rewirebio.iobenchmarks

Use caseCells and tissuesResearch only

Select therapeutic targets for validation

Which targets should I test to change a defined disease-relevant phenotype?

What the evidence shows

Three sources compare target-nomination methods against measured CRISPR screen outcomes, and all three are retrospective replays of published screens: a method picks genes and the screen's existing measurement is looked up.

Non-hits are genes the screen assayed that did not meet its criterion; genes a screen never assayed are outside the candidate pool or, in AssayBench's headline metric, removed before scoring, so these results say nothing about an untested target. Roohani et al. 2025 (ICLR) were run by the developers of the agent they test, two of whom are authors of two of the screens, and they state that patent applications have been filed on the findings. They report the fraction of each screen's hits found after five rounds of 128 genes.

With Claude 3.5 Sonnet the agent reached 0.095 on the interferon-gamma screen, 0.104 on interleukin-2, 0.130 on CAR-T proliferation, 0.326 on lysosomal choline recycling, 0.042 on T-cell inhibition resistance and 0.066 on tau level, against random selection at 0.037, 0.031, 0.033, 0.160, 0.036 and 0.034. Conventional baselines were close on some screens: Coreset reached 0.102 on interleukin-2 and 0.047 on T-cell inhibition resistance, above the agent's 0.042 there. Gupta et al. 2025 (Findings of EMNLP), independent of the agent's authors, replayed five of the same screens and report cumulative hits.

Their re-run of the Claude 3.5 Sonnet agent found fewer hits than the original numbers on three of four shared screens, for example 31.6 against 60.72 on tau level. Giving the agent randomly permuted feedback changed little: the permuted variant scored at least as high on three of five screens with each of the three backbones tested, for example 51 against 44 on interferon-gamma with Llama-3.1-8B, and the authors conclude that the models they tested do not perform in-context experimental design. Gaussian process optimisation over the same embeddings reached 147.8 hits on interleukin-2 against the agent's 39.4 with Llama-3.1-8B, from 654 ground-truth hits; the source prints identical Gaussian process values under both backbones.

De Brouwer et al. 2026, a preprint that is not peer reviewed, asked 16 systems to rank 100 genes for each of 571 benchmark entries, each a described screen. On the 334 test entries the best system was an evolved ensemble of language models at 0.1631 adjusted NDCG@100 and the best single model, Gemini 3 Pro, 0.1570, against 0.1334 for a baseline ranking genes by how often they are hits in training screens of the same phenotype and 0.2918 for a retrieval upper bound that uses the answer. Most systems scored lower on the 19 entries published after the models' training cutoff, the ensemble falling to 0.1088, which that source reads as partly prior exposure to the literature.

None of these sources tests a prospective validation batch, a target's usefulness, dependency, tractability or therapeutic window, or whether modulating a target benefits patients.

You bring
  • A defined disease, biological context and experimental phenotype
  • A candidate gene set and feasible ways to inhibit or activate each target
  • Dated genetic, expression and functional evidence, including conflicting findings
  • A validation budget and relevant normal-cell or selectivity controls
You want
A shortlist of target–disease–intervention hypotheses with supporting evidence, uncertainties and proposed validation experiments.
Evidence in this release
5 comparisons shown · 46 tools · 68 configurations
Kept up to date
Evidence last checked 9 October 2026 · re-checked monthly, next due 9 November 2026

Baseline

Random and pathway-based selection. There is no pre-machine-learning method for choosing which targets to perturb; the established comparators are random selection and genes chosen from relevant pathways. Agent and Bayesian optimisation methods are judged by how many more hits they find than these.

Machine-learning methods are compared with the baseline on the same data in one table: BioDiscoveryAgent benchmark: hit ratio on six CRISPR screens (developer-run). Baseline rows are marked in each table.

Tools compared

Comparisons

Each table is one study or protocol with its own truth set and scoring. Compare tools within a table, not across tables.

CPPC original Challenge 2 prospective target ranking score

Proxy evidenceAuthor-reported

Prospective target ranking: custom top-k overlap AUC under source-defined objective and filtering aggregation.

Sorted by CPPC top-k overlap AUC (higher is better). Showing the top 10 of 20 rows. The best value in each column is highlighted.

Show all 20 rowsShow the top 10 rows only
Caveats and method
  • Custom ranking AUC is not ROC AUC, prospective hit rate or efficacy.
  • Original model implementations/checkpoints are not pinned in the intake; no uncertainty printed.
  • Automated source review only; independent human scientific review remains outstanding.

