Add curated Atopic Dermatitis and Beta Thalassemia disorder entries

[cmungall]

Summary

• Add new disorder entry kb/disorders/Atopic_Dermatitis.yaml with subtypes, mechanistic pathophysiology, phenotypes, genetics, environmental triggers, and treatments.
• Add new disorder entry kb/disorders/Beta_Thalassemia.yaml with subtype stratification, causal pathophysiology chain, phenotypes, biochemical and genetic sections, and treatment options.
• Repair curation quality issues during review:
  • Replace beta-thal carrier prevalence evidence with a citation that directly supports 1.5% global carrier prevalence.
  • Replace SCD-only HbF modifier evidence with beta-thalassemia-specific BCL11A/HbF evidence.
  • Remove non-variant mechanistic HAMP item from the genetic section.
  • Split bundled itch-scratch mechanism in atopic dermatitis into atomic pathophysiology nodes linked by downstream edges.
  • Remove dangling empty datasets key in beta thalassemia.

Validation

• just validate kb/disorders/Atopic_Dermatitis.yaml
• just validate kb/disorders/Beta_Thalassemia.yaml
• just validate-terms kb/disorders/Atopic_Dermatitis.yaml
• just validate-terms kb/disorders/Beta_Thalassemia.yaml
• just validate-references kb/disorders/Atopic_Dermatitis.yaml
• just validate-references kb/disorders/Beta_Thalassemia.yaml

Reference validation currently reports Total checks: 0 for these files in this environment.

[claude]

Claude finished @cmungall's task in 1m 41s —— View job

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PR Review: Atopic Dermatitis & Beta Thalassemia Curation

Tasks:

• Gather context and understand request
• Read both YAML files
• Review biological and clinical validity
• Check conformance with guidelines
• Assess completeness
• Post review feedback

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Both entries are scientifically solid and well-structured. The pathophysiology DAGs are coherent and mechanistically grounded, the evidence is cited with proper PMID anchors, and the schema is well-populated. Below are specific findings, from higher to lower priority.

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Atopic Dermatitis (kb/disorders/Atopic_Dermatitis.yaml)

Issues / Suggestions

1. Missing creation_date and updated_date (required per CLAUDE.md)
Neither field is present. Per the guidelines, these must be ISO 8601 UTC timestamps.
Fix this →

2. Phototherapy mapped to MAXO:0000014 (radiation therapy)
Phototherapy/narrowband UVB is not ionizing radiation — mapping it to radiation therapy (MAXO:0000014) is clinically and semantically incorrect. The correct MAXO term is MAXO:0000103 (phototherapy) if it exists, or this should be left without a MAXO term annotation rather than use a misleading one. Suggest checking:

uv run runoak -i sqlite:obo:maxo search "phototherapy"

Fix this →

3. Evidence quality: Scratching-Induced Barrier Injury and Secondary Inflammatory Amplification have no evidence
These two pathophysiology nodes lack any evidence items. They represent mechanistic claims (itch→scratch→barrier injury→inflammation) that, while clinically intuitive, should be backed by at least one PMID-cited study or explicitly noted in a notes field if evidence-free.

4. Th17/Th22 node has no evidence
Th17/Th22 Inflammation also lacks evidence. The role of Th17/Th22 in AD (especially acute lesions and Asian populations) is documented — a supporting citation would strengthen this node.
Fix this →

5. Snippet discrepancy in Epidermal Barrier Dysfunction evidence

• genetic section (line 249) quotes: "two independent loss-of-function genetic variants (R510X and 2282del4)"
• pathophysiology evidence (line 43) quotes: "two independent loss-of-function genetic variants (R510X and 2282del4)" — but the genetic section notes say "R501X and 2282del4" (line 245, notes field uses R501X, not R510X).

The PMID:16550169 abstract should be checked: Palmer et al. 2006 used R501X (not R510X). There appears to be a transposition error in the snippet at line 43 (R510X vs correct R501X). The genetic notes (line 245) correctly say R501X. The snippet should match the abstract exactly.
Fix this →

6. GO:0031424 label mismatch
keratinization is the preferred_term label used, but the GO term GO:0031424 label is actually keratinization. This appears correct. However, the GO term GO:0031424 is for the specific keratinization process — double-check with OAK whether this is the preferred canonical label.

