Olamide Isreal
9e6a16c19b
Large reference/model files excluded from repo - to be staged to S3 or baked into Docker images.
210 lines
8.1 KiB
Markdown
210 lines
8.1 KiB
Markdown
# Digital Patient and Drug Response Pipeline - Comprehensive Implementation Plan
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## Pipeline Overview
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```mermaid
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flowchart TB
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subgraph Patient["Patient Profile Generation"]
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A1[1. Medical Records Creation] --> A2[2. Disease-specific Genome]
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A2 --> A3[3. Disease-specific Protein Variants]
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A3 --> A4[4. Disease-specific Transcriptome]
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A4 --> A5[5. Disease-specific Proteome]
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A5 --> A6[6. Disease-specific Metabolome]
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A6 --> A7[7. Disease-specific Immunome]
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end
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subgraph Drug["Drug Analysis & Modeling"]
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B1[8. Drug-Target PK] --> B1a[8a. Binding Site Prediction]
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B1a --> B1b[8b. Drug-Target Docking]
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B1b --> B2[9. Drug-Proteome Screening]
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B2 --> B3[10. Off-target Analysis]
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B3 --> B4[11. Drug-Compound Screening]
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B4 --> B5[12. Drug-Genome Sensitivity]
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end
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subgraph Response["Response Prediction"]
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C1[13. Transcriptomic Changes] --> C2[14. Disease Stage Evaluation]
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C2 --> C3[15-16. Proteomic & Metabolomic Changes]
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C3 --> C4[17-19. Biological & Immune Response]
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C4 --> C5[20-21. ADMET & Toxicity]
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end
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Patient --> Drug
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Drug --> Response
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```
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## Part 1: Digital Patient Generation
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### Implementation Status Overview
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| Step | Status | Tool/Method | Input | Output | Location | Validation Data | Dependencies/Notes |
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|------|--------|-------------|--------|---------|-----------|-----------------|-------------------|
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| 1. Medical Records | ✓ | Synthea | - | Demographics, records | /Workspace/next/registry/tools/synthea | Target: 1000 patients/disease | - |
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| 2. Disease Genome | ✓ | Omic-UKBB | Alleles, positions, frequencies | VCF (hg38) | Part of Synthea repo | - | Only storing variants |
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| 3. Protein Variants | ✓ | vcf2prot | VCF | Protein fasta | Part of Synthea repo (tbc) | - | Multi-tissue support needed |
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| 4. Transcriptome | 🚧 | borzoi | Genomic sequences | RNAseq (TPM) | - | ENCODE, GTEx (E-MTAB-6814) | NIH ENCODE standards |
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| 5. Proteome | 🚧 | clei2block | RNAseq (log2-FC) | Fold-change | github.com/stasaki/clei2block | CellModelPassport, TCGA | Requires GTEx training |
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| 6. Metabolome | ⏳ | corto | RNAseq (TPM) | Metabolite profiles | github.com/federicogiorgi/corto | CCLE, NCI-60 | - |
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| 7. Immunome | ⏳ | Ecotyper | RNAseq | Cell type profiles | - | SPICA30, SPICA17 | - |
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### Active Implementation Tasks
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#### Transcriptome Generation
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Current goal: Establish accurate transcriptome prediction pipeline
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- [x] Implement and evaluate primary models:
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* ~~enformer~~
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* ~~basenji~~
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* borzoi ~~for RNAseq profiles~~, built on basenji and enformer
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- [x] Add SequenceModelBenchmark ridge regression - built into borzoi (tbc)
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- [ ] Validate against ENCODE standards
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- [ ] Implement GTEx validation pipeline
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#### Multi-omic Integration
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Current goal: Create robust data transformation pipeline
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- [ ] Proteome prediction (clei2block):
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* Implement GTEx training pipeline
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* Add multi-tissue support
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* Create validation framework against CellModelPassport
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- [ ] Metabolome generation (corto):
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* Setup CCLE data integration
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* Implement NCI-60 validation
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- [ ] Immunome profiling:
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* ~~Evaluate Ecotyper vs CIBERTSORTx~~ CIBERTSORTx incorporated within Ecotyper
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* Integrate SPICA datasets
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* Setup immune cell validation pipeline
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## Part 2: Drug Discovery and Response
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### Drug Development Tools
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Current goal: Establish comprehensive drug analysis pipeline
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- [ ] Molecule Processing:
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* SELFIES library for biologics/peptides conversion
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* Implement molecule validation checks
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* Setup standardization pipeline
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- [ ] Structure Analysis:
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* DreamDock + ConPlex score pipeline
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* LightDock for membrane binding
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* Validation framework with crystal structures
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### Binding Site Prediction
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Current goal: Create consensus model for binding site prediction
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- [ ] Benchmark tools:
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* DiffDock implementation and testing
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* Qvina2 evaluation
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* P2Rank integration
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* FPocket analysis
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- [ ] Specific considerations:
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* Allosteric site detection
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* Multiple binding site handling
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* Protein flexibility modeling
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- [ ] Validation:
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* BindingDB integration
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* Crystal structure comparison pipeline
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* Edge case testing suite
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### Drug-Target Analysis
