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VAMP-Net: An Interpretable Multi-Path Network of Genomic Permutation-Invariant Set Attention and Quality-Aware 1D-CNN for MTB Drug Resistance

Genomic prediction of drug resistance in Mycobacterium tuberculosis is often hindered by complex epistatic interactions and variable sequencing quality. We present the Interpretable Variant-Aware Multi-Path Network (VAMP-Net), a novel architecture addressing these challenges through a dual-pathway approach. Path-1 utilizes a Set Attention Transformer to model permutation-invariant variant sets and capture epistatic dependencies, while Path-2 employs a 1D-CNN to analyze VCF quality metrics for adaptive confidence scoring. Evaluated on four critical anti-TB drugs, VAMP-Net significantly outperforms baseline CNN and MLP models, achieving accuracies > 95% and AUCs around 0.97 for Rifampicin and Rifabutin. Feature attribution analysis via Integrated Gradients successfully recovered canonical targets (rpoB, embB, katG) and discovered high-impact novel loci. Functional enrichment confirmed these novel variants constitute non-random metabolic modules (p=0.00239) centered on cell-wall remodeling. Furthermore, systematic ablation of the Quality-Aware pathway demonstrates that the model performs a learned "integrated audit," prioritizing the Fraction of Supporting Reads and relative confidence over raw depth to mitigate technical noise. This dual-layer interpretability, bridging genomic pathogenicity with technical reliability, establishes a new paradigm for robust, auditable, and clinically actionable resistance prediction, positioning VAMP-Net as an important tool for both diagnostic classification and mechanistic discovery in clinical genomics.

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