Discover, Falsify, Revise: Auditing Input-Use Claims from Source Code to Predictive Contribution in Agent-Discovered Cell Models

b001AI virtual cells aim to predict cellular responses to specified interventions, yet held-out predictive performance alone does not establish use of the supplied perturbation information. This prediction–claim gap is especially consequential in agentic model discovery, where language-model agents generate and revise predictors using predominantly score-based feedback. We introduce CellAudit, which audits registered input-use claims through three distinct questions: whether the input can enter the cited computation, whether fitted predictions depend on it, and whether that dependence improves prediction of observed responses. On a paired morphology–transcriptomics perturbation benchmark (BBBC047), an agent-selected predictor achieves a mean held-out Global Pearson correlation coefficient (PCC) of 0.3153 yet remains exactly invariant to compound replacement; a control-profile-only predictor reaches 0.3142. Source inspection identifies a compound-query pathway blocked by singleton key–value attention; the invariance persists after refitting with physically disjoint control wells for inputs and target references. In a stratified audit of 48 generated candidates across two linked tasks, 47 change predictions under compound replacement on both held-out folds, but only 20 show target-loss gains with intervals above zero on both folds. On BBBC047, falsification-guided revisions recover positive mean compound contributions while retaining predictive gains over the control-profile-only baseline. In matched sci-Plex searches, audit-enriched feedback shows higher mean held-out predictive performance and larger mean compound and dose contributions across five paired trajectories, although paired intervals span zero. Refitting fixed designs on an independently acquired cohort further shows predictive generalization need not imply generalization of input-use claims: dose contribution persists, whereas support for compound identity does not persist. CellAudit therefore adds a falsification layer to agentic model discovery, moving from generate–score–revise toward discover–falsify–revise. Project page: https://limengran98.github.io/CellAudit/.

1 Introduction

b003AI virtual cells aim to predict cellular responses to chemical and genetic interventions and ultimately support intervention design (Bunne et al., 2024). Yet a model can predict well by exploiting cellular context, control profiles, or other systematic structure while making little or no use of the supplied perturbation information (Ahlmann-Eltze et al., 2025; Viñas Torné et al., 2026). Predictive performance alone therefore does not establish perturbation use (D’Amour et al., 2022; Geirhos et al., 2020; Lapuschkin et al., 2019; DeGrave et al., 2021). We call a mismatch between a registered claim about input use and the model’s implementation or fitted behavior the prediction–claim gap.

b004This gap poses an additional challenge for agentic model discovery (Huang et al., 2024; Li et al., 2024; Jiang et al., 2025; Lu et al., 2026). Systems such as CellScientist (Li et al., 2026), CellForge (Tang et al., 2025), and HarmonyCell (Huang et al., 2026) generate executable predictors, train them, observe validation feedback, and iteratively revise or select candidates. When feedback primarily rewards predictive performance, search can favor high-scoring predictors without testing whether they use the inputs specified by their designs. As generated models become more numerous and diverse, manual verification becomes increasingly difficult. Agentic discovery therefore needs scalable tests of the claims attached to its selected models, not only mechanisms for proposing better predictors.

b005We introduce CellAudit, a framework that links registered input-use claims to evidence from source code and fitted models. It asks three non-equivalent questions: can the input enter the cited computation, do fitted predictions depend on it, and does that dependence improve prediction of the observed response? These correspond to source consumption, fitted dependence, and target-relevant predictive contribution. A cited pathway can be mathematically inactive; an executable pathway may have little effect after fitting; and input dependence need not provide predictive benefit. To distinguish these cases, CellAudit combines source inspection with matched input replacement (Fisher et al., 2019; Chamma et al., 2023) on frozen checkpoints, testing both whole-model dependence and target-relevant contribution. During development, the same diagnostics can guide revision; final claims are evaluated only after the selected source, checkpoint, and audit rules are frozen.

b006CellAudit reveals these distinctions in agent-generated cellular-response predictors. On a paired morphology–transcriptomics perturbation task built from BBBC047 (Bray et al., 2017; Haghighi et al., 2022), an agent-selected model reaches a mean held-out Global PCC of 0.3153, compared with 0.3142 for a control-profile-only predictor, while remaining exactly invariant to compound replacement. Source inspection identifies a singleton key–value attention pathway whose query cannot transmit compound information. The model remains invariant after refitting with physically disjoint control wells for inputs and target references. A broader audit separates fitted dependence from evidence of predictive contribution. In a stratified sample of 48 generated candidates across the two linked tasks, 47 change predictions under compound replacement on both held-out folds, but only 20 have registered target-loss scaffold intervals that lie entirely above zero on both folds.

b007These diagnostics also distinguish what a revision needs to address. Making a perturbation pathway executable does not by itself ensure a target-relevant contribution. On BBBC047, falsification-guided revisions learn a residual over a control-profile-only predictor, recovering positive compound contributions together with predictive gains. In matched sci-Plex searches (Srivatsan et al., 2020), audit-enriched feedback produces higher mean held-out predictive performance and larger mean compound and dose contributions than score-only feedback. However, paired confidence intervals for these differences across five trajectories include zero, so the evidence for improved discovery remains suggestive rather than conclusive.

b008Finally, we distinguish predictive generalization from claim generalization. The latter asks whether a registered input-use claim remains supported when a fixed model design is refit on an independently acquired cohort. When LINCS-selected designs are fixed and refit on LKCP (Keenan et al., 2018; Subramanian et al., 2017; Weisbart et al., 2024), predictive gains and dose contribution persist, whereas compound-identity contribution changes substantially. A separate CRISPRa evaluation applies the same auditing principle to unseen genetic combinations (Norman et al., 2019). Together, these studies trace input-use claims from source code through fitted dependence to predictive contribution, use the resulting evidence to guide revision, and re-evaluate those claims on new data.

2 Related work

b010Cellular perturbation models use latent transfer, compositional representations, neural transport, genetic graphs, and foundation models to predict chemical or genetic responses (Lotfollahi et al., 2019; Lotfollahi et al., 2023; Bunne et al., 2023; Roohani et al., 2024; Cui et al., 2024). Benchmarks standardize evaluation across splits and baselines (Wu et al., 2025; Wenteler et al., 2025), while recent studies examine linear references, shared response variation, calibrated metrics, and distribution shifts (Ahlmann-Eltze et al., 2025; Viñas Torné et al., 2026; Miller et al., 2025; Mao et al., 2026). These works ask how well perturbation responses can be predicted and evaluated; CellAudit asks whether registered input-use claims are supported by a model’s source code and fitted behavior.

b011Scientific agents generate and revise executable hypotheses, programs, and models (Boiko et al., 2023; Romera-Paredes et al., 2024; Jiang et al., 2025). Permutation reliance, conditional replacement, and behavioral testing probe fitted-model behavior under targeted input interventions (Fisher et al., 2019; Chamma et al., 2023; Ribeiro et al., 2020), while ConceptSMILE studies explanation reliability and POPPER automates hypothesis falsification (Mollapour et al., 2026; Huang et al., 2025). Unlike reliance tests that begin from prediction behavior, CellAudit starts with a registered input-use claim and its cited computation, then follows it through source consumption, fitted dependence, and target-relevant predictive contribution. This evidence can also guide model revision. Appendix K provides additional context.

3 Problem setup: predictive performance and registered input-use claims

b013Each example contains biological context cc, perturbation representation pp, optional attributes aa such as dose, and response y=[y(1),…,y(M)]y=[y^{(1)},\ldots,y^{(M)}]. Source ss and fitted parameters θ\theta define fs​(c,p,a,θ)f_{s}(c,p,a;\theta); outputs may include imaging, molecular, or other readouts. Before search, the task registers input coordinates and admissible interventions. Each audit records whether an input-use claim comes from a candidate or the task contract and, after selection, fixes its cited computation and test mapping. A prediction–claim gap occurs when the cited source contradicts a registered claim or fitted predictions are invariant to input replacement. Predictive performance affects the importance of the case, not the definition; target-relevant contribution is separate.

b014Data processing, budgets, evaluation, and selection rules are fixed before search. Folds 1–2 fit candidates; Fold 3 provides feedback and selects checkpoints. Selected checkpoints are evaluated on Folds 4 and 5, except prediction-score discovery also selects a source across policies on Fold 4 and refits it for Fold 5. Norman instead selects sources before Fold 4 and refits the same sources on Fold 5 without reselection. Appendices B and N.1 specify study-specific refitting and reuse rules.

4.1 Agentic model search with fixed data and evaluation

b017The existing CellScientist policy (Li et al., 2026) starts from a common predictor h0h_{0}. It receives the current model, development diagnostics, execution status, and compact history, and proposes a hypothesis and executable revision within the registered permissions. Shared preflight and training code provide up to three repairs per failed proposal; persistent failures consume a slot. Each executable candidate trains once, and a fixed Fold-3 rule selects the endpoint. Records preserve parent links, emitted hypotheses and declarations, source, diagnostics, repairs, checkpoint, and costs. The language model proposes revisions; input-use tests are deterministic.

4.2 Checking registered input-use claims in source code

b019Given registered inputs and cited source locations, CellAudit checks the computation attached to each input-use statement. Its abstract-syntax-tree checker returns implemented, implementation-contradicted, or unresolved. Coverage is the fraction of checked candidates whose cited locations are all resolved; unresolved code remains eligible for behavioral testing. With one key–value pair, attention has constant normalized weight and cannot transmit compound information through its query (Vaswani et al., 2017). This localizes a recognized implementation defect. Whole-model replacement then establishes whether fitted predictions depend on the input, including through other routes; target-loss contrasts test whether that dependence helps prediction.

4.3 Testing fitted dependence and predictive contribution

b021With checkpoint and targets fixed, CellAudit replaces one registered input xqx_{q} while retaining the others. Prediction distance measures target-blind dependence; zero identifies invariance on the tested replacements. To test predictive benefit, it computes the decrease in a higher-is-better score mm and the increase in loss:

b022Positive effects indicate benefit from the observed input relative to its registered replacements. Replacement distributions and their observed-support coverage are specified by task. We distinguish single-coordinate contrasts Δ​mq\Delta m_{q} from factorial effects EqE_{q}, which average over the other input’s two states in the 2×22\times 2 compound–context audit. Loss effects EqℒE^{\mathcal{L}}_{q} use the same averaging. The transfer analysis separates compound and dose allocations (Lundberg and Lee, 2017). Appendix L gives the full contrasts.

b023Maps are repeated measurements within a checkpoint, averaged before across-model inference. Continuous contributions have paired training-seed or trajectory intervals; fixed-model source-group resampling tests variation across biological groups. Known-truth checks distinguish fixed-dataset and population uncertainty (Appendix F.1). BBBC, LINCS, and LKCP separately report whether the effect quantile interval lies above, below, or across a reference threshold. A positive mean contribution can occur in any category. Appendix B defines the threshold, quantiles, and original category labels; Norman uses a separate loss-based criterion (Appendix D).

4.4 Using falsification evidence to guide the next search

b025The audit distinguishes two reasons to revise a model. A contradicted source path motivates an executable route; weak target contribution motivates learning an increment over context. Path-constrained discovery addresses the first by compiling structured design cards into models with an explicit compound route. BBBC falsification-guided discovery addresses the second through residual modeling and input-use feedback:

b026where g⁡(c)g(c) is fitted on Folds 1–2 and fixed. The compiler enforces centered perturbation/dose branches, context gates, and bias-free readouts, giving zero residual at their joint reference input. Training and Fold-3 feedback use prediction error and replacement loss changes. BBBC047 selects by predictive score among qualifying candidates; BBBC036 prioritizes compound loss gain among predictively noninferior candidates. Each trajectory evaluates the anchor plus nine proposals; the harness selects scale α\alpha and checkpoint on Fold 3 and freezes that model for Folds 4 and 5. These formulations test the joint design changes; Appendix B specifies their rules.

b027The sci-Plex comparison instead shares a context-plus-dose anchor g⁡(c,a)g(c,a) and permissions for direct predictors or anchor residuals. Score feedback supplies metrics and learning curves; Audit adds grouped errors, source checks, and development-set compound/dose replacements. After each fit, CellAudit computes these diagnostics and inserts them into the agent’s next prompt, linking input-path findings and measured contributions to model revision. Loss, optimizer, training limits, and PCC-first selection stay fixed. Paired outcomes evaluate the complete audit-enriched feedback package; selected sources and checkpoints are frozen before both held-out evaluations.

5.1 Development on linked multimodal perturbation tasks

b030Development uses linked tasks from one paired cellular-profile release: BBBC036, the known-bioactive subset, and its parent BBBC047 (Haghighi et al., 2022; Bray et al., 2017; Subramanian et al., 2017). Each predicts joint morphology–transcription responses from a same-plate control profile, compound representation, and dose. Response-blind Bemis–Murcko scaffold folds (Bemis and Murcko, 1996) hold out compound families. Global PCC on concatenated responses selects models; MSE and modality-specific metrics diagnose gains. Appendix A gives provenance, transformations, fold inventories, and a complementary plate-family split.

b031Prediction-score discovery compares CellScientist, AIDE, CellForge, and HarmonyCell policies (Li et al., 2026; Jiang et al., 2025; Tang et al., 2025; Huang et al., 2026) under a matched initial model, executor, feedback, and ten-candidate budget, with ten trajectories per task and five paired refits per selected model. Both follow-up formulations retain the folds and budget and carry all ten selected designs through Folds 4 and 5; failures, costs, and repeated designs are retained (Appendix C).

b032For BBBC047, each plate’s control wells are split into equal-size banks A/B. With the target reference fixed, shared and disjoint arms take the input profile from the same or the other bank, so their contrast isolates physical control-well overlap. Both orientations refit the score-selected source, a control-only source, and one fixed guided design under five seeds; all 60 checkpoints are fixed before evaluation on Folds 4 and 5 (Appendix A.1).

b033We predict 2,000-gene well-level responses in sci-Plex3 (Srivatsan et al., 2020), holding out compound–cell-line combinations, with whole treatment wells in one partition, while both marginals occur in training; gene selection and scaling use training wells only. Both conditions use the same DeepSeek serving model, five paired trajectory seeds, five new candidate slots per trajectory, and a shared anchor. All ten selected checkpoints are evaluated on two held-out combination partitions of this source. Compound replacements match dose and experimental context; dose replacements retain compound identity (Appendix N.1).

5.2 Testing input-use claims on new cohorts and perturbation types

b035The fixed falsification-guided protocol first runs on LINCS–Pilot1 (Keenan et al., 2018; Subramanian et al., 2017). Its ten selected designs and sources are then frozen and refit on independently acquired LKCP Batch 2 (Weisbart et al., 2024), with response- and fold-blind interface adaptation fixed before training. Compound permutations retain dose; dose permutations stay within compound (Appendix E). The Norman CRISPRa task predicts 5,045-gene responses for unseen double-perturbation combinations (Norman et al., 2019). Its registered input bundles multi-hot pair identity with the matching mean single-perturbation anchor. GEARS supplies a task-native reference (Roohani et al., 2024).

6.1 CellAudit detects compound invariance in a high-scoring predictor

b038CellAudit’s automated audit identifies the BBBC047 source selected on Fold 4 as compound-invariant. Its source-selection score is 0.30350.3035; mean Global PCC reaches 0.31530.3153 on held-out replication Fold 5. Compound shuffling changes PCC by 0.00000.0000 in every refit, whereas control replacement lowers PCC by 0.19320.1932 on Fold 4 and 0.20040.2004 on Fold 5 (Table 1). Control-only reaches 0.31420.3142 on Fold 5; Full−-control-only is +0.0011+0.0011 (95% CI [−0.0005,+0.0027][-0.0005,+0.0027]). Prediction-space distance is exactly zero under compound replacement and large under control replacement (Appendix I).

b039The source checker identifies a concrete computation to revise: the cited compound-conditioned cross-attention has one key and one value, making its normalized weight constant. The behavioral test establishes complete-model invariance; the source result localizes an inactive cited pathway. A compound-only positive control produces a shuffle effect of 0.0111±0.00100.0111\pm 0.0010, with all five refits above the reference threshold.

b040A source-stratified sample of 48 real candidates separates these outcomes further (Figure 2a,b). An implemented multi-tower source is exactly invariant; 47 candidates show fitted dependence on both folds, but only 20 have positive target-loss scaffold intervals on both. Source consumption and fitted dependence thus leave predictive contribution unresolved for many candidates (Appendix M.3). CellScientist supplies a competitive discovery setting: mean Best@10 and frontier AUC lead both linked tasks, with intervals versus HarmonyCell crossing zero (Table 19).

b041Control: control-only predictor. Reference: effect quantile interval above/below/across the reference threshold (Appendix B); distinct from a positive mean contribution. aOne-key attention cannot transmit compound identity. bCompiler-enforced compound path. cExplicit compound-residual path.

6.2 The mismatch persists with disjoint control references

b043We test whether the mismatch persists when control inputs and CP target references use disjoint physical wells. Newly reconstructed shared and disjoint arms have identical targets within each bank orientation (Figure 2c,d). In the disjoint arm, the score-selected source reaches Global PCC 0.30850.3085 and 0.31930.3193, while control-only reaches 0.30820.3082 and 0.31850.3185 on Folds 4 and 5. The score-selected source remains exactly compound-invariant in every refit and evaluation. All six shared–disjoint PCC comparisons have five-seed intervals crossing zero. The detected mismatch therefore persists without physical control-well reuse at this reference-construction layer.

b044The fixed guided design retains both predictive and compound-use increments under the same separation (Table 6). Relative to disjoint control-only, its PCC gain is +0.0028+0.0028 (95%95\% paired-seed CI [+0.0017,+0.0038][+0.0017,+0.0038]) on Fold 4 and +0.0025+0.0025 ([+0.0012,+0.0037][+0.0012,+0.0037]) on Fold 5. Compound replacement lowers PCC by 0.00430.0043 and 0.00330.0033 and increases target loss by 1.5106×10−41.5106\times 10^{-4} and 1.1939×10−41.1939\times 10^{-4}; each mean effect has a positive five-seed interval. Effects are slightly smaller than in the shared arm. Same-plate context and the original scaffold folds are retained (Appendix A.1).

6.3 An explicit compound route and its fitted contribution

b046Path-constrained discovery addresses the source defect by compiling an explicit compound route: all 200 candidate evaluations pass source and interface checks without candidate-code repair. On BBBC047, mean factorial compound effects are 0.00830.0083 and 0.00740.0074, with positive mean loss effects on Folds 4 and 5. Relative to the reference threshold, Fold 4 has six below-threshold and four overlapping cases; Fold 5 has seven and three. Control-profile effects exceed the threshold throughout (Table 1). An executable route therefore admits compound dependence without ensuring a consistently above-reference contribution in each model.

6.4 Guided residual discovery combines predictive gains with target-relevant compound contribution

b048Falsification-guided discovery next asks the perturbation residual to improve prediction beyond a fixed control-profile-only model. On BBBC047, the full predictor exceeds that baseline by +0.0037+0.0037 on Fold 4 and +0.0028+0.0028 on Fold 5. Mean factorial compound effects are 0.00530.0053 and 0.00480.0048, with positive loss effects (Table 1); joint model–scaffold intervals for these increments are above zero. The explicit-route models have larger compound effects but lower predictive scores. Guided discovery combines higher scores with positive target-relevant effects, although none of its ten models exceeds the reference-relative criterion.

b049For the original guided checkpoints, observed-support replacements retain positive contributions on BBBC047 while holding context and dose fixed. They cover 3341/43803341/4380 and 2927/38782927/3878 rows on Folds 4 and 5: compound PCC drops are 0.005340.00534 and 0.004040.00404, and loss gains are 1.84×10−41.84\times 10^{-4} and 1.44×10−41.44\times 10^{-4}, all with positive source-scaffold intervals. The score-selected model remains exactly invariant on these same eligible rows (Table 57).

b050Fixed residual learners clarify the trade-off: Ridge has strong compound sensitivity but low joint-response scores, and on BBBC047 the residual MLP has larger compound effects but lower scores than the guided models, which lead both references in mean Global PCC at all four BBBC evaluations. On BBBC036 Fold 5, their gain over the context anchor is −0.0020-0.0020, with model–scaffold intervals for predictive and compound increments crossing zero (Table 16).

b051Known-function experiments separate invariance, sensitivity without benefit, benefit, and harm across 6,400 independent simulated datasets. On the sensitive-without-benefit null, map-only intervals attain near-nominal coverage for the fixed-dataset conditional effect but severely undercover the population effect. Source-group intervals improve population coverage, with finite-group undercoverage remaining. Holding compound benefit fixed while changing reference-context variation can also change qualification. These checks support reporting continuous contribution, across-model uncertainty, and reference-relative status as distinct results (Appendix F.1).

6.5 Audit-enriched feedback yields higher mean held-out prediction

b053Do audit measurements help when returned to an agent? Figure 3a retains all five paired sci-Plex search frontiers. The context-plus-dose anchor already predicts much of the whole-expression profile, making incremental error reduction informative. Audit feedback yields higher mean PCC and lower mean MSE on both later partitions (Figure 3b): MSE is 9.58%9.58\% lower than Score on Fold 4 and 6.10%6.10\% lower on Fold 5. Both improve on the anchor.

b054The higher mean predictive performance of Audit is accompanied by higher mean compound and dose contributions (Figure 3c). Compound target-loss gain rises from 0.01860.0186 to 0.02200.0220 on Fold 4 and from 0.00640.0064 to 0.00790.0079 on Fold 5. Paired tt intervals for these Audit–Score contribution contrasts include zero at both folds (Table 68). Correct inputs help prediction in all five endpoints of both conditions. Audit–Score PCC is +0.0024+0.0024 (paired 95%95\% CI [−0.0013,+0.0060][-0.0013,+0.0060]) on Fold 4 and +0.0015+0.0015 ([−0.0005,+0.0034][-0.0005,+0.0034]) on Fold 5. Both means, and the favorable MSE and compound loss-gain directions, persist after removing any one trajectory pair (Figure 3d), whereas prediction-RMS differences can reverse after one omission. Percentile-bootstrap predictive intervals exclude zero even when resampling only trajectories, so uncertainty depends on interval construction at five pairs (Appendix N.2). Both conditions complete all 25 new candidates; Audit uses 38 versus 36 logical model calls and 592,347 versus at least 286,995 reported tokens (Table 65).

b055In the first registered Audit trajectory, CellAudit returns source checks, compound/dose replacement effects, grouped errors, and learning curves for the bilinear incumbent and a non-improving challenger. The agent returns to that incumbent and proposes simpler encoders with dropout, retaining dose-conditioned FiLM. Parameters decrease while selection PCC and compound loss gain increase (Figure 1D); search continues to a distinct final endpoint (Appendix O).

6.6 Predictive gains and input-use support generalize differently under independent acquisition

b057To test claim generalization, the frozen LINCS-selected designs are refit on LKCP without source revision, model reselection, or audit-rule changes. They improve over the control-profile-only baseline by +0.0104+0.0104 (95% CI [+0.0103,+0.0106][+0.0103,+0.0106]) on Fold 4 and +0.0211+0.0211 (95% CI [+0.0205,+0.0217][+0.0205,+0.0217]) on Fold 5. Figure 4a,b separates compound identity from dose. On Folds 4 and 5, the dose-replacement Shapley allocation is +0.0486+0.0486 and +0.0467+0.0467 Global PCC on LINCS and +0.0237+0.0237 and +0.0341+0.0341 on LKCP, whereas the compound-identity allocation is +0.0175+0.0175 and +0.0126+0.0126 on LINCS but −0.000070-0.000070 and +0.0033+0.0033 on LKCP. All 50 trajectory-endpoint refits pass the dose-use criterion at every cohort–fold boundary, but none passes the compound-identity criterion at either LKCP boundary. LINCS shows why average effects and per-model decisions must remain separate: its compound-identity criterion is passed by 35/50 refits on Fold 4 but 10/50 on Fold 5 (mean lower effect quantile 0.01390.0139 to 0.00900.0090), although average compound contribution remains positive.