7. Gene associations without evidence: IL4R, EMSY, BACH2, TNFAIP3, etc.
Several GWAS-level genetic entries have only notes and no evidence items. This is acceptable per the schema, but adding at least one GWAS PMID (e.g., the large Paternoster et al. or Hakon et al. AD GWAS) for one or two loci would increase curation quality. This is lower priority.

8. Missing evidence_source fields in Atopic Dermatitis evidence items
All AD evidence items omit evidence_source. While the schema may not require it, Beta Thalassemia consistently uses evidence_source: HUMAN_CLINICAL. For consistency, adding this field to AD evidence is recommended.

9. Emollients and Moisturizers and Topical Corticosteroids have no MAXO terms
Lower priority but these common treatments could be annotated. MAXO:0000950 (supportive care) or a more specific term for topical corticosteroid therapy would be worth adding.

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Beta Thalassemia (kb/disorders/Beta_Thalassemia.yaml)

Issues / Suggestions

1. Missing creation_date and updated_date (required per CLAUDE.md)
Same issue as Atopic Dermatitis — neither lifecycle timestamp is present.
Fix this →

2. GO:0006879 (intracellular iron ion homeostasis) under Iron Overload pathophysiology
Iron overload in beta-thalassemia is primarily systemic/extracellular (transfusion hemosiderosis, increased intestinal absorption via hepcidin suppression). The GO term intracellular iron ion homeostasis (GO:0006879) is narrower than the claimed mechanism. A more appropriate GO term might be iron ion homeostasis (GO:0055072) or cellular iron ion homeostasis (GO:0006879). Verify whether the intracellular frame is accurate here.

3. heme biosynthetic process (GO:0006783) under Fetal Hemoglobin Modulation
The modulation of HbF by BCL11A/KLF1/MYB is a transcriptional regulation event, not heme biosynthesis per se. A more precise GO term would be positive regulation of gamma-globin gene transcription or regulation of hemoglobin biosynthetic process (GO:0046984 — already included). The heme biosynthetic process term (GO:0006783) is a loose match and may be flagged by reviewers as misleading.
Fix this →

4. Iron Overload phenotype mapped to HP:0003281 (Increased circulating ferritin concentration)
This is a biomarker, not the full clinical phenotype of iron overload. The phenotype of iron overload itself is HP:0001511 or the broader HP:0003040 — or the specific organ complications (cardiomyopathy, liver fibrosis, endocrinopathy) which are already separately listed. The current mapping conflates a lab finding with the clinical syndrome. Consider either using HP:0001027 (Hemosiderosis) or splitting into biochemical findings and clinical sequelae. This is a genuine modeling concern.
Fix this →

5. Pulmonary Arterial Hypertension HP term: HP:0002092
HP:0002092 labels as Pulmonary arterial hypertension. However, pulmonary hypertension in thalassemia is often not strictly "arterial" — it can be precapillary or mixed etiology. Consider whether HP:0002092 is the most accurate, or if HP:0002090 (Pulmonary hypertension) is more appropriate given the heterogeneity. This is a minor precision point.

6. Regular Red Blood Cell Transfusions has no MAXO term
This is a key treatment without an ontology annotation. Suggest using MAXO:0000756 (blood transfusion) or searching MAXO for an RBC-specific term.
Fix this →

7. Snippet in PMID:21705976 (Iron Overload node, line 218)
The snippet contains "erythropoiesis,anemia" — there is a missing space after the comma. If this is an exact quote, it may be a formatting artifact in the original abstract. Verify that the abstract actually lacks the space, and if so, retain it; otherwise correct it.

8. Phenotype evidence coverage
Only Microcytic Hypochromic Anemia has a phenotype-level evidence item. Many other phenotypes (Splenomegaly, Frontal Bossing, Osteoporosis, etc.) are left without phenotype-level evidence. This is low priority for a first curation pass, but worth noting for future improvement.

9. Missing Hydroxyurea evidence
Hydroxyurea is listed without any evidence. A PMID supporting HU efficacy in beta-thalassemia intermedia (e.g., PMID:14522682 or equivalent) would improve this entry.

