@synsci/cli-darwin-x64 1.1.97 → 1.1.99

package/bin/skills/opentargets-database/references/evidence_types.md

@@ -1,306 +0,0 @@
-# Evidence Types and Data Sources
-
-## Overview
-
-Evidence represents any event or set of events that identifies a target as a potential causal gene or protein for a disease. Evidence is standardized and mapped to:
-- **Ensembl gene IDs** for targets
-- **EFO (Experimental Factor Ontology)** for diseases/phenotypes
-
-Evidence is organized into **data types** (broader categories) and **data sources** (specific databases/studies).
-
-## Evidence Data Types
-
-### 1. Genetic Association
-
-Evidence from human genetics linking genetic variants to disease phenotypes.
-
-#### Data Sources:
-
-**GWAS (Genome-Wide Association Studies)**
-- Population-level common variant associations
-- Filtered with Locus-to-Gene (L2G) scores >0.05
-- Includes fine-mapping and colocalization data
-- Sources: GWAS Catalog, FinnGen, UK Biobank, EBI GWAS
-
-**Gene Burden Tests**
-- Rare variant association analyses
-- Aggregate effects of multiple rare variants in a gene
-- Particularly relevant for Mendelian and rare diseases
-
-**ClinVar Germline**
-- Clinical variant interpretations
-- Classifications: pathogenic, likely pathogenic, VUS, benign
-- Expert-reviewed variant-disease associations
-
-**Genomics England PanelApp**
-- Expert gene-disease ratings
-- Green (confirmed), amber (probable), red (no evidence)
-- Focus on rare diseases and cancer
-
-**Gene2Phenotype**
-- Curated gene-disease relationships
-- Allelic requirements and inheritance patterns
-- Clinical validity assessments
-
-**UniProt Literature & Variants**
-- Literature-based gene-disease associations
-- Expert-curated from scientific publications
-
-**Orphanet**
-- Rare disease gene associations
-- Expert-reviewed and maintained
-
-**ClinGen**
-- Clinical genome resource classifications
-- Gene-disease validity assertions
-
-### 2. Somatic Mutations
-
-Evidence from cancer genomics identifying driver genes and therapeutic targets.
-
-#### Data Sources:
-
-**Cancer Gene Census**
-- Expert-curated cancer genes
-- Tier classifications (1 = strong evidence, 2 = emerging)
-- Mutation types and cancer types
-
-**IntOGen**
-- Computational driver gene predictions
-- Aggregated from large cohort studies
-- Statistical significance of mutations
-
-**ClinVar Somatic**
-- Somatic clinical variant interpretations
-- Oncogenic/likely oncogenic classifications
-
-**Cancer Biomarkers**
-- FDA/EMA approved biomarkers
-- Clinical trial biomarkers
-- Prognostic and predictive markers
-
-### 3. Known Drugs
-
-Evidence from clinical precedence showing drugs targeting genes for disease indications.
-
-#### Data Source:
-
-**ChEMBL**
-- Approved drugs (Phase 4)
-- Clinical candidates (Phase 1-3)
-- Withdrawn drugs
-- Drug-target-indication triplets with mechanism of action
-
-**Clinical Trial Information:**
-- `phase`: Maximum clinical trial phase (1, 2, 3, 4)
-- `status`: Active, terminated, completed, withdrawn
-- `mechanismOfAction`: How drug affects target
-
-### 4. Affected Pathways
-
-Evidence linking genes to disease through pathway perturbations and functional screens.
-
-#### Data Sources:
-
-**CRISPR Screens**
-- Genome-scale knockout screens
-- Cancer dependency and essentiality data
-
-**Project Score (Cancer Dependency Map)**
-- CRISPR-Cas9 fitness screens across cancer cell lines
-- Gene essentiality profiles
-
-**SLAPenrich**
-- Pathway enrichment analysis
-- Somatic mutation pathway impacts
-
-**PROGENy**
-- Pathway activity inference
-- Signaling pathway perturbations
-
-**Reactome**
-- Expert-curated pathway annotations
-- Biological pathway representations
-
-**Gene Signatures**
-- Expression-based signatures
-- Pathway activity patterns
-
-### 5. RNA Expression
-
-Evidence from differential gene expression in disease vs. control tissues.