6.7 The audit detects dependence on the perturbation-pair input bundle

b059On Norman, all five CellScientist refits pass the registered pair-input-bundle criterion on both held-out folds; shuffling the multi-hot pair identity together with its matching single-perturbation anchor reduces PCC by 0.55780.5578 and 0.62800.6280. Mean PCC exceeds h0h_{0} by +0.0060+0.0060 and +0.0045+0.0045 and the observed-single additive baseline by +0.0209+0.0209 and +0.0114+0.0114 (Table 26; Appendix D).

7 Discussion and conclusion

b061CellAudit shows that predictive success and claimed input use should be evaluated separately. Source consumption, fitted dependence, and target-relevant contribution can diverge: on BBBC047, a high-scoring source remains compound-invariant after disjoint control-reference refitting, while falsification-guided revisions recover positive compound contributions with predictive gains. The broader candidate audit shows this is not specific to singleton attention. In sci-Plex, audit-enriched feedback improves mean prediction and input contributions, but paired intervals over five trajectories span zero. Independent-acquisition refits further show that predictive generalization need not imply claim generalization.

b062These conclusions are conditional on the fitted model, evaluation setting, and registered replacement distribution. Positive contribution is distinct from passing the reference-relative criterion, and support for one fit should not be inherited by later refits. Observed-support replacements avoid unobserved combinations but do not establish biological exchangeability, mechanism, or causal effects. The sci-Plex study evaluates the complete audit-feedback package rather than individual diagnostics. CellAudit therefore adds a falsification layer to agentic model discovery, tracing input-use claims from cited computation to fitted behavior and predictive contribution.

Appendix A Data provenance, transformations, and task statistics

b065BBBC036 is the known-bioactive subset of its parent BBBC047 screen; the two tasks are therefore linked cohorts from one paired cellular-profile release rather than independent acquisitions. Their source collections in cpg0003-rosetta are CDRPBIO-BBBC036-Bray and CDRP-BBBC047-Bray, and the abbreviated task names retain the formal BBBC accession mapping (Ljosa et al., 2012). Inputs come from released replicate-level Cell Painting and L1000 profile tables (Weisbart et al., 2024; Haghighi et al., 2022). The morphology screen originates from the CDRP/BBBC047 Cell Painting resource (Bray et al., 2017), and the transcriptional profiles use the L1000 platform (Subramanian et al., 2017). Both assays apply matched compound–dose conditions on parallel plates and are joined at the condition level.

b066Table 2 reports both the released profile rows and the matched samples used for modeling. BBBC036 begins with 21,122 CP and 6,929 L1000 replicate profiles and retains 1,916 matched compound–dose conditions; BBBC047 begins with 153,386 CP and 68,120 L1000 profiles and retains 20,081 matched conditions. The matched subsets span 47 CP/22 L1000 treatment plates for BBBC036 and 273 CP/360 L1000 treatment plates for BBBC047. Before aggregation, 143 BBBC047 L1000 treatment profiles without a same-plate control are removed.

b067For each condition, cc is the featurewise median of same-plate control-only CP profiles. Compound identity pp is represented by a 2,048-bit radius-2 Morgan fingerprint (Rogers and Hahn, 2010), while the separate attribute aa is the log-transformed observed dose. Before treatment filtering and condition aggregation, numeric profile columns are converted to float32 and any column containing a non-finite value in the released profile table is removed. CP treatment responses undergo the empirical same-plate-control mid-CDF transform, are centered by subtracting 0.50.5, and are aggregated by condition median; L1000 responses are centered by the same-plate control median and likewise aggregated by condition median. The resulting joint targets contain 591 CP and 977 L1000 outputs for BBBC036, and 701 CP and 977 L1000 outputs for BBBC047, yielding 1,568 and 1,678 dimensions. For training, each target coordinate is centered and scaled using its Folds 1–2 mean and population standard deviation; scales at or below 10−810^{-8} are replaced by one. Reported metrics invert this standardization, retaining the control-transformed response scale. Bemis–Murcko groups (Bemis and Murcko, 1996) are assigned without response values and remain disjoint across all five folds. Table 3 lists the complete fold inventory and experimental roles.

b068For the complementary plate-family/context transfer, connected components are formed from released CP treatment-plate identifiers, their same-plate control contexts, linked L1000 treatment plates, and matched-condition counts, without reading responses. The construction yields six components for BBBC036 and 64 for BBBC047, assigning every CP/context and linked L1000 plate to exactly one role. Fit/selection/audit/replication condition counts are 640/320/637/319 for BBBC036 and 8,264/3,868/3,826/4,123 for BBBC047. BBBC036 therefore provides a six-family transfer case, while BBBC047 supplies broader 64-family coverage.

b069Cohort CP source profiles L1000 source profiles A. Released source profiles BBBC036 21,122 (17,594/3,528) 6,929 (3,451/3,478) BBBC047 153,386 (126,814/26,572) 68,120 (64,642/3,478)

b070Parentheses: treatment/control profile rows.

b071Cohort Matched conditions Unique SMILES Murcko groups CP/context dim. L1000 dim. Joint target dim. B. Matched samples and model dimensions BBBC036 1,916 1,916 1,196 591 977 1,568 BBBC047 20,081 20,068 4,540 701 977 1,678

b072Statistic Fold 1 Fold 2 Fold 3 Fold 4 Fold 5 BBBC036 Matched conditions 285 509 356 411 355 Murcko groups 206 244 258 265 223 CP replicate profiles 2,222 3,995 2,779 3,213 2,803 L1000 replicate profiles 519 919 626 739 648 BBBC047 Matched conditions 3,788 3,921 4,114 4,380 3,878 Murcko groups 853 912 941 913 921 CP replicate profiles 15,891 17,060 17,263 18,390 16,429 L1000 replicate profiles 10,722 10,692 11,531 12,252 10,815

b073Frozen source Audit Global PCC Replication Global PCC Audit CP PCC Audit L1000 PCC Parameters BBBC036 h0h_{0} -0.0030 [-0.0400, 0.0339] 0.0484 [0.0223, 0.0746] 0.0255 -0.0130 1,144,864 CellScientist 0.1921 [0.1903, 0.1939] 0.1567 [0.1517, 0.1617] 0.2758 0.1568 3,999,776 AIDE 0.1746 [0.1495, 0.1998] 0.1497 [0.1193, 0.1800] 0.2520 0.1400 4,419,872 CellForge -0.0091 [-0.0397, 0.0215] 0.0640 [0.0187, 0.1093] 0.0821 -0.0435 3,824,672 HarmonyCell 0.0657 [0.0378, 0.0936] 0.0102 [-0.0426, 0.0629] 0.0486 0.0719 2,061,343 BBBC047 h0h_{0} 0.1805 [0.1769, 0.1840] 0.2014 [0.1941, 0.2087] 0.2688 0.0494 1,201,294 CellScientist 0.1781 [0.1716, 0.1846] 0.2036 [0.1940, 0.2132] 0.2615 0.0469 1,777,486 AIDE 0.1805 [0.1769, 0.1840] 0.2014 [0.1941, 0.2087] 0.2688 0.0494 1,201,294 CellForge 0.1771 [0.1716, 0.1826] 0.2011 [0.1963, 0.2059] 0.2652 0.0444 2,531,982 HarmonyCell 0.1808 [0.1699, 0.1916] 0.1963 [0.1921, 0.2006] 0.2689 0.0484 2,284,875

b074Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b075The plate-family audit crosses the observed or permuted compound representation with the observed or an alternative control profile from the same plate family. Each selected model is refit under five fixed seeds, and each refit averages 32 permutations constructed without response values. Compounds are permuted within the observed control-profile group whenever possible, covering every held-out BBBC036 row and 98.8%98.8\% of BBBC047 rows; each remaining row receives a fixed donor with a different compound from the same held-out partition. Table 5 separates compound, control-profile, and interaction effects on Folds 4 and 5.

b076Model Global PCC Compound effect Control effect Interaction BBBC036 / Audit h0h_{0} -0.0030 [-0.0400, 0.0339] 0.0025 [0.0020, 0.0031] 0.0012 [-0.0126, 0.0150] -0.0005 [-0.0008, -0.0002] CellScientist 0.1921 [0.1903, 0.1939] 0.0000 [0.0000, 0.0000] 0.0146 [0.0114, 0.0178] 0.0000 [0.0000, 0.0000] AIDE 0.1746 [0.1495, 0.1998] 0.0024 [0.0019, 0.0028] 0.0260 [0.0076, 0.0445] -0.0008 [-0.0012, -0.0003] CellForge -0.0091 [-0.0397, 0.0215] 0.0018 [0.0011, 0.0025] -0.0086 [-0.0169, -0.0004] -0.0005 [-0.0010, 0.0001] HarmonyCell 0.0657 [0.0378, 0.0936] 0.0019 [0.0002, 0.0037] 0.0768 [0.0632, 0.0905] -0.0028 [-0.0044, -0.0013] BBBC047 / Audit h0h_{0} 0.1805 [0.1769, 0.1840] 0.0046 [0.0039, 0.0053] 0.0249 [0.0228, 0.0271] 0.0008 [0.0005, 0.0012] CellScientist 0.1781 [0.1716, 0.1846] 0.0000 [0.0000, 0.0000] 0.0295 [0.0243, 0.0346] 0.0000 [0.0000, 0.0000] AIDE 0.1805 [0.1769, 0.1840] 0.0046 [0.0039, 0.0053] 0.0249 [0.0228, 0.0271] 0.0008 [0.0005, 0.0012] CellForge 0.1771 [0.1716, 0.1826] 0.0050 [0.0039, 0.0061] 0.0208 [0.0163, 0.0252] 0.0014 [0.0004, 0.0023] HarmonyCell 0.1808 [0.1699, 0.1916] ×10−96.892\!\times\!10^{-9} [−1.390,2.768]×10−8[-1.390,2.768]\!\times\!10^{-8} 0.0365 [0.0245, 0.0484] ×10−81.211\!\times\!10^{-8} [−2.216,4.637]×10−8[-2.216,4.637]\!\times\!10^{-8} BBBC036 / Held-out replication h0h_{0} 0.0484 [0.0223, 0.0746] 0.0026 [×10−6,0.0053][9.873\!\times\!10^{-6},0.0053] 0.0043 [-0.0117, 0.0203] 0.0002 [-0.0006, 0.0009] CellScientist 0.1567 [0.1517, 0.1617] 0.0000 [0.0000, 0.0000] -0.0070 [-0.0088, -0.0053] 0.0000 [0.0000, 0.0000] AIDE 0.1497 [0.1193, 0.1800] 0.0013 [-0.0004, 0.0031] -0.0016 [-0.0168, 0.0136] -0.0001 [-0.0004, 0.0002] CellForge 0.0640 [0.0187, 0.1093] 0.0034 [0.0026, 0.0043] 0.0018 [-0.0087, 0.0123] 0.0001 [-0.0006, 0.0009] HarmonyCell 0.0102 [-0.0426, 0.0629] -0.0063 [-0.0100, -0.0025] -0.0038 [-0.0350, 0.0274] -0.0037 [-0.0080, 0.0005] BBBC047 / Held-out replication h0h_{0} 0.2014 [0.1941, 0.2087] 0.0030 [0.0023, 0.0038] 0.0136 [0.0077, 0.0194] 0.0002 [-0.0010, 0.0013] CellScientist 0.2036 [0.1940, 0.2132] 0.0000 [0.0000, 0.0000] 0.0231 [0.0168, 0.0293] 0.0000 [0.0000, 0.0000] AIDE 0.2014 [0.1941, 0.2087] 0.0030 [0.0023, 0.0038] 0.0136 [0.0077, 0.0194] 0.0002 [-0.0010, 0.0013] CellForge 0.2011 [0.1963, 0.2059] 0.0037 [0.0030, 0.0044] 0.0088 [0.0029, 0.0148] -0.0004 [-0.0010, 0.0002] HarmonyCell 0.1963 [0.1921, 0.2006] ×10−93.073\!\times\!10^{-9} [−5.460,11.61]×10−9[-5.460,11.61]\!\times\!10^{-9} 0.0205 [0.0142, 0.0268] ×10−92.608\!\times\!10^{-9} [−4.632,9.848]×10−9[-4.632,9.848]\!\times\!10^{-9}

b077Fixed residual baselines isolate a perturbation-specific function class while keeping the same task. They retain the selected control-profile predictor g⁡(c)g(c) and learn one joint residual h⁡(p,a)h(p,a) using either multi-output Ridge or a shallow multi-output MLP. Both baselines use Fold 3 for selection and are refit under the same five seeds. Their Fold-4 and Fold-5 predictive scores, compound effects, and target-loss gains are reported together in Table 48.

b078Two additional small-molecule cohorts test the final procedure beyond BBBC development. We first apply it to paired morphology–transcription LINCS–Pilot1, then transfer its ten trajectory-selected design instances to independently acquired Cell Painting LKCP Batch 2 under the same compound, dose, and control-profile inputs. Appendix E records data provenance, the order in which models and rules were fixed, the input permutations, and the compound–dose decomposition.

A.1 Physical separation of control inputs and target references

b080Model Fold Shared PCC Disjoint PCC Shared PCC drop Disjoint PCC drop Shared Loss gain Disjoint Loss gain Score F4 0.30810.3081 0.30850.3085 00 00 00 00 Control only F4 0.30840.3084 0.30820.3082 00 00 00 00 Guided F4 0.31110.3111 0.31100.3110 0.00470.0047 0.00430.0043 ×10−41.65\!\times\!10^{-4} ×10−41.51\!\times\!10^{-4} Score F5 0.31910.3191 0.31930.3193 00 00 00 00 Control only F5 0.31870.3187 0.31850.3185 00 00 00 00 Guided F5 0.32140.3214 0.32100.3210 0.00360.0036 0.00330.0033 ×10−41.31\!\times\!10^{-4} ×10−41.19\!\times\!10^{-4}

b081Means of five seeds, averaging directions A/B within seed; compound replacement uses 32 fixed maps. PCC drop and loss gain are correct-minus-replacement PCC and replacement-minus-correct MSE. Guided minus control-only disjoint-arm PCC: F4 0.00280.0028 [0.0017, 0.0038][0.0017,\,0.0038], F5 0.00250.0025 [0.0012, 0.0037][0.0012,\,0.0037] (paired-seed 95% tt CIs).

b082The shared and disjoint arms are newly constructed BBBC047 comparisons; the historical shared-control result is not their absolute baseline. Physical control wells are hash-sorted within each plate and well-row stratum and allocated to balanced, disjoint A/B banks (seed 2026091401). Within direction A, the target uses bank A as reference: shared context uses A, disjoint context uses B; direction B reverses these roles. CP targets are treated-well empirical mid-CDF values relative to the direction’s reference bank, centered by 0.50.5 and aggregated by condition medians. The 701 CP features are fixed from the historical schema; no new feature selection is performed. Shared/disjoint arms have byte-identical targets and row identities within direction, and L1000 targets are unchanged. A/B are averaged within each seed, not counted as independent replicas. This intervention separates physical wells at the reconstructed CP reference layer; it does not establish that all upstream preprocessing or biological dependence has been removed. No historical qualification label is changed.

b083Quantity Value Interpretation Predictor refits / anchors 60 / 20 80 training stages; 120 fold evaluations Seeds / directions 5 / 2 A/B are paired inside each seed F4 retained support 3341 / 4380 76.28% of evaluation rows F5 retained support 2927 / 3878 75.48% of evaluation rows F4 / F5 source scaffolds 913 / 921 Bootstrap over source-scaffold labels Maps / scaffold draws 32 / 2000 All refits and donor maps held fixed Donor kernel total variation 0 (both folds) Every eligible compound contributes one row Guided coordinate signs 40 / 40 positive RMS, loss gain and PCC drop, each record Score/control coordinates 80 / 80 exact zero All three compound coordinates Physical controls, A / B 9144 / 9144 Unique plate/well identities; banks disjoint CP plates / retained conditions 273 / 20081 0 conditions excluded

b084Only row-uniform maps were evaluated. An independent metadata calculation proves equality of row-uniform and compound-balanced donor probabilities on all 6268 retained source pools; pre-generated compound-balanced maps are not an additional evaluated sensitivity analysis. Kernel equality is not biological exchangeability.

b085Separately from the direction-specific bank targets, a full-bank CP mid-CDF reconstruction was compared with historical normalized CP ranks. It recorded a maximum absolute discrepancy of 0.191406250.19140625 and mean absolute discrepancy ×10−62.76\!\times\!10^{-6}, with 99.9799%99.9799\% agreement at 10−610^{-6}. This discrepancy was retained, not repaired by choosing a favorable target transform. The portable metadata retains the complete check.

b086Model Fold Dir. Arm Global PCC MSE CP PCC CP MSE L1000 PCC L1000 MSE Fold 4 Score F4 A Shared 0.30820.3082 0.04600.0460 0.33310.3331 0.05320.0532 0.28020.2802 0.04080.0408 Score F4 A Disjoint 0.30870.3087 0.04600.0460 0.33340.3334 0.05320.0532 0.28070.2807 0.04080.0408 Score F4 B Shared 0.30790.3079 0.04600.0460 0.33170.3317 0.05320.0532 0.28100.2810 0.04080.0408 Score F4 B Disjoint 0.30840.3084 0.04600.0460 0.33170.3317 0.05320.0532 0.28180.2818 0.04080.0408 Control only F4 A Shared 0.30930.3093 0.04600.0460 0.33270.3327 0.05320.0532 0.28280.2828 0.04080.0408 Control only F4 A Disjoint 0.30860.3086 0.04600.0460 0.33220.3322 0.05330.0533 0.28180.2818 0.04080.0408 Control only F4 B Shared 0.30740.3074 0.04600.0460 0.33030.3303 0.05330.0533 0.28130.2813 0.04080.0408 Control only F4 B Disjoint 0.30770.3077 0.04600.0460 0.33040.3304 0.05330.0533 0.28180.2818 0.04080.0408 Guided F4 A Shared 0.31220.3122 0.04590.0459 0.33840.3384 0.05300.0530 0.28230.2823 0.04080.0408 Guided F4 A Disjoint 0.31150.3115 0.04590.0459 0.33730.3373 0.05310.0531 0.28210.2821 0.04080.0408 Guided F4 B Shared 0.31000.3100 0.04590.0459 0.33500.3350 0.05310.0531 0.28140.2814 0.04080.0408 Guided F4 B Disjoint 0.31050.3105 0.04590.0459 0.33560.3356 0.05310.0531 0.28170.2817 0.04080.0408 Fold 5 Score F5 A Shared 0.32190.3219 0.04540.0454 0.34920.3492 0.05360.0536 0.28950.2895 0.03960.0396 Score F5 A Disjoint 0.32220.3222 0.04540.0454 0.35000.3500 0.05350.0535 0.28890.2889 0.03960.0396 Score F5 B Shared 0.31630.3163 0.04550.0455 0.33890.3389 0.05370.0537 0.28940.2894 0.03960.0396 Score F5 B Disjoint 0.31650.3165 0.04550.0455 0.33860.3386 0.05370.0537 0.29030.2903 0.03960.0396 Control only F5 A Shared 0.32170.3217 0.04540.0454 0.34800.3480 0.05360.0536 0.29040.2904 0.03960.0396 Control only F5 A Disjoint 0.32180.3218 0.04550.0455 0.34930.3493 0.05360.0536 0.28890.2889 0.03960.0396 Control only F5 B Shared 0.31560.3156 0.04550.0455 0.33730.3373 0.05380.0538 0.28970.2897 0.03960.0396 Control only F5 B Disjoint 0.31530.3153 0.04560.0456 0.33640.3364 0.05390.0539 0.29010.2901 0.03960.0396 Guided F5 A Shared 0.32490.3249 0.04540.0454 0.35360.3536 0.05340.0534 0.29050.2905 0.03960.0396 Guided F5 A Disjoint 0.32360.3236 0.04540.0454 0.35250.3525 0.05350.0535 0.28920.2892 0.03960.0396 Guided F5 B Shared 0.31780.3178 0.04550.0455 0.34160.3416 0.05370.0537 0.28950.2895 0.03960.0396 Guided F5 B Disjoint 0.31840.3184 0.04550.0455 0.34200.3420 0.05360.0536 0.29030.2903 0.03960.0396

b087Model Fold Dir. Arm Compound RMS Compound loss gain Compound PCC drop Fold 4 Score F4 A Shared 00 00 00 Score F4 A Disjoint 00 00 00 Score F4 B Shared 00 00 00 Score F4 B Disjoint 00 00 00 Control only F4 A Shared 00 00 00 Control only F4 A Disjoint 00 00 00 Control only F4 B Shared 00 00 00 Control only F4 B Disjoint 00 00 00 Guided F4 A Shared 0.01260.0126 ×10−41.75\!\times\!10^{-4} 0.00500.0050 Guided F4 A Disjoint 0.01180.0118 ×10−41.48\!\times\!10^{-4} 0.00410.0041 Guided F4 B Shared 0.01180.0118 ×10−41.55\!\times\!10^{-4} 0.00450.0045 Guided F4 B Disjoint 0.01180.0118 ×10−41.54\!\times\!10^{-4} 0.00440.0044 Fold 5 Score F5 A Shared 00 00 00 Score F5 A Disjoint 00 00 00 Score F5 B Shared 00 00 00 Score F5 B Disjoint 00 00 00 Control only F5 A Shared 00 00 00 Control only F5 A Disjoint 00 00 00 Control only F5 B Shared 00 00 00 Control only F5 B Disjoint 00 00 00 Guided F5 A Shared 0.01250.0125 ×10−41.43\!\times\!10^{-4} 0.00390.0039 Guided F5 A Disjoint 0.01160.0116 ×10−41.17\!\times\!10^{-4} 0.00320.0032 Guided F5 B Shared 0.01170.0117 ×10−41.19\!\times\!10^{-4} 0.00330.0033 Guided F5 B Disjoint 0.01170.0117 ×10−41.21\!\times\!10^{-4} 0.00340.0034

b088Contrast Fold Mean Seed 95% CI Scaffold 95% CI Global PCC (×103\times 10^{3}) Score: D−-S F4 0.4270.427 [−0.130, 0.984][-0.130,\,0.984] [−0.070, 0.945][-0.070,\,0.945] Score: D−-S F5 0.2430.243 [−0.583, 1.069][-0.583,\,1.069] [−0.158, 0.638][-0.158,\,0.638] Control only: D−-S F4 −0.186-0.186 [−0.769, 0.398][-0.769,\,0.398] [−0.794, 0.338][-0.794,\,0.338] Control only: D−-S F5 −0.136-0.136 [−1.679, 1.407][-1.679,\,1.407] [−0.687, 0.393][-0.687,\,0.393] Guided: D−-S F4 −0.099-0.099 [−0.972, 0.773][-0.972,\,0.773] [−0.442, 0.225][-0.442,\,0.225] Guided: D−-S F5 −0.327-0.327 [−0.963, 0.309][-0.963,\,0.309] [−0.640, 0.004][-0.640,\,0.004] Score−-control, S F4 −0.295-0.295 [−1.223, 0.633][-1.223,\,0.633] [−1.724, 1.066][-1.724,\,1.066] Score−-control, S F5 0.4280.428 [−0.662, 1.517][-0.662,\,1.517] [−0.938, 1.539][-0.938,\,1.539] Guided−-control, S F4 2.6882.688 [2.059, 3.317][2.059,\,3.317] [1.012, 4.541][1.012,\,4.541] Guided−-control, S F5 2.6742.674 [1.609, 3.739][1.609,\,3.739] [0.272, 5.761][0.272,\,5.761] Score−-control, D F4 0.3180.318 [−0.514, 1.149][-0.514,\,1.149] [−0.853, 1.491][-0.853,\,1.491] Score−-control, D F5 0.8070.807 [−0.037, 1.650][-0.037,\,1.650] [−0.554, 1.931][-0.554,\,1.931] Guided−-control, D F4 2.7752.775 [1.731, 3.818][1.731,\,3.818] [1.264, 4.468][1.264,\,4.468] Guided−-control, D F5 2.4832.483 [1.227, 3.739][1.227,\,3.739] [0.187, 5.548][0.187,\,5.548] MSE (×105\times 10^{5}) Score: D−-S F4 −1.079-1.079 [−2.884, 0.726][-2.884,\,0.726] [−2.847, 0.536][-2.847,\,0.536] Score: D−-S F5 −0.564-0.564 [−3.258, 2.131][-3.258,\,2.131] [−1.846, 0.775][-1.846,\,0.775] Control only: D−-S F4 1.9231.923 [−1.011, 4.858][-1.011,\,4.858] [0.232, 3.870][0.232,\,3.870] Control only: D−-S F5 1.4901.490 [−4.983, 7.964][-4.983,\,7.964] [−0.383, 3.538][-0.383,\,3.538] Guided: D−-S F4 1.0471.047 [−2.859, 4.954][-2.859,\,4.954] [−0.192, 2.309][-0.192,\,2.309] Guided: D−-S F5 1.7801.780 [−0.662, 4.222][-0.662,\,4.222] [0.555, 2.980][0.555,\,2.980] Score−-control, S F4 −0.598-0.598 [−3.662, 2.465][-3.662,\,2.465] [−4.858, 4.209][-4.858,\,4.209] Score−-control, S F5 −2.943-2.943 [−7.456, 1.569][-7.456,\,1.569] [−6.772, 1.784][-6.772,\,1.784] Guided−-control, S F4 −7.236-7.236 [−11.010,−3.463][-11.010,\,-3.463] [−13.811,−1.332][-13.811,\,-1.332] Guided−-control, S F5 −7.329-7.329 [−14.377,−0.282][-14.377,\,-0.282] [−18.153, 0.990][-18.153,\,0.990] Score−-control, D F4 −3.601-3.601 [−6.091,−1.110][-6.091,\,-1.110] [−7.476, 0.520][-7.476,\,0.520] Score−-control, D F5 −4.998-4.998 [−8.488,−1.507][-8.488,\,-1.507] [−8.982,−0.105][-8.982,\,-0.105] Guided−-control, D F4 −8.112-8.112 [−12.543,−3.681][-12.543,\,-3.681] [−14.199,−2.832][-14.199,\,-2.832] Guided−-control, D F5 −7.040-7.040 [−12.443,−1.636][-12.443,\,-1.636] [−17.585, 0.849][-17.585,\,0.849]

b089D−-S: disjoint minus shared wells. Within-arm contrasts subtract control only. Seed CIs use five A/B-averaged paired values (t4t_{4}). Scaffold CIs share each draw across all arms/models/directions and fix all five refits, 32 maps and the donor pool; 2000 draws, seed 2026091433+fold2026091433+\mathrm{fold}. PCC is recomputed after pooling sufficient statistics, never averaged across scaffold PCCs. These are source-scaffold, not compound-cluster, intervals; scaffold labels do not ensure fully independent biological groups.

