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Literature Deep Research - Quick Reference

Enhanced strategy with target disambiguation, evidence grading, and mandatory completeness.

Workflow Summary

1. CLARIFY → Target type? Scope? Aliases? Methods appendix needed?
2. DISAMBIGUATE → Resolve IDs, find collisions, gather baseline profile
3. SEARCH → High-precision seeds → Citation expansion → Collision-filtered broad
4. GRADE → Apply evidence tiers (T1-T4) to all claims
5. REPORT → Mandatory sections, biological model, testable hypotheses

Phase 1: Target Disambiguation (Default ON)

Tools to Use

Data Type Primary Tool Fallback
UniProt ID UniProt_search proteins_api_get_protein
Ensembl ID UniProt_id_mapping ensembl_lookup_gene
Domains InterPro_get_protein_domains UniProt features
Expression GTEx_get_median_gene_expression HPA_get_rna_expression_by_source
GO Terms GO_get_annotations_for_gene OpenTargets_get_target_gene_ontology_by_ensemblID
Pathways Reactome_map_uniprot_to_pathways kegg_get_gene_info
Location HPA_get_subcellular_location UniProt localization

Collision Detection

1. Search: "[SYMBOL]"[Title] in PubMed (first 20 results)
2. If >20% off-topic → identify collision terms
3. Build filter: NOT [collision1] NOT [collision2]

Phase 2: Query Strategy

Step 1: High-Precision Seeds

"[GENE_SYMBOL]"[Title] AND (mechanism OR function OR structure)
"[FULL_PROTEIN_NAME]"[Title]

Step 2: Citation Expansion (especially for sparse targets)

PubMed_get_cited_by(pmid) → Forward citations
EuropePMC_get_citations(pmid) → Fallback for forward
PubMed_get_related(pmid) → Related papers
EuropePMC_get_references(pmid) → Backward citations

Step 3: Collision-Filtered Broad

"[GENE]" AND ([pathway] OR [function]) NOT [collision_term]

Evidence Grading (Apply to ALL Claims)

Tier Label Criteria
T1 ★★★ Mechanistic Direct experimental evidence on target
T2 ★★☆ Functional Knockdown/overexpression phenotype
T3 ★☆☆ Association Screen hit, GWAS, correlation
T4 ☆☆☆ Mention Review, text-mining, peripheral

In report:

Target X regulates pathway Y [★★★: PMID:12345678] through direct 
phosphorylation [★★☆: PMID:23456789].

Mandatory Report Sections (ALL Required)

# Section Must Include
1 Identity/Aliases IDs, synonyms, collisions
2 Protein Architecture Domains, isoforms, sites
3 Complexes/Partners Interactors with evidence
4 Subcellular Localization Locations with confidence
5 Expression Top tissues, specificity
6 Core Mechanisms Function with evidence grades
7 Model Organism Evidence KO phenotypes or "none found"
8 Human Genetics/Variants Constraints, ClinVar, GWAS
9 Disease Links With evidence strength
10 Pathogens Or "none identified"
11 Key Assays/Readouts Biochemical, cellular, in vivo
12 Research Themes ≥3 papers/theme or "limited"
13 Open Questions/Gaps What's unknown
14 Biological Model + 3-5 testable hypotheses
15 Conclusions Confidence assessment

Theme Extraction

Papers Status
≥10 Major theme (full section)
3-9 Minor theme (subsection)
<3 Note as "limited evidence"

Standard themes (adapt to target):

  • Core function / Mechanism
  • Disease relevance
  • Signaling / Pathways
  • Trafficking / Localization
  • Genetics / Variants
  • Infection / Immunity
  • Methodology / Tools

Output Files

  1. [topic]_report.md - Main narrative (DEFAULT)
  2. [topic]_bibliography.json - Full deduplicated papers (ALWAYS)
  3. methods_appendix.md - Methodology (ONLY if requested)

Tool Failure Handling

Attempt 1 → fails → wait 2s → Attempt 2 → fails → wait 5s → Fallback tool
Primary Fallback
PubMed_get_cited_by EuropePMC_get_citations
PubMed_get_related SemanticScholar_search_papers
GTEx_* HPA_*
Unpaywall_check_oa_status Europe PMC/OpenAlex OA flags

OA Handling

With Unpaywall email: Full OA check for all DOIs Without: Best-effort using:

  • Europe PMC isOpenAccess field
  • PMC papers (all OA)
  • OpenAlex is_oa field

Label: *OA Status: Best-effort*

Completeness Checklist

Before delivery, verify ALL:

Identity

  • UniProt, Ensembl, NCBI, ChEMBL IDs
  • All synonyms documented
  • Collisions handled

Biology

  • Domains + architecture
  • Localization
  • Expression profile
  • GO terms + pathways
  • Interactors

Mechanism

  • Core function (with evidence grades)
  • Model organism data (or "none")
  • Assays described

Disease

  • Constraint scores + interpretation
  • Variants (ClinVar, gnomAD)
  • Disease links (graded by evidence)
  • Pathogens (or "none")

Synthesis

  • Themes with ≥3 papers each
  • Open questions listed
  • Biological model written
  • ≥3 testable hypotheses
  • Conclusions + confidence

Technical

  • All claims have sources
  • Evidence grades applied
  • Bibliography file created
  • Limitations noted

DO vs DON'T

DO DON'T
Resolve IDs first Jump straight to literature
Grade all evidence Treat all papers equally
State "limited evidence" Leave sections blank
Generate hypotheses Stop at description
Keep methodology internal Show search process
Use fallback tools Give up on first failure
Check for collisions Assume gene name is unambiguous

Communication Style

Brief progress updates:

  • "Resolving target identifiers..."
  • "Building core paper set..."
  • "Grading evidence and clustering themes..."

Never expose:

  • Raw tool outputs
  • Deduplication stats
  • Round-by-round search details
  • Database failure logs

Report = Deliverable (not search log)