@synsci/cli-darwin-x64-baseline 1.1.76 → 1.1.78

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

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+# Open Targets Platform API Reference
+
+## API Endpoint
+
+```
+https://api.platform.opentargets.org/api/v4/graphql
+```
+
+Interactive GraphQL playground with documentation:
+```
+https://api.platform.opentargets.org/api/v4/graphql/browser
+```
+
+## Access Methods
+
+The Open Targets Platform provides multiple access methods:
+
+1. **GraphQL API** - Best for single entity queries and flexible data retrieval
+2. **Web Interface** - Interactive platform at https://platform.opentargets.org
+3. **Data Downloads** - FTP at https://ftp.ebi.ac.uk/pub/databases/opentargets/platform/
+4. **Google BigQuery** - For large-scale systematic queries
+
+## Authentication
+
+No authentication is required for the GraphQL API. All data is freely accessible.
+
+## Rate Limits
+
+For systematic queries involving multiple targets or diseases, use dataset downloads or BigQuery instead of repeated API calls. The API is optimized for single-entity and exploratory queries.
+
+## GraphQL Query Structure
+
+GraphQL queries consist of:
+1. Query operation with optional variables
+2. Field selection (request only needed fields)
+3. Nested entity traversal
+
+### Basic Python Example
+
+```python
+import requests
+import json
+
+# Define the query
+query_string = """
+  query target($ensemblId: String!){
+    target(ensemblId: $ensemblId){
+      id
+      approvedSymbol
+      biotype
+      geneticConstraint {
+        constraintType
+        exp
+        obs
+        score
+      }
+    }
+  }
+"""
+
+# Define variables
+variables = {"ensemblId": "ENSG00000169083"}
+
+# Make the request
+base_url = "https://api.platform.opentargets.org/api/v4/graphql"
+response = requests.post(base_url, json={"query": query_string, "variables": variables})
+data = json.loads(response.text)
+print(data)
+```
+
+## Available Query Endpoints
+
+### /target
+Retrieve gene annotations, tractability assessments, and disease associations.
+
+**Common fields:**
+- `id` - Ensembl gene ID
+- `approvedSymbol` - HGNC gene symbol
+- `approvedName` - Full gene name
+- `biotype` - Gene type (protein_coding, etc.)
+- `tractability` - Druggability assessment
+- `safetyLiabilities` - Safety information
+- `expressions` - Baseline expression data
+- `knownDrugs` - Approved/clinical drugs
+- `associatedDiseases` - Disease associations with evidence
+
+### /disease
+Retrieve disease/phenotype data, known drugs, and clinical information.
+
+**Common fields:**
+- `id` - EFO disease identifier
+- `name` - Disease name
+- `description` - Disease description
+- `therapeuticAreas` - High-level disease categories
+- `synonyms` - Alternative names
+- `knownDrugs` - Drugs indicated for disease
+- `associatedTargets` - Target associations with evidence
+
+### /drug
+Retrieve compound details, mechanisms of action, and pharmacovigilance data.
+
+**Common fields:**
+- `id` - ChEMBL identifier
+- `name` - Drug name
+- `drugType` - Small molecule, antibody, etc.
+- `maximumClinicalTrialPhase` - Development stage
+- `indications` - Disease indications
+- `mechanismsOfAction` - Target mechanisms
+- `adverseEvents` - Pharmacovigilance data
+
+### /search
+Search across all entities (targets, diseases, drugs).
+
+**Parameters:**
+- `queryString` - Search term
+- `entityNames` - Filter by entity type(s)
+- `page` - Pagination
+
+### /associationDiseaseIndirect
+Retrieve target-disease associations including indirect evidence from disease descendants in ontology.
+
+**Key fields:**
+- `rows` - Association records with scores
+- `aggregations` - Aggregated statistics
+
+## Example Queries
+
+### Query 1: Get target information with disease associations
+
+```python
+query = """
+  query targetInfo($ensemblId: String!) {
+    target(ensemblId: $ensemblId) {
+      approvedSymbol
+      approvedName
+      tractability {
+        label
+        modality
+        value
+      }
+      associatedDiseases(page: {size: 10}) {
+        rows {
+          disease {
+            name
+          }
+          score
+          datatypeScores {
+            componentId
+            score
+          }
+        }
+      }
+    }
+  }
+"""
+variables = {"ensemblId": "ENSG00000157764"}
+```
+
+### Query 2: Search for diseases
+
+```python
+query = """
+  query searchDiseases($queryString: String!) {
+    search(queryString: $queryString, entityNames: ["disease"]) {
+      hits {
+        id
+        entity
+        name
+        description
+      }
+    }
+  }
+"""
+variables = {"queryString": "alzheimer"}
+```
+
+### Query 3: Get evidence for target-disease pair
+
+```python
+query = """
+  query evidences($ensemblId: String!, $efoId: String!) {
+    disease(efoId: $efoId) {
+      evidences(ensemblIds: [$ensemblId], size: 100) {
+        rows {
+          datasourceId
+          datatypeId
+          score
+          studyId
+          literature
+        }
+      }
+    }
+  }
+"""
+variables = {"ensemblId": "ENSG00000157764", "efoId": "EFO_0000249"}
+```
+
+### Query 4: Get known drugs for a disease
+
+```python
+query = """
+  query knownDrugs($efoId: String!) {
+    disease(efoId: $efoId) {
+      knownDrugs {
+        uniqueDrugs
+        rows {
+          drug {
+            name
+            id
+          }
+          targets {
+            approvedSymbol
+          }
+          phase
+          status
+        }
+      }
+    }
+  }
+"""
+variables = {"efoId": "EFO_0000249"}
+```
+
+## Error Handling
+
+GraphQL returns status code 200 even for errors. Check the response structure:
+
+```python
+if 'errors' in response_data:
+    print(f"GraphQL errors: {response_data['errors']}")
+else:
+    print(f"Data: {response_data['data']}")
+```
+
+## Best Practices
+
+1. **Request only needed fields** - Minimize data transfer and improve response time
+2. **Use variables** - Make queries reusable and safer
+3. **Handle pagination** - Most list fields support pagination with `page: {size: N, index: M}`
+4. **Explore the schema** - Use the GraphQL browser to discover available fields
+5. **Batch related queries** - Combine multiple entity fetches in a single query when possible
+6. **Cache results** - Store frequently accessed data locally to reduce API calls
+7. **Use BigQuery for bulk** - Switch to BigQuery/downloads for systematic analyses
+
+## Data Licensing
+
+All Open Targets Platform data is freely available. When using the data in research or commercial products, cite the latest publication:
+
+Ochoa, D. et al. (2025) Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research, 53(D1):D1467-D1477.

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

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+# 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.