CADS: Measuring the Incremental Contribution of LLM Proposers in Sequential Biological Screens

Overview & Synopsis

Large language models are increasingly used to guide sequential biological screens, yet standard evaluations rely on raw hit counts that conflate a proposer's value with the discovery capacity of the underlying algorithmic harness. Adaptive sampling and corrupted experimental readouts also leave standard feedback comparisons without a false-discovery guarantee. We present Certified Agentic Discovery Screens (CADS), an error-controlled measurement framework that quantifies a proposer's incremental value against an identical LLM-free loop. By integrating capped likelihood-ratio bounds, e-processes, and complete-family e-BH, CADS controls the terminal false discovery rate under the stated null and corruption conditions despite arbitrary dependence, adaptive sampling, and optional stopping. In DepMap-backed simulations, CADS exposes two evaluation artifacts: the LLM-free harness alone clears the feedback gate, and raw origin counts overstate LLM contributions because LLM picks displace fallback discoveries. On the initial 20 seeds, supplying tested-candidate history to Qwen2.5-7B shifts its net contribution from +0.35, with a 95% interval covering zero, to +2.90, with the interval above zero. This initial net effect did not persist in a 50-seed matched-quota replication. These results support net gain over an LLM-free loop, measured between separately certified sets, as the appropriate measure of proposer contribution.