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Analyzes CRISPR drug-modifier (chemogenomic) screens with drugZ (Colic et al. 2019 Genome Med), a bidirectional Z-score method that identifies synthetic-lethal sensitizing genes and resistance-conferring suppressor genes from vehicle vs drug comparisons. Covers vehicle-anchored design (not Day-0), the bidirectional Z math giving greater sensitivity to small-effect hits than MAGeCK / STARS / edgeR / RIGER on drug screens, per-gene sumZ and normZ, synth (sensitizer) vs supp (suppressor) FDR, multi-dose handling, integration with control sgRNAs, and comparison with MAGeCK MLE with dose covariate. Use when running a drug-modifier CRISPR screen, identifying sensitizing or resistance genes for a drug candidate, choosing drugZ vs MAGeCK MLE for chemogenomic analysis, troubleshooting low-effect drug screens where MAGeCK lacks sensitivity, or designing a drug-screen layout (vehicle vs drug arms).

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Detect positive (diversifying / episodic / pervasive) selection using codon dN/dS frameworks. Implements PAML codeml site models (M0/M1a/M2a/M7/M8/M8a), branch models, branch-site model A (Zhang 2005), and HyPhy methods (BUSTED, BUSTED-S, BUSTED-MH, BUSTED-PH, MEME, FEL, FUBAR, aBSREL, SLAC, RELAX, GARD, FUBAR-MH). Includes McDonald-Kreitman framework (asymptotic alpha, impMKT, polyDFE, DFE-alpha, GRAPES) for within-species + divergence inference, RERconverge for trait-correlated rate shifts, CSUBST for convergent substitution, and PhyloAcc for accelerated noncoding evolution. Use when testing adaptive evolution at codons, branches, or full gene; running GARD recombination pre-screen; controlling alignment-error and gBGC false positives; reconciling PAML vs HyPhy results; or performing genome-scale selection scans.

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Quantify homologous recombination deficiency (HRD) from tumor copy number using the three genomic-scar metrics — loss of heterozygosity (LOH), large-scale state transitions (LST), and telomeric allelic imbalance (TAI) — with scarHRD, and via the whole-genome HRDetect and CHORD models. Covers the genomic instability score, the PARP-inhibitor clinical context, whole-genome-doubling correction, and the scar-versus-state distinction. Use when computing an HRD score for PARP-inhibitor eligibility, deriving LOH/LST/TAI scars from allele-specific copy number, deciding between scar-based and mutational-signature HRD methods, or interpreting an HRD result in a BRCA-reverted or low-purity tumor.

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Normalize read-depth copy-ratio profiles and segment them into copy-number regions using circular binary segmentation (CBS, DNAcopy), hidden Markov models, HaarSeg, and fused-lasso methods. Covers GC-content, mappability, and replication-timing (wave-artifact) bias correction, panel-of-normals/PCA denoising, diploid-baseline centering, and algorithm selection by sequencing depth and event size. Use when choosing a segmentation algorithm, correcting depth bias, diagnosing oversegmentation or a mis-centered baseline, tuning CBS or HMM parameters, or understanding why a downstream CNV caller produced fragmented or shifted segments.

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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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Performs subgroup and heterogeneous treatment effect (HTE) analyses for clinical trials. Covers Mantel-Haenszel pooling, Breslow-Day, interaction tests in regression, RERI for additive interaction, modern data-adaptive HTE methods (STEPP, SIDES, causal forests, X/R-learners), Bayesian shrinkage (Dixon-Simon, MAP, EXNEX), graphical multiplicity (Bretz-Maurer), and credibility frameworks (Sun BMJ, EMA 2019). Use when analyzing treatment effects across patient subgroups for regulatory submissions or precision-medicine claims.

