Precision Medicine Patient Stratification

Transform patient genomic and clinical profiles into actionable risk stratification, treatment recommendations, and personalized therapeutic strategies.

Reasoning Before Searching

Stratification means splitting patients into groups that respond differently to a treatment or have different prognoses. Ask these questions before running any tools:

1. What molecular feature predicts response? Candidates: somatic mutation (e.g., EGFR L858R), germline variant (e.g., BRCA1 LoF), expression level (e.g., HER2 overexpression), germline pharmacogenomic variant (e.g., CYP2C19 PM), or composite biomarker (e.g., TMB-H + MSI-H).
2. Is the predictive feature actionable? Knowing it must change treatment — either the drug choice, dose, or monitoring plan. A variant with prognostic value but no therapeutic consequence is not a stratification biomarker.
3. What is the evidence level for the stratifier? FDA-approved companion diagnostic (T1) vs. exploratory (T4) changes how much weight to place on the finding.

Route to the correct Phase 3 path BEFORE running Phase 2 tools — cancer, metabolic, CVD, rare disease, and autoimmune pipelines require different stratifiers.

LOOK UP DON'T GUESS: Never assume a variant is pathogenic, never assume a gene is relevant to a disease, never assign metabolizer status without PharmGKB or CPIC evidence.

KEY PRINCIPLES:

1. Report-first - Create report file FIRST, then populate progressively
2. Disease-specific logic - Cancer vs metabolic vs rare disease pipelines diverge at Phase 3
3. Multi-level integration - Germline + somatic + expression + clinical data layers
4. Evidence-graded - Every finding has an evidence tier (T1-T4)
5. Quantitative output - Precision Medicine Risk Score (0-100)
6. Source-referenced - Every statement cites the tool/database source
7. English-first queries - Always use English terms in tool calls

Reference files (same directory):

• TOOLS_REFERENCE.md - Tool parameters, response formats, phase-by-phase tool lists
• SCORING_REFERENCE.md - Scoring matrices, risk tiers, pathogenicity tables, PGx tables
• REPORT_TEMPLATE.md - Output report template, treatment algorithms, completeness requirements
• EXAMPLES.md - Six worked examples (cancer, metabolic, NSCLC, CVD, rare, neuro)
• QUICK_START.md - Sample prompts and output summary

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COMPUTE, DON'T DESCRIBE

When analysis requires computation (statistics, data processing, scoring, enrichment), write and run Python code via Bash. Don't describe what you would do — execute it and report actual results. Use ToolUniverse tools to retrieve data, then Python (pandas, scipy, statsmodels, matplotlib) to analyze it.

When to Use

Apply when user asks about patient risk stratification, treatment selection, prognosis prediction, or personalized therapeutic strategy for any disease with genomic/clinical data.

NOT for (use other skills instead):

• Single variant interpretation -> tooluniverse-variant-interpretation
• Immunotherapy-specific prediction -> tooluniverse-immunotherapy-response-prediction
• Drug safety profiling only -> tooluniverse-adverse-event-detection
• Target validation -> tooluniverse-drug-target-validation
• Clinical trial search only -> tooluniverse-clinical-trial-matching
• Drug-drug interaction only -> tooluniverse-drug-drug-interaction
• PRS calculation only -> tooluniverse-polygenic-risk-score

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Input Parsing

Required

• Disease/condition: Free-text disease name
• At least one of: Germline variants, somatic mutations, gene list, or clinical biomarkers

Optional (improves stratification)

• Age, sex, ethnicity, disease stage, comorbidities, prior treatments, family history
• Current medications (for DDI and PGx), stratification goal

Disease Type Classification

Classify into one category (determines Phase 3 routing):

Category	Examples
CANCER	Breast, lung, colorectal, melanoma
METABOLIC	Type 2 diabetes, obesity, NAFLD
CARDIOVASCULAR	CAD, heart failure, AF
NEUROLOGICAL	Alzheimer, Parkinson, epilepsy
RARE/MONOGENIC	Marfan, CF, sickle cell, Huntington
AUTOIMMUNE	RA, lupus, MS, Crohn's

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Critical Tool Parameter Notes

See TOOLS_REFERENCE.md for full details. Key gotchas:

• MyGene_query_genes: param is query (NOT q)
• EnsemblVEP_annotate_rsid: param is variant_id (NOT rsid)
• ensembl_lookup_gene: REQUIRES species='homo_sapiens'
• DrugBank tools: ALL require 4 params: query, case_sensitive, exact_match, limit
• cBioPortal_get_mutations: gene_list is a STRING (space-separated), not array
• PubMed_search_articles: Returns a plain list of dicts, NOT {articles: [...]}
• fda_pharmacogenomic_biomarkers: Use limit=1000 for all results
• gnomAD: May return "Service overloaded" - skip gracefully
• OpenTargets: Always nested {data: {entity: {field: ...}}} structure

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Workflow Overview

Phase 1: Disease Disambiguation & Profile Standardization
Phase 2: Genetic Risk Assessment
Phase 3: Disease-Specific Molecular Stratification (routes by disease type)
Phase 4: Pharmacogenomic Profiling
Phase 5: Comorbidity & Drug Interaction Risk
Phase 6: Molecular Pathway Analysis
Phase 7: Clinical Evidence & Guidelines
Phase 8: Clinical Trial Matching
Phase 9: Integrated Scoring & Recommendations

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Phase 1: Disease Disambiguation & Profile Standardization

