Review and classify events in pathophysiology section

[caufieldjh]

Discussed at Monarch Data Call on Feb 12 2026.

Many different types of events are currently included in pathophysiology sections, from initial infection events in pathogenic disease (e.g., Lyme Disease), to biochemical events (e.g., in Narcolepsy), physical obstructions and malformations (e.g., in Silent Sinus Syndrome), microbiome disruption (e.g., in Irritable Bowel Syndrome), and well beyond.

This suggests a need for more in-depth review and classification, both to define curation scope and to provide a more detailed picture of pathogenesis.

[github-actions]

Analysis: Pathophysiology Event Classification in Dismech

I've conducted a comprehensive analysis of pathophysiological events across the dismech knowledge base to understand the diversity of mechanisms and inform classification strategy.

Summary

The knowledge base captures 7 major categories of pathophysiological events, with ~60% of disorders demonstrating multi-category integration and ~40% having single-category mechanisms.

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Major Event Categories Identified

1. INFECTIOUS/PATHOGEN-MEDIATED EVENTS

Direct pathogenic disruption through microbial replication, toxin production, or parasitic damage.

Examples:

• Lyme Disease (kb/disorders/Lyme_Disease.yaml): Spirochete invasion and dissemination via Borrelia burgdorferi through Ixodes tick bites
• AIDS: CD4+ T cell depletion via HIV infection using CD4/CCR5/CXCR4 co-receptors
• Bacterial Meningitis: Invasive bacteria overcome blood-brain barrier, trigger inflammasome activation
• Botulism: Botulinum toxin blocks acetylcholine release at neuromuscular junctions
• Lymphatic Filariasis: Adult filariae physically block lymph vessels

2. BIOCHEMICAL/MOLECULAR EVENTS

Disruption of cellular signaling, enzyme activity, hormones, or metabolic processes.

Examples:

• Narcolepsy (kb/disorders/Narcolepsy.yaml): Orexin/hypocretin deficiency from >90% loss of hypocretin-secreting neurons in lateral hypothalamus
• Achondroplasia: FGFR3 G380R gain-of-function causing constitutive receptor activation → enhanced STAT1/MAPK signaling → premature chondrocyte cell cycle arrest
• Type 2 Diabetes: Multi-pathway including insulin resistance (fatty acid-induced IRS-1 impairment), hepatic glucose overproduction, beta cell mitochondrial dysfunction
• Essential Hypertension: RAAS overactivation leading to sodium retention and vasoconstriction

3. STRUCTURAL/ANATOMICAL EVENTS

Malformation, obstruction, degeneration, or abnormal tissue remodeling.

Examples:

• Silent Sinus Syndrome (kb/disorders/Silent_Sinus_Syndrome.yaml):
  • Ostiomeatal complex obstruction → gas resorption → negative intrasinus pressure
  • Maxillary sinus atelectasis → progressive wall collapse
  • Orbital floor resorption and descent → enophthalmos and hypoglobus
  • Perfect example of cascading structural events
• Asthma: Airway remodeling with goblet cell hyperplasia, basement membrane thickening, peri-bronchial fibrosis
• Primary Ciliary Dyskinesia: Ciliary structural defects (DNAH5/DNAI1) impairing mucociliary clearance
• Lymphatic Filariasis: Lymphatic valve damage and vessel dilation → lymphedema → elephantiasis

4. IMMUNOLOGICAL/INFLAMMATORY EVENTS

Dysregulated immune responses, autoimmune attack, or chronic inflammation.

Examples:

• Lyme Disease:
  • Autoimmune activation after persistent Borrelia exposure
  • Inflammatory response with IL-6, IL-8, TNF, chemokine production → tissue damage
  • Lyme arthritis shows neutrophilic inflammation even after spirochete clearance
• Narcolepsy: Autoimmune destruction of hypocretin neurons (HLA-DQB1*06:02 association, T-cell mediated, triggered by H1N1/Pandemrix)
• Ulcerative Colitis: Dysregulated Th2-skewed response, IL-13 driving epithelial dysfunction, NLRP3 inflammasome activation
• Multiple Sclerosis: Autoimmune demyelination destroying myelin sheaths
• Alopecia Areata: CD8+ T cells attack hair follicles after loss of immune privilege

5. MICROBIOME-RELATED EVENTS

Dysbiosis, loss of protective commensals, pathobiont expansion.

Examples:

• Irritable Bowel Syndrome (kb/disorders/Irritable_Bowel_Syndrome.yaml): Microbiome dysbiosis contributing to symptoms; post-infectious IBS following gastroenteritis
• Ulcerative Colitis:
  • Loss of microbial diversity (decreased Shannon/Chao1 indices)
  • Depletion of butyrate-producers (Faecalibacterium prausnitzii, Roseburia)
  • Pathobiont expansion (adherent-invasive E. coli, Fusobacterium nucleatum)
  • Decreased SCFA production
  • Demonstrates cascading dysbiotic events

6. GENETIC/GENOMIC EVENTS

Gene mutations causing loss-of-function, gain-of-function, or expression alterations.

Examples:

• Achondroplasia: >95% from c.1138G>A (p.Gly380Arg) FGFR3 mutation - remarkable genetic homogeneity
• Primary Ciliary Dyskinesia: Autosomal recessive DNAH5/DNAI1 mutations
• Asthma: Polygenic susceptibility (ADAM33, IL4, IL13, GSDMB, HLA-DQ, ORMDL3)

7. ENVIRONMENTAL EXPOSURES

External toxins, allergens, physical factors, or lifestyle triggers.