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Trains and applies base-resolution deep learning models on ChIP-seq / ChIP-nexus / CUT&RUN data. Uses BPNet (Avsec 2021 Nat Genet 53:354; soft motif syntax from ChIP-nexus), chromBPNet (Pampari A et al 2024 bioRxiv; bias-factorized base-resolution profiles), EnFormer (Avsec 2021 Nat Methods 18:1196; 196 kb input, ~100 kb effective receptive field), DeepSEA (Zhou 2015; multi-task CNN), and JASPAR 2026 deep-learning collection (1259 BPNet ChIP models). Performs in silico mutagenesis for variant-effect prediction, DeepLIFT/Grad attribution, and TF-MoDISco motif discovery from attribution scores. Use when predicting variant effects on TF binding, discovering soft motif syntax / cooperativity, integrating ChIP-seq with sequence-only predictions, or applying precomputed JASPAR Deep Learning models to new variants.

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Performs molecular similarity searching using Tanimoto, Tversky, Dice, and cosine coefficients on bit/count fingerprints with explicit choice rules for symmetric vs asymmetric measures, scaffold-hopping vs lead-optimization regimes, activity-cliff diagnosis, and large-library nearest-neighbor methods (BulkTanimoto, MHFP6 LSH forest, USRCAT). Use when ranking compounds by structural resemblance to a query, clustering libraries, finding analogs, or diagnosing activity cliffs.

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Analyzes alternative splicing at single-cell resolution. The first decision is library chemistry — 10X 3' is fundamentally limited (RT primes from poly-A, R2 falls in 3' UTR, <0.1 junction read per cell per AS event). Plate-based full-length methods (Smart-seq3, FLASH-seq, VASA-seq, STORM-seq) and single-cell long-read (MAS-Iso-seq, scISOr-Seq2) are the chemistries that give per-cell isoform structure. Tools include MARVEL (R, Smart-seq integrated), BRIE2 (Bayesian PSI with regulatory features and ELBO_gain test), scQuint (junction-cluster, plate-based; not for 10X), SpliZ (annotation-free Z-score), Psix (graph-smoothness regulated AS), and Sierra (alternative polyadenylation, often confused with AS). Use when analyzing isoform usage in scRNA-seq, identifying cell-type-specific splicing, or determining whether scRNA-seq chemistry supports splicing analysis at all.

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Test whether two or more traits share a causal variant at a locus using Bayesian colocalization (coloc.abf, coloc.susie, HyPrColoc, moloc, eCAVIAR, SMR/HEIDI, PWCoCo, SharePro). Use when integrating GWAS with eQTL/sQTL/pQTL/mQTL, distinguishing shared causal variants from LD-driven coincidence, handling allelic heterogeneity, choosing between single-causal vs multi-causal methods, picking PP.H4 thresholds, running sensitivity over p12, or harmonising summary statistics for colocalization.

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Apply Swift API Design Guidelines to name, label, and document Swift APIs. Covers argument label rules (prepositional phrase rule, grammatical phrase rule, first-label omission), mutating/nonmutating pair naming (-ed/-ing participle pattern, form- prefix, sort/sorted, formUnion/union), side-effect naming (noun for pure, verb for mutating), documentation comment structure (summary by declaration kind, O(1) complexity rule), clarity at call site, role-based naming, protocol naming (-able/-ible/-ing), default arguments over method families, casing conventions, and terminology. Use when designing new Swift APIs, reviewing naming and argument labels, writing documentation comments, or refactoring for call site clarity.

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Design and implement real-time audio processing chains using Audio Toolbox streaming objects. Use when building frame-based audio processing loops, multiband filters, dynamic range control, parametric EQ, level metering, loudness metering, SPL metering, octave-band analysis, sample rate conversion, frequency-domain filtering (long impulse responses, custom filter banks), or audio chains in Simulink. Covers visualization (visualize method), interactive tuning (parameterTuner), MIDI control, and Audio Toolbox Simulink blocks. Use when the user says "real-time audio", "streaming audio", "audio filter", "compressor", "equalizer", "level meter", "loudness meter", "SPL meter", "octave bands", "crossover filter", "audio chain", "MIDI control", "convolution reverb", "impulse response streaming", "frequency-domain filter", or asks to process audio frame-by-frame.

