Automated Deep Learning-Based Diagnosis and Molecular Characterization of Acute Myeloid Leukemia Using Flow Cytometry

Abstract

The current flow cytometric analysis of blood and bone marrow samples for diagnosis of acute myeloid leukemia (AML) relies heavily on manual intervention in the processing and analysis steps, introducing significant subjectivity into resulting diagnoses and necessitating highly trained personnel. Furthermore, concurrent molecular characterization via cytogenetics and targeted sequencing can take multiple days, delaying patient diagnosis and treatment. Attention-based multi-instance learning models (ABMILMs) are deep learning models that make accurate predictions and generate interpretable insights regarding the classification of a sample from individual events/cells; nonetheless, these models have yet to be applied to flow cytometry data. In this study, we developed a computational pipeline using ABMILMs for the automated diagnosis of AML cases based exclusively on flow cytometric data. Analysis of 1820 flow cytometry samples shows that this pipeline provides accurate diagnoses of acute leukemia (area under the receiver operating characteristic curve [AUROC] 0.961) and accurately differentiates AML vs B- and T-lymphoblastic leukemia (AUROC 0.965). Models for prediction of 9 cytogenetic aberrancies and 32 pathogenic variants in AML provide accurate predictions, particularly for t(15;17)(PML::RARA) [AUROC 0.929], t(8;21)(RUNX1::RUNX1T1) (AUROC 0.814), and NPM1 variants (AUROC 0.807). Finally, we demonstrate how these models generate interpretable insights into which individual flow cytometric events and markers deliver optimal diagnostic utility, providing hematopathologists with a data visualization tool for improved data interpretation, as well as novel biological associations between flow cytometric marker expression and cytogenetic/molecular variants in AML. Our study is the first to illustrate the feasibility of using deep learning-based analysis of flow cytometric data for automated AML diagnosis and molecular characterization.

Keywords: acute myeloid leukemia; attention-based multi-instance learning models; automated deep-learning based analysis; automated diagnosis; flow cytometry.