Artificial intelligence (AI) applied to single-cell data has the potential to transform our understanding of biological systems by revealing patterns and mechanisms that simpler traditional methods miss. Here, we develop a general-purpose, interpretable AI pipeline consisting of two deep learning models: the Multi- Input Set Transformer++ (MIST) model for prediction and the single-cell FastShap model for interpretability. We apply this pipeline to a large set of routine clinical data containing single-cell measurements of circulating red blood cells (RBC), white blood cells (WBC), and platelets (PLT) to study population fluxes and homeostatic hematological mechanisms. We find that MIST can use these single-cell measurements to explain 70-82% of the variation in blood cell population sizes among patients (RBC count, PLT count, WBC count), compared to 5-20% explained with current approaches. MIST’s accuracy implies that substantial information on cellular production and clearance is present in the single-cell measurements. MIST identified substantial crosstalk among RBC, WBC, and PLT populations, suggesting co-regulatory relationships that we validated and investigated using interpretability maps generated by single-cell FastShap. The maps identify granular single-cell subgroups most important for each population’s size, enabling generation of evidence-based hypotheses for co-regulatory mechanisms. The interpretability maps also enable rational discovery of a single-WBC biomarker, “Down Shift”, that complements an existing marker of inflammation and strengthens diagnostic associations with diseases including sepsis, heart disease, and diabetes. This study illustrates how single-cell data can be leveraged for mechanistic inference with potential clinical relevance and how this AI pipeline can be applied to power scientific discovery.

The authors have declared no competing interest.

This work was supported by NSF Award 1922658 NRT-HDR: FUTURE Foundations, Translation, and Responsibility for Data Science, a DeepMind Fellowship, and NIH Awards R01HL148248, R01DK123330, and R01HD104756.

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The Mass General Brigham Institutional Review Board approved the study and waived the requirement for informed consent.

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