-
-#### Data Source:
-
-**Expression Atlas**
-- Differential expression data
-- Baseline expression across tissues/conditions
-- RNA-Seq and microarray studies
-- Log2 fold-change and p-values
-
-### 6. Animal Models
-
-Evidence from in vivo studies showing phenotypes associated with gene perturbations.
-
-#### Data Source:
-
-**IMPC (International Mouse Phenotyping Consortium)**
-- Systematic mouse knockout phenotypes
-- Phenotype-disease mappings via ontologies
-- Standardized phenotyping procedures
-
-### 7. Literature
-
-Evidence from text-mining of biomedical literature.
-
-#### Data Source:
-
-**Europe PMC**
-- Co-occurrence of genes and diseases in abstracts
-- Normalized citation counts
-- Weighted by publication type and recency
-
-## Evidence Scoring
-
-Each evidence source has its own scoring methodology:
-
-### Score Ranges
-- Most scores normalized to 0-1 range
-- Higher scores indicate stronger evidence
-- Scores are NOT confidence levels but relative strength indicators
-
-### Common Scoring Approaches:
-
-**Binary Classifications:**
-- ClinVar: Pathogenic (1.0), Likely pathogenic (0.99), etc.
-- Gene2Phenotype: Confirmed/probable ratings
-- PanelApp: Green/amber/red classifications
-
-**Statistical Measures:**
-- GWAS: L2G scores incorporating multiple lines of evidence
-- Gene Burden: Statistical significance of variant aggregation
-- Expression: Adjusted p-values and fold-changes
-
-**Clinical Precedence:**
-- Known Drugs: Phase weights (Phase 4 = 1.0, Phase 3 = 0.8, etc.)
-- Clinical status modifiers
-
-**Computational Predictions:**
-- IntOGen: Q-values from driver mutation analysis
-- PROGENy/SLAPenrich: Pathway activity/enrichment scores
-
-## Evidence Interpretation Guidelines
-
-### Strengths by Data Type
-
-**Genetic Association** - Strongest human genetic evidence
-- Direct link between genetic variation and disease
-- Mendelian diseases: high confidence
-- GWAS: requires L2G to identify causal gene
-- Consider ancestry and population-specific effects
-
-**Somatic Mutations** - Direct evidence in cancer
-- Strong for oncology indications
-- Driver mutations indicate therapeutic potential
-- Consider cancer type specificity
-
-**Known Drugs** - Clinical validation
-- Highest confidence: approved drugs (Phase 4)
-- Consider mechanism relevance to new indication
-- Phase 1-2: early evidence, higher risk
-
-**Affected Pathways** - Mechanistic insights
-- Supports biological plausibility
-- May not predict clinical success
-- Useful for hypothesis generation
-
-**RNA Expression** - Observational evidence
-- Correlation, not causation
-- May reflect disease consequence vs. cause
-- Useful for biomarker identification
-
-**Animal Models** - Translational evidence
-- Strong for understanding biology
-- Variable translation to human disease
-- Most useful when phenotype matches human disease
-
-**Literature** - Exploratory signal
-- Text-mining captures research focus
-- May reflect publication bias
-- Requires manual literature review for validation
-
-### Important Considerations
-
-1. **Multiple evidence types strengthen confidence** - Convergent evidence from different data types provides stronger support
-
-2. **Under-studied diseases score lower** - Novel or rare diseases may have strong evidence but lower aggregate scores due to limited research
-
-3. **Association scores are not probabilities** - Scores rank relative evidence strength, not success probability
-
-4. **Context matters** - Evidence strength depends on:
-   - Disease mechanism understanding
-   - Target biology and druggability
-   - Clinical precedence in related indications
-   - Safety considerations
-
-5. **Data source reliability varies** - Weight expert-curated sources (ClinGen, Gene2Phenotype) higher than computational predictions
-
-## Using Evidence in Queries
-
-### Filtering by Data Type
-
-```python
-query = """