1. Resolve disease to EFO ID using OpenTargets_get_disease_id_description_by_name
2. Classify disease type (CANCER/METABOLIC/CVD/NEUROLOGICAL/RARE/AUTOIMMUNE)
3. Parse genomic data into structured format (gene, variant, type)
4. Resolve gene IDs using MyGene_query_genes to get Ensembl/Entrez IDs

Phase 2: Genetic Risk Assessment

1. Germline variant pathogenicity: ClinVar_search_variants, EnsemblVEP_annotate_rsid/_hgvs
2. Gene-disease association: OpenTargets_target_disease_evidence
3. GWAS polygenic risk: gwas_get_associations_for_trait, OpenTargets_search_gwas_studies_by_disease
4. Population frequency: gnomad_get_variant
5. Gene constraint: gnomad_get_gene_constraints (pLI, LOEUF scores)

Scoring: See SCORING_REFERENCE.md for genetic risk score component (0-35 points).

Phase 3: Disease-Specific Molecular Stratification

CANCER PATH

1. Molecular subtyping: cBioPortal_get_mutations, HPA_get_cancer_prognostics_by_gene
2. TMB/MSI/HRD: fda_pharmacogenomic_biomarkers for FDA cutoffs
3. Prognostic stratification: Combine stage + molecular features

METABOLIC PATH

1. Genetic risk integration: GWAS_search_associations_by_gene, OpenTargets_target_disease_evidence
2. Complication risk: Based on HbA1c, duration, existing complications

CVD PATH

1. FH gene check: ClinVar_search_variants for LDLR, APOB, PCSK9
2. Statin PGx: PharmGKB_get_clinical_annotations for SLCO1B1

RARE DISEASE PATH

1. Causal variant identification: ClinVar_search_variants
2. Genotype-phenotype: UniProt_get_disease_variants_by_accession

Scoring: See SCORING_REFERENCE.md for disease-specific tables.

Phase 4: Pharmacogenomic Profiling

1. Drug-metabolizing enzymes: PharmGKB_get_clinical_annotations, PharmGKB_get_dosing_guidelines
2. FDA PGx biomarkers: fda_pharmacogenomic_biomarkers (use limit=1000)
3. Treatment-specific PGx: PharmGKB_get_drug_details

Scoring: See SCORING_REFERENCE.md for PGx risk score (0-10 points).

Phase 5: Comorbidity & Drug Interaction Risk

1. Disease overlap: OpenTargets_get_associated_targets_by_disease_efoId
2. DDI check: drugbank_get_drug_interactions_by_drug_name_or_id, FDA_get_drug_interactions_by_drug_name
3. PGx-amplified DDI: If PM genotype + CYP inhibitor, flag compounded risk

Phase 6: Molecular Pathway Analysis

1. Pathway enrichment: enrichr_gene_enrichment_analysis (libs: KEGG_2021_Human, Reactome_2022, GO_Biological_Process_2023)
2. Reactome mapping: ReactomeAnalysis_pathway_enrichment, Reactome_map_uniprot_to_pathways
3. Network analysis: STRING_get_interaction_partners, STRING_functional_enrichment
4. Druggable targets: OpenTargets_get_target_tractability_by_ensemblID

Phase 7: Clinical Evidence & Guidelines

1. Guidelines search: PubMed_Guidelines_Search (fallback: PubMed_search_articles)
2. FDA-approved therapies: OpenTargets_get_associated_drugs_by_disease_efoId, FDA_get_indications_by_drug_name
3. Biomarker-drug evidence: civic_search_evidence_items, civic_search_assertions

Phase 8: Clinical Trial Matching

1. Biomarker-driven trials: search_clinical_trials with condition + intervention
2. Precision medicine trials: search_clinical_trials for basket/umbrella trials

Phase 9: Integrated Scoring & Recommendations

Score Components (total 0-100)

• Genetic Risk (0-35): Pathogenicity + gene-disease association + PRS
• Clinical Risk (0-30): Stage/biomarkers/comorbidities
• Molecular Features (0-25): Driver mutations, subtypes, actionable targets
• Pharmacogenomic Risk (0-10): Metabolizer status, HLA alleles

Risk Tiers

Score	Tier	Management
75-100	VERY HIGH	Intensive treatment, subspecialty referral, clinical trial
50-74	HIGH	Aggressive treatment, close monitoring
25-49	INTERMEDIATE	Standard guideline-based care, PGx-guided dosing
0-24	LOW	Surveillance, prevention, risk factor modification

Output

Generate report per REPORT_TEMPLATE.md. See SCORING_REFERENCE.md for detailed scoring matrices.

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Common Use Patterns

See EXAMPLES.md for six detailed worked examples:

1. Cancer + actionable mutation: Breast cancer, BRCA1, ER+/HER2- -> Score ~55-65 (HIGH)
2. Metabolic + PGx concern: T2D, CYP2C19 PM on clopidogrel -> Score ~55-65 (HIGH)
3. NSCLC comprehensive: EGFR L858R, TMB 25, PD-L1 80% -> Score ~75-85 (VERY HIGH)
4. CVD risk: LDL 190, SLCO1B1*5, family hx MI -> Score ~50-60 (HIGH)
5. Rare disease: Marfan, FBN1 variant -> Score ~55-65 (HIGH)
6. Neurological risk: APOE e4/e4, family hx Alzheimer's -> Score ~60-72 (HIGH)