was pathogenically related to the index stroke (Model #1). We will also develop, among patients with both a CS and a PFO, a predictive model to estimate patient-specific stroke recurrence risk based on clinical, radiographic and echocardiographic characteristics. (Model #2). We will then combine Models #1 and #2 into a composite index that can rank patients with CS and PFO by their conditional probability that their PFO was pathogenically related to the index stroke and the risk of stroke recurrence. Finally, we will apply this composite index to completed clinical trials (currently on-going) testing endovascular PFO closure against medical therapy, to stratify patients from low-expected-benefit to high-expected-benefit. Background Approximately 40% of all strokes are classified as cryptogenic, meaning that the cause is unknown despite an extensive work up [ 1 ]. While patent foramen ovale (PFO) is a common and generally benign condition found on autopsy in about 25% of the population [ 2 - 4 ], approximately 40% to 50% of patients younger than age 55 with cryptogenic stroke (CS) have PFO on transesophageal echocardiography (TEE) [ 4 - 7 ]. Furthermore, a PFO is found more frequently in patients with CS than in patients with a known cause of stroke, even in the elderly patient [ 7 - 9 ], These association suggest that PFO has an etiological role in CS, presumably via paradoxical emboli (PE) (i.e. venous emboli that gain access to the arterial circulation through a PFO) [ 7 ]. Thus, many physicians will recommend PFO