework for structure and functional annotation of HLA molecules. Role: Co-investigator
National Marrow Donor Program (NMDP) Sponsored Project 2015-09-01 to 2024-08-31
“HLA Bioinformatics”
The goal of this sponsored project is to continue my collaboration with the NMDP Bioinformatics Research department in improving informatics systems and population genetics reference data for registry HLA matching in stem cell transplantation. Through this funding, my access to the tools and datasets I developed during my 12 years of employment at NMDP will be maintained indefinitely for adaptation and translation to adjacent areas such as solid organ transplantation and immunogenomic disease association studies.
Role: PI
United Network for Organ Sharing (UNOS) Sponsored Project 2020-08-01 to 2023-12-31 “Update CPRA Calculation”
This sponsored project funded development of a calculated panel reactive antibody (CPRA) calculator to measure HLA sensitization for the Organ Procurement and Transplantation Network (OPTN) organ allocation system. The CPRA calculator implementation released on January 26, 2023 utilizes a reference panel of stem cell donor HLA genotyping from NMDP to include high resolution unacceptable antigens across all 11 classical HLA loci. Our recent publication in AJT provides the rationale for our novel approach of utilizing stem cell donors for a more accurate, comprehensive, and specific CPRA metric that will improve equity in allocation.
Role: PI
Citations that I would like to highlight include:
1. Kransdorf E, Pando M, Stewart D, Lindblad K, Patel J, Kim I, Zhang X, Maiers M, Kobashigawa J, Gragert L. (2021) Stem Cell Donor HLA Typing Improves CPRA in Kidney Allocation. American Journal of Transplantation 21(1):138-147.
2. Gragert L, Kadatz M, Alcorn J, Stewart D, Chang D, Gill J, Liwski R, Gebel HM, Gill J, Lan JH. (2022) ABO-adjusted calculated panel reactive antibody (cPRA): A unified metric for immunologic compatibility in kidney transplantation. American Journal of Transplantation 22(12):3093-3100. [PMCID: PMC10087664]
3. Mankowski MA, Gragert L, Segev DL, Montgomery R, Gentry SE, Mangiola M. (2024) Balancing Equity and HLA Matching in Deceased-Donor Kidney Allocation with Eplet Mismatch. MedRxiv DOI: 10.1101/2022.01.13.22269268 [Preprint]
4. Mankowski MA, Akizhanov D, Sentry SE, Segev DL, Gragert L. (2024) ABO-Compatible Kidney Allocation with ABO-Adjusted CPRA. American Journal of Transplantation 24(6) Supp.1 S545 [ATC Oral Abstract]
