数据与 AI技能

Performs ML-based protein-ligand pose prediction and scoring using DiffDock-L (diffusion-based), Boltz-1 / Boltz-2 (foundation model with affinity), Chai-1, AlphaFold3 ligand, EquiBind, TANKBind, NeuralPLexer, and hybrid workflows (DiffDock pose + GNINA rescore + PoseBusters QC). Explicit handling of when ML beats classical docking, when classical beats ML, the PB-invalid pose problem, and rescoring as the standard production hybrid. Use when modern docking is needed: foundation-model ligand-pose prediction, AI rescoring of classical poses, or scaffold-hopping in cross-docking scenarios.

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Builds QSAR / QSPR models using chemprop D-MPNN, MolFormer, Uni-Mol, ChemBERTa, random forest baselines, and Gaussian processes with explicit handling of OECD 5 principles, applicability domain (kNN, leverage, conformal prediction, Mahalanobis), scaffold-balanced splits, ensemble uncertainty, calibration (Platt, isotonic), feature importance (SHAP, atomic attribution), and prospective validation. Use when building target-specific predictive models from in-house bioassay data, ADMET endpoints, or selectivity profiles.

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Reads, validates, and prepares CDISC SDTM and ADaM clinical trial data for analysis. Covers SDTM domain joins (DM, AE, EX, VS, LB, DS), ADaM architecture (ADSL, BDS, OCCDS, ADTTE) with traceability, treatment-emergent AE conventions, baseline derivation, SUPPQUAL/NSV handling, Define-XML 2.1, and Pinnacle 21 / CORE validation. Use when working with clinical trial datasets in CDISC SDTM/ADaM format, preparing analysis-ready data, or validating for regulatory submission.

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Designs Bayesian clinical trials including Phase I dose-finding (BOIN, CRM, EWOC, mTPI-2), meta-analytic-predictive (MAP) priors with robust mixtures for external data borrowing, EXNEX for basket trials, hierarchical models for safety AE (Berry-Berry), Bayesian platform trials (I-SPY 2, GBM AGILE, REMAP-CAP), and posterior probability stopping rules. Covers FDA Bayesian Devices Guidance (2010), FDA Bayesian Methodology in Drugs Draft (January 2026), BOIN Fit-for-Purpose qualification (December 2021), and Project Optimus dose-optimisation. Use when designing dose-finding studies, platform trials, or sensitivity analyses with informative priors.

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Standardizes molecular structures using ChEMBL chembl_structure_pipeline and RDKit rdMolStandardize covering sanitization, salt/solvent stripping, neutralization, tautomer canonicalization, stereochemistry standardization, mixture handling, and isotope normalization. Explicitly compares ChEMBL pipeline, canSARchem, and PubChem standardization choices. Use when preparing libraries for QSAR training, joining datasets across sources, deduplicating compound collections, or building canonical compound registries.

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Implements multiplicity control for confirmatory clinical trials using graphical procedures (Bretz-Maurer-Hommel), gatekeeping (parallel, serial, mixed), Hochberg/Hommel/Holm with PRDS, and the closed-testing principle (Marcus-Peritz-Gabriel; Goeman 2021 admissibility). Covers FDA Multiple Endpoints Final Guidance (October 2022), graphical procedures via R gMCP, primary + key-secondary + subgroup hierarchies, and FWER vs FDR distinction. Use when designing the multiplicity strategy for confirmatory trials with multiple primary or key secondary endpoints.

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Calculates molecular fingerprints (ECFP/Morgan, FCFP, MACCS, RDKit, AtomPair, TopologicalTorsion, Avalon, MAP4, MHFP6) and physicochemical descriptors (Lipinski, QED, TPSA, Crippen LogP, 3D shape) with explicit choice tables, bit vs count semantics, and partial-charge model selection. Use when featurizing molecules for similarity, QSAR, virtual screening, or ML, or selecting the correct fingerprint for a chemotype-aware task.