Protocol: CPPC original Challenge 2 prospective target ranking score

AssayBench: ranking 100 genes for described CRISPR screens (preprint)

Proxy evidenceAuthor-reportedIndependent study

AnDCG@100, Precision@100 and dFDR@100 for 16 systems on 571 screen-ranking entries across a validation, test and post-cutoff cohort: frontier and open-weight language models, fine-tuned and prompt-optimised variants, an agent, a single-cell language model, a trained relevance predictor and retrieval and frequency baselines

Sorted by Adjusted NDCG at 100 (higher is better). Showing the top 10 of 16 rows. The best value in each column is highlighted.

Scroll sideways to see all 9 columns.

ToolAdjusted NDCG at 100 (post-cutoff cohort; mean over benchmark entries)Adjusted NDCG at 100 (test cohort; mean over benchmark entries)Adjusted NDCG at 100 (validation cohort; mean over benchmark entries)Directional false discovery rate at 100 (post-cutoff cohort; mean over benchmark entries)Directional false discovery rate at 100 (test cohort; mean over benchmark entries)Directional false discovery rate at 100 (validation cohort; mean over benchmark entries)Precision at 100 (post-cutoff cohort; mean over benchmark entries; denominator min(100, positive-relevance genes))Precision at 100 (test cohort; mean over benchmark entries; denominator min(100, positive-relevance genes))Precision at 100 (validation cohort; mean over benchmark entries; denominator min(100, positive-relevance genes))
Oracle kNNconventional0.2307 (best in column)0.2918 (best in column)0.3992 (best in column)Not reported0.0037 (best in column)0.0025 (best in column)0.3079 (best in column)0.3798 (best in column)0.4755 (best in column)
Gemini 3 Flash (GEPA)foundation model0.13970.14060.1922Not reported0.02140.01020.30700.19870.3444
Gemini 3 Pro (Few-shot)foundation model0.12970.15370.1687Not reported0.02130.01550.24490.21340.2876
Gemini 3 Profoundation model0.11130.15700.1716Not reported0.01640.02080.23400.22260.3710
GPT-OSS-120B (SFT)foundation model0.10880.12240.1296Not reported0.02550.01970.19210.17380.2273
LLM Ensemblefoundation model0.10880.16310.1864Not reported0.01780.01450.24770.21960.3235
GPT-OSS-120B (SFT + GRPO)foundation model0.10120.12930.1361Not reported0.02520.01650.25250.16990.2307
GPT-5.4foundation model0.09820.14700.1658Not reported0.02060.01620.22180.19800.3262
Gemini 3 Flashfoundation model0.09080.14460.1556Not reported0.01800.02600.23510.20090.2495
Gene-frequency (by phenotype)conventional0.08880.13340.1691Not reported0.02920.06060.18660.22040.4103
GPT-OSS-120Bfoundation model0.08260.12110.1268Not reported0.02230.01640.24970.17570.2292
Biomni A1 (Claude 4)foundation model0.07280.10790.1410Not reported0.01760.01640.02140.17010.2474
Gene-relevance predictormachine learning0.06600.05650.1409Not reported0.03060.03160.15410.15770.2155
Qwen3.5-2Bfoundation model0.03240.02840.0237Not reported0.02160.02160.13420.07550.0695
Embedding kNNconventional0.02710.06460.0697Not reported0.02260.03210.11270.10620.1027
C2S (Gemma-2B)foundation model0.00780.03550.0842Not reported0.02180.04290.07840.08630.1200
Show all 16 rowsShow the top 10 rows only
Caveats and method
  • AnDCG@100 removes genes the screen did not assay before scoring, so for the headline metric untested genes are not negatives. The printed Precision@100 and dFDR@100 formulas sum over the top 100 predictions without that step, so an unassayed gene adds nothing to Precision@100 and counts in the dFDR@100 denominator; the text calls them measures over in-screen predictions, so whether they were condensed is unclear.
  • Hits follow each screen's own significance criterion, so the phenotype and threshold vary between entries.
  • Retrospective replay of published screens; no new experiment was run.
  • Phenotype descriptions and effect directions come from an LLM-assisted curation step over BioGRID metadata.
  • The post-cutoff cohort has 19 screens against 334 in the test cohort. Most systems score lower on it, which the source reads as partly prior exposure to the literature; the trained gene-relevance predictor (0.0660 against 0.0565) and Qwen3.5-2B (0.0324 against 0.0284) score higher.
  • Precision@100 divides by min(100, number of positive-relevance genes), so it is not precision over a fixed 100 predictions when a screen has fewer than 100 hits.
  • The gene-frequency baseline is competitive mainly through fitness and viability screens, where frequently recurring essential genes give a phenotype-level prior (section 5.4).
  • No linked benchmark here runs a prospective validation batch or measures target usefulness, dependency, tractability, therapeutic window or patient benefit.