-  query evidenceByType($ensemblId: String!, $efoId: String!, $dataTypes: [String!]) {
-    disease(efoId: $efoId) {
-      evidences(ensemblIds: [$ensemblId], datatypes: $dataTypes) {
-        rows {
-          datasourceId
-          score
-        }
-      }
-    }
-  }
-"""
-variables = {
-    "ensemblId": "ENSG00000157764",
-    "efoId": "EFO_0000249",
-    "dataTypes": ["genetic_association", "somatic_mutation"]
-}
-```
-
-### Accessing Data Type Scores
-
-Data type scores aggregate all source scores within that type:
-
-```python
-query = """
-  query associationScores($ensemblId: String!, $efoId: String!) {
-    target(ensemblId: $ensemblId) {
-      associatedDiseases(efoIds: [$efoId]) {
-        rows {
-          disease {
-            name
-          }
-          score
-          datatypeScores {
-            componentId
-            score
-          }
-        }
-      }
-    }
-  }
-"""
-```
-
-## Evidence Quality Assessment
-
-When evaluating evidence:
-
-1. **Check multiple sources** - Single source may be unreliable
-2. **Prioritize human genetic evidence** - Strongest disease relevance
-3. **Consider clinical precedence** - Known drugs indicate druggability
-4. **Assess mechanistic support** - Pathway evidence supports biology
-5. **Review literature manually** - For critical decisions, read primary publications
-6. **Validate in primary databases** - Cross-reference with ClinVar, ClinGen, etc.

package/bin/skills/opentargets-database/references/target_annotations.md

@@ -1,401 +0,0 @@
-# Target Annotations and Features
-
-## Overview
-
-Open Targets defines a target as "any naturally-occurring molecule that can be targeted by a medicinal product." Targets are primarily protein-coding genes identified by Ensembl gene IDs, but also include RNAs and pseudogenes from canonical chromosomes.
-
-## Core Target Annotations
-
-### 1. Tractability Assessment
-
-Tractability evaluates the druggability potential of a target across different modalities.
-
-#### Modalities Assessed:
-
-**Small Molecule**
-- Prediction of small molecule druggability
-- Based on structural features, chemical precedence
-- Buckets: Clinical precedence, Discovery precedence, Predicted tractable
-
-**Antibody**
-- Likelihood of antibody-based therapeutic success
-- Cell surface/secreted protein location
-- Precedence categories similar to small molecules
-
-**PROTAC (Protein Degradation)**
-- Assessment for targeted protein degradation
-- E3 ligase compatibility
-- Emerging modality category
-
-**Other Modalities**
-- Gene therapy, RNA-based therapeutics
-- Oligonucleotide approaches
-
-#### Tractability Levels:
-
-1. **Clinical Precedence** - Target of approved/clinical drug with similar mechanism
-2. **Discovery Precedence** - Target of tool compounds or compounds in preclinical development
-3. **Predicted Tractable** - Computational predictions suggest druggability
-4. **Unknown** - Insufficient data to assess
-
-### 2. Safety Liabilities
-
-Safety information aggregated from multiple sources to identify potential toxicity concerns.
-
-#### Data Sources:
-
-**ToxCast**
-- High-throughput toxicology screening data
-- In vitro assay results
-- Toxicity pathway activation
-
-**AOPWiki (Adverse Outcome Pathways)**
-- Mechanistic pathways from molecular initiating event to adverse outcome
-- Systems toxicology frameworks
-
-**PharmGKB**
-- Pharmacogenomic relationships
-- Genetic variants affecting drug response and toxicity
-
-**Published Literature**
-- Expert-curated safety concerns from publications
-- Clinical trial adverse events
-
-#### Safety Flags:
-
-- **Organ toxicity** - Liver, kidney, cardiac effects
-- **Target safety liability** - Known on-target toxic effects
-- **Off-target effects** - Unintended activity concerns
-- **Clinical observations** - Adverse events from drugs targeting gene
-
-### 3. Baseline Expression
-
-Gene/protein expression across tissues and cell types from multiple sources.