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Calls ChIP-seq peaks with MACS3, MACS2, HOMER, or SPP across narrow (TF) and broad (histone) modes. Handles input control matching, fragment-size modeling vs --nomodel, effective genome size, ENCODE-style IDR vs naive overlap, hyper-ChIPable artifacts, and aligner-specific shifts. Use when calling peaks from ChIP-seq alignments, choosing between narrow vs broad mode for a histone mark, deciding model vs nomodel for low-depth data, applying ENCODE pseudoreplicate IDR, or reconciling MACS vs HOMER vs SPP results.

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Implements missing-data sensitivity analyses for confirmatory clinical trials including MMRM under MAR (with Kenward-Roger correction), reference-based multiple imputation (J2R, CR, CIR, LMCF per Carpenter-Roger 2013), Permutt delta-adjustment / tipping-point analysis, pattern-mixture identifying restrictions (CCMV, NCMV, ACMV), and the Cro vs Bartlett variance debate. Use when handling missing primary or secondary endpoint data in regulatory submissions following NRC 2010 and ICH E9(R1).

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Normalizes ChIP-seq data using exogenous spike-in (ChIP-Rx with Drosophila chromatin per Orlando 2014 / Egan 2016; E. coli carryover for CUT&RUN/CUT&Tag). Distinguishes RRPM from Rx-Input scaling, integrates with DiffBind / DESeq2 / edgeR / csaw via sizeFactors and DiffBind library-size vectors, and applies the Patel et al 2024 *Nat Biotechnol* review's failure-mode framework to validate that normalization is correctly applied at the read level (not peak counts). Use when global signal shifts are expected (HDACi, BETi, EZH2i, dosage, target knockdown), when ChIPseqSpikeInFree detects post-hoc shifts, or when validating internal-control regions before publication.

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Performs alchemical free-energy calculations including relative binding free energy (RBFE / FEP+) and absolute binding free energy (ABFE) via OpenFE, FEP+, GROMACS, AMBER pmemd, and OpenMM with explicit lambda window scheduling, soft-core potentials, REST2 enhanced sampling, MBAR/BAR analysis, and cycle closure validation. Compares ML alternatives (Boltz-2 affinity, DeepDock). Use when ranking analogs by binding affinity beyond docking accuracy, performing prospective lead optimization, or validating SAR predictions.

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Performs gene-level association from GWAS summary statistics via genetically predicted tissue expression using FUSION, PrediXcan, S-PrediXcan, S-MultiXcan, UTMOST, MOSTWAS, kTWAS, EpiXcan, TIGAR-V2, and probabilistic fine-mapping with FOCUS and MA-FOCUS. Use when running TWAS from GWAS sumstats, prioritising candidate causal genes from a GWAS lead locus, picking single-tissue vs cross-tissue models, identifying LD-induced TWAS false positives, choosing ancestry-matched prediction weights, fine-mapping co-regulated TWAS hits, or triangulating TWAS with cis-eQTL Mendelian randomization and colocalization to nominate a causal gene.

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Segments the genome into chromatin states from combinatorial histone modification and chromatin factor ChIP-seq data. Uses ChromHMM (multivariate HMM on binarized signal, v1.27), Segway (Dynamic Bayesian Network on continuous signal), EpiSegMix (flexible-distribution HMM with duration modeling, 2024), EpiLogos (multi-biosample visualization), IDEAS (cell-type-aware joint), and full-stack ChromHMM (Vu Ernst 2022) for cross-cell-type segmentations. Handles state-count selection (15 vs 18 vs 25 states), binarization choice, OverlapEnrichment / NeighborhoodEnrichment downstream analysis, and cross-biosample integration. Use when learning chromatin states from a histone mark panel, characterizing learned states by genomic feature enrichment, or comparing chromatin landscapes across cell types.