Protocol: AssayBench: rank 100 candidate genes for a described CRISPR screen

Independent replication: cumulative hits on five CRISPR screens

Proxy evidenceIndependent studyCompiled from papers

Cumulative hits after 5 rounds of 128 selected genes on five of the same screens, for the agent, the agent given randomly permuted feedback, linear bandits and Gaussian process optimisation, alongside the originally reported numbers

Sorted by True positives (higher is better). The best value in each column is highlighted.

ToolTrue positives (cumulative hits after round 5; mean of 5 runs)
GPover llama-3-1-8b embeddingsmachine learning147.80 (best in column)
GPover qwen-2-7b embeddingsmachine learning147.80 (best in column)
Linear UCBover qwen-2-7b embeddingsmachine learning93.00
BDA (Reported Numbers)foundation model68.01
BDA (Replicated)foundation model59.40
BDA-Randclaude-3-5-sonnet backbonefoundation model57.60
BDAllama-3-1-8b backbonefoundation model39.40
BDA-Randllama-3-1-8b backbonefoundation model37.00
Linear UCBover llama-3-1-8b embeddingsmachine learning35.00
BDAqwen-2-7b backbonefoundation model33.20
BDA-Randqwen-2-7b backbonefoundation model29.00
Caveats and method
  • Offline replay of five of the same screens; untested genes are absent from the candidate pool rather than negative.
  • Cumulative hits is a count, so values are comparable only within a screen.
  • The Claude 3.5 Sonnet 'Reported Numbers' row is converted from Roohani et al. 2025, not re-run here; the source's own replication of that setting is lower on three of the four screens with a reported value (interleukin-2, interferon-gamma, tau) and higher on one (Carnevale).
  • The source does not print the hit threshold; it prints its own ground-truth hit counts per screen.
  • No linked benchmark here runs a prospective validation batch or measures target usefulness, dependency, tractability, therapeutic window or patient benefit.

Protocol: Independent replication of 1-gene perturbation design: cumulative hits after 5 rounds of 128 genes

BioDiscoveryAgent benchmark: hit ratio on six CRISPR screens (developer-run)

Proxy evidenceAuthor-reportedIndependent study

Hit ratio after 5 rounds of 128 selected genes, over all genes and over non-essential genes only, for 20 selection methods on six CRISPR screens: random selection, a human pathway baseline, seven acquisition functions, DiscoBAX, nine LLM agents and one hybrid

Sorted by Recall (higher is better). Showing the top 10 of 20 rows. The best value in each column is highlighted.

Scroll sideways to see all 2 columns.

ToolRecall (hit ratio after round 5, all genes; mean of 10 runs)Recall (hit ratio after round 5, non-essential genes only; mean of 10 runs)
Sonnet + Coresetfoundation model0.133 (best in column)0.092
Claude 3 Opusfoundation model0.1040.132 (best in column)
Claude 3.5 Sonnetfoundation model0.1040.122
Coresetmachine learning0.1020.084
o1-minifoundation model0.0960.120
o1-previewfoundation model0.0910.114
Claude v1foundation model0.0890.110
Claude 3 Sonnetfoundation model0.0880.111
Badgemachine learning0.0770.058
DiscoBaxmachine learning0.0740.057
GPT-4ofoundation model0.0740.090
K-Means (D)machine learning0.0740.060
Claude 3 Haikufoundation model0.0720.083
Top Uncertainmachine learning0.0720.050
K-Means (E)machine learning0.0640.053
GPT-3.5-Turbofoundation model0.0610.073
Margin Samplemachine learning0.0610.047
Soft Uncertainmachine learning0.0370.035
RandomBaselineconventional0.0310.031
HumanBaselineconventional0.0290.034
Show all 20 rowsShow the top 10 rows only
Caveats and method
  • Offline replay of six existing screens: the candidate pool is the genes each screen assayed, so untested genes are absent rather than negative.
  • Hit ratio measures recovery of that screen's own hits, not whether a target is useful.
  • Hits are defined by a threshold tau on the screen's phenotypic response; the source does not print tau or the hit count per screen.
  • All rows were run by the agent's developers. Two authors (Steinhart, Marson) are authors of the Schmidt et al. 2022 screens, the CAR-T screen is unpublished, and the conflicts statement says patent applications have been filed on the findings.
  • Gupta et al. 2025 report that the same agent performs about the same when its experimental feedback is replaced by randomly permuted outcomes: in their Table 1 the permuted variant scores at least as high on three of five screens with each of three backbones. These numbers should not be read as evidence that the agent learns from each round's results.
  • No linked benchmark here runs a prospective validation batch or measures target usefulness, dependency, tractability, therapeutic window or patient benefit.