b090Contrast Fold Mean Seed 95% CI Scaffold 95% CI Compound RMS (×103\times 10^{3}) Score: D−-S F4 00 [0, 0][0,\,0] [0, 0][0,\,0] Score: D−-S F5 00 [0, 0][0,\,0] [0, 0][0,\,0] Control only: D−-S F4 00 [0, 0][0,\,0] [0, 0][0,\,0] Control only: D−-S F5 00 [0, 0][0,\,0] [0, 0][0,\,0] Guided: D−-S F4 −0.414-0.414 [−1.567, 0.738][-1.567,\,0.738] [−0.495,−0.333][-0.495,\,-0.333] Guided: D−-S F5 −0.406-0.406 [−1.563, 0.750][-1.563,\,0.750] [−0.490,−0.327][-0.490,\,-0.327] Score−-control, S F4 00 [0, 0][0,\,0] [0, 0][0,\,0] Score−-control, S F5 00 [0, 0][0,\,0] [0, 0][0,\,0] Guided−-control, S F4 12.22012.220 [11.209, 13.231][11.209,\,13.231] [11.249, 13.186][11.249,\,13.186] Guided−-control, S F5 12.08512.085 [11.011, 13.158][11.011,\,13.158] [11.456, 12.679][11.456,\,12.679] Score−-control, D F4 00 [0, 0][0,\,0] [0, 0][0,\,0] Score−-control, D F5 00 [0, 0][0,\,0] [0, 0][0,\,0] Guided−-control, D F4 11.80511.805 [9.826, 13.784][9.826,\,13.784] [10.884, 12.725][10.884,\,12.725] Guided−-control, D F5 11.67811.678 [9.740, 13.616][9.740,\,13.616] [11.106, 12.221][11.106,\,12.221] Compound loss gain (×105\times 10^{5}) Score: D−-S F4 00 [0, 0][0,\,0] [−×10−12,×10−12][-2.36\!\times\!10^{-12},\,2.64\!\times\!10^{-12}] Score: D−-S F5 00 [0, 0][0,\,0] [−×10−12,×10−12][-2.71\!\times\!10^{-12},\,1.87\!\times\!10^{-12}] Control only: D−-S F4 00 [0, 0][0,\,0] [−×10−12,×10−12][-2.91\!\times\!10^{-12},\,1.53\!\times\!10^{-12}] Control only: D−-S F5 00 [0, 0][0,\,0] [−×10−12,×10−12][-1.46\!\times\!10^{-12},\,3.05\!\times\!10^{-12}] Guided: D−-S F4 −1.403-1.403 [−4.179, 1.374][-4.179,\,1.374] [−2.134,−0.809][-2.134,\,-0.809] Guided: D−-S F5 −1.163-1.163 [−3.432, 1.107][-3.432,\,1.107] [−1.938,−0.376][-1.938,\,-0.376] Score−-control, S F4 00 [0, 0][0,\,0] [−×10−12,×10−12][-2.43\!\times\!10^{-12},\,2.50\!\times\!10^{-12}] Score−-control, S F5 00 [0, 0][0,\,0] [−×10−12,×10−12][-1.39\!\times\!10^{-12},\,3.26\!\times\!10^{-12}] Guided−-control, S F4 16.50916.509 [13.377, 19.640][13.377,\,19.640] [10.136, 24.392][10.136,\,24.392] Guided−-control, S F5 13.10213.102 [10.729, 15.475][10.729,\,15.475] [5.985, 20.741][5.985,\,20.741] Score−-control, D F4 00 [0, 0][0,\,0] [−×10−12,×10−12][-1.32\!\times\!10^{-12},\,3.12\!\times\!10^{-12}] Score−-control, D F5 00 [0, 0][0,\,0] [−×10−12,×10−12][-2.57\!\times\!10^{-12},\,2.01\!\times\!10^{-12}] Guided−-control, D F4 15.10615.106 [9.906, 20.305][9.906,\,20.305] [9.267, 22.336][9.267,\,22.336] Guided−-control, D F5 11.93911.939 [7.423, 16.455][7.423,\,16.455] [5.390, 18.963][5.390,\,18.963]

b091D−-S: disjoint minus shared wells. Within-arm contrasts subtract control only. Seed CIs use five A/B-averaged paired values (t4t_{4}). Scaffold CIs share each draw across all arms/models/directions and fix all five refits, 32 maps and the donor pool; 2000 draws, seed 2026091433+fold2026091433+\mathrm{fold}. PCC is recomputed after pooling sufficient statistics, never averaged across scaffold PCCs. These are source-scaffold, not compound-cluster, intervals; scaffold labels do not ensure fully independent biological groups.

b092Contrast Fold Mean Seed 95% CI Scaffold 95% CI Score: D−-S F4 00 [0, 0][0,\,0] [−×10−13,×10−13][-1.50\!\times\!10^{-13},\,1.83\!\times\!10^{-13}] Score: D−-S F5 00 [0, 0][0,\,0] [−×10−13,×10−13][-1.89\!\times\!10^{-13},\,1.78\!\times\!10^{-13}] Control only: D−-S F4 00 [0, 0][0,\,0] [−×10−13,×10−13][-1.61\!\times\!10^{-13},\,1.83\!\times\!10^{-13}] Control only: D−-S F5 00 [0, 0][0,\,0] [−×10−13,×10−13][-2.33\!\times\!10^{-13},\,1.44\!\times\!10^{-13}] Guided: D−-S F4 −0.424-0.424 [−1.191, 0.342][-1.191,\,0.342] [−0.627,−0.248][-0.627,\,-0.248] Guided: D−-S F5 −0.337-0.337 [−0.944, 0.270][-0.944,\,0.270] [−0.559,−0.115][-0.559,\,-0.115] Score−-control, S F4 00 [0, 0][0,\,0] [−×10−13,×10−13][-2.05\!\times\!10^{-13},\,1.11\!\times\!10^{-13}] Score−-control, S F5 00 [0, 0][0,\,0] [−×10−13,×10−13][-2.28\!\times\!10^{-13},\,1.33\!\times\!10^{-13}] Guided−-control, S F4 4.7084.708 [3.832, 5.583][3.832,\,5.583] [2.949, 6.840][2.949,\,6.840] Guided−-control, S F5 3.6253.625 [2.955, 4.296][2.955,\,4.296] [1.650, 5.741][1.650,\,5.741] Score−-control, D F4 00 [0, 0][0,\,0] [−×10−13,×10−13][-2.22\!\times\!10^{-13},\,1.33\!\times\!10^{-13}] Score−-control, D F5 00 [0, 0][0,\,0] [−×10−13,×10−13][-1.89\!\times\!10^{-13},\,1.67\!\times\!10^{-13}] Guided−-control, D F4 4.2834.283 [2.823, 5.744][2.823,\,5.744] [2.673, 6.238][2.673,\,6.238] Guided−-control, D F5 3.2883.288 [2.042, 4.535][2.042,\,4.535] [1.471, 5.215][1.471,\,5.215]

b093D−-S: disjoint minus shared wells. Within-arm contrasts subtract control only. Seed CIs use five A/B-averaged paired values (t4t_{4}). Scaffold CIs share each draw across all arms/models/directions and fix all five refits, 32 maps and the donor pool; 2000 draws, seed 2026091433+fold2026091433+\mathrm{fold}. PCC is recomputed after pooling sufficient statistics, never averaged across scaffold PCCs. These are source-scaffold, not compound-cluster, intervals; scaffold labels do not ensure fully independent biological groups.

b094The guided model has positive compound RMS, target-loss gain and PCC drop in all 40 evaluations, whereas Score and control only are exactly invariant. The guided disjoint-arm PCC advantage over control only remains positive under both reported interval methods. However, all guided disjoint-minus-shared coordinate differences include zero under the five-seed interval while their fixed-refit source-scaffold intervals are negative; the two uncertainty scopes do not establish an unchanged effect. The F5 guided-minus-control MSE contrast likewise crosses zero under the source-scaffold interval despite a negative seed interval. A positive prediction RMS indicates input use, not target benefit. RMS is the mean over maps of the square root of mean squared prediction distance, not the square root after averaging maps.

Appendix B Exact protocol, decision rules, and statistical units

b096The fixed executor owns joint inputs (c,p,a)(c,p,a), the response target, data transformations, folds, evaluator, checkpoint rule, and training configuration; candidate code cannot alter data loading, targets, folds, or metrics. Discovery accesses Folds 1–3 only. Global PCC is one Pearson correlation after flattening all post-search rows and all dimensions of the inverse-standardized joint output. CP and L1000 PCC use the same operation within each response block. MSE is averaged over every element of the inverse-standardized joint output. At search step tt, the policy maps the current model, Fold-3 diagnostics, and compact search history to a proposed revision,

b097where edits are limited to architecture, fusion, response readout, loss, optimizer, and scheduler. The experiment log stores the proposal’s parent, hypothesis, source or structured design, declared input use, execution and repair results, checkpoint, metrics, provider usage, and compute. Within each ten-slot prediction-score trajectory, the incumbent changes only under a strict improvement in Fold-3 Global PCC. After all ten trajectories finish, the first, within-policy selection chooses one source per search policy from that policy’s complete executable candidate pool by maximum Fold-3 Global PCC, with lower Fold-3 MSE, fewer parameters, and stable candidate identity as tie-breakers. Neither Fold 4 nor Fold 5 enters this within-policy selection. The four policy-selected agent sources and three distinct diagnostic sources are then refit under five paired seeds and evaluated on Fold 4; the h0h_{0} source is also displayed under its simple-concatenation role. A second, pre-specified across-policy score rule chooses the agent source with the highest mean Fold-4 PCC for transfer to Fold 5. Within source selection, Fold 4 enters only this disclosed across-policy choice, while Fold 5 never enters. The path-constrained and falsification-guided studies instead carry all ten Fold-3 winners through Folds 4 and 5 without Fold-4 reselection. Before Fold 4, each study freezes the candidate set and registers the source-check rules, input-intervention construction, map seeds, threshold-construction rule, status rule, and aggregation. The realized model-specific thresholds are computed from the 32 reference scores on the fold being audited. For the prediction-score panel, Fold 5 independently refits the frozen source on Folds 1–2, selects its checkpoint on Fold 3 under the same paired-seed schedule, and evaluates Fold 5 once. Thus Fold 5 does not reuse Fold-4 weights and never changes the selected source. LINCS and LKCP subsequently test the final procedure outside BBBC development.

b098The compound intervention first seeks a different-fingerprint derangement within rows sharing the same observed control-profile vector. If that class derangement is impossible, a deterministic partition-wide donor with a different fingerprint is used and recorded. Only the compound representation changes: the source control profile and dose remain fixed. The resulting effect is measured under this control-stratified, dose-preserving replacement distribution. The control intervention maps each row to a different observed control-vector class; donor reuse is allowed to ensure that every control vector changes. Dose maps replace only the scalar dose, with observed-dose support checked against the source compound’s released BRD identity and available cell/time annotations. None of these maps uses responses, model predictions, or evaluation scores to choose donors.

b099For the primary scaffold-fold compound maps, within-control-group derangements cover 411/411411/411 and 355/355355/355 rows on BBBC036, 4330/43804330/4380 and 3831/38783831/3878 on BBBC047, 847/847847/847 and 868/868868/868 on LINCS, and 378/405378/405 and 378/432378/432 on LKCP, respectively on Folds 4 and 5. The remaining rows use partition-wide donors. These counts specify control matching; the response contrasts retain the source dose, including when the donor compound was not observed at that dose. The plate-family analysis uses its separately specified maps in Appendix A.

b100For the 2×22\times 2 audit, the model-specific reference values are derived from the intervened predictions rather than from responses used to choose a permutation. For compound use they are bj,r(chem)=12​(mp~​c,r+mp~​c~,r)b^{(\mathrm{chem})}_{j,r}=\tfrac{1}{2}(m_{\tilde{p}c,r}+m_{\tilde{p}\tilde{c},r}); for control-profile use, bj,r(context)=12​(mp​c~,r+mp~​c~,r)b^{(\mathrm{context})}_{j,r}=\tfrac{1}{2}(m_{p\tilde{c},r}+m_{\tilde{p}\tilde{c},r}); and for their interaction, bj,r(int)=mp~​c,r−mp~​c~,rb^{(\mathrm{int})}_{j,r}=m_{\tilde{p}c,r}-m_{\tilde{p}\tilde{c},r}. Dose uses the prediction score under a within-compound dose permutation. In every case, τj,q\tau_{j,q} is the 95th percentile of absolute pairwise differences among the 32 fixed reference values. The lower and upper bounds used for the status are the empirical 2.5th and 97.5th percentiles of the 32 effect values; the interaction uses absolute effects. A model is qualified when the lower bound exceeds τj,q\tau_{j,q}, unsupported when the upper bound does not exceed τj,q\tau_{j,q}, and inconclusive otherwise. Inputs without enough legal interventions are reported as not identifiable. For the five-refit prediction-score panel, each refit receives its own status and an aggregate status requires agreement in at least four of five refits; if no category reaches four of five, the aggregate is inconclusive. Path-constrained and falsification-guided results report status counts across ten selected models without a vote. The 50-refit coordinate analysis is descriptive at the refit level and uses the ten trajectory-selected endpoint instances as the policy-distribution units. These instances contain six unique configurations; repeated configurations are retained because they are independent trajectory selections. For the BBBC, LINCS, and LKCP panels, the 32 permutations are repeated measurements within a trained model, not independent sample units. The sci-Plex feedback study uses 32 development maps and 128 final held-out maps, which are likewise repeated measurements; Norman uses a separate set of 32 complete derangements (Appendix D).

b101The falsification-guided trainer evaluates α∈{0.05,0.10,0.20,0.35,0.50,0.75,1.00}\alpha\in\{0.05,0.10,0.20,0.35,0.50,0.75,1.00\} on Fold 3. Predictive noninferiority allows at most a 0.0030.003 decrease from the control-only predictor in Global PCC, a 0.0050.005 decrease in either response block, and a 0.00050.0005 increase in MSE. Search qualification uses eight fixed Fold-3 replacement maps. The empirical 2.5th percentile of their compound-related Δ​ℒ\Delta\mathcal{L} values (increases in inverse-standardized joint-output MSE) must exceed both the 95th percentile of absolute pairwise differences among the replaced-input losses and 0.0010.001 times the reference loss. Here reference loss is the current candidate’s Fold-3 MSE with correct inputs. Dose uses the same rule when eligible, with reference loss restricted to eligible rows. These eight development maps are separate from the 32 held-out audit maps. The discovery code groups equal Morgan fingerprints for its replacement maps. Its dose gate requires at least 32 eligible rows and eight fingerprint groups in both the fit partition and Fold 3, with at least 0.10.1 log-dose contrast. For each candidate, epoch/scale selection maximizes Fold-3 Global PCC among qualifying states, breaking ties by lower MSE; if none qualifies, the best predictive state is retained with its qualification status recorded.

b102Trajectory selection is distinct from this within-candidate checkpoint rule. BBBC047 selects the highest-PCC qualifying candidate, with lower MSE as tie-breaker, or reports no qualified endpoint. BBBC036 prefers predictively noninferior candidates and ranks them by compound-related loss increase, then Global PCC, lower MSE, and stable candidate identity. If none is noninferior, that ordering retains a predictive-fallback endpoint from the executable candidates. Strict qualification is reported separately for BBBC036. These cohort-specific rules select the ten sources before either post-search boundary; held-out results never reselect them.

b103Held-out dose testing requires at least 64 eligible rows and coverage of at least 10% of the partition. The prediction-score and path-constrained tests accept any observed within-compound dose change; the falsification-guided test additionally requires eight compounds and an absolute log-dose difference of 0.10.1. Compound identity here is the BRD compound identifier, with sample/batch suffixes removed, rather than a fingerprint-equivalence class. On BBBC047, the resulting coverage is 0/43800/4380 rows on Fold 4 and 14/387814/3878 rows from seven compounds on Fold 5 (0.3610%0.3610\%); neither boundary meets the minimum, and neither contains a legal 0.10.1-log-dose contrast. Dose is therefore not identifiable in the BBBC047 panels (Table 50). Equal-fingerprint grouping alone would merge distinct released identities. On LINCS and LKCP, all replacement dose values in the 32 frozen maps are observed for the source BRD compound and its available cell/time annotations; the original input tensors and effect estimates are retained. The held-out PCC threshold is computed from fold-specific reference-score variation and is separate from the Fold-3 loss gate.

b104The prediction-score discovery study contains 80 ten-slot trajectories: two tasks, four search methods, and ten independent trajectory seeds. Each trajectory’s budget includes the common initial predictor, and discovery intervals treat paired trajectory identifiers as the statistical unit because all policies share the same candidate-training seed schedule within an identifier. Selected-model comparisons use five paired fitting seeds on the relevant held-out fold. Path-constrained and falsification-guided studies retain all ten trajectory winners and report their distributions. All summaries are computed from fixed experiment logs that retain failed slots, repairs, and provider attempts.

b105The accompanying package separates three reproducibility targets. Numerical source records and deterministic renderers regenerate reported tables. Frozen-source refitting trains new parameters under the recorded data and selection rules. Checkpoint replay takes the selected source, matching fitted weights, prepared data, and replacement specification to recompute predictions and input-use effects by inference. Its standalone feedback entry point verifies checkpoint and data hashes and writes fresh outputs. Biological matrices and fitted weights are supplied as external inputs; tabulated records include checkpoint identities and counterfactual sufficient statistics. The package’s docs/REPRODUCIBILITY.md gives the corresponding commands and required assets.

b106Comparator Best@10 Δ\Delta [95% CI]; pp Frontier AUC Δ\Delta [95% CI]; pp BBBC036 AIDE +0.0084 [+0.0044, +0.0124] p=9.638×10−4p=9.638\times 10^{-4} +0.0054 [-0.0003, +0.0111] p=6.157×10−2p=6.157\times 10^{-2} CellForge +0.0151 [+0.0107, +0.0196] p=3.24×10−5p=3.24\times 10^{-5} +0.0106 [+0.0056, +0.0155] p=9.601×10−4p=9.601\times 10^{-4} HarmonyCell +0.0046 [-0.0007, +0.0100] p=8.064×10−2p=8.064\times 10^{-2} +0.0025 [-0.0016, +0.0066] p=1.962×10−1p=1.962\times 10^{-1} BBBC047 AIDE +0.0214 [+0.0105, +0.0324] p=1.636×10−3p=1.636\times 10^{-3} +0.0180 [+0.0078, +0.0282] p=3.18×10−3p=3.18\times 10^{-3} CellForge +0.0181 [+0.0057, +0.0304] p=9.051×10−3p=9.051\times 10^{-3} +0.0159 [+0.0046, +0.0271] p=1.086×10−2p=1.086\times 10^{-2} HarmonyCell +0.0028 [-0.0168, +0.0223] p=7.56×10−1p=7.56\times 10^{-1} +0.0094 [-0.0033, +0.0220] p=1.293×10−1p=1.293\times 10^{-1}

b107Comparator Δ\Delta Global PCC 95% CI pp nn BBBC036 HarmonyCell -0.0015 [-0.0037, +0.0007] 1.228×10−11.228\times 10^{-1} 5 AIDE +0.0117 [+0.0030, +0.0205] 2.027×10−22.027\times 10^{-2} 5 CellForge +0.0158 [+0.0095, +0.0222] 2.307×10−32.307\times 10^{-3} 5 TabM +0.0048 [+0.0016, +0.0081] 1.445×10−21.445\times 10^{-2} 5 RealMLP +0.0118 [-0.0103, +0.0338] 2.13×10−12.13\times 10^{-1} 5 Standard MLP +0.0193 [+0.0072, +0.0313] 1.128×10−21.128\times 10^{-2} 5 h0h_{0} +0.0207 [+0.0130, +0.0283] 1.733×10−31.733\times 10^{-3} 5 Joint TabR +0.0369 [+0.0343, +0.0395] 2.576×10−62.576\times 10^{-6} 5 Ridge +0.2324 [+0.2301, +0.2347] 1.033×10−91.033\times 10^{-9} 5 BBBC047 HarmonyCell +0.0012 [-0.0083, +0.0108] 7.394×10−17.394\times 10^{-1} 5 AIDE +0.0337 [+0.0283, +0.0390] 6.271×10−56.271\times 10^{-5} 5 CellForge +0.0293 [+0.0256, +0.0330] 2.57×10−52.57\times 10^{-5} 5 TabM +0.0181 [+0.0150, +0.0211] 7.867×10−57.867\times 10^{-5} 5 RealMLP +0.0202 [+0.0154, +0.0250] 3.062×10−43.062\times 10^{-4} 5 Standard MLP +0.0337 [+0.0275, +0.0398] 1.103×10−41.103\times 10^{-4} 5 h0h_{0} +0.0337 [+0.0283, +0.0390] 6.271×10−56.271\times 10^{-5} 5 Joint TabR +0.0500 [+0.0451, +0.0549] 9.339×10−69.339\times 10^{-6} 5 Ridge +0.2541 [+0.2530, +0.2552] 3.077×10−113.077\times 10^{-11} 5

b108For chemical-generalization contrasts, complete held-out Murcko-scaffold clusters are jointly resampled across all five paired refits, and Global PCC is recomputed from cluster sufficient statistics. This preserves within-scaffold response dependence and quantifies uncertainty over held-out chemical families. The Holm step-down adjustment applies to the three registered discovery-policy contrasts reported in Table 18; the broader frozen-predictor comparison is descriptive and reports its unadjusted paired intervals explicitly (Holm, 1979).