Examples:

• Lyme Disease: Tick exposure (Ixodes scapularis, I. ricinus), geographic location, seasonal exposure (May-August peak), outdoor activities
• Asthma: Allergen exposure, air pollution, tobacco smoke, occupational exposures, exercise
• Essential Hypertension: High-salt environment activating antigen-presenting cells
• IBS: Psychological stress, dietary triggers (FODMAPs), antibiotics, early life stress

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Complex Multi-Category Integrations

Several disorders demonstrate sophisticated multi-category mechanisms:

Irritable Bowel Syndrome (5 categories)

1. Visceral Hypersensitivity (Biochemical): TRPV1-immunoreactive fiber increase (3.5-fold), mast cell mediators excite nociceptive neurons
2. Gut Dysmotility (Biochemical): Dysregulated 5-HT signaling affecting peristalsis
3. Gut-Brain Axis Dysfunction (Neurological): Bidirectional communication disruption via autonomic/neuroendocrine pathways
4. Intestinal Barrier Dysfunction (Structural): Increased permeability in ~39% of IBS-D patients (lactulose/mannitol ratio)
5. Immune Activation (Immunological): Mast cell degranulation near enteric nerves, low-grade mucosal inflammation
6. Microbiome Dysbiosis (Microbiome): Post-infectious IBS, altered gut microbiota composition

Ulcerative Colitis (6 categories)

• Immunological, Microbiome, Structural, Biochemical - creates cascading amplification loop

Lyme Disease (4 categories)

• Infectious (spirochete invasion) → Immunological (autoimmune activation + inflammatory response) → Environmental (tick exposure) → Genetic susceptibility (HLA-DR4)

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Quantitative Analysis

Based on systematic review of disorder files:

• Total pathophysiological categories: 7 major types
• Single-category mechanisms: ~40% (e.g., Botulism [toxin], Achondroplasia [genetic])
• Multi-category integration: ~60% (e.g., Asthma, UC, IBS, T2DM, MS)
• Most represented category: Immunological/Inflammatory (~35% of disorders)
• Most complex integrations: Ulcerative Colitis, Type 2 Diabetes Mellitus, IBS (5-6 mechanisms each)

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Recommendations for Classification Strategy

Option 1: Hierarchical Classification

Add a mechanism_type field to Pathophysiology class with primary/secondary categories:

pathophysiology:
  - name: Spirochete Invasion and Dissemination
    mechanism_type: 
      primary: INFECTIOUS
      secondary: [STRUCTURAL]

Option 2: Multi-Label Tagging

Tag each pathophysiology entry with applicable mechanism types:

pathophysiology:
  - name: Visceral Hypersensitivity
    mechanism_tags: [BIOCHEMICAL, IMMUNOLOGICAL, NEUROLOGICAL]

Option 3: Mechanistic Process Ontology

Map to GO/pathway terms + create dismech-specific mechanism classification extending Gene Ontology biological processes (already partially captured via biological_processes field).

Option 4: Cascading Event Modeling

Explicitly model event sequences using enhanced downstream relationships:

pathophysiology:
  - name: Ostiomeatal Complex Obstruction
    mechanism_type: STRUCTURAL
    downstream:
      - target: Maxillary Sinus Atelectasis
        mechanism_type: STRUCTURAL
        downstream:
          - target: Orbital Floor Resorption
            mechanism_type: STRUCTURAL

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Scope Considerations

The diversity of event types raises important curation scope questions:

1. Initial triggers vs. downstream pathology: Should we capture environmental exposures (tick bites, allergens) as pathophysiology entries or keep them in environmental fields?

2. Molecular detail granularity: How deep into signaling cascades should we go? (e.g., FGFR3 → STAT1/MAPK → cell cycle arrest)

3. Cross-disorder mechanisms: Many mechanisms (e.g., inflammasome activation, barrier dysfunction) recur across disorders - should we develop standardized templates?

4. Evidence source stratification: Should mechanism type influence evidence requirements? (e.g., INFECTIOUS requires human clinical data, BIOCHEMICAL may rely more on IN_VITRO)

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Related Schema Elements

The current schema already has relevant fields that could support classification:

• biological_processes (GO terms)
• cell_types (CL terms)
• locations (UBERON terms)
• triggers (initiating factors)
• downstream (causal relationships)
• mechanisms (nested sub-mechanisms)

Classification could build on these existing structures rather than creating parallel taxonomy.

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Next Steps

1. Community discussion: Which classification approach best serves curation and computational use cases?
2. Pilot implementation: Test chosen approach on 10-15 representative disorders
3. Schema updates: Extend Pathophysiology class with classification fields
4. Curation guidelines: Document how to assign mechanism types during curation
5. Validation: Ensure classification supports downstream queries (e.g., "find all disorders with autoimmune mechanisms")

The examples from Lyme Disease, Narcolepsy, Silent Sinus Syndrome, and Irritable Bowel Syndrome demonstrate the rich diversity already captured - a well-designed classification system will make this knowledge more discoverable and analyzable.

[caufieldjh]

Another note: some events currently included in pathophysiology sections are more like phenotypes.
We may need to update the documentation and curation instructions to make this distinction more clear.