bioinformatics platform developers

Abstract: Individual-level genotype data underpin genetic discovery, disease-risk modeling, and therapeutic development, yet many critical settings remain data-limited, including underrepresented ancestries, rare or imbalanced disease cohorts, and restricted-access biobanks. Conditional synthetic genome generation would support privacy-aware benchmarking, simulation, and data augmentation, but requires learning an ultra-high-dimensional discrete distribution over hundreds of thousands to tens of millions of correlated single-nucleotide polymorphisms (SNPs), or sites of DNA variation. We introduce HELICS: High-fidelity gEneration via Latent Interpolant Conditional Synthesis, a phasing-free latent flow matching framework for genome-wide SNP-level generation from biobank-scale genotype data. HELICS tokenizes chromosomes with convolutional autoencoders, reducing >600K SNPs to 4,096 continuous latent tokens, and trains a transformer parameterized conditional flow matching model over the concatenated multi-chromosome latent representation. Trained on over 417K genomes in the UK Biobank, HELICS generates genome-wide common-variant synthetic cohorts without haplotype phasing and achieves stronger fidelity to real genotypes than existing haplotype-based simulators, including high allele-frequency agreement in external evaluation and superior preservation of local and long-range SNP correlation structure. Conditioning on ancestry and genetic liability summaries enables targeted generation across genetic risk profiles; in perturbation analyses, by increasing the conditioned disease trait liability, HELICS induces SNP-level dosage changes in generated genomes that are highly correlated with published association weights. HELICS provides a scalable generative modeling framework for SNP-level genome data and a path toward conditional synthetic cohorts for data-limited genetic studies.

Abstract: We envision a general-purpose protein foundation model as a unified, interactive model of sequence, structure, and function, capable of understanding, generation, and cross-modal translation while retaining the instruction-following and reasoning capabilities of modern LLMs. Toward this vision, we introduce Trion-1, the first native, unified, multimodal diffusion language model (dLLM) for proteins. Trion-1 is built on two key design choices: (1) a unified discrete token space that jointly represents sequence, structure, and natural language; (2) a dLLM backbone that replaces strict left-to-right factorization with bidirectional or semi-bidirectional token interactions, enabling global residue communication and long-range contact modeling that are naturally suited to structure modeling. This formulation unifies six core capabilities: folding, inverse folding, sequence understanding, structure understanding, sequence design, and structure design, while retaining the native language capabilities of general-purpose LLMs. On established benchmarks, Trion-1 achieves broadly competitive performance. In folding, Trion-1 achieves a TM-score above 0.8 with a single sample under strict homology control, matching or exceeding the existing tri-modal model using 200 samples. For sequence understanding, Trion-1 performs on par with top-tier LLMs such as Claude Opus 4.7 (62.37%). These results support well-aligned sequence-structure-language representations and strong cross-modal generative capabilities.

Abstract: Reliable microbial taxonomic inference is challenged by the rapid growth of newly sequenced organisms and incomplete reference coverage. While alignment- and database-driven tools remain essential for reference-backed identification, they are not designed for learned inference over species absent from genome-level training. We introduce HyperTaxa, a taxonomy-aligned representation learning framework for open-set microbial taxonomic inference. HyperTaxa encodes whole genomes as multiscale hyperspectral k-mer transition fields and aligns these representations to a taxonomy-derived semantic space using a two-stage Node2Vec-to-MDS procedure that combines local graph structure with global hierarchical distance preservation. The resulting space supports zero-shot inference over species excluded from genome-level training but represented in the taxonomy, generalized zero-shot inference over seen and unseen species, and cascaded genus-to-species prediction. Across benchmark and large-scale disjoint-species evaluations, HyperTaxa improves taxonomic prediction over pseudo-image and transformer-graph baselines, with the strongest gains at higher taxonomic ranks. Ablations further show that multiscale transition encoding and taxonomy-aware alignment are key contributors to generalization. These results position HyperTaxa as a complementary taxonomy-aware representation and candidate-generation framework for microbial identification under incomplete reference coverage and open-set uncertainty.

