Summary
Diagnosing specific genetic mutations in a type of blood cancer called acute myeloid leukemia (AML) usually takes weeks, which delays important treatment decisions. The authors show that data collected quickly from standard blood tests, called flow cytometry, can be used to predict these mutations much earlier. Their computer model looks at individual cells in the test and uses patterns to decide if the mutations are present. This approach matches or beats other prediction methods and clearly links to known biology, making the results easier to understand and trust. This could help doctors start the right treatment sooner without additional tests or costs.
What this means in practice
- •For clinical laboratory teams: Use routine flow cytometry data to predict AML mutation status quickly, enabling faster treatment decisions without waiting for molecular testing.
- •For clinical software developers: Integrate interpretable multi-instance learning models into diagnostic tools to provide real-time mutation predictions from flow cytometry data.
Authors
Jonathan Legrand, Aguirre Mimoun, Baudouin Denis de Senneville, Audrey Bidet, Pierre-Yves Dumas, Christèle Etchegaray
Abstract
Background: Molecular testing for NPM1 and FLT3-ITD mutations guides critical early treatment decisions in acute myeloid leukemia (AML), but results can take weeks, long after these decisions must be made. Flow cytometry, already performed within hours of admission as part of routine care, may carry enough signal to predict these mutations directly, without added cost or delay. Methods: We developed an interpretable multi-instance learning classifier based on a decision tree, in which each patient sample is modeled as a collection of individual cells and mutation status is inferred from cell-level predictions. The model was benchmarked against a random forest trained on clinical variables and a deep convolutional neural network adapted for multitube flow cytometry data. Performance was assessed by cross-validation on a discovery cohort of 197 patients and tested on an independent cohort of 161 patients, using the area under the receiver operating characteristic curve (AUROC) and positive predictive value. Results: In cross-validation on the discovery cohort, the MIL model achieved mean AUROCs of 0.96 (SD=0.05) for NPM1 and 0.86 (SD=0.10) for FLT3-ITD, outperforming the clinical baseline and matching deep learning approaches. The model then successfully generalized to the independent test cohort of 161 patients, reaching AUROCs of 0.90 (NPM1) and 0.82 (FLT3-ITD), with positive predictive values of 0.87 and 0.68, respectively. Cell-level interpretation recovered established immunophenotypic signatures (CD33${}^{+}$ /CD34___ for NPM1-mutated cases, CD33${}^{+}$ /low side-scatter for FLT3-ITD), directly linking model predictions to known biology. Conclusions: These results show that an interpretable model applied to data already collected in routine care can predict AML molecular status within hours, offering a practical route to earlier, biology-informed treatment decisions.