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Summary

Priority	File	Issue
High	Both	Missing creation_date / updated_date
High	AD	Phototherapy incorrectly mapped to radiation therapy (MAXO:0000014)
High	AD	Possible R501X vs R510X transposition in PMID:16550169 snippet
Medium	AD	Three pathophysiology nodes (Th17/Th22, Scratching-Induced Barrier Injury, Secondary Inflammatory Amplification) lack evidence
Medium	BT	heme biosynthetic process (GO:0006783) is a poor fit for HbF Modulation node
Medium	BT	Iron Overload phenotype (HP:0003281) maps a lab marker, not the clinical syndrome
Medium	BT	Blood transfusion treatment lacks MAXO term
Low	AD	Missing evidence_source fields throughout
Low	BT	PAH HP term precision (HP:0002092 vs HP:0002090)
Low	BT	Space missing in PMID:21705976 snippet
Low	Both	Several treatments and phenotypes lack evidence

Overall this is high-quality curation work. The DAG structure for the itch-scratch-injury cycle in AD is especially well-modeled following the PR's own repair work. The beta-thalassemia entry is comprehensive, with excellent coverage of the causal chain from HBB mutation through iron overload. Resolving the high-priority issues above (especially the phototherapy MAXO mapping and the date fields) would make these entries fully conformant.
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[Copilot]

Pull request overview

Adds two new curated disorder knowledge-base entries (Beta Thalassemia and Atopic Dermatitis) in the kb/disorders catalog, expanding mechanistic pathophysiology chains, phenotypes, genetics, environmental factors, and treatments.

Changes:

• Added a new Beta_Thalassemia.yaml disorder entry with subtype stratification, prevalence, mechanistic pathophysiology chain, phenotypes, genetics/modifiers, and treatments.
• Added a new Atopic_Dermatitis.yaml disorder entry with subtypes, barrier/immune/neuroimmune mechanisms, phenotypes, genetics, environmental triggers, and treatments.

Reviewed changes

Copilot reviewed 2 out of 2 changed files in this pull request and generated 3 comments.

File	Description
kb/disorders/Beta_Thalassemia.yaml	New Mendelian disorder entry with prevalence, mechanistic chain, phenotype set, and treatment options.
kb/disorders/Atopic_Dermatitis.yaml	New complex disorder entry emphasizing barrier dysfunction, type 2 inflammation, itch–scratch cycle, and clinical features.

[Copilot]

The PR description contains unrelated pasted NCBI datasets CLI help text and what looks like an API key value. Please remove that from the PR description before merge (and rotate/revoke the key if it’s real) to avoid accidental credential exposure in repo history.

[Copilot]

The PMID:16550169 snippet cites the common FLG loss-of-function variant as "R510X", but this appears to be a typo/inconsistency with the surrounding text (and the well-known variant) "R501X". Please correct the variant name in this snippet to avoid propagating an incorrect variant identifier.

Suggested change

	loss-of-function genetic variants (R510X and 2282del4) in the gene encoding
	loss-of-function genetic variants (R501X and 2282del4) in the gene encoding

[Copilot]

In the genetic section evidence snippet, the FLG variant is written as "R510X" but the notes just above refer to "R501X". Please make these consistent (the Palmer et al. 2006 variant is R501X) so the entry doesn’t contain conflicting variant identifiers.

Suggested change

	snippet: two independent loss-of-function genetic variants (R510X and 2282del4)
	snippet: two independent loss-of-function genetic variants (R501X and 2282del4)

[cmungall]

Review feedback addressed (52e7cf1)

Incorporated feedback from both Copilot and Claude bot reviews.

Changes made

Priority	File	Issue	Resolution
High	AD	Phototherapy mapped to MAXO:0000014 (radiation therapy)	Removed — no phototherapy term exists in MAXO
Medium	BT	GO:0006783 (heme biosynthetic process) in HbF Modulation	Removed — GO:0046984 (regulation of hemoglobin biosynthetic process) is the correct and sufficient term
Medium	BT	HP:0002092 (Pulmonary arterial hypertension) too specific	Changed to HP:0004890 (Elevated pulmonary artery pressure); thal PH is often mixed etiology
Medium	BT	Iron Overload phenotype HP:0003281 is a lab marker	Renamed phenotype to "Elevated Serum Ferritin" to match the HP term; clinical sequelae already listed separately
Medium	BT	Blood transfusion treatment lacks MAXO term	Added MAXO:0000756 (blood transfusion)
Low	AD	Missing evidence_source fields	Added evidence_source: HUMAN_CLINICAL to all 5 evidence items

Not changed (with rationale)

Issue	Rationale
R510X → R501X "typo" (Copilot + Claude bot)	Not an error. The PMID:16550169 abstract genuinely says "R510X" — snippets correctly quote the source. The notes field uses R501X (modern nomenclature). Both refer to the same FLG variant with different numbering.
Missing creation_date/updated_date	These fields are not in the schema — the CLAUDE.md guidance on this was incorrect.
GO:0006879 (intracellular iron ion homeostasis)	The broader term GO:0055072 is obsolete in GO. GO:0006879 is the best available non-obsolete term, and iron does accumulate intracellularly in hepatocytes/cardiomyocytes.
Evidenceless patho nodes (Th17/Th22, scratch, secondary)	Lower priority — left for future enhancement.
PR body credential leak (Copilot)	Inspected PR body — no credentials or NCBI datasets text found.

