Initial commit

2025-11-30 08:30:14 +08:00
commit 1dd5bee3b4
335 changed files with 147360 additions and 0 deletions
--- a/skills/hypothesis-generation/references/literature_search_strategies.md
+++ b/skills/hypothesis-generation/references/literature_search_strategies.md
@@ -0,0 +1,535 @@
+# Literature Search Strategies
+
+## Effective Techniques for Finding Scientific Evidence
+
+Comprehensive literature search is essential for grounding hypotheses in existing evidence. This reference provides strategies for both PubMed (biomedical literature) and general scientific search.
+
+## Search Strategy Framework
+
+### Three-Phase Approach
+
+1. **Broad exploration:** Understand the landscape and identify key concepts
+2. **Focused searching:** Target specific mechanisms, theories, or findings
+3. **Citation mining:** Follow references and related articles from key papers
+
+### Before You Search
+
+**Clarify search goals:**
+- What aspects of the phenomenon need evidence?
+- What types of studies are most relevant (reviews, primary research, methods)?
+- What time frame is relevant (recent only, or historical context)?
+- What level of evidence is needed (mechanistic, correlational, causal)?
+
+## PubMed Search Strategies
+
+### When to Use PubMed
+
+Use WebFetch with PubMed URLs for:
+- Biomedical and life sciences research
+- Clinical studies and medical literature
+- Molecular, cellular, and physiological mechanisms
+- Disease etiology and pathology
+- Drug and therapeutic research
+
+### Effective PubMed Search Techniques
+
+#### 1. Start with Review Articles
+
+**Why:** Reviews synthesize literature, identify key concepts, and provide comprehensive reference lists.
+
+**Search strategy:**
+- Add "review" to search terms
+- Use PubMed filters: Article Type → Review, Systematic Review, Meta-Analysis
+- Look for recent reviews (last 2-5 years)
+
+**Example searches:**
+- `https://pubmed.ncbi.nlm.nih.gov/?term=wound+healing+diabetes+review`
+- `https://pubmed.ncbi.nlm.nih.gov/?term=gut+microbiome+cognition+systematic+review`
+
+#### 2. Use MeSH Terms (Medical Subject Headings)
+
+**Why:** MeSH terms are standardized vocabulary that captures concept variations.
+
+**Strategy:**
+- PubMed auto-suggests MeSH terms
+- Helps find papers using different terminology for same concept
+- More comprehensive than keyword-only searches
+
+**Example:**
+- Instead of just "heart attack," use MeSH term "Myocardial Infarction"
+- Captures papers using "MI," "heart attack," "cardiac infarction," etc.
+
+#### 3. Boolean Operators and Advanced Syntax
+
+**AND:** Narrow search (all terms must be present)
+- `diabetes AND wound healing AND inflammation`
+
+**OR:** Broaden search (any term can be present)
+- `(Alzheimer OR dementia) AND gut microbiome`
+
+**NOT:** Exclude terms
+- `cancer treatment NOT surgery`
+
+**Quotes:** Exact phrases
+- `"oxidative stress"`
+
+**Wildcards:** Variations
+- `gene*` finds gene, genes, genetic, genetics
+
+#### 4. Filter by Publication Type and Date
+
+**Publication types:**
+- Clinical Trial
+- Meta-Analysis
+- Systematic Review
+- Research Support, NIH
+- Randomized Controlled Trial
+
+**Date filters:**
+- Recent work (last 2-5 years): Cutting-edge findings
+- Historical work: Foundational studies
+- Specific time periods: Track development of understanding
+
+#### 5. Use "Similar Articles" and "Cited By"
+
+**Strategy:**
+- Find one highly relevant paper
+- Click "Similar articles" for related work
+- Use cited by tools to find newer work building on it
+
+### PubMed Search Examples by Hypothesis Goal
+
+**Mechanistic understanding:**
+```
+https://pubmed.ncbi.nlm.nih.gov/?term=(mechanism+OR+pathway)+AND+[phenomenon]+AND+(molecular+OR+cellular)
+```
+
+**Causal relationships:**
+```
+https://pubmed.ncbi.nlm.nih.gov/?term=[exposure]+AND+[outcome]+AND+(randomized+controlled+trial+OR+cohort+study)
+```
+
+**Biomarkers and associations:**
+```
+https://pubmed.ncbi.nlm.nih.gov/?term=[biomarker]+AND+[disease]+AND+(association+OR+correlation+OR+prediction)
+```
+
+**Treatment effectiveness:**
+```
+https://pubmed.ncbi.nlm.nih.gov/?term=[intervention]+AND+[condition]+AND+(efficacy+OR+effectiveness+OR+clinical+trial)
+```
+
+## General Scientific Web Search Strategies
+
+### When to Use Web Search
+
+Use WebSearch for:
+- Non-biomedical sciences (physics, chemistry, materials, earth sciences)
+- Interdisciplinary topics
+- Recent preprints and unpublished work
+- Grey literature (technical reports, conference proceedings)
+- Broader context and cross-domain analogies
+
+### Effective Web Search Techniques
+
+#### 1. Use Domain-Specific Search Terms
+
+**Include field-specific terminology:**
+- Chemistry: "mechanism," "reaction pathway," "synthesis"
+- Physics: "model," "theory," "experimental validation"
+- Materials science: "properties," "characterization," "synthesis"
+- Ecology: "population dynamics," "community structure"
+
+#### 2. Target Academic Sources
+
+**Search operators:**
+- `site:arxiv.org` - Preprints (physics, CS, math, quantitative biology)
+- `site:biorxiv.org` - Biology preprints
+- `site:edu` - Academic institutions
+- `filetype:pdf` - Academic papers (often)
+
+**Example searches:**
+- `superconductivity high temperature mechanism site:arxiv.org`
+- `CRISPR off-target effects site:biorxiv.org`
+
+#### 3. Search for Authors and Labs
+
+**When you find a relevant paper:**
+- Search for the authors' other work
+- Find their lab website for unpublished work
+- Identify key research groups in the field
+
+#### 4. Use Google Scholar Approaches
+
+**Strategies:**
+- Use "Cited by" to find newer related work
+- Use "Related articles" to expand search
+- Set date ranges to focus on recent work
+- Use author: operator to find specific researchers
+
+#### 5. Combine General and Specific Terms
+
+**Structure:**
+- Specific phenomenon + general concept
+- "tomato plant growth" + "bacterial promotion"
+- "cognitive decline" + "gut microbiome"
+
+**Boolean logic:**
+- Use quotes for exact phrases: `"spike protein mutation"`
+- Use OR for alternatives: `(transmissibility OR transmission rate)`
+- Combine: `"spike protein" AND (transmissibility OR virulence) AND mutation`
+
+## Cross-Database Search Strategies
+
+### Comprehensive Literature Search Workflow
+
+1. **Start with reviews (PubMed or Web Search):**
+   - Identify key concepts and terminology
+   - Note influential papers and researchers
+   - Understand current state of field
+
+2. **Focused primary research (PubMed):**
+   - Search for specific mechanisms
+   - Find experimental evidence
+   - Identify methodologies
+
+3. **Broaden with web search:**
+   - Find related work in other fields
+   - Locate recent preprints
+   - Identify analogous systems
+
+4. **Citation mining:**
+   - Follow references from key papers
+   - Use "cited by" to find recent work
+   - Track influential studies
+
+5. **Iterative refinement:**
+   - Add new terms discovered in papers
+   - Narrow if too many results
+   - Broaden if too few relevant results
+
+## Topic-Specific Search Strategies
+
+### Mechanisms and Pathways
+
+**Goal:** Understand how something works
+
+**Search components:**
+- Phenomenon + "mechanism"
+- Phenomenon + "pathway"
+- Phenomenon + specific molecules/pathways suspected
+
+**Examples:**
+- `diabetic wound healing mechanism inflammation`
+- `autophagy pathway cancer`
+
+### Associations and Correlations
+
+**Goal:** Find what factors are related
+
+**Search components:**
+- Variable A + Variable B + "association"
+- Variable A + Variable B + "correlation"
+- Variable A + "predicts" + Variable B
+
+**Examples:**
+- `vitamin D cardiovascular disease association`
+- `gut microbiome diversity predicts cognitive function`
+
+### Interventions and Treatments
+
+**Goal:** Evidence for what works
+
+**Search components:**
+- Intervention + condition + "efficacy"
+- Intervention + condition + "randomized controlled trial"
+- Intervention + condition + "treatment outcome"
+
+**Examples:**
+- `probiotic intervention depression randomized controlled trial`
+- `exercise intervention cognitive decline efficacy`
+
+### Methods and Techniques
+
+**Goal:** How to test hypothesis
+
+**Search components:**
+- Method name + application area
+- "How to measure" + phenomenon
+- Technique + validation
+
+**Examples:**
+- `CRISPR screen cancer drug resistance`
+- `measure protein-protein interaction methods`
+
+### Analogous Systems
+
+**Goal:** Find insights from related phenomena
+
+**Search components:**
+- Mechanism + different system
+- Similar phenomenon + different organism/condition
+
+**Examples:**