Abstract: Reverse target fishing identifies protein targets for a query molecule and is central to drug discovery and repurposing. Discriminative approaches adapted from virtual screening face sparse, long-tailed associations and missing-not-at-random measurements: treating unrecorded pairs as negatives can suppress genuine targets. We reformulate the task as generative retrieval and introduce GenFish. Residual vector quantization converts frozen protein language model features into shared semantic identifiers. Given a molecular fingerprint, GenFish autoregressively models codes conditioned on the query and preceding code, ranking proteins by identifier likelihood without explicitly labeling unrecorded pairs as negatives. We introduce ProTargetBench, the first proteome-scale benchmark for reverse target fishing to jointly support measured-panel discrimination and full-catalogue recovery of experimentally recorded positives. Covering 20,431 UniProt-reviewed human proteins, it integrates curated bioactivity evidence and distinguishes experimental inactivity from unmeasured associations. On 198 held-out molecules, GenFish achieves higher mean performance across all three full-catalogue retrieval metrics than four discriminative neural baselines and three non-neural baselines, including ligand-based methods. A controlled positive-hiding experiment shows that targeted removal of false-negative competition improves contrastive retrieval beyond matched random masking; GenFish remains stronger under the same incomplete supervision. Pfam alignment indicates that the semantic identifiers capture biologically meaningful relationships among proteins. These results establish generative retrieval as a principled paradigm for reverse target fishing under incomplete bioactivity records.

Abstract: Optical pooled screens connect genetic perturbations to changes in cell morphology and behavior, but turning the microscopy data into interpretable results takes complex, multi-day analyses. Established pipelines process this data, yet researchers still select parameters, inspect outputs, and resolve failures for each experiment. Here, we present Brieflow-auto, a pipeline-specific harness implemented as a Claude Code plugin that lets a coding large language model (LLM) operate Brieflow, an open-source end-to-end pipeline for optical pooled screening data. A researcher supplies experimental facts and approves the launch. An agent tunes parameters in an interactive notebook, and the harness validates the configuration, monitors execution, recovers from common failures, and checks output quality. For pipeline defects, the agent opens upstream issues proposing backward-compatible fixes for the broader community. In five previously analyzed screens, harness runs yielded more cells with a confident single-gene assignment than the original hand analyses. On a screen the pipeline was not designed for, the harness turned each failure into a reviewed upstream fix. More broadly, we propose that wrapping an established pipeline in a harness can substantially accelerate its use and the long-term reliability of its codebase.

Abstract: Computational biologists increasingly delegate substantial analyses to AI agents in long-horizon, multi-turn sessions, yet most benchmarks of agents' bioinformatics capabilities pose a single short task with a single-shot prompt. We present OmicsBench, a long-horizon, multi-turn bioinformatics benchmark for AI agents. Each of its 97 tasks links dependent subtasks into a directed acyclic graph, for 662 underlying subtasks in all. Each subtask is posed as one user turn and graded deterministically against an answer key, with optional in-context feedback on incorrect answers. Across 12 models on three harnesses, the slowest agent averages 3.6 hours per task, and no combination comes near saturating the benchmark, with mean scores of 0.43 to 0.57 out of a possible 1 without in-context feedback and 0.54 to 0.67 with it. Multi-turn evaluation also uncovers behavior that single-shot prompts cannot, as agents score lower on subtasks that depend on earlier subtasks, and in-context feedback helps agents recover some of that loss. Because deterministic scoring gives no qualitative account of how an agent failed, we also introduce an unsupervised failure mode discovery pipeline that describes, embeds, and clusters agents' failed attempts to surface emergent failure modes. Applied to OmicsBench, this pipeline exposes qualitative shortcomings in how agents carry out bioinformatics analyses, ranging from agents applying their own statistical filters in place of the specified ones to agents writing whole answers from memory.

