Artificial intelligence–driven quantification of sickle red blood cell morphology as an objective disease marker

Abstract: In patients with sickle cell disease (SCD), heterogeneity in erythrocyte morphology, attained via subjective interpretation with high interobserver variability, complicates erythrocyte morphology examination for clinical monitoring and treatment evaluation. We developed an observer-independent assay that quantifies different morphologically abnormal erythrocytes grouped with high discriminatory accuracy using an automated, artificial intelligence (AI) algorithm. This assay was used to investigate whether quantification of the fractions of morphologically abnormal erythrocytes in patients with SCD can be used as an objective measure of clinical severity, and to evaluate treatment efficacy. A total of 172 patients with SCD were included in the analyses. At 21% oxygen, patients with homozygous sickle cell anemia (HbSS) and compound heterozygous sickle cell–β⁰-thalassemia (HbSβ⁰) appeared to have significantly higher percentages of classic sickle cells and other aberrant cell types compared with patients with sickle cell hemoglobin C disease (HbSC). In addition, a present vaso-occlusive episode at the time of sampling was significantly associated with an increased number of aberrant erythrocyte morphologies. We also evaluated the applicability of our AI morphology-based assay for monitoring treatment effects in patients with SCD, by monitoring the effect of voxelotor on sickle erythrocyte morphologies in vitro. We observed increased erythrocyte sickling at low voxelotor doses compared with both higher doses and nontreated erythrocytes. The effects of voxelotor on erythrocyte sickling observed in this study may provide a possible explanation of the recently reported clinical side effects of this drug seen in patients with SCD, leading to the withdrawal of the drug from the market. These results show that our AI morphology-based assay might serve as an objective marker of disease severity and treatment efficacy.