PROJECT SUMMARY/ABSTRACT Chronic pain (CP) is a major cause of morbidity and poor quality of life in sickle cell disease (SCD). CP, defined as the presence of ‘pain on most days of the past 6 months’, is a major cause of morbidity and poor Health Related Quality of Life (HRQoL) in SCD. The impact of CP is variable, with some individuals experiencing severe, disabling pain and pain interference with daily activities, while others experience CP without activity limitations. High-Impact Chronic Pain (HICP), defined as chronic pain with disability, represents a severely-impacted sub-group with CP that has not been characterized in SCD, which represents a critical knowledge gap. In the candidate’s K23 award, she found compelling evidence for the presence of a severely- affected subgroup of CP in the Pain in Sickle Cell Epidemiology Study (PiSCES), the largest natural history study of pain in SCD. To better study HICP in SCD in the clinical setting, patients seeking consultation for curative hematopoietic cell transplant (HCT) were formally screened for HICP, as HICP had been added as an inclusion criteria for clinical trials of HCT in SCD in 2019. By identifying the clinical correlates of HICP in this existing cohort (Aim 1), the candidate will develop a draft prototype for an electronic health record (EHR)- derived “computational phenotype”, which is a defined and reproducible set of data elements that can be used for automated identification of HICP from the EHR in future studies. This unique cohort with SCD and HICP will be studied in conjunction with existing longitudinal EHR data allowing the candidate to explore longitudinal trajectories of pain episode frequency in HICP over several years. To compliment the study of HICP in children with SCD, the candidate will also perform a secondary analyses of the PiSCES data to characterize outcomes in adults with CP analogous to HICP, i.e. those with severe or frequent pain interference, and identify predictors of severe or frequent pain interference (Aim 2). The completion of these aims will characterize the phenotype of HICP in SCD, its impact on outcomes, and develop a draft prototype of a computational phenotype to identify individuals with HICP from the EHR. The candidate’s preliminary findings and access to unique existing cohorts provide unprecedented opportunities to investigate HICP in SCD, addressing a major knowledge gap. This proposal is a new but related extension of the candidate’s K23 award, and these key preliminary data will directly inform the candidate’s R01 proposal, allowing her to becoming a successful, independent investigator in chronic pain in SCD.