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Generate and structure MATLAB unit tests using matlab.unittest and matlab.uitest features, including class-based tests, parameterized testing, fixtures, mocking, and app testing with gestures. Use when writing, generating, or adding tests, creating test classes, adding test methods, parameterizing tests, setting up fixtures, mocking dependencies, or testing App Designer apps. Do NOT use for running tests, collecting coverage, or CI/CD configuration.

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Optimize e-commerce checkout flow to reduce cart abandonment. Friction analysis, payment method optimization, trust signals, and checkout UX best practices.

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Compare and optimize shipping rates across carriers and fulfillment methods. UPS, FedEx, USPS, DHL rate comparison, zone optimization, and shipping strategy to maximize margins.

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Conduct threat modeling using STRIDE methodology. Identify threats, assess risks, and design security controls. Use when designing secure systems or assessing application security.

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Manage secrets and PKI with HashiCorp Vault. Configure secret engines, authentication methods, and policies. Use when implementing centralized secrets management, dynamic credentials, or certificate management.

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AWS EC2 virtual machine management — instances, security groups, key pairs, AMIs, EBS volumes, Auto Scaling Groups, Spot Instances, Session Manager, placement groups, and instance lifecycle automation. Trigger on ANY of these, even when EC2 isn't named explicitly: - Launching or provisioning: "spin up a server", "create a VM", "new instance", "run-instances", mention of instance types (t3, m5, c5, r6, g5, p4d, t4g, c7g, etc.) - SSH / connectivity problems: "connection refused", "connection timed out", "permission denied publickey", "can't connect to my instance", "SSH not working" - Instance management: resize, stop, start, terminate, reboot, change instance type - Cost optimization: stop dev instances overnight, save money on EC2, spot vs on-demand, reserved instances - Auto Scaling: ASG, launch template, mixed instances policy, scale to zero, scheduled scaling - Spot Instances: spot fleet, spot interruption, capacity-optimized, price-capacity-optimized - AMIs and backups: create image, custom AMI, EBS snapshot, DLM lifecycle policy, copy AMI - Monitoring: EC2 CPU utilization, CloudWatch metrics for instance, instance status checks, console output - Access methods: Session Manager, EC2 Instance Connect, bastion host, port forwarding - Security: IMDSv2, instance metadata, IAM role on instance, security group rules - User data and bootstrap scripts, cloud-init

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CloudBase Web Authentication Quick Guide for frontend integration after auth-tool has already been checked. Provides concise and practical Web authentication solutions with multiple login methods and complete user management.

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CloudBase auth provider configuration and login-readiness guide. This skill should be used when users need to inspect, enable, disable, or configure auth providers, publishable-key prerequisites, login methods, SMS/email sender setup, or other provider-side readiness before implementing a client or backend auth flow.

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Reduce defensive writing in drafts and revisions by removing unnecessary caveats, disclaimers, hedges, apology-like framing, negative self-limiting statements, and over-explanations while preserving necessary scope, accuracy, safety, legal, ethical, and methodological limits. Use when drafting or revising academic writing, papers, essays, abstracts, introductions, contribution statements, discussions, conclusions, technical explanations, grant writing, product writing, policy writing, professional reports, or any text the user wants to be clearer, stronger, more direct, more concise, more confident, less verbose, less caveated, less apologetic, or less defensive.

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Best practices for systematic research, source evaluation, and evidence gathering

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Create and manage Shopify products via the Admin GraphQL API or CSV import. Workflow: gather data, choose method, execute, verify. Use whenever the user wants to add products to Shopify, bulk-import a catalog from CSV/spreadsheet/URL, update variants or prices, manage inventory quantities, upload product images, or assign products to collections.

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Build one compact choice card at a genuine mathematical-modeling judgment point. Use before method screening, after a meaningful experiment, or before final claim/freeze approval so the human chooses the trade-off while AI handles mechanical consequences.

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