Abstract: Biomedical multi-hop reasoning over knowledge graphs requires identifying a semantically valid relation sequence that supports the answer. Existing methods can retrieve correct answers, yet often rank them poorly within a large pool of seemingly relevant candidates. Even when a correct answer is retrieved, its associated evidence and reasoning path may fail to support the relation composition required by the question. We term this disconnect between answer reachability and evidential validity the reachable-but-invalid problem. We present ReSemReason, which shares a question-induced distribution over typed, directed relation schemas between candidate discovery and evidence selection. Schema compatibility guides graph search; ReSemAttn then uses relation-conditioned key/value projections and an uncertainty-weighted path prior to attend to candidate-specific evidence. A separate absolute-support score complements normalized attention when all retrieved paths are weak. The reported experiments on BioHopR, PrimeKGQA, and MedReason show improvements in answer ranking and answer-set quality. Path-discrimination analyses examine the distinction between endpoint correctness and evidential support. We also specify matched controls for search, attention, and schema uncertainty.

Abstract: Recent advances in foundation models and large-scale cellular perturbation datasets have driven growing interest in using LLMs to predict and reason about cellular responses. Biological reasoning in this setting involves relating molecular mechanisms, cellular responses, and functional outcomes across scales. Evaluating foundation models therefore requires assessing not only whether their predictions are correct, but also how those predictions depend on the biological evidence provided. We introduce CellChain, an experimentally grounded benchmark comprising 590 biological cases and 2,360 matched evidence-condition instances across gene-dependency prediction, cytokine-axis identification, and drug-sensitivity ranking. CellChain links perturbation experiments and external biological resources through a provenance-aware evidence graph spanning molecular, pathway, transcriptional, and phenotypic information. Task-specific conditions vary evidence coverage, composition, or assignment while preserving questions, candidate answers, reference targets, and scoring rules. Across 18 foundation models, the highest accuracies under prespecified target-evidence conditions are 57.5%, 75.5%, and 70.8%, respectively, and broader evidence coverage does not consistently improve accuracy. On the drug-sensitivity benchmark cohort, matched reference histories outperform swapped histories by an average of 13.0 percentage points in cluster-weighted accuracy. Decision-transition analysis separates corrections, newly introduced errors, and wrong-answer switches, revealing substantial answer changes hidden by small net accuracy differences. CellChain provides controlled comparisons for attributing changes in model predictions to prespecified expansions of biological context, including changes in evidence coverage, composition, and biological assignment.

Abstract: Protein foundation models support mutation-effect and structural prediction, but predictive performance alone does not reveal which forms of biological interaction information remain accessible through model depth. We ask whether ESM-2 retains higher-order epistatic information as strongly as first- and second-order information across its representation hierarchy, introducing ORBIT-FMIB, a diagnostic framework combining Walsh-based interaction decomposition with subset-conditioned neural dependence estimation. The method is validated on synthetic landscapes with known interaction structure before being applied to the dense four-site GB1 fitness landscape using frozen ESM-2 representations. An initial production run suggested ESM-2 retains higher-order epistatic information less well than lower-order information ($Δ_{\mathrm{HO-LO}}=-0.107$). An independent replication of the complete measurement grid, under matched GPU hardware and identical critic seeds, substantially reduced this contrast ($Δ_{\mathrm{HO-LO}}=-0.017$), and its sign was unstable across otherwise-defensible evaluation-pairing choices applied to the same trained critics ($-0.011$ to $+0.015$). We therefore do not currently have robust evidence that ESM-2 selectively loses higher-order epistatic information, nor that retention is equal across orders; the directional question remains open. The measurement protocol itself, including its documented removal of a positional-subset shortcut in pooled critics, remains validated and is unaffected by this finding. ORBIT-FMIB is offered as a diagnostic framework for probing interaction structure in protein foundation models; this study's own replication result illustrates why such probing requires adequately-powered reproducibility checks before its output is treated as a biological finding.

Abstract: Spatial transcriptomics enables spatially resolved gene expression analysis from slide-level images while preserving morphological features, providing valuable information for studying disease mechanisms and developing treatments. However, spatial gene expression profiling typically requires expensive and time-consuming tests. While existing image-based prediction optimizations mostly revolve around including positional embeddings and further image-based changes, text-based optimizations remain relatively unexplored. We present GATE-ST, which incorporates text-based inputs into image-based spatial gene expression predictions. With this approach, generated text descriptions of genes are utilized to better spatial transcriptomics prediction results. Gene summaries are put through a text encoder, generating embeddings that integrate with image embeddings through cross-attention layers to align with morphological features. We demonstrate the effectiveness of such text inputs by benchmarking performance against random gene embeddings and multiple other image-text fusion architectures, and show that GATE-ST outperforms these alternatives. Our results demonstrate the effectiveness of GATE-ST in pathology imaging, which may greatly reduce the time and cost of accurate spatial transcriptomic predictions, proving the potential of text-guided spatial gene expression prediction.