-
-#### Data Sources:
-
-**Expression Atlas**
-- RNA-Seq expression across tissues/conditions
-- Normalized expression levels (TPM, FPKM)
-- Differential expression studies
-
-**GTEx (Genotype-Tissue Expression)**
-- Comprehensive tissue expression from healthy donors
-- Median TPM across 53 tissues
-- Expression variation analysis
-
-**Human Protein Atlas**
-- Protein expression via immunohistochemistry
-- Subcellular localization
-- Tissue specificity classifications
-
-#### Expression Metrics:
-
-- **TPM (Transcripts Per Million)** - Normalized RNA abundance
-- **Tissue specificity** - Enrichment in specific tissues
-- **Protein level** - Correlation with RNA expression
-- **Subcellular location** - Where protein is found in cell
-
-### 4. Molecular Interactions
-
-Protein-protein interactions, complex memberships, and molecular partnerships.
-
-#### Interaction Types:
-
-**Physical Interactions**
-- Direct protein-protein binding
-- Complex components
-- Sources: IntAct, BioGRID, STRING
-
-**Pathway Membership**
-- Biological pathways from Reactome
-- Functional relationships
-- Upstream/downstream regulators
-
-**Target Interactors**
-- Direct interactors relevant to disease associations
-- Context-specific interactions
-
-### 5. Gene Essentiality
-
-Dependency data indicating if gene is essential for cell survival.
-
-#### Data Sources:
-
-**Project Score**
-- CRISPR-Cas9 fitness screens
-- 300+ cancer cell lines
-- Scaled essentiality scores (0-1)
-
-**DepMap Portal**
-- Large-scale cancer dependency data
-- Genetic and pharmacological perturbations
-- Common essential genes identification
-
-#### Essentiality Metrics:
-
-- **Score range**: 0 (non-essential) to 1 (essential)
-- **Context**: Cell line specific vs. pan-essential
-- **Therapeutic window**: Selectivity between disease and normal cells
-
-### 6. Chemical Probes and Tool Compounds
-
-High-quality small molecules for target validation.
-
-#### Sources:
-
-**Probes & Drugs Portal**
-- Chemical probes with characterized selectivity
-- Quality ratings and annotations
-- Target engagement data
-
-**Structural Genomics Consortium (SGC)**
-- Target Enabling Packages (TEPs)
-- Comprehensive target reagents
-- Freely available to academia
-
-**Probe Criteria:**
-- Potency (typically IC50 < 100 nM)
-- Selectivity (>30-fold vs. off-targets)
-- Cell activity demonstrated
-- Negative control available
-
-### 7. Pharmacogenetics
-
-Genetic variants affecting drug response for drugs targeting the gene.
-
-#### Data Source: ClinPGx
-
-**Information Included:**
-- Variant-drug pairs
-- Clinical annotations (dosing, efficacy, toxicity)
-- Evidence level and sources
-- PharmGKB cross-references
-
-**Clinical Utility:**
-- Dosing adjustments based on genotype
-- Contraindications for specific variants
-- Efficacy predictors
-
-### 8. Genetic Constraint
-
-Measures of negative selection against variants in the gene.
-
-#### Data Source: gnomAD
-
-**Metrics:**
-
-**pLI (probability of Loss-of-function Intolerance)**
-- Range: 0-1
-- pLI > 0.9 indicates intolerant to LoF variants
-- High pLI suggests essentiality
-
-**LOEUF (Loss-of-function Observed/Expected Upper bound Fraction)**
-- Lower values indicate greater constraint
-- More interpretable than pLI across range
-
-**Missense Constraint**
-- Z-scores for missense depletion
-- O/E ratios for missense variants
-
-**Interpretation:**
-- High constraint suggests important biological function
-- May indicate safety concerns if inhibited
-- Essential genes often show high constraint
-
-### 9. Comparative Genomics
-
-Cross-species gene conservation and ortholog information.
-
-#### Data Source: Ensembl Compara
-
-**Ortholog Data:**
-- Mouse, rat, zebrafish, other model organisms
-- Orthology confidence (1:1, 1:many, many:many)
-- Percent identity and similarity
-
-**Utility:**
-- Model organism studies transferability
-- Functional conservation assessment
-- Evolution and selective pressure
-
-### 10. Cancer Annotations
-
-Cancer-specific target features for oncology indications.