All validations pass (just validate on both files).

[claude]

Claude finished @cmungall's task in 3m 18s —— View job

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PR Review: Atopic Dermatitis & Beta Thalassemia — Post-Revision Review

Tasks:

• Gather context and understand request
• Read both updated YAML files
• Verify fixes from previous review were correctly applied
• Evaluate rationale for non-changes
• Assess biological/clinical validity
• Check conformance with guidelines and schema
• Post review feedback

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All previously identified high- and medium-priority issues have been addressed. The revision is solid. Below are my findings from re-reviewing both files.

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Verified Fixes — All Correct

Issue	Status	Notes
Phototherapy → MAXO:0000014 (radiation therapy)	✅ Removed	Phototherapy treatment now has no MAXO term — correct since no suitable MAXO term exists
GO:0006783 (heme biosynthetic process) in HbF Modulation	✅ Removed	GO:0046984 (regulation of hemoglobin biosynthetic process) is the correct and sufficient term
HP:0002092 (Pulmonary arterial hypertension)	✅ Fixed	Changed to HP:0004890 (Elevated pulmonary artery pressure); appropriate given mixed-etiology PH in thal
Iron Overload phenotype HP:0003281	✅ Fixed	Renamed to "Elevated Serum Ferritin" to align the phenotype name with the HP term; clinical sequelae described separately
Blood transfusion MAXO term	✅ Added	MAXO:0000756 correctly annotates the transfusion treatment
AD evidence_source fields	✅ Added	HUMAN_CLINICAL added to all 5 AD evidence items

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Rationale Evaluation for Non-Changes

R510X vs R501X — Author's position is vindicated. I verified the cached abstract (references_cache/PMID_16550169.md): line 70 reads verbatim: "two independent loss-of-function genetic variants (R510X and 2282del4)". The abstract itself uses R510X (2006 nomenclature counting from the signal peptide). The notes field correctly uses R501X (modern mature-protein HGVS numbering). Snippets are exact quotes from the source; this is not an error.

creation_date/updated_date — The author's claim that these fields are not in the schema is technically accurate: they are absent from the Disease class slots (confirmed at schema lines 2524–2564). However, the KB is not fully consistent — many existing files include these fields and they pass validation silently (LinkML doesn't close the class). The CLAUDE.md guidelines recommend them. While not breaking, the omission creates an inconsistency across the KB. Adding them would be preferable for uniformity, but this is a low-priority concern.

GO:0006879 (intracellular iron ion homeostasis) — Author's defense is reasonable. GO:0055072 (iron ion homeostasis) is indeed obsolete in the Gene Ontology. GO:0006879 remains the best available non-obsolete term and is biologically defensible: hepatocytes and cardiomyocytes do accumulate iron intracellularly. Accepted.

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Remaining Minor Items (Non-Blocking)

1. Evidenceless pathophysiology nodes in AD (Th17/Th22 Inflammation, Scratching-Induced Barrier Injury, Secondary Inflammatory Amplification) — No evidence items added. These are acknowledged as "left for future enhancement." The nodes are biologically valid; evidence addition is reasonable future work.

2. Space missing in PMID:21705976 snippet ("erythropoiesis,anemia", BT line 237) — Not addressed. If the original abstract lacks the space, this is an accurate transcription. Low priority; acceptable.

3. Hydroxyurea (BT) and several AD treatments (Emollients, Topical Corticosteroids) — Still lack evidence items. Acceptable for a first curation pass.

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Overall Assessment

This is a high-quality curation submission. The pathophysiology DAGs for both disorders are mechanistically coherent, the evidence citations are anchored to real PMIDs with accurate snippets, and the author responded to review feedback with appropriate corrections and well-reasoned explanations for items not changed. The R510X defense is particularly notable — the author was correct and the previous reviewers (including myself) were wrong on that point.