b109Contrast Evaluation Δ\Delta Global PCC [95% CI] BBBC036 CellScientist −- control-only Audit -0.0002 [-0.0020, +0.0015] CellScientist −- HarmonyCell Audit -0.0014 [-0.0032, +0.0003] score-selected −- h0h_{0} Replication +0.0344 [+0.0195, +0.0514] BBBC047 CellScientist −- control-only Audit +0.0016 [+0.0001, +0.0032] CellScientist −- HarmonyCell Audit +0.0052 [+0.0034, +0.0069] score-selected −- h0h_{0} Replication +0.0366 [+0.0308, +0.0424]

b110For the central falsification-guided study, effects are first computed from all 32 fixed within-model input permutations. The conditional interval resamples held-out Murcko scaffolds while holding the ten selected models fixed; the hierarchical sensitivity interval jointly resamples selected models and scaffolds. Models and scaffolds are the resampling units, whereas the 32 permutations remain fixed repeated measurements within a model.

b111Quantity Estimate Scaffold 95% CI Model×\timesscaffold 95% CI BBBC036 / Fold 4 Full −- anchor PCC +0.0046 [-0.0042, +0.0165] [-0.0043, +0.0164] Compound PCC drop +0.0091 [+0.0001, +0.0211] [+1.78×10−5+1.78\times 10^{-5}, +0.0213] Compound target-loss gain +0.00039 [+0.00002, +0.00089] [+0.00002, +0.00090] BBBC036 / Fold 5 Full −- anchor PCC -0.0020 [-0.0104, +0.0052] [-0.0102, +0.0053] Compound PCC drop +0.0022 [-0.0050, +0.0090] [-0.0051, +0.0092] Compound target-loss gain +0.00009 [-0.00022, +0.00038] [-0.00022, +0.00039] BBBC047 / Fold 4 Full −- anchor PCC +0.0037 [+0.0018, +0.0060] [+0.0018, +0.0060] Compound PCC drop +0.0053 [+0.0033, +0.0078] [+0.0033, +0.0078] Compound target-loss gain +0.00018 [+0.00011, +0.00026] [+0.00011, +0.00026] BBBC047 / Fold 5 Full −- anchor PCC +0.0028 [+0.0003, +0.0061] [+0.0002, +0.0061] Compound PCC drop +0.0048 [+0.0024, +0.0079] [+0.0023, +0.0079] Compound target-loss gain +0.00017 [+0.00009, +0.00026] [+0.00009, +0.00026]

b112The larger BBBC047 cohort retains positive hierarchical intervals for all three quantities on both held-out folds: Full−-control-only PCC, compound-shuffle PCC drop, and compound target-loss gain. On BBBC036, Fold-4 compound and target-loss intervals remain positive, whereas Fold-5 intervals include zero. Scaffold resampling therefore shows which compound-family effects persist without selecting models or permutations again.

b113Trajectory-level Best@10 Global PCC is the primary discovery outcome, with frontier AUC as the co-primary search-efficiency summary. Each contrast pairs the shared trajectory seed and reports its effect estimate, two-sided paired interval, and complete ten-trajectory distribution. Holm adjustment is applied to the three pre-specified policy contrasts within each task and outcome (Table 18). Response blocks, response-sensitive metrics, cost records, code-check outcomes, and input-shuffle effects retain their own estimands and statistical units rather than being pooled into one omnibus claim. Input permutations are repeated transformations within a trained refit and are never treated as independent biological replicates.

b114Comparator Best@10 pHolmp_{\mathrm{Holm}} Frontier AUC pHolmp_{\mathrm{Holm}} BBBC036 AIDE 1.9×10−31.9\times 10^{-3} 1.231×10−11.231\times 10^{-1} CellForge 1×10−41\times 10^{-4} 2.9×10−32.9\times 10^{-3} HarmonyCell 8.06×10−28.06\times 10^{-2} 1.962×10−11.962\times 10^{-1} BBBC047 AIDE 4.9×10−34.9\times 10^{-3} 9.5×10−39.5\times 10^{-3} CellForge 1.81×10−21.81\times 10^{-2} 2.17×10−22.17\times 10^{-2} HarmonyCell 7.56×10−17.56\times 10^{-1} 1.293×10−11.293\times 10^{-1}

Appendix C Search trajectories, reliability, and cost

b116Table 19 summarizes the competitive discovery setting, and Tables 20 and 21 give the complete trajectory and selected-predictor comparisons. Fixed-model references include the pre-tuned RealMLP (Holzmüller et al., 2024), TabM’s parameter-efficient ensemble (Gorishniy et al., 2025), and a joint-output adaptation of TabR (Gorishniy et al., 2024). Table 23 reports valid candidates, failures, repairs, success by budget, model-provider calls, tokens, GPU training time, and trajectory wall time; failed slots and provider attempts remain charged. The RBDE score provides a joint efficiency summary alongside its separate quality and cost columns.

b117Search Best@3 ↑\uparrow Best@5 ↑\uparrow Best@10 ↑\uparrow AUC ↑\uparrow Valid ↑\uparrow Calls Tokens (K) BBBC036 CellScientist 0.2833 ±\pm 0.0075 0.2856 ±\pm 0.0052 0.2924 ±\pm 0.0037 0.2845 ±\pm 0.0046 0.990 ±\pm 0.023 10.50 ±\pm 1.59 51.7 ±\pm 6.4 AIDE 0.2765 ±\pm 0.0036 0.2804 ±\pm 0.0033 0.2840 ±\pm 0.0030 0.2791 ±\pm 0.0023 1.000 ±\pm 0.000 11.10 ±\pm 0.98 41.8 ±\pm 3.8 CellForge 0.2708 ±\pm 0.0016 0.2757 ±\pm 0.0025 0.2772 ±\pm 0.0027 0.2739 ±\pm 0.0015 0.910 ±\pm 0.092 16.30 ±\pm 2.39 44.2 ±\pm 7.9 HarmonyCell 0.2803 ±\pm 0.0037 0.2845 ±\pm 0.0045 0.2877 ±\pm 0.0038 0.2820 ±\pm 0.0036 0.950 ±\pm 0.051 11.80 ±\pm 1.46 38.8 ±\pm 4.7 BBBC047 CellScientist 0.3052 ±\pm 0.0127 0.3084 ±\pm 0.0127 0.3097 ±\pm 0.0119 0.3058 ±\pm 0.0111 0.940 ±\pm 0.077 12.50 ±\pm 3.20 59.2 ±\pm 10.4 AIDE 0.2875 ±\pm 0.0015 0.2882 ±\pm 0.0014 0.2883 ±\pm 0.0012 0.2878 ±\pm 0.0013 0.990 ±\pm 0.023 12.30 ±\pm 1.17 45.2 ±\pm 4.4 CellForge 0.2891 ±\pm 0.0015 0.2901 ±\pm 0.0010 0.2917 ±\pm 0.0011 0.2899 ±\pm 0.0008 0.940 ±\pm 0.090 12.90 ±\pm 2.75 36.1 ±\pm 7.4 HarmonyCell 0.2918 ±\pm 0.0043 0.2965 ±\pm 0.0035 0.3070 ±\pm 0.0083 0.2964 ±\pm 0.0034 0.950 ±\pm 0.051 13.20 ±\pm 1.99 41.6 ±\pm 5.8

b118Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b119Method Best@3 PCC ↑\uparrow Best@5 ↑\uparrow Best@10 ↑\uparrow Best MSE ↓\downarrow CP PCC ↑\uparrow L1000 PCC ↑\uparrow Frontier AUC ↑\uparrow Lift AUC ↑\uparrow BBBC036 CellScientist 0.2833 ±\pm 0.0075 0.2856 ±\pm 0.0052 0.2924 ±\pm 0.0037 0.0607 ±\pm 0.0001 0.2824 ±\pm 0.0015 0.2965 ±\pm 0.0052 0.2845 ±\pm 0.0046 0.0172 ±\pm 0.0046 AIDE 0.2765 ±\pm 0.0036 0.2804 ±\pm 0.0033 0.2840 ±\pm 0.0030 0.0612 ±\pm 0.0001 0.2762 ±\pm 0.0028 0.2875 ±\pm 0.0034 0.2791 ±\pm 0.0023 0.0118 ±\pm 0.0028 CellForge 0.2708 ±\pm 0.0016 0.2757 ±\pm 0.0025 0.2772 ±\pm 0.0027 0.0617 ±\pm 0.0003 0.2687 ±\pm 0.0038 0.2810 ±\pm 0.0032 0.2739 ±\pm 0.0015 0.0066 ±\pm 0.0020 HarmonyCell 0.2803 ±\pm 0.0037 0.2845 ±\pm 0.0045 0.2877 ±\pm 0.0038 0.0609 ±\pm 0.0002 0.2821 ±\pm 0.0034 0.2905 ±\pm 0.0045 0.2820 ±\pm 0.0036 0.0147 ±\pm 0.0038 BBBC047 CellScientist 0.3052 ±\pm 0.0127 0.3084 ±\pm 0.0127 0.3097 ±\pm 0.0119 0.0451 ±\pm 0.0004 0.3351 ±\pm 0.0048 0.2806 ±\pm 0.0212 0.3058 ±\pm 0.0111 0.0201 ±\pm 0.0108 AIDE 0.2875 ±\pm 0.0015 0.2882 ±\pm 0.0014 0.2883 ±\pm 0.0012 0.0458 ±\pm 0.0000 0.3269 ±\pm 0.0028 0.2433 ±\pm 0.0025 0.2878 ±\pm 0.0013 0.0021 ±\pm 0.0014 CellForge 0.2891 ±\pm 0.0015 0.2901 ±\pm 0.0010 0.2917 ±\pm 0.0011 0.0457 ±\pm 0.0001 0.3315 ±\pm 0.0040 0.2449 ±\pm 0.0049 0.2899 ±\pm 0.0008 0.0042 ±\pm 0.0016 HarmonyCell 0.2918 ±\pm 0.0043 0.2965 ±\pm 0.0035 0.3070 ±\pm 0.0083 0.0452 ±\pm 0.0003 0.3373 ±\pm 0.0041 0.2724 ±\pm 0.0151 0.2964 ±\pm 0.0034 0.0107 ±\pm 0.0039

b120Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b121Model Global PCC ↑\uparrow MSE ↓\downarrow CP PCC ↑\uparrow L1000 PCC ↑\uparrow Parameters Train (s) Selected epoch BBBC036 CellScientist 0.3101 ±\pm 0.0023 0.0586 ±\pm 0.0001 0.3107 ±\pm 0.0025 0.3098 ±\pm 0.0032 4.00M 7.2 ±\pm 1.2 21.8 ±\pm 17.0 AIDE 0.2984 ±\pm 0.0091 0.0593 ±\pm 0.0006 0.3085 ±\pm 0.0043 0.2950 ±\pm 0.0124 4.42M 6.3 ±\pm 1.2 4.8 ±\pm 1.0 CellForge 0.2942 ±\pm 0.0043 0.0593 ±\pm 0.0002 0.3052 ±\pm 0.0048 0.2902 ±\pm 0.0056 3.82M 6.2 ±\pm 1.3 2.0 ±\pm 0.0 HarmonyCell 0.3116 ±\pm 0.0013 0.0586 ±\pm 0.0001 0.3117 ±\pm 0.0024 0.3115 ±\pm 0.0020 2.06M 6.7 ±\pm 1.4 17.2 ±\pm 12.5 h0h_{0} 0.2894 ±\pm 0.0081 0.0597 ±\pm 0.0003 0.2984 ±\pm 0.0048 0.2860 ±\pm 0.0098 1.14M 5.9 ±\pm 1.2 3.2 ±\pm 0.6 Standard MLP 0.2908 ±\pm 0.0114 0.0594 ±\pm 0.0004 0.3058 ±\pm 0.0089 0.2845 ±\pm 0.0125 2.42M 5.8 ±\pm 1.2 1.8 ±\pm 0.6 RealMLP 0.2983 ±\pm 0.0202 0.0592 ±\pm 0.0007 0.3170 ±\pm 0.0129 0.2902 ±\pm 0.0260 3.47M 5.9 ±\pm 0.7 – TabM 0.3053 ±\pm 0.0039 0.0589 ±\pm 0.0001 0.3175 ±\pm 0.0063 0.3004 ±\pm 0.0044 2.37M 11.4 ±\pm 1.7 2.8 ±\pm 1.0 Joint TabR 0.2732 ±\pm 0.0033 0.0604 ±\pm 0.0001 0.2835 ±\pm 0.0036 0.2687 ±\pm 0.0044 2.17M 2.6 ±\pm 0.3 7.6 ±\pm 1.1 Ridge 0.0777 ±\pm 0.0000 0.2048 ±\pm 0.0000 0.0812 ±\pm 0.0000 0.0763 ±\pm 0.0000 4.14M 1.5 ±\pm 0.4 – BBBC047 CellScientist 0.3033 ±\pm 0.0011 0.0457 ±\pm 0.0000 0.3254 ±\pm 0.0010 0.2787 ±\pm 0.0015 1.78M 24.3 ±\pm 3.7 36.6 ±\pm 10.5 AIDE 0.2696 ±\pm 0.0047 0.0468 ±\pm 0.0002 0.3167 ±\pm 0.0062 0.2125 ±\pm 0.0101 1.20M 9.5 ±\pm 0.7 2.0 ±\pm 0.9 CellForge 0.2740 ±\pm 0.0035 0.0467 ±\pm 0.0001 0.3178 ±\pm 0.0061 0.2216 ±\pm 0.0060 2.53M 9.6 ±\pm 0.8 1.8 ±\pm 1.0 HarmonyCell 0.3021 ±\pm 0.0098 0.0458 ±\pm 0.0003 0.3265 ±\pm 0.0016 0.2743 ±\pm 0.0196 2.28M 26.0 ±\pm 9.2 41.8 ±\pm 27.1 h0h_{0} 0.2696 ±\pm 0.0047 0.0468 ±\pm 0.0002 0.3167 ±\pm 0.0062 0.2125 ±\pm 0.0101 1.20M 9.3 ±\pm 0.9 2.0 ±\pm 0.9 Standard MLP 0.2696 ±\pm 0.0059 0.0468 ±\pm 0.0002 0.3167 ±\pm 0.0062 0.2127 ±\pm 0.0067 2.53M 9.6 ±\pm 0.9 1.2 ±\pm 0.6 RealMLP 0.2831 ±\pm 0.0042 0.0463 ±\pm 0.0001 0.3259 ±\pm 0.0038 0.2326 ±\pm 0.0049 3.62M 13.7 ±\pm 0.8 – TabM 0.2852 ±\pm 0.0033 0.0463 ±\pm 0.0001 0.3282 ±\pm 0.0023 0.2350 ±\pm 0.0105 2.51M 16.7 ±\pm 2.1 2.6 ±\pm 0.7 Joint TabR 0.2533 ±\pm 0.0049 0.0475 ±\pm 0.0002 0.2951 ±\pm 0.0050 0.2027 ±\pm 0.0066 2.25M 10.8 ±\pm 1.1 4.6 ±\pm 0.7 Ridge 0.0492 ±\pm 0.0000 0.3880 ±\pm 0.0000 0.0547 ±\pm 0.0000 0.0438 ±\pm 0.0000 4.62M 1.3 ±\pm 0.2 –

b122Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b123Formulation Generated artifact Max output Slots Prediction-score policies Executable source 9000 10 Path-constrained Structured design card 2400 10 Falsification-guided Semantic design card 1800 10

b124Shared settings: model deepseek-v4-flash; temperature 0.2; reasoning effort not set; fallback disabled. Max output is the token limit per request.

b125A. Execution quality and budget efficiency

b126Method RBDE ↑\uparrow Valid rate ↑\uparrow Failed slots ↓\downarrow Repairs ↓\downarrow Success@3/5/10 ↑\uparrow BBBC036 CellScientist 0.0104 0.990 ±\pm 0.023 0.10 ±\pm 0.23 1.50 ±\pm 1.59 8/10/10 AIDE 0.0096 1.000 ±\pm 0.000 0.00 ±\pm 0.00 2.10 ±\pm 0.98 9/10/10 CellForge 0.0044 0.910 ±\pm 0.092 0.90 ±\pm 0.92 7.30 ±\pm 2.39 8/10/10 HarmonyCell 0.0102 0.950 ±\pm 0.051 0.50 ±\pm 0.51 2.80 ±\pm 1.46 9/10/10 BBBC047 CellScientist 0.0064 0.940 ±\pm 0.077 0.60 ±\pm 0.77 3.50 ±\pm 3.20 7/8/9 AIDE 0.0008 0.990 ±\pm 0.023 0.10 ±\pm 0.23 3.30 ±\pm 1.17 5/8/9 CellForge 0.0027 0.940 ±\pm 0.090 0.60 ±\pm 0.90 3.90 ±\pm 2.75 8/9/9 HarmonyCell 0.0057 0.950 ±\pm 0.051 0.50 ±\pm 0.51 4.20 ±\pm 1.99 8/10/10

b128Method Calls Tokens (K) GPU training (s) Wall time (s) BBBC036 CellScientist 10.50 ±\pm 1.59 51.7 ±\pm 6.4 19.8 ±\pm 2.2 716.3 ±\pm 101.3 AIDE 11.10 ±\pm 0.98 41.8 ±\pm 3.8 16.6 ±\pm 2.5 559.0 ±\pm 212.1 CellForge 16.30 ±\pm 2.39 44.2 ±\pm 7.9 15.7 ±\pm 1.4 578.0 ±\pm 86.4 HarmonyCell 11.80 ±\pm 1.46 38.8 ±\pm 4.7 16.8 ±\pm 1.1 610.8 ±\pm 158.2 BBBC047 CellScientist 12.50 ±\pm 3.20 59.2 ±\pm 10.4 111.7 ±\pm 21.3 821.9 ±\pm 116.0 AIDE 12.30 ±\pm 1.17 45.2 ±\pm 4.4 60.3 ±\pm 3.9 533.0 ±\pm 152.3 CellForge 12.90 ±\pm 2.75 36.1 ±\pm 7.4 56.7 ±\pm 5.8 533.0 ±\pm 83.6 HarmonyCell 13.20 ±\pm 1.99 41.6 ±\pm 5.8 72.9 ±\pm 11.0 680.5 ±\pm 228.0

b129CP response block L1000 response block Model PCC @20 ↑\uparrow PCC @50 ↑\uparrow RMSE @20 ↓\downarrow RMSE @50 ↓\downarrow PCC @20 ↑\uparrow PCC @50 ↑\uparrow RMSE @20 ↓\downarrow RMSE @50 ↓\downarrow BBBC036 CellScientist 0.4620 ±\pm 0.0035 0.4454 ±\pm 0.0033 0.2411 ±\pm 0.0005 0.2385 ±\pm 0.0004 0.2828 ±\pm 0.0051 0.3167 ±\pm 0.0043 0.5135 ±\pm 0.0008 0.4497 ±\pm 0.0007 AIDE 0.4636 ±\pm 0.0024 0.4445 ±\pm 0.0025 0.2408 ±\pm 0.0006 0.2386 ±\pm 0.0004 0.2611 ±\pm 0.0200 0.3005 ±\pm 0.0160 0.5190 ±\pm 0.0054 0.4540 ±\pm 0.0048 CellForge 0.4607 ±\pm 0.0050 0.4430 ±\pm 0.0034 0.2412 ±\pm 0.0006 0.2388 ±\pm 0.0005 0.2598 ±\pm 0.0081 0.2966 ±\pm 0.0099 0.5176 ±\pm 0.0011 0.4531 ±\pm 0.0013 HarmonyCell 0.4633 ±\pm 0.0023 0.4464 ±\pm 0.0024 0.2409 ±\pm 0.0005 0.2383 ±\pm 0.0004 0.2823 ±\pm 0.0040 0.3170 ±\pm 0.0031 0.5137 ±\pm 0.0006 0.4497 ±\pm 0.0004 h0h_{0} 0.4526 ±\pm 0.0034 0.4357 ±\pm 0.0032 0.2426 ±\pm 0.0005 0.2399 ±\pm 0.0005 0.2555 ±\pm 0.0079 0.2983 ±\pm 0.0034 0.5210 ±\pm 0.0056 0.4545 ±\pm 0.0031 Standard MLP 0.4608 ±\pm 0.0077 0.4404 ±\pm 0.0070 0.2412 ±\pm 0.0011 0.2391 ±\pm 0.0009 0.2473 ±\pm 0.0048 0.2923 ±\pm 0.0111 0.5197 ±\pm 0.0006 0.4536 ±\pm 0.0017 RealMLP 0.4668 ±\pm 0.0081 0.4497 ±\pm 0.0080 0.2402 ±\pm 0.0013 0.2378 ±\pm 0.0011 0.2476 ±\pm 0.0332 0.2945 ±\pm 0.0320 0.5200 ±\pm 0.0053 0.4540 ±\pm 0.0047 TabM 0.4640 ±\pm 0.0023 0.4477 ±\pm 0.0021 0.2408 ±\pm 0.0005 0.2382 ±\pm 0.0003 0.2603 ±\pm 0.0079 0.3066 ±\pm 0.0033 0.5180 ±\pm 0.0031 0.4518 ±\pm 0.0016 Joint TabR 0.4433 ±\pm 0.0041 0.4235 ±\pm 0.0045 0.2437 ±\pm 0.0005 0.2414 ±\pm 0.0006 0.2389 ±\pm 0.0124 0.2812 ±\pm 0.0120 0.5231 ±\pm 0.0024 0.4567 ±\pm 0.0020 Ridge 0.1172 ±\pm 0.0000 0.1153 ±\pm 0.0000 0.4678 ±\pm 0.0000 0.4603 ±\pm 0.0000 0.0807 ±\pm 0.0000 0.0903 ±\pm 0.0000 0.9852 ±\pm 0.0000 0.8401 ±\pm 0.0000 BBBC047 CellScientist 0.4003 ±\pm 0.0028 0.4061 ±\pm 0.0018 0.2689 ±\pm 0.0002 0.2547 ±\pm 0.0002 0.3262 ±\pm 0.0025 0.3154 ±\pm 0.0019 0.3703 ±\pm 0.0004 0.3250 ±\pm 0.0003 AIDE 0.4127 ±\pm 0.0124 0.4078 ±\pm 0.0083 0.2676 ±\pm 0.0022 0.2549 ±\pm 0.0015 0.2577 ±\pm 0.0090 0.2486 ±\pm 0.0060 0.3789 ±\pm 0.0009 0.3323 ±\pm 0.0006 CellForge 0.4117 ±\pm 0.0095 0.4069 ±\pm 0.0032 0.2678 ±\pm 0.0010 0.2550 ±\pm 0.0007 0.2684 ±\pm 0.0051 0.2583 ±\pm 0.0041 0.3776 ±\pm 0.0009 0.3312 ±\pm 0.0007 HarmonyCell 0.4029 ±\pm 0.0049 0.4079 ±\pm 0.0026 0.2686 ±\pm 0.0009 0.2545 ±\pm 0.0004 0.3234 ±\pm 0.0156 0.3130 ±\pm 0.0148 0.3705 ±\pm 0.0021 0.3252 ±\pm 0.0016 h0h_{0} 0.4127 ±\pm 0.0124 0.4078 ±\pm 0.0083 0.2676 ±\pm 0.0022 0.2549 ±\pm 0.0015 0.2577 ±\pm 0.0090 0.2486 ±\pm 0.0060 0.3789 ±\pm 0.0009 0.3323 ±\pm 0.0006 Standard MLP 0.4125 ±\pm 0.0157 0.4083 ±\pm 0.0089 0.2678 ±\pm 0.0023 0.2548 ±\pm 0.0013 0.2626 ±\pm 0.0135 0.2531 ±\pm 0.0123 0.3782 ±\pm 0.0018 0.3316 ±\pm 0.0015 RealMLP 0.4142 ±\pm 0.0072 0.4137 ±\pm 0.0043 0.2667 ±\pm 0.0010 0.2536 ±\pm 0.0005 0.2883 ±\pm 0.0034 0.2798 ±\pm 0.0028 0.3750 ±\pm 0.0004 0.3287 ±\pm 0.0003 TabM 0.4152 ±\pm 0.0107 0.4142 ±\pm 0.0050 0.2666 ±\pm 0.0015 0.2536 ±\pm 0.0007 0.2784 ±\pm 0.0051 0.2685 ±\pm 0.0067 0.3763 ±\pm 0.0010 0.3300 ±\pm 0.0008 Joint TabR 0.3751 ±\pm 0.0078 0.3810 ±\pm 0.0061 0.2757 ±\pm 0.0007 0.2599 ±\pm 0.0006 0.2482 ±\pm 0.0101 0.2409 ±\pm 0.0084 0.3806 ±\pm 0.0012 0.3336 ±\pm 0.0009 Ridge 0.0833 ±\pm 0.0000 0.0808 ±\pm 0.0000 0.7616 ±\pm 0.0000 0.7251 ±\pm 0.0000 0.0583 ±\pm 0.0000 0.0583 ±\pm 0.0000 1.1990 ±\pm 0.0000 1.0275 ±\pm 0.0000

b130Task Score PCC Path PCC Δ\Delta Tokens (K) Valid Repairs Linked BBBC036 0.2924 ±\pm 0.0037 0.2925 ±\pm 0.0019 +0.0001 21.9 ±\pm 1.4 100.0% 0.00 ±\pm 0.00 100/100 BBBC047 0.3097 ±\pm 0.0119 0.3008 ±\pm 0.0012 -0.0090 21.7 ±\pm 1.2 100.0% 0.00 ±\pm 0.00 100/100