+- If studying plant-microbe symbiosis: search `nitrogen fixation rhizobia legumes`
+- If studying drug resistance: search `antibiotic resistance evolution mechanisms`
+
+## Evaluating Source Quality
+
+### Primary Research Quality Indicators
+
+**Strong quality signals:**
+- Published in reputable journals
+- Large sample sizes (for statistical power)
+- Pre-registered studies (reduces bias)
+- Appropriate controls and methods
+- Consistent with other findings
+- Transparent data and methods
+
+**Red flags:**
+- No peer review (use cautiously)
+- Conflicts of interest not disclosed
+- Methods not clearly described
+- Extraordinary claims without extraordinary evidence
+- Contradicts large body of evidence without explanation
+
+### Review Quality Indicators
+
+**Systematic reviews (highest quality):**
+- Pre-defined search strategy
+- Explicit inclusion/exclusion criteria
+- Quality assessment of included studies
+- Quantitative synthesis (meta-analysis)
+
+**Narrative reviews (variable quality):**
+- Expert synthesis of field
+- May have selection bias
+- Useful for context and framing
+- Check author expertise and citations
+
+## Time Management in Literature Search
+
+### Allocate Search Time Appropriately
+
+**For straightforward hypotheses (30-60 min):**
+- 1-2 broad review articles
+- 3-5 targeted primary research papers
+- Quick web search for recent developments
+
+**For complex hypotheses (1-3 hours):**
+- Multiple reviews for different aspects
+- 10-15 primary research papers
+- Systematic search across databases
+- Citation mining from key papers
+
+**For contentious topics (3+ hours):**
+- Systematic review approach
+- Identify competing perspectives
+- Track historical development
+- Cross-reference findings
+
+### Diminishing Returns
+
+**Signs you've searched enough:**
+- Finding the same papers repeatedly
+- New searches yield mostly irrelevant papers
+- Sufficient evidence to support/contextualize hypotheses
+- Multiple independent lines of evidence converge
+
+**When to search more:**
+- Major gaps in understanding remain
+- Conflicting evidence needs resolution
+- Hypothesis seems inconsistent with literature
+- Need specific methodological information
+
+## Documenting Search Results
+
+### Information to Capture
+
+**For each relevant paper:**
+- Full citation (authors, year, journal, title)
+- Key findings relevant to hypothesis
+- Study design and methods
+- Limitations noted by authors
+- How it relates to hypothesis
+
+### Organizing Findings
+
+**Group by:**
+- Supporting evidence for hypothesis A, B, C
+- Methodological approaches
+- Conflicting findings requiring explanation
+- Gaps in current knowledge
+
+**Synthesis notes:**
+- What is well-established?
+- What is controversial or uncertain?
+- What analogies exist in other systems?
+- What methods are commonly used?
+
+### Citation Organization for Hypothesis Reports
+
+**For report structure:** Organize citations for two audiences:
+
+**Main Text (15-20 key citations):**
+- Most influential papers (highly cited, seminal studies)
+- Recent definitive evidence (last 2-3 years)
+- Key papers directly supporting each hypothesis (3-5 per hypothesis)
+- Major reviews synthesizing the field
+
+**Appendix A: Comprehensive Literature Review (40-60+ citations):**
+- **Historical context:** Foundational papers establishing field
+- **Current understanding:** Recent reviews and meta-analyses
+- **Hypothesis-specific evidence:** 8-15 papers per hypothesis covering:
+  - Direct supporting evidence
+  - Analogous mechanisms in related systems
+  - Methodological precedents
+  - Theoretical framework papers
+- **Conflicting findings:** Papers representing different viewpoints
+- **Knowledge gaps:** Papers identifying limitations or unanswered questions
+
+**Target citation density:** Aim for 50+ total references to provide comprehensive support for all claims and demonstrate thorough literature grounding.
+
+**Grouping strategy for Appendix A:**
+1. Background and context papers
+2. Current understanding and established mechanisms
+3. Evidence supporting each hypothesis (separate subsections)
+4. Contradictory or alternative findings
+5. Methodological and technical papers
+
+## Practical Search Workflow
+
+### Step-by-Step Process
+
+1. **Define search goals (5 min):**
+   - What aspects of phenomenon need evidence?
