Classification of Stroke Etiology Using Advanced Computational Approaches

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PROJECT SUMMARY/ABSTRACT This proposal is an application for the K23 Mentored Patient-Oriented Research Career Development Award designed to prepare Dr.Richa Sharma, MD, MPH for a career in independent, patient-oriented academic vascular neurology. Dr.Sharma is an early career clinician scientist who holds an Assistant Professor appointment at the Yale School of Medicine. Her long-term goal is to establish a stroke clinical research laboratory that applies advanced computational techniques to better inform implementation of evidence-based secondary stroke prevention treatments as well as discovery of novel therapeutics. In order to accomplish this goal, Dr.Sharma seeks to fulfill her training objectives of: 1) furthering her skills in data science to manage and process high-dimensional datasets; 2) gaining facility with advanced computational techniques; 3) developing a foundation in biomarker-based clinical trial methodology; and 4) acquiring core competencies necessary to independently lead a research program. Through the mechanism of this training grant, Dr.Sharma will have the opportunity to complete directly relevant formal coursework, master fundamental research methodologies, and generate a portfolio of work that will be critical for obtaining independent research funding. Dr.Sharma has the full support of her mentoring team which includes Dr.Harlan Krumholz, a cardiologist and outcomes researcher who specializes in harnessing big data to improve care; co-mentor Dr.Lauren Sansing, a vascular neurologist and a translational scientist with expertise in stroke and investigation of biologic data; co-mentor Dr.Cynthia Brandt, an emergency medicine physician and an informatician who is an expert in electronic medical record research; co-mentor Dr.Hongyu Zhao, an expert biostatistician adept at analysis of data from a myriad of sources including health record and biologic data; and co-mentor Dr.Hooman Kamel, a neurointensivist and a prolific stroke clinical researcher. This mentorship team, along with collaborators and esteemed advisory committee, will provide Dr.Sharma with the guidance, resources, and support necessary to reach these goals and transition to academic independence. There are nearly 800,000 ischemic strokes per year, of which the underlying cause of 20-40% of these strokes is unknown. Consequently, secondary stroke therapies may not specifically target the pathology that led to the stroke, potentially resulting in an unmitigated risk for a recurrent, potentially more devastating ischemic stroke. We aim to address this diagnostic uncertainty through a series of analyses. The proposed research will utilize novel methods to analyze electronic health record data of patients admitted with acute ischemic stroke to 3 healthcare systems (Yale-New Haven Hospital, Massachusetts General Hospital, and the Veterans Affair Health Administration Hospitals in the United States), proteomic, neuroimaging, and survey data from a subgroup of stroke patients, and clinical trial data to achieve 2 specific aims: 1) to classify non-cryptogenic ischemic stroke etiologies assigned to patients during hospitalization using EHR inputs; 2) to predict the diagnosis of initially cryptogenic patients whose strokes are resolved to a specific etiology by 1-year follow-up.