Appendix D Input-use claims in combinatorial genetic-perturbation prediction

b132Boundary Predictor Global PCC ↑\uparrow Input Δ\DeltaPCC ↑\uparrow Support Fold 4 audit GEARS 0.6819 [0.6714, 0.6924] 0.3029 5/5 Initial model (h0h_{0}) 0.8960 [0.8909, 0.9011] 0.5425 5/5 CellScientist 0.9020 [0.8988, 0.9051] 0.5578 5/5 Fold 5 replication GEARS 0.6676 [0.6568, 0.6784] 0.3599 5/5 Initial model (h0h_{0}) 0.9051 [0.9023, 0.9079] 0.6193 5/5 CellScientist 0.9096 [0.9051, 0.9142] 0.6280 5/5

b133The transfer task is reconstructed from the count layer of the Norman K562 CRISPRa Perturb-seq experiment (GEO GSE133344) (Norman et al., 2019). Its source matrix contains 91,205 cells and 5,045 genes, including 7,353 control cells. Per-cell counts are library-size normalized to 10,000 and log-transformed, after which canonical condition means are centered by the control mean. The 284 source labels resolve to 237 canonical conditions: 105 observed singles, 131 doubles, and one control. The common discovery interface receives a pair-input bundle containing a 105-dimensional multi-hot perturbation identity and its matching mean single-perturbation anchor, and returns the full 5,045-gene response without external pathway features or cell-type covariates. GEARS retains its task-native graph inputs as described below.

b134The five-fold assignment is constructed without expression responses and balances pair count, source-cell count, and perturbation-gene incidence. All singles and controls remain fit-only with the Fold-1/2 doubles; Fold 3 supplies discovery feedback, and Folds 4 and 5 are successive held-out evaluation folds. Table 27 lists every held-out double-perturbation block. The comparison predicts unseen double combinations whose constituent single-gene responses are available during fitting.

b135Each held-out boundary contains 26 unseen double-perturbation conditions. Before Fold 4 is opened, we construct 32 distinct complete derangements of the 26 row positions; each is a one-to-one permutation with no fixed point and is reused positionally on Fold 5. For each source condition, the registered intervention replaces both coordinates of the pair-input bundle (its 105-dimensional pair-identity vector and matching mean single-perturbation anchor) with the donor pair’s values while retaining the source response target. Replacing both coordinates prevents a residual predictor from retaining pair information through the anchor; consequently, the test measures dependence on the complete bundle rather than attributing the effect to the multi-hot coordinate alone. The maps use neither responses nor model outputs and do not require donor pairs to be gene-disjoint from source pairs.

b136For refit jj and map rr, let LjL_{j} be joint-output MSE under the correct pair-input bundle and Lj,rshufL^{\mathrm{shuf}}_{j,r} the MSE after the bundle shuffle. We define gj,r=Lj,rshuf−Ljg_{j,r}=L^{\mathrm{shuf}}_{j,r}-L_{j} and g~j,r=gj,r/max⁡(Lj,10−12)\tilde{g}_{j,r}=g_{j,r}/\max(L_{j},10^{-12}). A refit is qualified under the pair-input-use criterion when 32−1​∑rg~j,r>0.00132^{-1}\sum_{r}\tilde{g}_{j,r}>0.001 and Q0.05​({gj,r}r=132)>0Q_{0.05}(\{g_{j,r}\}_{r=1}^{32})>0. It is unsupported when the first quantity lies within [−0.001,0.001][-0.001,0.001] and inconclusive otherwise. The Global-PCC drop is reported as a continuous effect but does not enter this categorical rule. The 32 maps are repeated interventions within a refit; the five refits are the statistical units for model-performance intervals and support counts.

b137GEARS is evaluated through the shared task boundary while retaining its original multigene-perturbation formulation (Roohani et al., 2024): GO and coexpression graphs, native GNN/decoder, optimization objective, and validation-selected checkpoint. It shares count normalization, response target, fold roles, and held-out metrics with the other predictors. Table 28 records the architecture, graph scope, optimizer, and checkpoint rule used in the comparison.

b138Fold Role Double perturbations Source cells Component genes 1 Fit 26 7,301 40 2 Fit 26 7,849 41 3 Discovery/selection 27 6,817 42 4 Independent audit 26 6,541 40 5 Final replication 26 6,937 38

b139Across ten trajectories, all 77 nonduplicate CellScientist candidates pass source, shape, and training checks; the 23 duplicate design cards still consume their candidate slots, and no Fold-4 or Fold-5 response enters proposal or selection. The trajectories account for 154 provider calls, 403,762 tokens, 17.8 H100 fit-minutes, and 50.5 minutes of end-to-end time. Held-out input-use testing is deterministic and uses zero model-provider calls.

b140A. Search performance BB Best@3 Best@5 Best@10 Frontier AUC Δ​h0\Delta h_{0} [95% CI] 10 0.9192 0.9201 0.9210 0.9194 +0.0062 [+0.0036, +0.0087]

b141B. Completion and resources Positive Executed Calls Tokens 10/10 77/100 154 403,762

b142Predictor Global PCC ↑\uparrow MSE ↓\downarrow Condition PCC ↑\uparrow Rank corr. ↑\uparrow DEG-20 PCC ↑\uparrow DEG-50 PCC ↑\uparrow Full-state PCC ↑\uparrow Input-use support Fold 4 audit Matching mean 0.8810 0.0059 0.8966 0.4902 0.9702 0.9634 0.9915 supported Additive singles 0.8810 0.0046 0.8966 0.4902 0.9702 0.9634 0.9932 supported Ridge 0.8989 0.0033 0.8965 0.4584 0.9724 0.9665 0.9951 supported GEARS 0.6819 0.0122 0.6826 0.2512 0.9078 0.8915 0.9843 5/5 h0h_{0} 0.8960 0.0037 0.8999 0.4288 0.9664 0.9618 0.9945 5/5 CellScientist 0.9020 0.0039 0.9098 0.4345 0.9750 0.9697 0.9943 5/5 Fold 5 replication Matching mean 0.8982 0.0043 0.8799 0.4681 0.9614 0.9469 0.9938 supported Additive singles 0.8982 0.0033 0.8799 0.4681 0.9614 0.9469 0.9952 supported Ridge 0.8959 0.0029 0.8813 0.4375 0.9672 0.9546 0.9957 supported GEARS 0.6676 0.0115 0.6156 0.2267 0.8021 0.8096 0.9853 5/5 h0h_{0} 0.9051 0.0027 0.8844 0.4065 0.9542 0.9474 0.9961 5/5 CellScientist 0.9096 0.0028 0.8944 0.4071 0.9650 0.9554 0.9960 5/5

b143The matched transfer analysis gives CellScientist, AIDE, CellForge, and HarmonyCell the same initial model, design language, Fold-3 feedback, physical budget, and model-selection rule; each policy generates its own candidates. CellScientist has the highest mean Best@10 and frontier AUC. Its paired Best@10 effect is +0.0029+0.0029 versus AIDE (95% CI [−0.0003,+0.0061][-0.0003,+0.0061]), +0.0058+0.0058 versus CellForge ([+0.0037,+0.0080][+0.0037,+0.0080]), and +0.0006+0.0006 versus HarmonyCell ([−0.0005,+0.0016][-0.0005,+0.0016]). After selection, all sources are refit under five paired seeds and audited without provider calls. Global-PCC ordering varies across folds, while all four selected models pass the pair-input-bundle test in 5/5 refits; CellScientist leads condition-, DEG-20-, and DEG-50-PCC at Fold 5.

b144Policy Best@3 ↑\uparrow Best@5 ↑\uparrow Best@10 ↑\uparrow Frontier AUC ↑\uparrow Δ​h0\Delta h_{0} [95% CI] ↑\uparrow Positive ↑\uparrow Executed slots ↑\uparrow Calls ↓\downarrow Tokens ↓\downarrow CellScientist 0.9192 0.9201 0.9210 0.9194 +0.0062 [+0.0036,+0.0087] 10/10 77/100 154 403,762 AIDE 0.9164 0.9168 0.9181 0.9170 +0.0033 [+0.0011,+0.0054] 9/10 91/100 120 335,610 CellForge 0.9151 0.9152 0.9152 0.9151 +0.0003 [−-0.0004,+0.0010] 1/10 97/100 108 309,742 HarmonyCell 0.9191 0.9203 0.9204 0.9193 +0.0056 [+0.0028,+0.0084] 9/10 88/100 117 328,705

b145Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b146A. Selected architecture Policy Architecture Width Depth Dropout PCC–MSE weight CellScientist Gated MLP 512 4 0.1 0.3 AIDE Gated MLP 512 4 0.2 0.2 CellForge Residual MLP 256 3 0.1 0.1 HarmonyCell Residual MLP 384 4 0.2 0.1

b147B. Optimization and selection Policy Optimizer / learning rate Parameters Fold-3 PCC CellScientist AdamW / 0.001 5,850,037 0.9237 AIDE AdamW / 0.0005 5,850,037 0.9234 CellForge AdamW / 0.001 1,850,549 0.9195 HarmonyCell AdamW / 0.001 3,758,261 0.9247

b148Policy Global PCC ↑\uparrow [95% CI] MSE ↓\downarrow Condition PCC ↑\uparrow DEG-20 PCC ↑\uparrow DEG-50 PCC ↑\uparrow Bundle drop Bundle-use support Fold 4 audit CellScientist 0.9020 [0.8988,0.9051] 0.00388 0.9098 0.9750 0.9697 0.5578 5/5 AIDE 0.8981 [0.8920,0.9042] 0.00407 0.9038 0.9682 0.9637 0.5458 5/5 CellForge 0.8960 [0.8909,0.9011] 0.00372 0.8999 0.9664 0.9618 0.5425 5/5 HarmonyCell 0.8960 [0.8920,0.9000] 0.00369 0.9019 0.9693 0.9641 0.5506 5/5 Fold 5 replication CellScientist 0.9096 [0.9051,0.9142] 0.00277 0.8944 0.9650 0.9554 0.6280 5/5 AIDE 0.9125 [0.9088,0.9161] 0.00285 0.8912 0.9567 0.9488 0.6270 5/5 CellForge 0.9051 [0.9023,0.9079] 0.00267 0.8844 0.9542 0.9474 0.6193 5/5 HarmonyCell 0.9088 [0.9029,0.9148] 0.00255 0.8867 0.9597 0.9505 0.6294 5/5

b149Bold/underline: best/second distinct displayed predictive mean within each task or fold. Ties share a rank; interval bounds and diagnostic/resource columns are unranked.

b150Comparator Δ\Delta Global PCC [95% CI] PCC wins Δ\Delta bundle drop [95% CI] Fold 4 audit AIDE +0.0039 [−-0.0044,+0.0122] 4/5 +0.0121 [−-0.0004,+0.0245] CellForge +0.0060 [−-0.0008,+0.0128] 4/5 +0.0154 [+0.0030,+0.0277] HarmonyCell +0.0060 [−-0.0009,+0.0129] 4/5 +0.0072 [−-0.0061,+0.0205] Fold 5 replication AIDE −-0.0028 [−-0.0103,+0.0046] 2/5 +0.0010 [−-0.0059,+0.0078] CellForge +0.0045 [−-0.0004,+0.0094] 5/5 +0.0087 [+0.0037,+0.0137] HarmonyCell +0.0008 [−-0.0056,+0.0072] 4/5 −-0.0015 [−-0.0131,+0.0101]

Appendix E Independent-acquisition test of small-molecule claim generalization

b152After the final falsification-guided procedure is fixed, LINCS–Pilot1 provides an out-of-development-cohort test. It uses an observed control profile, compound identity, and dose to predict a joint 2,719-dimensional morphology–transcription response across 4,155 matched conditions and 1,108 Murcko groups. The ten trajectory-selected design instances are then fixed for transfer to cpg0004/LKCP/2017_12_05_Batch2, an independently acquired Cell Painting release (Weisbart et al., 2024). Its 134 files contain 11,904 rows; 8,958 treatment and 2,946 control rows yield 1,728 retained conditions and 64 compound-held-out groups. Response- and fold-blind interface quality control removes 110 non-finite or extreme release features from 1,781 common morphology columns, retaining a 1,671-dimensional same-plate control profile and response.

b153The scientific question and model designs precede LKCP transfer. The final dataset adapter is fixed after interface quality control and before LKCP training or held-out-fold access. The transferred designs, input-permutation construction, map seeds, threshold-construction rule, and decision rule are registered and hash-bound at that point. Each design is then refit under five paired seeds with no further source edit or model reselection. Compound permutations hold dose fixed; dose permutations use only observed doses of the same compound, require at least a 0.10.1 log-dose contrast, and retain the same eligibility rule. Across 22 cohorts ×\times 22 folds ×\times 1010 designs ×\times 55 seeds, the analysis contains 200 cohort–fold–design–seed refit boundaries. Each boundary reuses the 32 registered ordered compound–dose permutation pairs, yielding 6,400 matched within-refit permutation units; these maps are repeated measurements rather than independent statistical units. For U11U_{11} with both inputs correct, U01U_{01} with compound shuffled, U10U_{10} with dose shuffled, and U00U_{00} with both shuffled, the two-player allocation is ϕchem=12​[(U11−U01)+(U10−U00)]\phi_{\mathrm{chem}}=\tfrac{1}{2}[(U_{11}-U_{01})+(U_{10}-U_{00})] and ϕdose=12​[(U11−U10)+(U01−U00)]\phi_{\mathrm{dose}}=\tfrac{1}{2}[(U_{11}-U_{10})+(U_{01}-U_{00})]. These allocate the contrast U11−U00U_{11}-U_{00}; adding the residual U00−UanchorU_{00}-U_{\mathrm{anchor}} gives Full−-control-only to numerical precision. The component allocations thus refer to the fixed replacement baseline, while Full−-control-only measures the separately fitted predictors’ performance difference.

b154A. LINCS–Pilot1 Contrast Fold 4 [95% CI] Fold 5 [95% CI] Full−-control-only +0.0293 [+0.0281, +0.0305] +0.0233 [+0.0226, +0.0241] Compound identity +0.0175 [+0.0164, +0.0186] +0.0126 [+0.0117, +0.0134] Dose +0.0486 [+0.0473, +0.0498] +0.0467 [+0.0456, +0.0478] Both-shuffled residual -0.0368 [-0.0378, -0.0358] -0.0359 [-0.0370, -0.0349] Interaction +0.0050 [+0.0033, +0.0067] +0.0042 [+0.0027, +0.0058]

b155B. LKCP Batch 2 Contrast Fold 4 [95% CI] Fold 5 [95% CI] Full−-control-only +0.0104 [+0.0103, +0.0106] +0.0211 [+0.0205, +0.0217] Compound identity -0.00007000 [-0.00028998, +0.00014998] +0.0033 [+0.0027, +0.0039] Dose +0.0237 [+0.0228, +0.0247] +0.0341 [+0.0331, +0.0350] Both-shuffled residual -0.0132 [-0.0140, -0.0124] -0.0163 [-0.0170, -0.0157] Interaction +0.00004049 [-0.00001503, +0.00009601] +0.0002 [+0.0001, +0.0003]

b156Cohort Fold Mean effect Lower-effect quantile Threshold Reference margin Refits above Chemical identity LINCS–Pilot1 4 0.0200 0.0139 0.0112 +0.0028 35/50 LINCS–Pilot1 5 0.0147 0.0090 0.0100 -0.0010 10/50 LKCP Batch 2 4 0.00003872 -0.0016 0.0303 -0.0319 0/50 LKCP Batch 2 5 0.0032 0.0013 0.0307 -0.0294 0/50 Dose LINCS–Pilot1 4 0.0510 0.0467 0.0068 +0.0398 50/50 LINCS–Pilot1 5 0.0488 0.0452 0.0059 +0.0393 50/50 LKCP Batch 2 4 0.0238 0.0205 0.0060 +0.0145 50/50 LKCP Batch 2 5 0.0342 0.0267 0.0125 +0.0142 50/50

Appendix F Full selected-model audit panel and calibration

b158The full Fold-4 panel contains the Fold-3-selected source from each of the four agents together with three distinct diagnostic sources: control-only, compound-only, and the shared h0h_{0}/simple-concatenation source shown under both reference roles. Predictive estimates use a separate five-seed refit panel from Table 21; model source or design, data fingerprint, population, and every non-seed fitting setting are identical. Each within-policy source is fixed before Fold 4; the pre-specified across-policy score rule then uses mean Fold-4 Global PCC to choose the single prediction-score source carried to Fold 5, which includes its paired control-only comparator. Controlled fixtures check recognized input consumption, the one-key attention contradiction, missing declarations, abstention, and known input dependence. A fixed compound-strength sweep characterizes threshold crossing in those fixtures; Appendix L explains the criterion’s reference-relative interpretation.

b159A. Predictive performance Model Global PCC MSE CP PCC L1000 PCC BBBC036 CellScientist 0.3096 ±\pm 0.0029 0.0586 ±\pm 0.0001 0.3113 ±\pm 0.0014 0.3089 ±\pm 0.0041 AIDE 0.2970 ±\pm 0.0075 0.0593 ±\pm 0.0004 0.3052 ±\pm 0.0031 0.2944 ±\pm 0.0102 CellForge 0.2960 ±\pm 0.0036 0.0592 ±\pm 0.0002 0.3056 ±\pm 0.0043 0.2925 ±\pm 0.0037 HarmonyCell 0.3110 ±\pm 0.0016 0.0586 ±\pm 0.0001 0.3109 ±\pm 0.0020 0.3110 ±\pm 0.0017 h0h_{0} 0.2879 ±\pm 0.0040 0.0598 ±\pm 0.0004 0.2981 ±\pm 0.0016 0.2839 ±\pm 0.0056 Control-only 0.3098 ±\pm 0.0024 0.0586 ±\pm 0.0001 0.3094 ±\pm 0.0013 0.3099 ±\pm 0.0028 Chemical-only 0.2239 ±\pm 0.0002 0.0616 ±\pm 0.0000 0.2998 ±\pm 0.0003 0.1832 ±\pm 0.0002 Simple concat 0.2879 ±\pm 0.0040 0.0598 ±\pm 0.0004 0.2981 ±\pm 0.0016 0.2839 ±\pm 0.0056 BBBC047 CellScientist 0.3035 ±\pm 0.0008 0.0457 ±\pm 0.0000 0.3260 ±\pm 0.0016 0.2784 ±\pm 0.0017 AIDE 0.2697 ±\pm 0.0048 0.0469 ±\pm 0.0002 0.3148 ±\pm 0.0047 0.2152 ±\pm 0.0116 CellForge 0.2727 ±\pm 0.0019 0.0467 ±\pm 0.0001 0.3175 ±\pm 0.0035 0.2190 ±\pm 0.0059 HarmonyCell 0.2983 ±\pm 0.0110 0.0459 ±\pm 0.0003 0.3271 ±\pm 0.0030 0.2654 ±\pm 0.0231 h0h_{0} 0.2697 ±\pm 0.0048 0.0469 ±\pm 0.0002 0.3148 ±\pm 0.0047 0.2152 ±\pm 0.0116 Control-only 0.3019 ±\pm 0.0015 0.0458 ±\pm 0.0001 0.3223 ±\pm 0.0011 0.2789 ±\pm 0.0023 Chemical-only 0.2159 ±\pm 0.0012 0.0480 ±\pm 0.0000 0.2935 ±\pm 0.0022 0.0924 ±\pm 0.0028 Simple concat 0.2697 ±\pm 0.0048 0.0469 ±\pm 0.0002 0.3148 ±\pm 0.0047 0.2152 ±\pm 0.0116

b160B. Input-use evidence Model EchemE_{\rm chem} EcontrolE_{\rm control} Ichem,controlI_{\rm chem,control} Q/U/I Status BBBC036 CellScientist 0.0000 ±\pm 0.0000 0.1622 ±\pm 0.0095 0.0000 ±\pm 0.0000 0/5/0 Unsup. AIDE 0.0029 ±\pm 0.0017 0.1577 ±\pm 0.0118 -0.0021 ±\pm 0.0016 0/5/0 Unsup. CellForge 0.0089 ±\pm 0.0052 0.1464 ±\pm 0.0063 -0.0000 ±\pm 0.0007 0/5/0 Unsup. HarmonyCell 0.0000 ±\pm 0.0000 0.1693 ±\pm 0.0033 -0.0000 ±\pm 0.0000 0/5/0 Unsup. h0h_{0} 0.0193 ±\pm 0.0087 0.1359 ±\pm 0.0057 -0.0003 ±\pm 0.0007 1/2/2 Inc. Control-only 0.0000 ±\pm 0.0000 0.1719 ±\pm 0.0067 0.0000 ±\pm 0.0000 – N/C Chemical-only 0.0011 ±\pm 0.0002 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0/0/5 Inc. Simple concat 0.0193 ±\pm 0.0087 0.1359 ±\pm 0.0057 -0.0003 ±\pm 0.0007 1/2/2 Inc. BBBC047 CellScientist 0.0000 ±\pm 0.0000 0.1932 ±\pm 0.0044 0.0000 ±\pm 0.0000 0/5/0 Unsup. AIDE 0.0118 ±\pm 0.0052 0.1119 ±\pm 0.0121 0.0013 ±\pm 0.0009 0/1/4 Inc. CellForge 0.0100 ±\pm 0.0045 0.1114 ±\pm 0.0059 0.0012 ±\pm 0.0008 0/2/3 Inc. HarmonyCell 0.0006 ±\pm 0.0010 0.1866 ±\pm 0.0225 0.0009 ±\pm 0.0015 0/5/0 Unsup. h0h_{0} 0.0118 ±\pm 0.0052 0.1119 ±\pm 0.0121 0.0013 ±\pm 0.0009 0/1/4 Inc. Control-only 0.0000 ±\pm 0.0000 0.2030 ±\pm 0.0054 0.0000 ±\pm 0.0000 – N/C Chemical-only 0.0111 ±\pm 0.0010 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 5/0/0 Sup. Simple concat 0.0118 ±\pm 0.0052 0.1119 ±\pm 0.0121 0.0013 ±\pm 0.0009 0/1/4 Inc.

