scHFBiMamba: a bidirectional Mamba autoencoder for cardiac disease-state classification from single-nucleus RNA-seq data

Abstract

To evaluate whether a compact bidirectional state-space autoencoder improves joint classification of species, cell type, and disease state from single-nucleus RNA-sequencing profiles in heart failure (HF), while yielding interpretable gene attributions. Building on the dense denoising autoencoder (DAE) and MLP framework of Ruz Jurado et al., we developed scHFBiMamba, combining a bidirectional Mamba autoencoder (BiMambaAE) with an MLP head. BiMambaAE maps 16,545-gene profiles to 350-dimensional latent representations using 13.2M parameters, about 14.6-fold fewer than the dense DAE (192.9M). We compared six encoder-classifier configurations on 38,275 held-out cardiac nuclei using McNemar tests with Benjamini-Hochberg correction, and assessed nine classifiers on frozen representations. Biological relevance was evaluated by comparing SHAP-derived differentially explained genes with differentially expressed genes against curated HF-related Gene Ontology keywords. BiMambaAE+MLP achieved the highest aggregate F1: pooled macro-F1 across 13 outputs was 0.966 versus 0.957 for DAE+MLP, and the mean category macro-F1 was 0.977 versus 0.970. It significantly improved cell-type and disease-state accuracy (adjusted p=7.1e-3 and p=4.8e-6, respectively), with species F1 of 1.000. SHAP-derived differentially explained genes achieved a pathway-enrichment benchmark F1 of 0.105 versus 0.053 for differentially expressed genes. Compact bidirectional state-space autoencoders can outperform substantially larger dense autoencoders for joint cardiac transcriptomic classification while reducing parameters. scHFBiMamba enables accurate multi-task prediction and hypothesis-generating gene-level interpretation. Code: https://github.com/UgoLomoio/scHFBiMamba.