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

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

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+# 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