BRIDGE: Bottleneck-Aware Regulator-Set Inference and Diagnosis for Cooperative Gene Regulatory Recovery

Abstract

Cooperative gene regulation often depends on groups of regulators acting jointly, but most gene regulatory network (GRN) inference methods output pairwise regulator-target rankings. We introduce Bottleneck-Aware Regulator-Set Inference and Diagnosis (BRIDGE), a framework for complete regulator-set recovery, and Targeted Recovery Attribution for Cooperative Evaluation (TRACE), a diagnostic suite that attributes failures to retrieval, set-level scoring, decoding, and evaluation bottlenecks. TRACE includes a leak-free mechanism-mismatch cooperativity stress test in which cooperative targets are generated by random nonlinear mechanisms rather than product interactions. This design avoids feature-mechanism circularity: Residual higher-order set scoring (Residual HOS2) operates on raw expression vectors without handcrafted product-correlation features. Across 30 matched seed-cooperativity settings, Residual HOS2 improves Jaccard similarity from 0.382 to 0.460, recall from 0.522 to 0.597, and exact recovery from 0.053 to 0.113 over a decomposable pairwise set scorer (PairS2), although exact recovery remains low. On SERGIO DS3, oracle retrieval and TRACE show that candidate coverage is necessary but insufficient because set-level misranking remains the dominant source of exact-recovery failure. PairS2 proposal followed by Residual HOS2 reranking reduces HOS2-scored candidate sets by 94-97% while largely preserving exact-recovery behavior. These results distinguish edge ranking, candidate retrieval, set-level scoring, and exact cooperative regulator-set recovery as separate objectives.