Scalable and semi-automated Boolean network inference from multi-condition single-cell transcriptomes with scBOLT

Predictive logical models have made substantial contributions to biomedical research by facilitating the identification of regulatory mechanisms driving biological processes. Yet, their construction remains a major bottleneck, as it typically relies on extensive prior knowledge at the genome scale. The emergence of high-throughput omics technologies has opened new opportunities for data-driven logical model construction by providing high-resolution observations of biological states. In parallel, formal constraint-based approaches have emerged, reformulating executable model inference as a constraint-satisfaction problem. However, transforming omics observations into biologically meaningful Boolean state abstractions and dynamical constraints suitable for logical synthesis engines remains challenging, particularly for poorly understood biological systems and multi-condition experimental settings. To address these challenges, we introduce scBOLT, a semi-automated framework for Boolean constraint engineering and logical model inference from multi-condition single-cell transcriptomes. Beyond these methodological contributions, scBOLT substantially improves computational tractability, enabling the inference of Boolean networks comprising several hundred components within practical runtimes.