Development of the sickle cell outcome grading system (SCOGS), a novel classification system for sickle cell disease severity

Abstract

Abstract Background Sickle cell disease (SCD) is a chronic, multisystem condition. This disorder causes red blood cells to sickle, resulting in vaso-occlusion, hemolysis, and progressive end-organ damage. As individuals with SCD age, they are increasingly at risk for both acute and chronic complications. These complications contribute to significantly diminished quality of life, high health care utilization, and early mortality. Despite the known burden of disease, there remains no universally accepted method to quantify or classify the severity of SCD complications in a standardized and reproducible manner. The absence of a consensus severity grading system has created challenges in clinical care, research, quality improvement, and design of therapeutic trials. Objective We aimed to develop an ordinal disease severity grading system specifically for SCD complications. The resulting system, named the Sickle Cell Outcome Grading System (SCOGS), is intended to serve as a uniform framework to standardize how complications of SCD are classified and graded. SCOGS will allow for more consistent phenotyping of patients across studies and institutions, facilitate objective assessment of disease burden. Methods We employed a three-round Delphi consensus methodology to develop the grading system. A total of 34 SCD clinical experts from across North America were invited to participate, and 29 accepted the invitation. Of these, 16 (55.2%) were pediatric hematologists, 5 (17.2%) were adult hematologists, and 8 (27.6%) were trained in both internal medicine and pediatrics. The core study team first compiled a comprehensive list of 50 known SCD-related complications through expert input and literature review. Each outcome was mapped to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, which uses a five-point ordinal severity scale. Where CTCAE criteria did not fully capture the SCD-specific nature of an outcome, the definitions and grading criteria were adapted to SCD using experts and relevant literature. For each outcome, we documented the rationale for the grading and identified diagnostic criteria. The initial SCOGS definitions were circulated to the panelists, who were asked to rate their agreement with the classification of each outcome using a 9-point Likert scale (1 = completely disagree; 9 = completely agree). Free-text feedback was collected for each response. Consensus was predefined as ≥70% of panelists selecting scores of 7–9 for agreement. Outcomes that failed to reach consensus were revised based on feedback and resubmitted in subsequent rounds. Following each round, reviewer comments were analyzed, and iterative modifications were made. In areas of continued disagreement or complexity, the core team consulted with 18 ad hoc content experts to include additional expertise to inform the development of the classification. Results The response rates for each Delphi round were: 29/29 (100%) in round 1, 28/29 (97%) in round 2, and 27/29 (94%) in round 3. In round 1, consensus was achieved for 26 of 50 (52%) outcomes. Based on reviewer feedback, 2 outcomes were removed, and 3 new outcomes were added. In round 2, 18 of 22 (82%) outcomes reached consensus. In the third round, consensus was achieved for 2 of 4 (50%) outcomes, and 2 additional outcomes were added. Throughout the process, expert commentary led to meaningful refinements in definitions, diagnoses, and grading to ensure clinical applicability. The final SCOGS framework consists of 53 SCD outcomes spanning hematologic, neurologic, cardiopulmonary, musculoskeletal, renal, hepatobiliary, ophthalmologic, reproductive, and psychosocial domains. Conclusion Through a structured Delphi process that engaged a panel of SCD experts, we successfully developed SCOGS, a comprehensive, consensus-based disease severity classification tool. SCOGS encompasses 53 graded outcomes reflecting the full clinical spectrum of SCD. It provides a standardized approach to classifying and comparing disease burden, which can enhance clinical trials, epidemiological research, and quality improvement initiatives. By enabling a more objective, reproducible, and detailed phenotypic assessment of individuals with SCD, SCOGS holds promise as a foundational tool for improving both clinical care and research infrastructure. Validation studies are underway using a large, longitudinal cohort of individuals living with SCD to test feasibility, reliability, and clinical utility.