Protocol: BioDiscoveryAgent 1-gene perturbation design: hit ratio after 5 rounds of 128 genes

CPPC prospective nomination of desired T-cell states

Proxy evidenceAuthor-reported

Prospective nomination campaign: count of named targets improving the defined T-cell state objective.

Single reported result.

CPPC submitted-method nomination campaign

Count (nominated targets reaching desired state)
two
Caveats and method
  • No matched-budget conventional/random prospective comparison; no antitumor efficacy, rescue or selectivity result in this endpoint.
  • 61 nominations / Results 57 selected targets / README 59 targets / 50 post-QC perturbations need reconciliation; no success fraction calculated.
  • Preprint v1; original and reimplemented ranking scores kept separate. Screen2 ranking population is enriched by original nomination methods.
  • Automated source review only; independent human scientific review remains outstanding.

Protocol: CPPC prospective nomination of desired T-cell states

Not covered yet

  • 61 nominations / Results 57 selected targets / README 59 targets / 50 post-QC perturbations need reconciliation; no success fraction calculated.
  • Automated source review only; independent human scientific review remains outstanding.
  • Custom ranking AUC is not ROC AUC, prospective hit rate or efficacy.
  • No matched-budget conventional/random prospective comparison; no antitumor efficacy, rescue or selectivity result in this endpoint.
  • Original model implementations/checkpoints are not pinned in the intake; no uncertainty printed.
  • Preprint v1; original and reimplemented ranking scores kept separate. Screen2 ranking population is enriched by original nomination methods.
  • The multi-method comparisons added on 2026-10-09 are retrospective replays of published screens, not prospective validation batches: a method selects genes and the screen's existing measurement is looked up.
  • An independent replication reports that the agent compared in Roohani et al. 2025 performs about the same when its experimental feedback is replaced by randomly permuted outcomes (at least as high on three of five screens with each of three backbones), so its margin over the baselines should not be read as learning from each round's results.
  • No benchmark found scores target nominations against a therapeutic window, selectivity, dependency or tractability, and none establishes patient benefit.
  • AssayBench reports lower scores for most systems on screens published after the models' training cutoff, which its authors read as partly prior exposure to the literature; that cohort has 19 screens, and two systems score higher on it.

Contribute evidence or propose a correction

Question, sources and review

Who this is for, setting and exclusions

Select targets and modulation directions for a validation batch, with clear tests of the proposed disease mechanism.

Who this is for
  • Disease biologists
  • Translational discovery teams
Biological setting
Research planning for one disease and a prespecified experimental system. The intended comparison tests whether rankings improve the yield of useful target effects.
Research setting
Research only. Target prioritisation does not establish treatment benefit or support patient-specific treatment decisions.

Outside this use case

  • Untested targets cannot be treated as negative examples.
  • Cellular dependency, target tractability and a therapeutic window require different evidence.
  • A target association does not establish that modulating it will benefit patients.
  • Recovering a published screen's own hits is not evidence that a nominated target is worth pursuing.
Evidence collection plan
Evidence collection planCollecting evidence

Already on record: 5 comparisons shown · 46 tools, in the evaluated evidence above. The status above describes only the specific comparison in this plan, which remains open; it does not mean no evidence has been collected. The plan defines a comparison to investigate; it does not establish model performance or suitability.

Comparison question

Does a proposed ranking identify more reproducible disease-relevant target effects than conventional evidence aggregation at the same validation budget?

Baselines, outcomes and validation requirements

Baselines to include

  • Genetics-only and expression-only rankings
  • Simple dependency ranking or conventional evidence aggregation

Outcomes to measure

  • Confirmed useful target effects among all candidates tested
  • Reproducibility, rescue and context/selectivity
  • Failed experiments and uncertainty about modulation direction

Validation requirements

  • Define the disease, candidate universe, intervention direction, phenotype and budget before comparing rankings.
  • Freeze input evidence before validation outcomes and audit overlap between discovery and validation data.
  • Include failed experiments and normal-cell controls; retain untested candidates as untested.
  • Keep target association, dependency, tractability and clinical success separate.

Next collection task

Close the remaining endpoint, independence and comparator gaps documented in the 30 September 2026 audit and linked article issue; obtain qualified scientific review.

Related articles
Sources, review and downloads

Automated source review · 2026-09-30 · Codex source curation, independent worker cross-review and root integration review

Source-backed literature curation with independent automated transcription and scope checks. No new model execution, independent experimental replication, qualified human scientific review or clinical validation.

Release 2026-11-02-a7f03c9e55a5 · question use-case-therapeutic-target-validation

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