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Process and analyze single-cell ATAC-seq data with Signac, ArchR, SnapATAC2, or Cell Ranger ATAC. Use when handling 10X scATAC or 10X Multiome (paired RNA+ATAC) data, performing per-cell QC, choosing between ArchR/Signac/SnapATAC2 ecosystems, building per-cluster consensus peaksets, integrating with paired scRNA-seq, doublet detection (AMULET vs ArchR vs scDblFinder), or running pseudobulk differential accessibility per cluster.

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Parse and analyze multiple sequence alignments using Biopython. Extract sequences, identify conserved regions, analyze gaps, work with annotations, and manipulate alignment data for downstream analysis. Use when parsing or manipulating multiple sequence alignments.

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Generate alignment statistics using samtools flagstat, stats, depth, coverage, and mosdepth. Use when assessing alignment quality, calculating coverage, or generating QC reports.

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集群数据管理 Skill —— 涵盖数据使用规范、压缩优化、数据共享（ACL）、文件扫描与清理、文件完整性校验、genozip 基因组压缩等全流程。Use when the user asks about: managing data on the HPC cluster, compressing genomic files (fq/bam/vcf), sharing data between users/groups, scanning for large files or cleaning up disk space, checking file integrity (md5/gzip/bam), using genozip, checking disk quota, or any data lifecycle management task on the NCPGR HPC cluster.

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Generate pileup data for variant calling using samtools mpileup and pysam. Use when preparing data for variant calling, analyzing per-position read data, or calculating allele frequencies.

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Calculate alignment statistics including sequence identity, conservation scores, substitution matrices, and similarity metrics. Use when comparing alignment quality, measuring sequence divergence, and analyzing evolutionary patterns.

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Build a differential-ready consensus peakset from per-replicate ATAC-seq peaks using iterative overlap removal, fixed-width re-centering, and majority-rule overlap. Use when generating a stable peak coordinate system for downstream differential accessibility, ML feature engineering, cross-sample comparison, or fixed-width peak counts; covers Corces 2018 iterative overlap (501 bp), DiffBind summit re-centering, and ENCODE consistency rules.

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Detects aberrant splicing in single rare-disease patients vs a control panel using FRASER 2.0 (Bioconductor; Beta-binomial autoencoder on Intron Jaccard Index, default delta cutoff 0.1, q hyperparameter), OUTRIDER (gene-level outlier expression via autoencoder denoising), LeafcutterMD (Dirichlet-multinomial outlier mode of LeafCutter for annotation-free junctions), and DROP (Snakemake pipeline integrating FRASER2 + OUTRIDER + monoallelic expression for clinical diagnostics). The statistical model is fundamentally different from differential splicing — single-sample-vs-cohort outlier detection rather than two-group comparison. Standard tool in EU rare-disease (Solve-RD) and NIH UDN programs. Use when applying RNA-seq to undiagnosed Mendelian disease, validating predicted splice variants in clinical samples, or detecting cryptic splicing in disease tissue.

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Detects differential alternative splicing between conditions using rMATS-turbo (binomial LRT on junction counts), leafcutter (Dirichlet-multinomial GLM on intron clusters), MAJIQ V3 deltapsi/HET (Bayesian posterior on LSVs), SUPPA2 (empirical-null on TPM-derived PSI), or Shiba (junction-imbalance-corrected, 2025 SOTA at low coverage). Reports FDR-corrected significance and delta PSI effect sizes. Tools differ in statistical model, annotation dependence, calibration regime, and replicate-count requirements. Use when comparing splicing patterns between treatment groups, tissues, or disease states.

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Validate alignment quality with insert size distribution, proper pairing rates, GC bias, strand balance, and other post-alignment metrics. Use when verifying alignment data quality before variant calling or quantification.

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Perform multiple sequence alignment using MAFFT, MUSCLE5, ClustalOmega, or T-Coffee. Guides tool and algorithm selection based on dataset size, sequence divergence, and downstream application. Use when aligning three or more homologous sequences for phylogenetics, conservation analysis, or evolutionary studies.

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