Beyond Fixed Acquisition Functions: Temporal Difference Active Learning for Perturbation Discovery

High-throughput gene perturbation experiments can test several genetic interventions in parallel, yet experimental budgets remain limited. A central goal is hit discovery: identifying as many perturbations as possible whose phenotypic effect exceeds a predefined threshold. Pure exploration strategies are statistically inefficient, wasting budget on low-value regions. Bayesian optimization methods offer a principled alternative but target a single global optimum, over-exploiting dominant modes while neglecting other high-value regions. We formalize hit discovery as a sequential experimental design problem and propose Probability-of-Hit, an acquisition function that directly targets threshold exceedance by ranking candidates according to their posterior probability of being a hit. We prove asymptotic optimality of this approach and demonstrate strong empirical performance on both synthetic benchmarks and real biological immunology datasets, including up to 6.4% improvement over baselines on the Schmidt IL-2 dataset.

Real-world deployment of active learning typically forces practitioners to choose an acquisition strategy before any data is labeled. This is a daunting task: strategy performance varies widely across settings (e.g. datasets, surrogate models) and cannot be assessed without deployment. Existing strategy selection methods explore one strategy from a portfolio at each round and identify the optimal one using bandit feedback or model retraining. Many acquisition rounds are therefore spent exploring strategies rather than collecting the most informative data. Such overhead is a major barrier to AL-driven design of high-throughput experiments, such as genetic perturbation screens and directed evolution, where AL runs consist of only a few rounds with large batch sizes. This regime permits a natural alternative: acquiring data using multiple AL strategies within a single batch. We refer to this as soft strategy selection and introduce FractAL, a method specifically designed for this task. FractAL infers a per-strategy reward using influence-function-based data attribution, which requires no additional retraining, and then computes budget shares for each strategy in the portfolio using online mirror descent. We benchmark FractAL across 7 setups spanning classification, regression, and genetic perturbation effect prediction. The results highlight that strategy selection is a hard problem: every existing method performs worse than random sampling on at least one setup. FractAL, however, matches or outperforms every baseline, including random sampling, on all 7 setups. Its allocations concentrate budget on the strongest strategies in the portfolio while pruning the weakest. FractAL is therefore a reliable choice for real-world deployments, where the optimal strategy is unknown in advance, an important step towards making AL practical for high-throughput experiments and modern scientific discovery.

Many biological discovery problems require experiments to be selected sequentially under constrained budgets. CRISPR screening is a prominent example, as exhaustive perturbation testing is often infeasible and candidate perturbations must instead be prioritized over multiple experimental rounds. Despite the importance of this problem, existing benchmarks for adaptive hit discovery remain limited in scale and diversity. Here, we introduce AssayBench-Loop, a large-scale benchmark for adaptive hit discovery comprising 1,389 CRISPR screens across five phenotype categories. Beyond enabling systematic evaluation, its scale makes it possible to learn acquisition strategies across historical experiments. Building on this resource, we introduce AssayLoop, a sequential experimental design framework combining AssayFormer, a transformer-based amortized acquisition policy trained across historical screens to adapt from experimental feedback, with LLM-derived biological priors through an adaptive handoff. In this view, completed experiments become training data for learning how accumulated evidence should guide what to test next, while LLMs provide prior biological knowledge to seed the search. We further introduce AssayLLM, showing that the same principle can be extended directly to an LLM through task-specific post-training. On temporally held-out screens, AssayLoop achieves a 5.67-fold enrichment over random selection and recovers 27.7% of hits after assaying approximately 5% of the candidate library, outperforming existing adaptive-design methods and standalone LLMs, and AssayFormer alone. Performance improves with increasing historical training data and transfers to phenotype categories excluded from training. These results demonstrate the value of learning acquisition policies across historical experiments and combining them with broad biological priors for efficient adaptive hit discovery.