PROJECT SUMMARY Over 95% of liver transplant (LT) recipients have only one opportunity to receive a new liver during their lifetimes and long-term patient survival depends upon prolonged graft functioning. As a result of advances in immunosuppression (IS), over 70% of recipients survive more than 5 years after LT, yet wide variability exists in clinical outcomes at the center-level. Most late post-LT deaths are not directly due to liver failure, but reflect the adverse consequences of prolonged IS therapy. Due to the lack of national recommendations to guide IS after LT, its management differs across centers. Moreover, comparative efficacy and safety data for IS regimens are only available from small trials and meta-analyses. Their interpretation and generalizability are limited due to the following factors: 1) care is often provided in settings that do not reflect “real world” clinical practice; 2) few IS regimens are compared, often at a single time point; 3) late or rare outcomes are missed, and 4) publication bias is evident. Population-level research is therefore needed to evaluate comprehensively the comparative effectiveness and safety of IS regimens for LT. Understanding center differences in IS management will also identify suboptimal practices, and further encourage the development of standardized guidelines. Since fewer than 10% of the observed variability in post-transplant outcomes can be explained by pre-LT factors, we hypothesize that targeting differences in post-LT management, such as IS regimen selection, has the potential to change practice and improve outcomes on a wider scale. Using a novel linkage of transplant data from the United Network for Organ Sharing and Medicare claims, the primary aims of the proposed research are the following: Aim 1 – to describe center variability in IS management in the US; Aim 2 – to evaluate the association between IS regimen and the risks of graft failure and mortality; and Aim 3 – to determine the association between IS regimen and the risks of acute rejection, severe infection and de novo cancer as potential mechanisms for the relationships identified in Aim 2. This proposal will also foster Dr. Bittermann's career development into a fully independent NIH-funded clinical investigator with a scientific focus in LT pharmacoepidemiology and practice variability, facilitated through a comprehensive mentorship plan. This will be accomplished by: 1) additional coursework on advanced methodologies through the Center for Clinical Epidemiology and Biostatistics (CCEB) at the University of Pennsylvania, 2) direct implementation of these acquired techniques under the close supervision of a carefully selected team of faculty with extensive expertise in pharmacoepidemiology, transplant hepatology, and outcomes research, as well as longstanding experience with successfully mentoring prior grant recipients, 3) involvement in the Center for Pharmacoepidemiology Research and Training in the CCEB, and 4) dev...