Abstract: The Model Context Protocol (MCP) isolates servers by design: only the host can orchestrate cross-server workflows. When the host is a large language model, the resulting orchestrations are non-deterministic, non-reproducible, and pay one inference round-trip per tool call. We present a coordination architecture in which a Hierarchical Task Network (HTN) planner generates a verifiable cross-server plan once, and a runtime middleware executes it deterministically across multiple MCP servers, binding cross-action data dependencies via a template mechanism (\verb|${context.X}|) substituted at execution time. The architecture mirrors MCP's isolation constraint: each compound task decomposes into server-local primitive actions, and inter-server data flow is bound at execution time via JSON-path output extractors. We instantiate the architecture on five HTN domains spanning laboratory robotics, bioinformatics and multiscale modelling, and demonstrate end-to-end execution from a browser-based plan controller against eight live third-party MCP servers querying real biological databases.

Abstract: Single-cell foundation models (scGPT, scBERT, Geneformer) achieve cell-type classification accuracy up to 97.5% in our experiments, yet this aggregate accuracy can mask systematic failure on rare, often disease-relevant cell populations that long-tail loss functions are widely assumed to address. We present a systematic benchmark of six long-tail loss functions (cross-entropy, weighted CE, class-balanced loss, focal loss, LDAM, logit-adjusted softmax) across three architectures and three datasets (Multiple Sclerosis, Zheng68K, human Pancreas), totaling 162 controlled training runs (3 backbones x 3 datasets x 6 losses x 3 seeds). The gap between overall accuracy, Macro-F1, and rare-class recall under plain cross-entropy is consistent across all nine (architecture, dataset) settings, driven by dataset structure rather than pretraining. Rare-class failure itself splits into two regimes with distinct embedding-geometry signatures, visible before any loss is chosen: some classes are recoverable by the right loss, while others retain linear separability yet are absorbed into unrelated classes' neighborhoods under every evaluated loss and architecture. Among the recoverable classes, the efficacy of reweighting is predicted by a class's absolute training-set size, rather than its share of the dataset or the dataset's overall imbalance ratio. Class-balanced loss and LDAM are the most consistent choices across all nine settings, while logit adjustment trades rare-class precision for recall rather than improving both. Our results give both a reusable benchmark and mechanism-grounded practical guidelines for combining foundation models with imbalanced biological data.

Abstract: Aging clocks quantify biological aging and help characterize individual health status. What protein interactions are important for accurate aging clocks, and are they zeroth-order or higher-order? Addressing these questions requires learning from large molecular datasets distributed across medical centers, where privacy constraints prevent centralized data sharing. Federated learning offers a natural solution but faces four challenges in this setting: limited local sample sizes, sparse and directional inter-center trust, the need to retain discriminative age prediction while supporting interpretation, and model drift and forgetting under heterogeneous cross-center data. We propose TNFL, a trust-network-based federated learning framework that progressively propagates models along directed pairwise trust relations without centralized aggregation. TNFL combines an age-aware mixture-of-experts model with generative replay to preserve previously learned information and reduce forgetting and drift. Experiments across multiple molecular datasets show that TNFL enables effective aging-clock prediction with limited local data, provides interpretable age-dependent prediction patterns, and maintains stable performance across interaction orders. To investigate the biological questions, we analyze TNFL-identified pairwise protein interactions and their higher-order organization through functional and network analyses. The identified interactions repeatedly form coordinated higher-order subnetworks spanning multiple aging-related biological systems, with several proteins recurring across subnetworks. These findings suggest that TNFL captures molecular relationships beyond isolated pairwise associations and reveals coherent higher-order biological organization associated with aging.