Candidate: Zachary S. Wallace, MD is an Instructor in Medicine at Harvard Medical School (HMS) and an Assistant in Medicine in the Rheumatology Unit at Massachusetts General Hospital (MGH). After his undergraduate degree in History from Cornell University, he received his MD at Georgetown University. He completed his medicine residency and rheumatology fellowship at MGH, during which Dr. Wallace began working with Hyon Choi, MD, DrPH. Dr. Wallace conducts patient-oriented research of multi-system rheumatic conditions, especially ANCA-associated vasculitis (AAV), which has resulted in 20 peer-reviewed original papers, with 10 as the first author and 6 in Arthr Rheum and Ann Rheum Dis. Dr. Wallace is completing his Master of Science in Epidemiology at Harvard University. His goal is to become an independent investigator and world-class leader in patient-oriented research of AAV and multi-system rheumatic conditions. Mentorship, Training Activities, and Environment: Dr. Wallace will conduct the proposed project at MGH under the mentorship of Hyon Choi, MD, DrPH and co-mentorship of John Stone, MD, MPH and Rochelle Walensky, MD, MPH. Dr. Choi is a world-renowned, NIH-funded physician scientist in advanced clinical epidemiology of rheumatic conditions, ranging from common disorders to rare but serious disorders (e.g., AAV). He has severed as a mentor for several prior K awardees. Dr. Stone is a clinical investigator and expert in AAV who has led landmark trials in AAV and other vasculitides. Dr. Walensky is an expert in decision science, simulation modeling, and cost-effectiveness analysis. Dr. Wallace' research will also benefit from the specific expertise of his key collaborators, including covariate definition algorithms, lipid analysis, quality of life measures, and external validation. To complement the expertise of his mentors, he will acquire new skills through didactics on advanced clinical epidemiology, pharmacoepidemiology, and simulation modeling. Research: Despite advances in AAV care, it continues to carry a 4-fold higher risk of cardiovascular disease (CVD), a 2-fold higher risk of death, and a significant quality-of-life impairment compared to the general population. The central goal of this research is to improve long-term AAV outcomes by determining the impact of key potential predictors such as ANCA types and initial treatment choice (rituximab (RTX) & cyclo- phosphamide (CYC)) on CVD risk, mortality, and quality-adjusted life years (QALYs). To achieve this goal, he will examine the impact of ANCA type and initial treatment choice on CVD and mortality in a large longitudinal AAV cohort using validated algorithms to assess covariates in electronic medical records (Aims 1& 2). He will also study the effect of RTX and CYC on lipid profiles using frozen samples from a randomized trial (Aim 2). Finally, he will project QALYs associated with initial induction therapy choice and ANCA type in a simulation model (Aim 3). Completion of this proposal and training plan will position Dr. Wallace with the vital experience to become an independent clinical investigator in patient-oriented research of AAV and similar conditions.

PROJECT NARRATIVE The management of ANCA-associated vasculitis (AAV) has evolved in recent years and led to remarkable improvements in the care of AAV patients. However, AAV remains associated with excess cardiovascular disease and death as well as impaired quality of life when compared to the general population. This Career Development Award focuses on applying advanced clinical epidemiology and simulation modeling to understand how ANCA type and induction treatment strategies impact these long-term patient-oriented outcomes with the expectation that this knowledge will impact management decisions.