b161Aggregate status: Sup., claim-supported; Unsup., unsupported; Inc., inconclusive; N/C, not claimed.

b162A. Predictive performance Policy Model Global PCC ↑\uparrow MSE ↓\downarrow CP PCC ↑\uparrow L1000 PCC ↑\uparrow BBBC036 h0h_{0} reference h0h_{0} 0.2588 ±\pm 0.0059 0.0608 ±\pm 0.0004 0.2596 ±\pm 0.0100 0.2586 ±\pm 0.0094 Score-selected HarmonyCell 0.2932 ±\pm 0.0020 0.0590 ±\pm 0.0001 0.2909 ±\pm 0.0018 0.2942 ±\pm 0.0023 BBBC047 h0h_{0} reference h0h_{0} 0.2786 ±\pm 0.0031 0.0465 ±\pm 0.0003 0.3220 ±\pm 0.0091 0.2243 ±\pm 0.0105 Score-selected CellScientist 0.3153 ±\pm 0.0014 0.0452 ±\pm 0.0000 0.3393 ±\pm 0.0007 0.2872 ±\pm 0.0025

b163B. Input-use evidence and replication Model EchemE_{\rm chem} EcontrolE_{\rm control} Ichem,controlI_{\rm chem,control} Q/U/I Status Status replicated? BBBC036 h0h_{0} 0.0047 ±\pm 0.0031 0.1202 ±\pm 0.0085 0.0042 ±\pm 0.0011 0/5/0 Unsup. no HarmonyCell 0.0000 ±\pm 0.0000 0.1516 ±\pm 0.0035 -0.0000 ±\pm 0.0000 0/5/0 Unsup. yes BBBC047 h0h_{0} 0.0096 ±\pm 0.0037 0.1199 ±\pm 0.0109 0.0012 ±\pm 0.0007 0/1/4 Inc. yes CellScientist 0.0000 ±\pm 0.0000 0.2004 ±\pm 0.0061 0.0000 ±\pm 0.0000 0/5/0 Unsup. yes

b164Score-selected denotes prediction-score selection. Aggregate status: Unsup., unsupported; Inc., inconclusive.

b165Task Score-selected model Selected-model PCC ↑\uparrow Control-only PCC ↑\uparrow Paired Δ\Delta [95% CI] BBBC036 HarmonyCell 0.2932 ±\pm 0.0020 0.2921 ±\pm 0.0017 +0.0011 [−-0.0008, +0.0030] BBBC047 CellScientist 0.3153 ±\pm 0.0014 0.3142 ±\pm 0.0012 +0.0011 [−-0.0005, +0.0027]

b166A. BBBC036 Model Residual PCC ↑\uparrow Mean [95% CI] MSE ↓\downarrow Pert. effect ↑\uparrow h0h_{0} 0.0474 [0.0371, 0.0577] 0.0598 0.0381 CellScientist 0.0294 [0.0052, 0.0535] 0.0586 0.0000 AIDE 0.0301 [0.0236, 0.0366] 0.0593 0.0050 CellForge 0.0336 [0.0234, 0.0438] 0.0592 0.0223 HarmonyCell 0.0341 [0.0226, 0.0455] 0.0586 0.0000 Control-only Zero increment 0.0586 – Chemical-only 0.0052 [-0.0044, 0.0148] 0.0616 0.0012 Simple concat 0.0474 [0.0371, 0.0577] 0.0598 0.0381 B. BBBC047 Model Residual PCC ↑\uparrow Mean [95% CI] MSE ↓\downarrow Pert. effect ↑\uparrow h0h_{0} 0.0558 [0.0510, 0.0606] 0.0469 0.0205 CellScientist 0.0538 [0.0422, 0.0654] 0.0457 0.0000 AIDE 0.0558 [0.0510, 0.0606] 0.0469 0.0205 CellForge 0.0553 [0.0510, 0.0596] 0.0467 0.0174 HarmonyCell 0.0567 [0.0470, 0.0663] 0.0459 0.0020 Control-only Zero increment 0.0458 – Chemical-only 0.0457 [0.0382, 0.0532] 0.0480 0.0104 Simple concat 0.0558 [0.0510, 0.0606] 0.0469 0.0205

F.1 Known-truth measurement and uncertainty checks

b168The fixed-context simulator uses f⁡(z,c)=(a​z,c)f(z,c)=(az,c) and Y=(b​z+e,c)Y=(bz+e,c). Matched replacement draws an independent normal z′z^{\prime} while fixing c,Yc,Y. The loss is the sum of squared errors over both channels, so the population paired loss increment is τ=2​a​b\tau=2ab; the mean squared Euclidean prediction distance is η=2​a2\eta=2a^{2}, not RMS. Groups receive equal weight and rows equal weight within group. The experiment evaluates equal-group-weighted population contrasts; real-data row-weighted resampling is reported separately. Four classes are invariant (a,b)=(0,.2)(a,b)=(0,.2), sensitive without benefit (.2,0)(.2,0), beneficial (.2,.2)(.2,.2), and harmful (−.2,.2)(-.2,.2). Their loss truths are 0,0,.08,−.080,0,.08,-.08 and distance truths 0,.08,.08,.080,.08,.08,.08.

b169The frozen 24=162^{4}=16 scenarios cross G∈{8,32}G\in\{8,32\} independent source groups, balanced size 8 or independently sampled sizes {2,4,8,32}\{2,4,8,32\} with equal probabilities, within-group correlation ρ∈{0,.6}\rho\in\{0,.6\}, and noise SD σ∈{.25,1}\sigma\in\{.25,1\}. Each scenario has 400 independent datasets (6400 total). Maps 32/128 are nested on the same datasets, not independent cohorts. Group-percentile intervals use 999 bootstrap draws; group-tt uses G−1G-1 degrees of freedom. Source/donor, bootstrap and context seeds are 2026091401, 2026091402 and 2026091403.

b170Map-only intervals target the donor-integrated contrast of one fixed dataset; group-aware intervals target the population expectation over independent groups. Their coverage is therefore reported against both truths. Positive evidence means a strictly positive lower bound of a two-sided 95% CI: the positive one-tail nominal Type-I error is .025.025, not .05.05. Power is positive-direction evidence for benefit and negative-direction evidence for harm. Prediction distance does not test target benefit. Invariant data and intervals are identically zero and are reported as a deterministic check, not “100% calibrated” stochastic coverage.

b171Endpoint / class CI method Population coverage Conditional coverage Directed evidence rate 32 donor maps Null loss Map only [0.1500, 0.3000][0.1500,\,0.3000] [0.9275, 0.9675][0.9275,\,0.9675] [0.2850, 0.5000][0.2850,\,0.5000] Null loss Group tt [0.9200, 0.9775][0.9200,\,0.9775] [1.0000, 1.0000][1.0000,\,1.0000] [0.0150, 0.0725][0.0150,\,0.0725] Null loss Group bootstrap [0.8175, 0.9400][0.8175,\,0.9400] [1.0000, 1.0000][1.0000,\,1.0000] [0.0350, 0.1475][0.0350,\,0.1475] Beneficial loss Map only [0.1425, 0.3350][0.1425,\,0.3350] [0.9250, 0.9650][0.9250,\,0.9650] [0.7100, 1.0000][0.7100,\,1.0000] Beneficial loss Group tt [0.9100, 0.9650][0.9100,\,0.9650] [0.9975, 1.0000][0.9975,\,1.0000] [0.1200, 1.0000][0.1200,\,1.0000] Beneficial loss Group bootstrap [0.8350, 0.9425][0.8350,\,0.9425] [0.9975, 1.0000][0.9975,\,1.0000] [0.2650, 1.0000][0.2650,\,1.0000] Harmful loss Map only [0.1050, 0.2750][0.1050,\,0.2750] [0.9375, 0.9650][0.9375,\,0.9650] [0.6775, 1.0000][0.6775,\,1.0000] Harmful loss Group tt [0.8625, 0.9725][0.8625,\,0.9725] [1.0000, 1.0000][1.0000,\,1.0000] [0.0550, 1.0000][0.0550,\,1.0000] Harmful loss Group bootstrap [0.8300, 0.9400][0.8300,\,0.9400] [1.0000, 1.0000][1.0000,\,1.0000] [0.1900, 1.0000][0.1900,\,1.0000] Squared distance Map only [0.2175, 0.5250][0.2175,\,0.5250] [0.9400, 0.9700][0.9400,\,0.9700] [1.0000, 1.0000][1.0000,\,1.0000] Squared distance Group tt [0.8375, 0.9525][0.8375,\,0.9525] [1.0000, 1.0000][1.0000,\,1.0000] [0.9975, 1.0000][0.9975,\,1.0000] Squared distance Group bootstrap [0.7800, 0.9375][0.7800,\,0.9375] [0.9975, 1.0000][0.9975,\,1.0000] [1.0000, 1.0000][1.0000,\,1.0000] 128 donor maps Null loss Map only [0.0675, 0.1625][0.0675,\,0.1625] [0.9225, 0.9725][0.9225,\,0.9725] [0.3600, 0.5375][0.3600,\,0.5375] Null loss Group tt [0.9125, 0.9775][0.9125,\,0.9775] [1.0000, 1.0000][1.0000,\,1.0000] [0.0125, 0.0775][0.0125,\,0.0775] Null loss Group bootstrap [0.8200, 0.9350][0.8200,\,0.9350] [1.0000, 1.0000][1.0000,\,1.0000] [0.0350, 0.1450][0.0350,\,0.1450] Beneficial loss Map only [0.0750, 0.1750][0.0750,\,0.1750] [0.9175, 0.9650][0.9175,\,0.9650] [0.7675, 1.0000][0.7675,\,1.0000] Beneficial loss Group tt [0.9075, 0.9725][0.9075,\,0.9725] [1.0000, 1.0000][1.0000,\,1.0000] [0.1200, 1.0000][0.1200,\,1.0000] Beneficial loss Group bootstrap [0.8400, 0.9450][0.8400,\,0.9450] [1.0000, 1.0000][1.0000,\,1.0000] [0.2475, 1.0000][0.2475,\,1.0000] Harmful loss Map only [0.0400, 0.1450][0.0400,\,0.1450] [0.9125, 0.9600][0.9125,\,0.9600] [0.7025, 1.0000][0.7025,\,1.0000] Harmful loss Group tt [0.8600, 0.9700][0.8600,\,0.9700] [1.0000, 1.0000][1.0000,\,1.0000] [0.0500, 1.0000][0.0500,\,1.0000] Harmful loss Group bootstrap [0.8200, 0.9425][0.8200,\,0.9425] [1.0000, 1.0000][1.0000,\,1.0000] [0.1875, 1.0000][0.1875,\,1.0000] Squared distance Map only [0.0925, 0.2900][0.0925,\,0.2900] [0.9350, 0.9600][0.9350,\,0.9600] [1.0000, 1.0000][1.0000,\,1.0000] Squared distance Group tt [0.8425, 0.9500][0.8425,\,0.9500] [1.0000, 1.0000][1.0000,\,1.0000] [0.9975, 1.0000][0.9975,\,1.0000] Squared distance Group bootstrap [0.8025, 0.9350][0.8025,\,0.9350] [1.0000, 1.0000][1.0000,\,1.0000] [1.0000, 1.0000][1.0000,\,1.0000]

b172Each rate uses 400 independent datasets per scenario; ranges are minima/maxima over scenarios, not pooled coverage. The last column is positive Type I for null loss (nominal .025), correctly directed power for beneficial/harmful loss, and positive-distance evidence for distance. Conditional and population targets differ. Invariant cases are excluded from stochastic coverage.

b173GG/size/ρ\rho/σ\sigma Map only Group tt Group bootstrap tt Type-I MCSE tt Type-I Wilson 95% CI 8/B/0/0.25 0.1275 0.4600 0.9500 0.0400 0.8675 0.0950 0.00980.0098 [0.0248, 0.0640][0.0248,\,0.0640] 8/B/0/1 0.1175 0.4925 0.9550 0.0325 0.8950 0.0700 0.00890.0089 [0.0191, 0.0548][0.0191,\,0.0548] 8/B/0.6/0.25 0.0875 0.5075 0.9325 0.0600 0.8200 0.1450 0.01190.0119 [0.0406, 0.0877][0.0406,\,0.0877] 8/B/0.6/1 0.0675 0.4925 0.9650 0.0225 0.8525 0.0850 0.00740.0074 [0.0119, 0.0422][0.0119,\,0.0422] 8/I/0/0.25 0.1300 0.4675 0.9325 0.0650 0.8500 0.1275 0.01230.0123 [0.0447, 0.0935][0.0447,\,0.0935] 8/I/0/1 0.1550 0.3600 0.9775 0.0125 0.8825 0.0650 0.00560.0056 [0.0054, 0.0289][0.0054,\,0.0289] 8/I/0.6/0.25 0.0725 0.5375 0.9350 0.0650 0.8400 0.1375 0.01230.0123 [0.0447, 0.0935][0.0447,\,0.0935] 8/I/0.6/1 0.0825 0.4625 0.9600 0.0250 0.8300 0.1000 0.00780.0078 [0.0136, 0.0454][0.0136,\,0.0454] 32/B/0/0.25 0.1125 0.4275 0.9325 0.0300 0.9225 0.0375 0.00850.0085 [0.0172, 0.0517][0.0172,\,0.0517] 32/B/0/1 0.1350 0.4500 0.9625 0.0225 0.9350 0.0350 0.00740.0074 [0.0119, 0.0422][0.0119,\,0.0422] 32/B/0.6/0.25 0.0850 0.4650 0.9325 0.0575 0.9175 0.0675 0.01160.0116 [0.0386, 0.0848][0.0386,\,0.0848] 32/B/0.6/1 0.0875 0.4600 0.9600 0.0250 0.9350 0.0350 0.00780.0078 [0.0136, 0.0454][0.0136,\,0.0454] 32/I/0/0.25 0.1450 0.3975 0.9450 0.0425 0.9225 0.0500 0.01010.0101 [0.0267, 0.0670][0.0267,\,0.0670] 32/I/0/1 0.1625 0.4175 0.9450 0.0375 0.9225 0.0425 0.00950.0095 [0.0229, 0.0609][0.0229,\,0.0609] 32/I/0.6/0.25 0.0975 0.4900 0.9125 0.0775 0.8925 0.0850 0.01340.0134 [0.0551, 0.1079][0.0551,\,0.1079] 32/I/0.6/1 0.0750 0.4450 0.9375 0.0450 0.9025 0.0625 0.01040.0104 [0.0287, 0.0700][0.0287,\,0.0700]

b174B/I: balanced/imbalanced. Type-I nominal .025. MCSE is p⁡(1−p)/400\sqrt{p(1-p)/400} (worst possible .025); Wilson intervals are pointwise Monte Carlo intervals, not simultaneous bounds over 16 scenarios.

b175Endpoint / class Maps Truth Bias range Bias MCSE range Null loss 32 00 [−×10−3,×10−3][-8.41\!\times\!10^{-3},\,4.95\!\times\!10^{-3}] [×10−4,×10−3][3.84\!\times\!10^{-4},\,5.21\!\times\!10^{-3}] Null loss 128 00 [−×10−3,×10−3][-8.42\!\times\!10^{-3},\,5.48\!\times\!10^{-3}] [×10−4,×10−3][3.82\!\times\!10^{-4},\,5.14\!\times\!10^{-3}] Beneficial loss 32 0.080.08 [−×10−3,×10−3][-7.32\!\times\!10^{-3},\,4.58\!\times\!10^{-3}] [×10−4,×10−3][3.50\!\times\!10^{-4},\,5.14\!\times\!10^{-3}] Beneficial loss 128 0.080.08 [−×10−3,×10−3][-7.47\!\times\!10^{-3},\,5.06\!\times\!10^{-3}] [×10−4,×10−3][3.47\!\times\!10^{-4},\,5.06\!\times\!10^{-3}] Harmful loss 32 −0.08-0.08 [−×10−3,×10−3][-4.17\!\times\!10^{-3},\,6.55\!\times\!10^{-3}] [×10−4,×10−3][5.70\!\times\!10^{-4},\,5.48\!\times\!10^{-3}] Harmful loss 128 −0.08-0.08 [−×10−3,×10−3][-4.68\!\times\!10^{-3},\,6.51\!\times\!10^{-3}] [×10−4,×10−3][5.65\!\times\!10^{-4},\,5.40\!\times\!10^{-3}] Squared distance 32 0.080.08 [−×10−4,×10−4][-4.19\!\times\!10^{-4},\,7.09\!\times\!10^{-4}] [×10−4,×10−4][1.69\!\times\!10^{-4},\,7.60\!\times\!10^{-4}] Squared distance 128 0.080.08 [−×10−4,×10−4][-3.08\!\times\!10^{-4},\,5.67\!\times\!10^{-4}] [×10−4,×10−4][1.68\!\times\!10^{-4},\,7.49\!\times\!10^{-4}]

b176All CI methods share the same point estimator. Bias MCSE is the empirical SD of estimation error divided by 400\sqrt{400}; full-precision per-scenario bias, RMSE, coverage and Wilson intervals are in the portable CSV.

b177Class Amplitude Mean effect Mean QQ Support-rate range Invariant 00 00 00 [0, 0][0,\,0] Invariant 0.20.2 00 0.087920.08792 [0, 0][0,\,0] Invariant 2.02.0 00 8.792308.79230 [0, 0][0,\,0] Sensitive/no benefit 00 −0.00067-0.00067 0.077440.07744 [0, 0.007][0,\,0.007] Sensitive/no benefit 0.20.2 −0.00067-0.00067 0.120340.12034 [0, 0.003][0,\,0.003] Sensitive/no benefit 2.02.0 −0.00067-0.00067 8.792748.79274 [0, 0][0,\,0] Beneficial 00 0.079460.07946 0.082260.08226 [0, 1.000][0,\,1.000] Beneficial 0.20.2 0.079460.07946 0.122600.12260 [0, 0.110][0,\,0.110] Beneficial 2.02.0 0.079460.07946 8.792798.79279 [0, 0][0,\,0] Harmful 00 −0.07961-0.07961 0.082180.08218 [0, 0][0,\,0] Harmful 0.20.2 −0.07961-0.07961 0.122760.12276 [0, 0][0,\,0] Harmful 2.02.0 −0.07961-0.07961 8.792488.79248 [0, 0][0,\,0]

b178Means average all 16 scenarios; support ranges remain scenario-specific. This replays the historical formula on negative squared-loss scores, not historical PCC. Changing orthogonal context changes its reference threshold while keeping the chemical contrast fixed. Non-support is not a false negative for the different proposition τ>0\tau>0; both map budgets and all original statuses remain in the portable CSV.

b179The group-aware methods still under-cover in some scenarios; the bootstrap is particularly weak with few groups, and positive null declarations can exceed the nominal one-tail rate. Independent normal donors, independent groups, and correct context matching are explicit simulation assumptions, not demonstrations of real biological conditional exchangeability or support. Finite reused donor pools and dependent biological groups require additional dependence handling. More maps reduce conditional Monte Carlo error but do not create more biological replicates.