-
-#### Data Sources:
-
-**Cancer Gene Census**
-- Role in cancer (oncogene, TSG, fusion)
-- Tier classification (1 = established, 2 = emerging)
-- Tumor types and mutation types
-
-**Cancer Hallmarks**
-- Functional roles in cancer biology
-- Hallmarks: proliferation, apoptosis evasion, metastasis, etc.
-- Links to specific cancer processes
-
-**Oncology Clinical Trials**
-- Drugs in development targeting gene for cancer
-- Trial phases and indications
-
-### 11. Mouse Phenotypes
-
-Phenotypes from mouse knockout/mutation studies.
-
-#### Data Source: MGI (Mouse Genome Informatics)
-
-**Phenotype Data:**
-- Knockout phenotypes
-- Disease model associations
-- Mammalian Phenotype Ontology (MP) terms
-
-**Utility:**
-- Predict on-target effects
-- Safety liability identification
-- Mechanism of action insights
-
-### 12. Pathways
-
-Biological pathway annotations placing target in functional context.
-
-#### Data Source: Reactome
-
-**Pathway Information:**
-- Curated biological pathways
-- Hierarchical organization
-- Pathway diagrams with target position
-
-**Applications:**
-- Mechanism hypothesis generation
-- Related target identification
-- Systems biology analysis
-
-## Using Target Annotations in Queries
-
-### Query Template: Comprehensive Target Profile
-
-```python
-query = """
-  query targetProfile($ensemblId: String!) {
-    target(ensemblId: $ensemblId) {
-      id
-      approvedSymbol
-      approvedName
-      biotype
-
-      # Tractability
-      tractability {
-        label
-        modality
-        value
-      }
-
-      # Safety
-      safetyLiabilities {
-        event
-        effects {
-          dosing
-          organsAffected
-        }
-      }
-
-      # Expression
-      expressions {
-        tissue {
-          label
-        }
-        rna {
-          value
-          level
-        }
-        protein {
-          level
-        }
-      }
-
-      # Chemical probes
-      chemicalProbes {
-        id
-        probeminer
-        origin
-      }
-
-      # Known drugs
-      knownDrugs {
-        uniqueDrugs
-        rows {
-          drug {
-            name
-            maximumClinicalTrialPhase
-          }
-          phase
-          status
-        }
-      }
-
-      # Genetic constraint
-      geneticConstraint {
-        constraintType
-        score
-        exp
-        obs
-      }
-
-      # Pathways
-      pathways {
-        pathway
-        pathwayId
-      }
-    }
-  }
-"""
-
-variables = {"ensemblId": "ENSG00000157764"}
-```
-
-## Annotation Interpretation Guidelines
-
-### For Target Prioritization:
-
-1. **Druggability (Tractability):**
-   - Clinical precedence >> Discovery precedence > Predicted
-   - Consider modality relevant to therapeutic approach
-   - Check for existing tool compounds
-
-2. **Safety Assessment:**
-   - Review organ toxicity signals
-   - Check expression in critical tissues
-   - Assess genetic constraint (high = safety concern if inhibited)
-   - Evaluate clinical adverse events from drugs
-
-3. **Disease Relevance:**
-   - Combine with association scores
-   - Check expression in disease-relevant tissues
-   - Review pathway context
-
-4. **Validation Readiness:**
-   - Chemical probes available?
-   - Model organism data supportive?
-   - Known drugs provide mechanism insight?
-
-5. **Clinical Path Considerations:**
-   - Pharmacogenetic factors
-   - Expression pattern (tissue-specific is better for selectivity)
-   - Essentiality (non-essential better for safety)
-
-### Red Flags:
-
-- **High essentiality + ubiquitous expression** - Poor therapeutic window
-- **Multiple safety liabilities** - Toxicity concerns
-- **High genetic constraint (pLI > 0.9)** - Critical gene, inhibition may be harmful
-- **No tractability precedence** - Higher risk, longer development
-- **Conflicting evidence** - Requires deeper investigation
-
-### Green Flags:
-
-- **Clinical precedence + related indication** - De-risked mechanism
-- **Tissue-specific expression** - Better selectivity
-- **Chemical probes available** - Faster validation
-- **Low essentiality + disease relevance** - Good therapeutic window
-- **Multiple evidence types converge** - Higher confidence