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The pathologic diagnosis of bone marrow disorders relies in part on the microscopic analysis of bone marrow aspirate (BMA) smears and the manual counting of marrow nucleated cells to obtain a differential cell count (DCC). This manual process has significant limitations, including the analysis of only a small subset of optimal slide areas and nucleated cells, as well as interobserver variability due to differences in cell selection and classification. To address these shortcomings, we developed an automated machine learning-based pipeline for obtaining 11-component DCCs on whole-slide BMAs. This pipeline uses a sequential process of identifying optimal BMA regions with high proportions of marrow nucleated cells, detecting individual cells within these optimal areas, and classifying these cells into 1 of 11 DCC components. Convolutional neural network models were trained on 396,048 BMA region, 28,914 cell boundary, and 1,510,976 cell class images from manual annotations. The resulting automated pipeline produced 11-component DCCs that demonstrated a high statistical and diagnostic concordance with manual DCCs among a heterogeneous group of testing BMA slides with varying pathologies and cellularities. Additionally, we demonstrated that an automated analysis can reduce the intraslide variance in DCCs by analyzing the whole slide and marrow nucleated cells within all optimal regions. Finally, the pipeline outputs of region classification, cell detection, and cell classification can be visualized using whole-slide image analysis software. This study demonstrates the feasibility of a fully automated pipeline for generating DCCs on scanned whole-slide BMA images, with the potential for improving the current standard of practice for utilizing BMA smears in the laboratory analysis of hematologic disorders., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Bone marrow aspirate (BMA) differential cell counts (DCCs) are critical for the classification of hematologic disorders. While manual counts are considered the gold standard, they are labor intensive, time consuming, and subject to bias. A reliable automated counter has yet to be developed, largely due to the inherent complexity of bone marrow specimens. Digital pathology imaging coupled with machine learning algorithms represents a highly promising emerging technology for this purpose. Yet, training datasets for BMA cellular constituents, critical for building and validating machine learning algorithms, are lacking. Herein, we report our experience creating and employing such datasets to develop a machine learning algorithm to detect and classify BMA cells. Utilizing a web-based system that we developed for annotating and managing digital pathology images, over 10,000 cells from scanned whole slide images of BMA smears were manually annotated, including all classes that comprise the standard clinical DCC. We implemented a two-stage, detection and classification approach that allows design flexibility and improved classification accuracy. In a sixfold cross-validation, our algorithms achieved high overall accuracy in detection (0.959 ± 0.008 precision-recall AUC) and classification (0.982 ± 0.03 ROC AUC) using nonneoplastic samples. Testing on a small set of acute myeloid leukemia and multiple myeloma samples demonstrated similar detection and classification performance. In summary, our algorithms showed promising early results and represent an important initial step in the effort to devise a reliable, objective method to automate DCCs. With further development to include formal clinical validation, such a system has the potential to assist in disease diagnosis and prognosis, and significantly impact clinical practice.