Appendix G Complete input-intervention results

b181The complete intervention matrix reports search performance, held-out predictive performance, compound-identity effect, control-profile effect, target-loss gain, and input-use status in separate columns. Rows summarize the full pre-specified model sets, and −⁣−-- marks contrasts that cannot be identified under the protocol. Response-block decompositions are diagnostic views of the same selected models and fitted checkpoints. Figure 6 follows the compound and control effects of the falsification-guided checkpoints across both held-out folds.

b182A. Selection record Task Search setting Selected source Fold-3 PCC BBBC036 Prediction-score HarmonyCell 0.2985 BBBC036 Path-constrained 10-endpoint cohort 0.2925 ±\pm 0.0019 BBBC036 Falsification-guided 10-endpoint cohort 0.3006 ±\pm 0.0006 BBBC047 Prediction-score CellScientist 0.3231 BBBC047 Path-constrained 10-endpoint cohort 0.3008 ±\pm 0.0012 BBBC047 Falsification-guided 10-endpoint cohort 0.3238 ±\pm 0.0002

b183B. Fold 4: held-out input-use evidence Search setting PCC EcmpdE_{\rm cmpd} EcmpdℒE^{\mathcal{L}}_{\rm cmpd} EctrlE_{\rm ctrl} Q/U/I BBBC036 Prediction-score 0.3110 ±\pm 0.0016 0.0000 ±\pm 0.0000 0.00000 ±\pm 0.00000 0.1693 ±\pm 0.0033 0/5/0 Path-constrained 0.3034 ±\pm 0.0029 0.0007 ±\pm 0.0006 0.00003 ±\pm 0.00003 0.1592 ±\pm 0.0050 0/10/0 Falsification-guided 0.3167 ±\pm 0.0013 0.0091 ±\pm 0.0010 0.00039 ±\pm 0.00004 0.1716 ±\pm 0.0042 0/10/0 BBBC047 Prediction-score 0.3035 ±\pm 0.0008 0.0000 ±\pm 0.0000 0.00000 ±\pm 0.00000 0.1932 ±\pm 0.0044 0/5/0 Path-constrained 0.2822 ±\pm 0.0017 0.0083 ±\pm 0.0016 0.00024 ±\pm 0.00005 0.1388 ±\pm 0.0052 0/6/4 Falsification-guided 0.3060 ±\pm 0.0004 0.0053 ±\pm 0.0002 0.00018 ±\pm 0.00001 0.1988 ±\pm 0.0027 0/10/0

b184C. Fold 5: held-out input-use evidence Search setting PCC EcmpdE_{\rm cmpd} EcmpdℒE^{\mathcal{L}}_{\rm cmpd} EctrlE_{\rm ctrl} Q/U/I BBBC036 Prediction-score 0.2932 ±\pm 0.0020 0.0000 ±\pm 0.0000 0.00000 ±\pm 0.00000 0.1516 ±\pm 0.0035 0/5/0 Path-constrained 0.2886 ±\pm 0.0018 0.0039 ±\pm 0.0022 0.00016 ±\pm 0.00009 0.1423 ±\pm 0.0050 0/10/0 Falsification-guided 0.2897 ±\pm 0.0008 0.0022 ±\pm 0.0012 0.00009 ±\pm 0.00005 0.1515 ±\pm 0.0037 0/10/0 BBBC047 Prediction-score 0.3153 ±\pm 0.0014 0.0000 ±\pm 0.0000 0.00000 ±\pm 0.00000 0.2004 ±\pm 0.0061 0/5/0 Path-constrained 0.2922 ±\pm 0.0018 0.0074 ±\pm 0.0017 0.00022 ±\pm 0.00005 0.1477 ±\pm 0.0057 0/7/3 Falsification-guided 0.3173 ±\pm 0.0004 0.0048 ±\pm 0.0004 0.00017 ±\pm 0.00001 0.2051 ±\pm 0.0024 0/10/0

b185A. Predictive performance Task Fold Control-only PCC Full PCC Δ\Delta Full−-Control BBBC036 Fold 4 0.3121 ±\pm 0.0011 0.3167 ±\pm 0.0013 0.0046 ±\pm 0.0006 BBBC036 Fold 5 0.2917 ±\pm 0.0006 0.2897 ±\pm 0.0008 -0.0020 ±\pm 0.0009 BBBC047 Fold 4 0.3023 ±\pm 0.0004 0.3060 ±\pm 0.0004 0.0037 ±\pm 0.0003 BBBC047 Fold 5 0.3145 ±\pm 0.0005 0.3173 ±\pm 0.0004 0.0028 ±\pm 0.0004

b186B. Input-use evidence Task Fold EcmpdE_{\rm cmpd} EcmpdℒE^{\mathcal{L}}_{\rm cmpd} EctrlE_{\rm ctrl} Model Q/U/I BBBC036 Fold 4 0.0091 ±\pm 0.0010 0.00039 ±\pm 0.00004 0.1716 ±\pm 0.0042 0/10/0 BBBC036 Fold 5 0.0022 ±\pm 0.0012 0.00009 ±\pm 0.00005 0.1515 ±\pm 0.0037 0/10/0 BBBC047 Fold 4 0.0053 ±\pm 0.0002 0.00018 ±\pm 0.00001 0.1988 ±\pm 0.0027 0/10/0 BBBC047 Fold 5 0.0048 ±\pm 0.0004 0.00017 ±\pm 0.00001 0.2051 ±\pm 0.0024 0/10/0

b187Predictor Global PCC [95% CI] Chemical PCC drop [95% CI] Target-loss gain [95% CI] BBBC036 / Fold 4 Falsification-guided 0.3167 [0.3154, 0.3181] 0.0091 [0.0081, 0.0101] 0.00039 [0.00034, 0.00043] Residual MLP 0.3056 [0.3027, 0.3085] 0.0036 [0.0028, 0.0044] 0.00015 [0.00012, 0.00019] Joint Ridge 0.0892 [0.0867, 0.0917] 0.0153 [0.0147, 0.0159] 0.00299 [0.00290, 0.00308] BBBC036 / Fold 5 Falsification-guided 0.2897 [0.2890, 0.2905] 0.0022 [0.0010, 0.0034] 0.00009 [0.00004, 0.00014] Residual MLP 0.2861 [0.2829, 0.2892] 0.0007 [0.0001, 0.0013] 0.00003 [0.00000, 0.00005] Joint Ridge 0.1114 [0.1092, 0.1136] 0.0336 [0.0328, 0.0344] 0.00569 [0.00557, 0.00582] BBBC047 / Fold 4 Falsification-guided 0.3060 [0.3056, 0.3064] 0.0053 [0.0051, 0.0055] 0.00018 [0.00017, 0.00019] Residual MLP 0.3031 [0.3007, 0.3055] 0.0119 [0.0094, 0.0145] 0.00042 [0.00033, 0.00050] Joint Ridge 0.0774 [0.0765, 0.0783] 0.0082 [0.0079, 0.0085] 0.00420 [0.00416, 0.00423] BBBC047 / Fold 5 Falsification-guided 0.3173 [0.3169, 0.3177] 0.0048 [0.0044, 0.0052] 0.00017 [0.00015, 0.00018] Residual MLP 0.3154 [0.3135, 0.3174] 0.0113 [0.0095, 0.0132] 0.00040 [0.00033, 0.00047] Joint Ridge 0.0704 [0.0693, 0.0715] 0.0052 [0.0050, 0.0053] 0.00394 [0.00393, 0.00395]

b188Fold Perturbation Context Interaction CP L1000 CP L1000 CP L1000 Path-constrained / BBBC036 F4 0.0012 ±\pm 0.0009 0.0004 ±\pm 0.0005 0.0250 ±\pm 0.0023 0.2164 ±\pm 0.0057 0.0003 ±\pm 0.0004 -0.0003 ±\pm 0.0006 F5 0.0008 ±\pm 0.0004 0.0053 ±\pm 0.0031 0.0290 ±\pm 0.0024 0.1935 ±\pm 0.0056 0.0005 ±\pm 0.0002 0.0013 ±\pm 0.0008 Path-constrained / BBBC047 F4 0.0130 ±\pm 0.0026 0.0020 ±\pm 0.0002 0.0911 ±\pm 0.0037 0.2178 ±\pm 0.0054 0.0026 ±\pm 0.0012 0.0007 ±\pm 0.0002 F5 0.0118 ±\pm 0.0026 0.0013 ±\pm 0.0005 0.1005 ±\pm 0.0054 0.2251 ±\pm 0.0054 0.0011 ±\pm 0.0012 -0.0001 ±\pm 0.0003 Falsification-guided / BBBC036 F4 0.0141 ±\pm 0.0023 0.0069 ±\pm 0.0007 0.0248 ±\pm 0.0015 0.2363 ±\pm 0.0041 0.0000 ±\pm 0.0000 0.0001 ±\pm 0.0000 F5 -0.0014 ±\pm 0.0016 0.0039 ±\pm 0.0013 0.0284 ±\pm 0.0016 0.2088 ±\pm 0.0035 0.0001 ±\pm 0.0000 0.0002 ±\pm 0.0001 Falsification-guided / BBBC047 F4 0.0088 ±\pm 0.0003 0.0014 ±\pm 0.0001 0.1338 ±\pm 0.0031 0.2759 ±\pm 0.0013 0.0002 ±\pm 0.0001 0.0001 ±\pm 0.0000 F5 0.0079 ±\pm 0.0007 0.0013 ±\pm 0.0002 0.1421 ±\pm 0.0025 0.2806 ±\pm 0.0014 -0.0000 ±\pm 0.0001 0.0001 ±\pm 0.0000

b189Task Fold Δdose\Delta_{\rm dose} Compound Control Dose Compound×\times control Path-constrained BBBC036 4 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC036 5 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC047 4 – 0/6/4/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC047 5 – 0/7/3/0 10/0/0/0 0/0/0/10 0/10/0/0 Falsification-guided BBBC036 4 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC036 5 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC047 4 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0 BBBC047 5 – 0/10/0/0 10/0/0/0 0/0/0/10 0/10/0/0

Appendix H All-candidate source checking

b191Table 51 applies the deterministic checker to every retained prediction-score candidate and separates execution failure from checker abstention. Resolution coverage is the fraction of checked candidates whose cited source locations are all resolved. For candidates without a structured manifest declaring input use, the checker reports findings supported by pre-specified source locations. The one-key attention certificate is a code-level finding; complete-model replacement tests provide the corresponding behavioral evidence.

b192Candidate slots Code checker Coverage Policy Total Exec. Checked Resolved Singleton Abstain Resolved/ checked Checked/ slots BBBC036 CellScientist 100 99 99 60 15 39 60.6% 99.0% AIDE 100 100 100 100 0 0 100.0% 100.0% CellForge 100 91 91 91 0 0 100.0% 91.0% HarmonyCell 100 95 95 94 0 1 98.9% 95.0% BBBC047 CellScientist 100 94 94 48 17 46 51.1% 94.0% AIDE 100 99 99 99 0 0 100.0% 99.0% CellForge 100 94 94 94 0 0 100.0% 94.0% HarmonyCell 100 95 95 94 0 1 98.9% 95.0%

b193Search Slots Exec. Resolved Singleton Abstain Resolve % Exec. % BBBC036 Prediction-score 100 99 60 15 39 60.6% 99.0% Path-constrained 100 100 100 0 0 100.0% 100.0% BBBC047 Prediction-score 100 94 48 17 46 51.1% 94.0% Path-constrained 100 100 100 0 0 100.0% 100.0%

b194A deterministic hash selects model sources within each checker category for source-interface inspection. The inspection is restricted to pre-specified source locations and public fusion interfaces; fixed behavioral replacements remain applicable across all code-check categories.

b195A linked sample of 48 real candidate sources extends testing beyond the one-key attention case. Of these, 47 change their predictions after compound replacement at both boundaries; 20 have positive target-loss scaffold intervals at both. An implemented multi-tower source is exactly invariant. Source consumption, fitted dependence, and target benefit thus separate in diverse generated code (Appendix M).

Appendix I Prediction-space dependence

b197The prediction-space analysis measures normalized RMS change and cosine change between f⁡(c,p,a)f(c,p,a) and predictions obtained after fixed input permutations. Table 54 reports prediction-change RMS divided by the target RMS after centering each output feature across evaluation rows, with a denominator floor of 10−1210^{-12}. Both RMS quantities average over rows and features within the reported response block. This complements target-based effects: near-zero distance indicates negligible prediction change on the tested replacements, whereas nonzero distance with near-zero target-loss gain indicates sensitivity with little measured benefit on the observed response. The calculation requires inference only over fixed checkpoints.

b198Model Compound replacement Control replacement Global CP L1000 Global BBBC036 CellScientist 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.3112 ±\pm 0.0246 Chemical-only 0.0560 ±\pm 0.0013 0.0580 ±\pm 0.0014 0.0552 ±\pm 0.0013 0.0000 ±\pm 0.0000 Control-only 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.3390 ±\pm 0.0199 BBBC047 CellScientist 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.3593 ±\pm 0.0207 Chemical-only 0.1253 ±\pm 0.0066 0.1467 ±\pm 0.0093 0.1025 ±\pm 0.0055 0.0000 ±\pm 0.0000 Control-only 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.0000 ±\pm 0.0000 0.4011 ±\pm 0.0199

Appendix J Representative discovery records

b200The main text follows one model from selection through source checking and held-out replication. This section complements that input-use analysis with two preselected trajectory-level run records: a representative successful search and a search containing code repair. Each record preserves the initial hypothesis, decisive score changes, component edits, failures, repair actions, prompt and source hashes, and final selection. The complete ten-slot traces show both successful and failed execution paths.

b201The two cases are selected using Fold-3 run records only: a lower-median BBBC036 trajectory and the highest-scoring BBBC047 trajectory among those with at least one recorded candidate-code repair. Their records include the initial program, complete candidate sequence, parent hashes, structured decision context, candidate source, execution and repair outcomes, provider request/response hashes, and the versioned prompt constructor that defines the generation input.

J.1 Representative multimodal discovery trace

b203The initial candidate is a reproducible concatenation–MLP joint predictor with joint input fusion, a shared response program, a joint readout, response loss, and AdamW optimization; it obtains Fold-3 Global PCC 0.26680.2668. The recorded decision context for the retained final revision is: “Make one final diagnosis-driven revision of the best incumbent; prioritize a complete, executable perturbation-response hypothesis over a hyperparameter-only change.” The selected multi-head cross-modal-attention candidate uses separate control, compound, and dose encoders, cross-modal attention fusion, a shared response program, joint readout, block-weighted MSE, AdamW, and cosine scheduling, reaching 0.29280.2928. The trace contains 11 documented provider calls (53,096 reported tokens), each with a request hash, response hash, status, and token record.

J.2 Repair-containing discovery trace

b205The second trace begins from the same initial program at Fold-3 Global PCC 0.28810.2881. Its structured agenda specifies separate control, compound, and dose encoders; compound-query/control-key-value interaction with a dose residual; a shared response program; joint response prediction; CP/L1000 block-weighted MSE (0.4/0.6); AdamW; and cosine scheduling. Its selected first revision implements this design, resolves an output-shape mismatch by returning a [batch,target][\mathrm{batch},\mathrm{target}] tensor, and reaches 0.32300.3230. The complete trace contains 13 provider calls (63,572 reported tokens); a later slot exhausts all three repair attempts and remains recorded as a failed slot.

Appendix K Extended related work

b207Cell Painting, L1000, Perturb-seq, and sci-Plex measure morphological and transcriptional responses across chemical and genetic interventions (Bray et al., 2016; Caicedo et al., 2017; Subramanian et al., 2017; Dixit et al., 2016; Srivatsan et al., 2020). Matched resources and harmonized collections broaden this coverage (Haghighi et al., 2022; Chandrasekaran et al., 2024; Peidli et al., 2024). Predictors use latent-state transfer, compositional models, neural transport, genetic graphs, and foundation models (Lotfollahi et al., 2019; Lotfollahi et al., 2023; Bunne et al., 2023; Roohani et al., 2024; Cui et al., 2024); cycleCDR adds cycle-consistency constraints to learn transferable perturbation representations (Huang and Liu, 2024). CIPHER combines unperturbed-cell covariance with the specified perturbation to predict responses, illustrating the predictive value of baseline cellular structure (Kuznets-Speck et al., 2025). CellAudit asks whether a selected predictor uses the particular perturbation input invoked by its design.

b208PerturbBench and PertEval-scFM standardize predictive comparisons across splits and baselines (Wu et al., 2025; Wenteler et al., 2025). Deep predictors need not outperform linear references, and common metrics can reward systematic variation shared across perturbations (Ahlmann-Eltze et al., 2025; Viñas Torné et al., 2026). Other studies show that well-calibrated predictive metrics and informative foundation-model representations reveal gains over simple baselines (Miller et al., 2025; Hasanaj et al., 2025; Cole et al., 2026). In-the-wild evaluation further examines context and perturbation shifts (Mao et al., 2026). Together, these studies establish the importance of metrics, representations, and transfer conditions. CellAudit tests a complementary property: whether registered input-use claims are supported from cited source computation through fitted dependence to target-relevant predictive contribution.

b209Scientific agents span laboratory workflows, program search, and iterative machine-learning experimentation (Boiko et al., 2023; Romera-Paredes et al., 2024; Huang et al., 2024; Li et al., 2024; Lu et al., 2026; Jiang et al., 2025). CellScientist, CellForge, and HarmonyCell apply related search procedures to cellular prediction (Li et al., 2026; Tang et al., 2025; Huang et al., 2026). The existing CellScientist policy supplies candidate models in these experiments; CellAudit links their registered input-use claims to deterministic tests of source consumption, fitted dependence, and target-relevant predictive contribution.

b210Permutation reliance measures performance changes after input disruption; conditional permutations account for dependence among inputs (Fisher et al., 2019; Chamma et al., 2023). Shortcut and underspecification studies show that benchmark success can coexist with unintended or unstable decision rules (D’Amour et al., 2022; Geirhos et al., 2020; Lapuschkin et al., 2019; DeGrave et al., 2021). Attribution sanity checks, removal-based evaluation, and behavioral suites test explanations and capabilities under targeted interventions (Adebayo et al., 2018; Hooker et al., 2019; Ribeiro et al., 2020). ConceptSMILE audits concept-explanation reliability through input perturbations and local surrogate modeling (Mollapour et al., 2026); POPPER tests free-form hypotheses through agentic sequential falsification with statistical error control (Huang et al., 2025). CellAudit follows one selected cellular-response model and its registered input-use claim from the cited code to complete fitted predictions and later-data evaluation. This links source implementation, fitted dependence, and target-loss changes under registered replacements, distinguishing a blocked pathway, sensitivity without predictive benefit, and a contribution that recurs on new data.

Appendix L Factorial contrasts and stability summaries

b212An explicit input route establishes a possible computation; its fitted contribution is tested with the checkpoint and observed targets held fixed. We adapt permutation reliance and behavioral testing to the registered biological inputs (Fisher et al., 2019; Ribeiro et al., 2020). For a chemical-response model, the 2×22\times 2 test combines the correct or shuffled perturbation with the correct or an alternative control profile. Let mp​cm_{pc} denote the response score with both correct inputs, mp~​cm_{\tilde{p}c} the score after a matched perturbation shuffle, mp​c~m_{p\tilde{c}} the score after a control-profile swap, and mp~​c~m_{\tilde{p}\tilde{c}} the score after both. For a higher-is-better metric mm,

b213These are factorial contrasts in predictive score under the registered replacement distribution: EpertE_{\mathrm{pert}} averages perturbation-replacement effects across the two tested contexts, while Ipert,contextI_{\mathrm{pert,context}} measures their nonadditivity in score. For compound inputs we write EcmpdE_{\rm cmpd} and EctrlE_{\rm ctrl} in tables. The loss contrast EcmpdℒE^{\mathcal{L}}_{\rm cmpd} similarly averages the increase after compound replacement over both context states. Each checkpoint uses 32 fixed permutations constructed without response values or model scores. Continuous effects and their intervals are the primary quantitative evidence. For a per-model stability summary, let τ\tau be the 95th percentile of absolute pairwise differences among the corresponding reference scores. A contribution is qualified if its effect’s empirical 2.5th percentile exceeds τ\tau, unsupported if its 97.5th percentile does not exceed τ\tau, and inconclusive otherwise. These labels summarize effect stability relative to map-induced score variation; an unsupported effect may still be positive. The empirical quantiles describe replacement variability within a checkpoint; Appendix B specifies the reference scores and separate across-model uncertainty.

b214Reference-score variation can include variation induced by the other input. Holding the compound effect fixed while increasing this variation can therefore change the status. An existing synthetic check separates invariant, sensitive-without-benefit, target-relevant, and harmful predictors. All 96 target-relevant instances have positive mean effects, while 32 of 96 exceed the reference-relative criterion, identically with 32, 128, or 512 maps. The continuous measurements recover predictive benefit, whereas the categorical rule asks whether that benefit exceeds the specified reference variation. Its threshold is an operational effect scale. The additional 6,400-dataset study in Appendix F.1 tests estimator bias, interval coverage, and sensitivity to the reference scale; it distinguishes conditional replacement uncertainty from population uncertainty and retains the observed finite-group undercoverage.

M.1 Single-coordinate replay on observed support

b217The frozen replay changes one encoded coordinate while holding the source row’s other inputs fixed. Eligible donors satisfy the recorded metadata constraints and produce an actual input change. Table 57 reports the supported populations separately from the original context-averaged factorial summaries. Score-selected BBBC047 remains exactly invariant; the path-constrained and guided panels retain positive compound effects on both boundaries. On LKCP, dose intervals are positive and compound intervals include zero. For the replay and real-source audit below, 95% intervals resample source groups while conditioning on the selected checkpoint set, donor pools, and 128 replacement maps; BBBC and LINCS use Murcko source scaffolds, and LKCP uses registered BRD identifier groups. The matched-reference and control-bank intervals instead describe paired training-seed variation at the fixed task split. Individual intervals and positive-interval counts are descriptive and unadjusted.

b218Original-entry-weighted means: score-selected BBBC047 has 5 entries per fold; path-constrained and guided BBBC047 have 10 each; LINCS and LKCP have 50 each. LKCP’s 50 entries contain 30 unique weight hashes. Path-constrained and guided checkpoints are fixed across the two boundary evaluations. BBBC047 has no registered observed-support dose contrast.

M.2 Complete matched input-reference family

b220The four input subsets use the same masked-MLP family, loss, fit budget, and five paired training seeds. Each selected checkpoint is evaluated on both held-out folds. Here cc denotes context, pp compound representation, and aa dose. Dose improves the LINCS reference; its increment is small on BBBC and LKCP. On LKCP Fold 5, the full reference has a positive PCC increment over g⁡(c,a)g(c,a), while its MSE interval includes zero. These trained-subset comparisons describe the fixed reference family; within-checkpoint replacement measures use in the separately selected agent models.

b221Paired increments and their 95% intervals appear in Table 59; the portable source preserves all per-reference and paired intervals at full precision.

M.3 Linked source and behavior in real candidates

b223A fixed, dataset–policy-balanced and source-structure-stratified sample links 48 source records to 96 same-checkpoint boundary evaluations. Implemented source consumption coexists with distinct fitted outcomes: an implemented MultiTowerFusion source is exactly invariant on both boundaries, whereas 47 sources change predictions and 20 have positive target-loss intervals on both boundaries. Unresolved source locations also admit complete-model behavioral tests.

b224The middle behavioral category has positive prediction distance but lacks a positive target-loss interval on at least one fold. Source status describes the cited computation. Counts describe this structurally sampled set and its scripted source classifications. Claim origin remains task_contract where no candidate-authored manifest was emitted.

M.4 Control-reference reuse on sci-Plex

b226The existing control-bank comparison holds the response target Y−RY-R fixed and changes whether the context input reuses reference bank RR or uses the other bank. Reference A/B assignment is fixed before fitting and counterbalanced within cell-line, replicate, and control-layout strata (24 plate groups per orientation). Three input sets, two bank assignments, and five paired seeds give 30 fitted checkpoints. All six shared-minus-disjoint PCC intervals include zero. This comparison measures control-reference reuse on sci-Plex.

Appendix N Matched feedback: predictive outcomes and input contribution

b228Predictor F4 PCC ↑\uparrow F4 MSE ↓\downarrow F5 PCC ↑\uparrow F5 MSE ↓\downarrow Anchor g⁡(c,a)g(c,a) 0.9664 ±\pm 0.0001 0.0308 ±\pm 0.0001 0.9728 ±\pm 0.0002 0.0251 ±\pm 0.0001 Score 0.9756 ±\pm 0.0027 0.0225 ±\pm 0.0025 0.9764 ±\pm 0.0015 0.0219 ±\pm 0.0013 Audit 0.9779 ±\pm 0.0004 0.0204 ±\pm 0.0004 0.9778 ±\pm 0.0002 0.0205 ±\pm 0.0002

b229The anchor is shared within each seed. F4 and F5 are held-out combination boundaries of the sci-Plex development source.

b230Set Feedback Chemical PCC drop Chemical loss gain Dose PCC drop Dose loss gain F4 Score 0.0203 ±\pm 0.0046 0.0186 ±\pm 0.0042 0.0068 ±\pm 0.0026 0.0062 ±\pm 0.0024 F4 Audit 0.0240 ±\pm 0.0016 0.0220 ±\pm 0.0015 0.0090 ±\pm 0.0006 0.0082 ±\pm 0.0006 F5 Score 0.0070 ±\pm 0.0016 0.0064 ±\pm 0.0015 0.0039 ±\pm 0.0017 0.0035 ±\pm 0.0015 F5 Audit 0.0086 ±\pm 0.0005 0.0079 ±\pm 0.0005 0.0049 ±\pm 0.0004 0.0045 ±\pm 0.0004

b231Positive values favor the correct input over its legal replacement. Each displayed coordinate metric is positive in 5/5 endpoints in both arms at both boundaries.

b232Set Metric Mean Δ\Delta Paired tt 95% CI Joint bootstrap 95% CI Wins F4 PCC +2.364 [-1.277, +6.005] [+0.253, +5.619] 4/5 F4 MSE -2.159 [-5.482, +1.164] [-5.136, -0.234] 4/5 F5 PCC +1.460 [-0.496, +3.416] [+0.202, +3.021] 3/5 F5 MSE -1.333 [-3.116, +0.450] [-2.748, -0.187] 3/5

b233Descriptive paired comparison. Paired tt: five trajectories, df=4. Joint bootstrap: 4,000 shared trajectory–compound draws. Wins favor higher PCC or lower MSE. Both uncertainty summaries retain all five trajectory pairs.

b234Feedback Selected PCC Valid Failed Repairs LLM calls Reported tokens Training wall s Score 0.9757 25/25 0 11 36 ≥\geq286,995 194.93 Audit 0.9781 25/25 0 13 38 592,347 217.41

b235Selected PCC averages the five discovery-selection scores. Calls include repairs; the Score token total is a lower bound with one missing usage receipt. Five shared anchors contribute a further 32.61 training seconds, counted once.