+   - What would support or refute hypotheses?
+
+2. **Broad review search (15-20 min):**
+   - Find 1-3 review articles
+   - Skim abstracts for relevance
+   - Note key concepts and terminology
+
+3. **Targeted primary research (30-45 min):**
+   - Search for specific mechanisms/evidence
+   - Read abstracts, scan figures and conclusions
+   - Follow most promising references
+
+4. **Cross-domain search (15-30 min):**
+   - Look for analogies in other systems
+   - Find recent preprints
+   - Identify emerging trends
+
+5. **Citation mining (15-30 min):**
+   - Follow references from key papers
+   - Use "cited by" for recent work
+   - Identify seminal studies
+
+6. **Synthesize findings (20-30 min):**
+   - Summarize evidence for each hypothesis
+   - Note patterns and contradictions
+   - Identify knowledge gaps
+
+### Iteration and Refinement
+
+**When initial search is insufficient:**
+- Broaden terms if too few results
+- Add specific mechanisms/pathways if too many results
+- Try alternative terminology
+- Search for related phenomena
+- Consult review articles for better search terms
+
+**Red flags requiring more search:**
+- Only finding weak or indirect evidence
+- All evidence comes from single lab or source
+- Evidence seems inconsistent with basic principles
+- Major aspects of phenomenon lack any relevant literature
+
+## Common Search Pitfalls
+
+### Pitfalls to Avoid
+
+1. **Confirmation bias:** Only seeking evidence supporting preferred hypothesis
+   - **Solution:** Actively search for contradicting evidence
+
+2. **Recency bias:** Only considering recent work, missing foundational studies
+   - **Solution:** Include historical searches, track development of ideas
+
+3. **Too narrow:** Missing relevant work due to restrictive terms
+   - **Solution:** Use OR operators, try alternative terminology
+
+4. **Too broad:** Overwhelmed by irrelevant results
+   - **Solution:** Add specific terms, use filters, combine concepts with AND
+
+5. **Single database:** Missing important work in other fields
+   - **Solution:** Search both PubMed and general web, try domain-specific databases
+
+6. **Stopping too soon:** Insufficient evidence to ground hypotheses
+   - **Solution:** Set minimum targets (e.g., 2 reviews + 5 primary papers per hypothesis aspect)
+
+7. **Cherry-picking:** Citing only supportive papers
+   - **Solution:** Represent full spectrum of evidence, acknowledge contradictions
+
+## Special Cases
+
+### Emerging Topics (Limited Literature)
+
+**When little published work exists:**
+- Search for analogous phenomena in related systems
+- Look for preprints (arXiv, bioRxiv)
+- Find conference abstracts and posters
+- Identify theoretical frameworks that may apply
+- Note the limited evidence in hypothesis generation
+
+### Controversial Topics (Conflicting Literature)
+
+**When evidence is contradictory:**
+- Systematically document both sides
+- Look for methodological differences explaining conflict
+- Check for temporal trends (has understanding shifted?)
+- Identify what would resolve the controversy
+- Generate hypotheses explaining the discrepancy
+
+### Interdisciplinary Topics
+
+**When spanning multiple fields:**
+- Search each field's primary databases
+- Use field-specific terminology for each domain
+- Look for bridging papers that cite across fields
+- Consider consulting domain experts
+- Translate concepts between disciplines carefully
+
+## Integration with Hypothesis Generation
+
+### Using Literature to Inform Hypotheses
+
+**Direct applications:**
+- Established mechanisms to apply to new contexts
+- Known pathways relevant to phenomenon
+- Similar phenomena in related systems
+- Validated methods for testing
+
+**Indirect applications:**
+- Analogies from different systems
+- Theoretical frameworks to apply
+- Gaps suggesting novel mechanisms
+- Contradictions requiring resolution
+
+### Balancing Literature Dependence
+
+**Too literature-dependent:**
+- Hypotheses merely restate known mechanisms
+- No novel insights or predictions
+- "Hypotheses" are actually established facts
+
+**Too literature-independent:**
+- Hypotheses ignore relevant evidence
+- Propose implausible mechanisms
+- Reinvent already-tested ideas
+- Inconsistent with established principles
+
+**Optimal balance:**
+- Grounded in existing evidence
+- Extend understanding in novel ways
+- Acknowledge both supporting and challenging evidence
+- Generate testable predictions beyond current knowledge