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Current goal: Robust docking and interaction prediction
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- [ ] Primary docking pipeline:
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* Uni-mol integration
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* DreamDock implementation
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* Path4Drug integration for pathways
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- [ ] Molecule type-specific handling:
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* Small molecule pipeline
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* Biologics pathway
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* PROTACs specific analysis
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* Prodrug processing
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- [ ] Interaction analysis:
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* Agonist vs antagonist classification
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* Protein-protein interaction integration
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* Chemical_checker for bioactivity signatures
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### Chemical Property Prediction
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Current goal: Comprehensive property prediction system
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- [ ] Model implementation:
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* Chemprop evaluation
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* Soltrannet integration
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* Custom ADMET model development
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- [ ] Property coverage:
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* Solubility prediction
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* BBB penetration
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* Chemical stability
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* Metabolic processing
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### Toxicity Prediction Pipeline
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Current goal: Multi-faceted toxicity assessment system
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- [ ] Core modules:
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* Cardiotoxicity (ion channel) prediction
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* Hepatotoxicity (Phase 1/2 proteins)
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* Nephrotoxicity assessment
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* Lung toxicity prediction
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* Neurotoxicity (BBB criteria)
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* Inflammatory response modeling
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* Bleeding/clotting risk analysis
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- [ ] Integration components:
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* Human Protein Atlas tissue proportion estimation
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* Reactome pathway analysis
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* Industry model benchmarking
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### Drug Response Analysis
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Current goal: Integrated response prediction system
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- [ ] Transcriptomic response:
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* LINCS data integration
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* Expression change prediction
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* Tissue-specific effects
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- [ ] Multi-omic response:
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* Proteomic change modeling
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* Metabolomic adjustment prediction
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* Immune response profiling
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- [ ] Special cases:
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* Multi-drug combinations
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* Time-dependent effects
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* Population-specific responses
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## Critical Dependencies & Requirements
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| Category | Component | Status | Notes |
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|----------|-----------|---------|--------|
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| **External Data** | BindingDB | ✓ Available | Binding affinities |
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| | LINCS | ✓ Available | Compound effects |
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| | PharmGKB | ⏳ Pending | Variant annotations |
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| | Human Cell Atlas | ⏳ Pending | Tissue-specific data |
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| **Compute** | GPU Cluster | 🚧 Scaling | For enformer/basenji |
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| | Storage | ✓ Configured | For variant data |
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| | Distribution | ⏳ Planned | For processing |
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## Validation Framework
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| Dataset | Usage | Status | Notes |
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|---------|--------|---------|--------|
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| ENCODE | Transcriptomics | ✓ Ready | Primary validation |
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| GTEx | Tissue-specific | ✓ Ready | E-MTAB-6814 |
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| CCLE/GDSC2 | Cell lines | 🚧 In Progress | Cancer validation |
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| TDC | ADMET | ⏳ Planned | Benchmark data |
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| Cross-species | Conservation | ⏳ Planned | Evolutionary validation |
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| Time-series | Metabolics | ⏳ Planned | Kinetic validation |
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## Edge Cases & Special Considerations
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### Complex Scenarios
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| Scenario | Implementation Status | Handling Strategy |
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|----------|---------------------|-------------------|
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| Rare variants | 🚧 In Progress | Population frequency weighting |
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| Multi-drug combinations | ⏳ Planned | Interaction matrix modeling |
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| Time-dependent effects | ⏳ Planned | PK/PD time series modeling |
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| Population specificity | 🚧 In Progress | Demographic stratification |
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### Special Drug Classes
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| Class | Special Requirements | Status |
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|-------|---------------------|---------|
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| Biologics | Membrane modeling, immunogenicity | ⏳ Planned |
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| Prodrugs | Metabolite prediction, activation | 🚧 In Progress |
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| Combination therapy | Interaction prediction, timing | ⏳ Planned |
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| PROTACs | Protein degradation modeling | ⏳ Planned |
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## Case Studies & Validation Examples
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| Drug | Outcome | Learning Points | Implementation Status |
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|------|---------|----------------|----------------------|
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| Amcenestrant | Efficacy failure | Target validation importance | ✓ Integrated |
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| Flupirtine | Liver toxicity | Metabolite prediction crucial | 🚧 In Progress |
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| Ranitidine | NDMA formation | Chemical stability prediction | ⏳ Planned |
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| Multi-drug Examples | Variable | Interaction modeling needed | ⏳ Planned | |