N.1 Score–audit feedback comparison: complete records

b237We analyze Score and Audit feedback using all five paired discovery trajectories and their shared context-plus-dose anchors. The descriptive comparison holds model space, trainer, selection rule, and candidate budget fixed, and reports every selected endpoint, paired effect, and uncertainty interval. Within the sci-Plex development source, compound–cell-line roles were reassigned and frozen before response preprocessing. F4 and F5 evaluate the same selected checkpoints on held-out combinations.

b238The fit, selection, F4, and F5 packages contain 2,666, 891, 438, and 442 treatment wells. Complete compound ×\times cell-line groups, including their doses and replicate wells, remain within one role; evaluated compounds and cell lines each appear among the fit marginals. The 2,000 target genes are selected by variance among fit treatment wells, with fit-only feature scaling. Control bank A supplies inputs and bank B the reference; they contain distinct wells matched on plate, cell line, and replicate, with control pools reused across these development roles. The target is the complete gene-expression profile.

b239Score supplies selection metrics, sampled learning curves, model size, timing, and past designs. Audit adds grouped errors, component-source clues, and chemical/dose replacement effects. This comparison estimates the complete enhanced-feedback package. Both arms share g⁡(c,a)g(c,a) within seed, five new candidate slots, and three repair opportunities per slot. The language model may revise encoders, fusion, readout, capacity, regularization, and residual scale; a direct predictor or frozen-anchor residual is equally available. Each new component is trained from scratch. Completed selection diagnostics inform subsequent proposals; final checkpoints are frozen before F4/F5 evaluation.

b240AdamW uses learning rate 10−310^{-3}, weight decay 10−510^{-5}, batch size 128, gradient clipping at 5, a 100-epoch maximum, and early-stopping patience 15. The shared loss is fit-standardized target MSE plus 0.02​(1−PCC)0.02(1-\mathrm{PCC}), using flattened Pearson correlation. The common limit is five million trainable parameters. Epoch and endpoint selection prioritize selection Global PCC, then lower MSE; endpoint ties additionally prefer fewer parameters and earlier slots. The anchor stays frozen in residual models.

b241SD uses denominator n−1n-1 across five trajectories; paired two-sided Student-tt intervals use df=4. Compound-only bootstrap fixes the fitted trajectories, trajectory-only bootstrap fixes the evaluated compounds, and joint bootstrap resamples both; each uses 4,000 shared-index draws. Appendix N.2 compares these intervals with complete leave-one-pair-out and exact sign-flip analyses. Maps are averaged within endpoints before trajectory inference. RMS measures sensitivity; PCC drop is correct-input minus replacement PCC, and loss gain is replacement minus correct-input MSE. Positive continuous effects are distinct from individual qualification or biological-mechanism evidence.

b242Recorded model identifier: deepseek-v41. All compared calls use this serving identity. Trajectory indices 1–5 correspond, in order, to seeds 2026091201, 2026091202, 2026091203, 2026091204, 2026091205. Full-precision endpoint, cost, and paired-effect tables accompany the renderer under results/feedback_comparison/.

b243Relative MSE reduction against the anchor is computed within seed as 1−MSEendpoint,s/MSEanchor,s1-\mathrm{MSE}_{\mathrm{endpoint},s}/\mathrm{MSE}_{\mathrm{anchor},s} and then averaged. A ratio of arm mean MSEs is reported separately when used. Costs retain failed attempts and recorded interruptions. Shared anchor training totals 32.611546 seconds and is counted once, separately from each condition’s candidate-training costs. Trainer and worker wall times overlap; missing token usage produces a lower bound.

b244Tr. Model Slot PCC MSE C-R C-P C-L D-R D-P D-L Fold 4 1 Anchor 0 0.96652 30.768 0.000 0.000 0.000 28.653 1.152 1.042 1 Score 5 0.97557 22.551 141.301 20.580 18.805 84.343 6.798 6.212 1 Audit 5 0.97806 20.278 142.171 23.162 21.173 94.176 8.838 8.081 2 Anchor 0 0.96646 30.836 0.000 0.000 0.000 25.007 0.985 0.896 2 Score 3 0.97740 20.889 136.127 21.774 19.882 84.750 7.580 6.923 2 Audit 4 0.97809 20.252 155.045 25.294 23.142 101.848 9.453 8.650 3 Anchor 0 0.96647 30.813 0.000 0.000 0.000 31.861 1.311 1.189 3 Score 3 0.97570 22.432 138.732 20.644 18.823 96.003 7.982 7.278 3 Audit 3 0.97817 20.181 138.099 22.698 20.763 91.844 8.613 7.880 4 Anchor 0 0.96646 30.820 0.000 0.000 0.000 26.818 1.066 0.960 4 Score 5 0.97807 20.274 157.142 25.704 23.535 96.377 9.070 8.307 4 Audit 5 0.97725 21.023 145.497 22.784 20.858 90.603 8.193 7.502 5 Anchor 0 0.96629 30.977 0.000 0.000 0.000 17.193 0.640 0.580 5 Score 4 0.97115 26.587 117.806 13.009 11.887 48.269 2.392 2.186 5 Audit 2 0.97815 20.203 159.745 26.108 23.941 102.759 9.697 8.893 Fold 5 1 Anchor 0 0.97265 25.253 0.000 0.000 0.000 27.811 0.712 0.647 1 Score 5 0.97586 22.332 100.896 7.672 7.048 65.922 3.595 3.306 1 Audit 5 0.97785 20.495 90.349 8.720 7.978 71.763 5.036 4.612 2 Anchor 0 0.97297 24.955 0.000 0.000 0.000 24.562 0.606 0.553 2 Score 3 0.97777 20.567 80.270 7.558 6.905 71.301 4.866 4.452 2 Audit 4 0.97772 20.619 90.797 8.556 7.835 74.695 4.693 4.303 3 Anchor 0 0.97297 24.957 0.000 0.000 0.000 31.737 0.839 0.764 3 Score 3 0.97626 21.947 92.154 7.588 6.919 75.540 4.604 4.202 3 Audit 3 0.97815 20.230 86.705 8.379 7.691 71.783 4.883 4.487 4 Anchor 0 0.97270 25.230 0.000 0.000 0.000 26.502 0.688 0.621 4 Score 5 0.97771 20.623 89.824 8.217 7.526 77.179 5.209 4.776 4 Audit 5 0.97758 20.744 88.060 7.995 7.320 70.291 4.508 4.131 5 Anchor 0 0.97292 24.999 0.000 0.000 0.000 17.108 0.399 0.363 5 Score 4 0.97425 23.789 75.832 4.122 3.769 40.870 1.079 0.988 5 Audit 2 0.97786 20.504 99.006 9.405 8.635 83.693 5.505 5.060

b245PCC is unscaled; all other numeric outcomes are in 10−310^{-3} units. C/D: chemical/dose; R: prediction RMS; P: PCC drop; L: target-loss gain. Slot 0 is the shared anchor. RMS has no preferred direction.

b246Tr. Arm Slot Sel. PCC Repair Calls HTTP Tokens Train s Work s Diag. s 1 Score 5 0.97491 1 6 7 ≥\geq50,685 48.09 67.26 7.10 1 Audit 5 0.97828 2 7 7 106,239 41.24 60.03 12.10 2 Score 3 0.97757 3 8 8 62,703 41.96 60.07 7.50 2 Audit 4 0.97783 3 8 8 125,047 42.32 61.01 12.94 3 Score 3 0.97628 4 9 9 70,709 40.04 58.06 7.36 3 Audit 3 0.97825 3 8 8 136,386 44.25 61.58 12.15 4 Score 5 0.97852 3 8 8 68,757 35.40 52.75 8.73 4 Audit 5 0.97798 3 8 8 129,227 39.60 55.93 12.24 5 Score 4 0.97145 0 5 5 34,141 29.44 46.61 6.75 5 Audit 2 0.97830 2 7 7 95,448 50.00 67.66 11.96

b247Every trajectory completed 5/5 new candidates and had zero fully failed slots. Train is known completed trainer wall time; Work is candidate worker wall time; Diag. is postfit diagnostic wall time. Logical calls and physical HTTP attempts are distinct. Complete token breakdowns and missing-cost flags are in the CSV.

b248Set Metric Mean Δ\Delta Paired 95% CI +/–/0 F4 PCC +2.364 [-1.277, +6.005] 4/1/0 F4 MSE -2.159 [-5.482, +1.164] 1/4/0 F4 Chem. RMS +9.890 [-16.189, +35.969] 3/2/0 F4 Chem. PCC drop +3.667 [-3.577, +10.912] 4/1/0 F4 Chem. loss gain +3.389 [-3.269, +10.048] 4/1/0 F4 Dose RMS +14.298 [-16.033, +44.628] 3/2/0 F4 Dose PCC drop +2.194 [-1.639, +6.028] 4/1/0 F4 Dose loss gain +2.020 [-1.496, +5.536] 4/1/0 F5 PCC +1.460 [-0.496, +3.416] 3/2/0 F5 MSE -1.333 [-3.116, +0.450] 2/3/0 F5 Chem. RMS +3.189 [-13.712, +20.089] 2/3/0 F5 Chem. PCC drop +1.580 [-1.069, +4.228] 4/1/0 F5 Chem. loss gain +1.458 [-0.979, +3.896] 4/1/0 F5 Dose RMS +8.283 [-16.535, +33.100] 3/2/0 F5 Dose PCC drop +1.054 [-1.483, +3.592] 3/2/0 F5 Dose loss gain +0.974 [-1.355, +3.303] 3/2/0

b249Descriptive effect estimates over all five paired trajectories. Signs count positive, negative, and exactly zero differences, not wins. Lower MSE is favorable; RMS has no favorable direction.

b250Set Metric Paired tt CI Compound-only CI Joint CI F4 PCC [-1.277, +6.005] [+1.300, +3.704] [+0.253, +5.619] F4 MSE [-5.482, +1.164] [-3.389, -1.197] [-5.136, -0.234] F5 PCC [-0.496, +3.416] [+1.006, +1.975] [+0.202, +3.021] F5 MSE [-3.116, +0.450] [-1.800, -0.924] [-2.748, -0.187]

b251Bootstrap intervals use 4,000 draws. No coordinate-effect bootstrap interval is substituted from predictive statistics, and no new confirmatory tests are introduced.

b252Set Coordinate Eligible wells Maps Unique First 32 unique F4 Chemical 438/438 128 128 32 F4 Dose 428/438 128 1 1 F5 Chemical 434/442 128 128 32 F5 Dose 436/442 128 1 1

b253Replacements match plate, cell line, replicate, and treatment time. Chemical replacement holds dose fixed; dose replacement holds compound fixed and requires at least 0.1 log-dose difference. No cross-group fallback is used. Discovery used 32 maps; final evaluation used 128, with only one distinct dose map. Unsupported wells are excluded, not assigned zero effect.

N.2 Robustness across the complete five trajectory pairs

b255This retrospective sensitivity analysis retains seeds 2026091201–2026091205 and all eight metrics at both boundaries. Audit minus Score is computed within each selected-trajectory pair; F4 and F5 reuse the same selected checkpoints and do not make N=10N=10. Means and descriptive two-sided 95% t4t_{4} intervals use all five pairs. All 32 sign assignments are enumerated for the absolute unstudentized mean under a pair-exchangeability/sign-symmetry null, not a randomized-assignment guarantee. The smallest attainable two-sided tail probability is 2/32=.06252/32=.0625; no multiplicity-adjusted confirmatory claim is made.

b256Fold Metric Mean Paired-tt 95% CI Median +/−/0+/-/0 Tail F4 Global PCC 2.3642.364 [−1.277, 6.005][-1.277,\,6.005] 2.4652.465 4/1/0 6/32 F4 MSE −2.159-2.159 [−5.482, 1.164][-5.482,\,1.164] −2.251-2.251 1/4/0 6/32 F4 Chemical RMS 9.8909.890 [−16.189, 35.969][-16.189,\,35.969] 0.8700.870 3/2/0 12/32 F4 Chemical loss gain 3.3893.389 [−3.269, 10.048][-3.269,\,10.048] 2.3682.368 4/1/0 8/32 F4 Chemical PCC drop 3.6673.667 [−3.577, 10.912][-3.577,\,10.912] 2.5822.582 4/1/0 8/32 F4 Dose RMS 14.29814.298 [−16.033, 44.628][-16.033,\,44.628] 9.8339.833 3/2/0 10/32 F4 Dose loss gain 2.0202.020 [−1.496, 5.536][-1.496,\,5.536] 1.7271.727 4/1/0 6/32 F4 Dose PCC drop 2.1942.194 [−1.639, 6.028][-1.639,\,6.028] 1.8731.873 4/1/0 6/32 F5 Global PCC 1.4601.460 [−0.496, 3.416][-0.496,\,3.416] 1.8881.888 3/2/0 8/32 F5 MSE −1.333-1.333 [−3.116, 0.450][-3.116,\,0.450] −1.716-1.716 2/3/0 8/32 F5 Chemical RMS 3.1893.189 [−13.712, 20.089][-13.712,\,20.089] −1.763-1.763 2/3/0 24/32 F5 Chemical loss gain 1.4581.458 [−0.979, 3.896][-0.979,\,3.896] 0.9300.930 4/1/0 4/32 F5 Chemical PCC drop 1.5801.580 [−1.069, 4.228][-1.069,\,4.228] 0.9990.999 4/1/0 4/32 F5 Dose RMS 8.2838.283 [−16.535, 33.100][-16.535,\,33.100] 3.3943.394 3/2/0 20/32 F5 Dose loss gain 0.9740.974 [−1.355, 3.303][-1.355,\,3.303] 0.2850.285 3/2/0 12/32 F5 Dose PCC drop 1.0541.054 [−1.483, 3.592][-1.483,\,3.592] 0.2790.279 3/2/0 12/32

b257Tail is the exact sign-flip count out of 32. All 16 paired-tt intervals contain zero and all exact tails are at least .125. RMS measures sensitivity; target-loss gain and PCC drop measure changes in loss and correlation.

b258Fold Metric Compound only Trajectory only Joint F4 Global PCC [1.300, 3.704][1.300,\,3.704] [0.144, 4.828][0.144,\,4.828] [0.253, 5.619][0.253,\,5.619] F4 MSE [−3.389,−1.197][-3.389,\,-1.197] [−4.408,−0.132][-4.408,\,-0.132] [−5.136,−0.234][-5.136,\,-0.234] F4 Chemical RMS [6.425, 13.160][6.425,\,13.160] [−4.738, 28.126][-4.738,\,28.126] [−5.652, 27.694][-5.652,\,27.694] F4 Chemical loss gain [2.032, 5.060][2.032,\,5.060] [−0.482, 8.094][-0.482,\,8.094] [−0.456, 8.402][-0.456,\,8.402] F4 Chemical PCC drop [2.201, 5.452][2.201,\,5.452] [−0.534, 8.787][-0.534,\,8.787] [−0.508, 9.067][-0.508,\,9.067] F4 Dose RMS [4.676, 22.279][4.676,\,22.279] [−2.007, 34.959][-2.007,\,34.959] [−3.228, 38.642][-3.228,\,38.642] F4 Dose loss gain [0.689, 3.753][0.689,\,3.753] [0.039, 4.490][0.039,\,4.490] [0.066, 5.631][0.066,\,5.631] F4 Dose PCC drop [0.750, 4.083][0.750,\,4.083] [0.028, 4.884][0.028,\,4.884] [0.068, 6.187][0.068,\,6.187] F5 Global PCC [1.006, 1.975][1.006,\,1.975] [0.302, 2.618][0.302,\,2.618] [0.202, 3.021][0.202,\,3.021] F5 MSE [−1.800,−0.924][-1.800,\,-0.924] [−2.392,−0.274][-2.392,\,-0.274] [−2.748,−0.187][-2.748,\,-0.187] F5 Chemical RMS [−1.073, 7.471][-1.073,\,7.471] [−6.751, 14.920][-6.751,\,14.920] [−7.875, 15.416][-7.875,\,15.416] F5 Chemical loss gain [0.824, 2.180][0.824,\,2.180] [0.248, 3.260][0.248,\,3.260] [0.143, 3.537][0.143,\,3.537] F5 Chemical PCC drop [0.892, 2.364][0.892,\,2.364] [0.266, 3.528][0.266,\,3.528] [0.146, 3.843][0.146,\,3.843] F5 Dose RMS [1.196, 15.103][1.196,\,15.103] [−3.716, 25.621][-3.716,\,25.621] [−5.151, 28.995][-5.151,\,28.995] F5 Dose loss gain [0.324, 1.866][0.324,\,1.866] [−0.261, 2.557][-0.261,\,2.557] [−0.253, 3.122][-0.253,\,3.122] F5 Dose PCC drop [0.349, 2.021][0.349,\,2.021] [−0.294, 2.768][-0.294,\,2.768] [−0.284, 3.397][-0.284,\,3.397]

b2594000 draws, seed 69313. Compound weights are shared across all paired arms and trajectories; trajectory draws resample the five paired indices. Joint draws resample both units. The 128 donor maps are fixed. Sufficient statistics are pooled before PCC; compound PCCs are not averaged. Compound-only intervals condition on five selected trajectories; trajectory-only intervals condition on the observed compound set, while joint intervals vary both empirical units.

b260Trajectory-only percentile bootstrap and paired-tt inference target the same conditional mean paired contrast; their different conclusions reflect the five-point empirical bootstrap distribution versus Student-tt sampling assumptions, not different estimands. Compound-only and joint intervals additionally have different resampling scopes. All predictive bootstrap intervals exclude zero, whereas the paired-tt intervals and exact sign-flip tails do not provide the same evidence. Increasing bootstrap draws does not add independent trajectories or establish broad generalization.

b261Fold Metric All-five mean Fifth-pair d5/5d_{5}/5 Omit-fifth mean All five LOO means F4 Global PCC 2.3642.364 1.3991.399 1.2061.206 [1.206, 3.160][1.206,\,3.160] F4 MSE −2.159-2.159 −1.277-1.277 −1.103-1.103 [−2.886,−1.103][-2.886,\,-1.103] F4 Chemical RMS 9.8909.890 8.3888.388 1.8771.877 [1.877, 15.273][1.877,\,15.273] F4 Chemical loss gain 3.3893.389 2.4112.411 1.2231.223 [1.223, 4.906][1.223,\,4.906] F4 Chemical PCC drop 3.6673.667 2.6202.620 1.3091.309 [1.309, 5.314][1.309,\,5.314] F4 Dose RMS 14.29814.298 10.89810.898 4.2494.249 [4.249, 19.315][4.249,\,19.315] F4 Dose loss gain 2.0202.020 1.3411.341 0.8480.848 [0.848, 2.726][0.848,\,2.726] F4 Dose PCC drop 2.1942.194 1.4611.461 0.9160.916 [0.916, 2.962][0.916,\,2.962] F5 Global PCC 1.4601.460 0.7220.722 0.9220.922 [0.922, 1.859][0.922,\,1.859] F5 MSE −1.333-1.333 −0.657-0.657 −0.845-0.845 [−1.697,−0.845][-1.697,\,-0.845] F5 Chemical RMS 3.1893.189 4.6354.635 −1.808-1.808 [−1.808, 6.622][-1.808,\,6.622] F5 Chemical loss gain 1.4581.458 0.9730.973 0.6060.606 [0.606, 1.875][0.606,\,1.875] F5 Chemical PCC drop 1.5801.580 1.0571.057 0.6540.654 [0.654, 2.030][0.654,\,2.030] F5 Dose RMS 8.2838.283 8.5658.565 −0.352-0.352 [−0.352, 12.075][-0.352,\,12.075] F5 Dose loss gain 0.9740.974 0.8150.815 0.1990.199 [0.199, 1.379][0.199,\,1.379] F5 Dose PCC drop 1.0541.054 0.8850.885 0.2110.211 [0.211, 1.493][0.211,\,1.493]

b262The fifth-pair column is its contribution to the five-pair mean, not its whole paired difference. Every leave-one-out estimate and t3t_{3} interval is retained in the portable CSV. F5 chemical and dose RMS have positive all-five means but negative omit-fifth means; the F5 chemical-RMS median is negative, whereas the dose-RMS median is positive. All five pairs remain in the primary estimate.

b263Retained full predictions independently verify global PCC/MSE and eligible-source correct statistics. Full counterfactual prediction arrays were not retained for this legacy feedback package, so coordinate reconstruction verifies stored sufficient statistics but is not a new independent full-array counterfactual check. These additional descriptions do not reselect checkpoints, retrain models, or revise historical qualification labels.

Appendix O Recorded feedback, source revisions, and frozen endpoints

b265The two cases are the first two registered trajectory seeds (2026091201 and 2026091202), selected by registration order. Each retains the common initial predictor and all five new audit-feedback proposals. Parent links denote design ancestry: every new candidate is trained from scratch, while the shared context-plus-dose predictor g⁡(c,a)g(c,a) is frozen. This anchor concatenates 2,000 context features with dose and uses a 2001–256–256–2000 MLP with 1,092,816 trainable parameters. Local metrics describe the development-selection partition. The public case package contains the hash-verified anchor source, actual system/user prompts, proposals, candidate source, diffs, and received feedback.

b266In the first trajectory, slot 2 is the incumbent after its child slot 3 fails to improve selection PCC. Before slot 4, the actual prompt contains slot 2’s best epoch (5), sampled learning curve, group-error diagnostics, source-check findings, and positive compound and dose replacement effects. The model hypothesizes overfitting and proposes reducing encoder capacity; compound memorization is a proposed explanation, not a separately measured biological or learning mechanism. Inspection of the emitted source verifies that each chemical/context encoder changes from two Linear layers to one, with dropout 0.1 added in the encoders and fusion. Dose-conditioned FiLM and the rank-128 bilinear interaction remain. Trainable parameters decrease from 4,056,400 to 2,754,896; total parameters including the fixed anchor are 5,149,216 and 3,847,712. Slot 2 versus slot 4 selection PCC is 0.97808647 versus 0.97818047; MSE is 0.02028296 versus 0.02019429; compound target-loss gain is 0.01846193 versus 0.01949683. The static checker reports syntactic return-dependency hints while leaving functional usefulness unresolved; fixed-model input replacement supplies the separate behavioral evidence.

b267Both first-case sources zero-initialize their output readout. Under the fixed residual wrapper this initializes the newly fitted predictor at g⁡(c,a)g(c,a). Slot 5 adds a dose-conditioned scalar interaction gate and an extra projected chemical feature before fusion, then wins by selection PCC. The emitted chem_direct feature enters the nonlinear fusion, whereas its proposal calls it a direct additive target-space path. Slot 5 has higher selection PCC but lower compound target-loss gain than slot 4; selection and input contribution therefore remain distinct. The same frozen slot-5 checkpoint is subsequently evaluated on the two held-out sci-Plex partitions.

b268For seed 2026091202, slot 2 decreases selection PCC from its slot-1 parent (0.977817 to 0.977703). Slot 3 improves on slot 2 but remains below slot 1. Slot 4 explicitly returns to slot 1 as its design parent and is selected at PCC 0.977826; its MSE (0.02053288) is slightly worse than slot 1’s (0.02052894), consistent with PCC-first selection. Slot 5 adds explicit pairwise projections but falls to PCC 0.977506 and is not selected. Its rationale claims that zero-initialized new terms preserve the parent, but the shared from-scratch training contract does not inherit fitted parent weights: this claim is preserved as an agent statement in the public proposal, not endorsed as a measured guarantee.

b269The first case uses one JSON-contract repair at each of slots 4 and 5; the second uses one at slot 4 and two at slot 5. These logged failures are completion-token-limit/JSON-contract failures. Lower-scoring, successfully trained candidates are retained without score-driven repair. The case package preserves these outcomes and the actual branch structure.