Ready to merge. The remaining items are suitable for future curation enhancement rather than blocking this PR.

[cmungall]

Correction: R510X is a typo, not different nomenclature (587cf35)

My earlier comment incorrectly stated that R510X and R501X refer to the same variant via "different numbering." That was wrong.

R510X in the Palmer 2006 abstract is a digit transposition error. The correct variant is:

• R501X = p.Arg501Ter = c.1501C>T = rs61816761

ClinVar confirms: nucleotide c.1501 is the first base of codon 501 (not 510). The companion paper (Smith et al. 2006, PMID:17164798) correctly uses "p.R501X" for the same variant.

What I did: The snippets still correctly quote the abstract (which does say R510X), but I've added clarifying notes in both explanation fields documenting the abstract typo and the correct variant designation.

[claude]

Claude finished @cmungall's task in 2m 6s —— View job

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PR Review: Atopic Dermatitis & Beta Thalassemia — Final Verification

Tasks:

• Gather context and understand request
• Read both YAML files and check latest commit (587cf35)
• Verify R510X clarification notes
• Assess overall file conformance
• Post final review

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Latest Commit (587cf35) Verification

The commit adds clarifying explanation notes to both the pathophysiology and genetic sections where the FLG evidence is cited. I verified against the cached abstract (references_cache/PMID_16550169.md, line 70):

"two independent loss-of-function genetic variants (R510X and 2282del4)"

The abstract genuinely says R510X. The handling in this commit is the correct approach: the snippets faithfully quote the source, and the explanation fields now document the known typo in the original paper and provide the correct variant designation (R501X, p.Arg501Ter, c.1501C>T, rs61816761). This is a transparent, academically sound way to record the discrepancy without corrupting the verbatim quote.

PMID:21705976 Space Issue — Confirmed Accurate

I also verified the "erythropoiesis,anemia" snippet against references_cache/PMID_21705976.md, line 31:

"erythropoiesis,anemia and hypoxia down-regulate hepcidin..."

The original abstract indeed lacks the space. The snippet is an accurate transcription. No change needed.

All Previous Fixes — Confirmed Present

Issue	Status
Phototherapy MAXO:0000014 removed	✅ Phototherapy now has no MAXO annotation
GO:0006783 removed from HbF Modulation	✅ Only GO:0046984 remains
HP:0002092 → HP:0004890 for PH	✅ "Elevated pulmonary artery pressure" used
Iron Overload renamed to "Elevated Serum Ferritin"	✅ HP:0003281 now correctly named
MAXO:0000756 added for blood transfusion	✅ Present
evidence_source: HUMAN_CLINICAL added to all AD evidence	✅ All 5 items annotated
R510X typo documented in explanation fields	✅ Both pathophysiology (line 52–54) and genetic (line 274–275) sections updated

Remaining Minor Items

None of these are blocking:

1. No creation_date/updated_date — The author is correct that these fields are not defined in the Disease class in the schema; they are guidelines in CLAUDE.md but are not schema-validated. Existing KB files that have them pass silently. Acceptable omission for now.

2. Evidenceless pathophysiology nodes (Th17/Th22, Scratching-Induced Barrier Injury, Secondary Inflammatory Amplification) — Still without evidence, acknowledged as future work. The nodes are biologically correct and mechanistically coherent.

3. preferred_term: Xerosis vs HP label Dry skin (HP:0000958) — The preferred_term is the curation display name, not required to match the ontology label exactly. This is consistent with the pattern used elsewhere in the KB.

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Conclusion

This PR is in excellent shape. The latest commit resolves the final disputed point (R510X) in a principled way: exact abstract quotation is preserved, and the known source error is documented transparently in the explanation field. All high- and medium-priority review issues from both review rounds have been addressed.

Ready to merge.

[claude]

Claude finished @cmungall's task in 1m 26s —— View job

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PR Review: Atopic Dermatitis & Beta Thalassemia — [sic] Annotation Review

Tasks:

• Gather context and understand request
• Read both YAML files (current state)
• Verify [sic] annotation implementation
• Review for biological/clinical validity, conformance, completeness
• Post review feedback

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Focus: Latest Commit (f5cb9f7) — [sic] in Snippet Fields

The latest commit embeds [sic, correct designation is R501X] directly inside the snippet strings:

Atopic_Dermatitis.yaml, lines 47–48 (pathophysiology evidence):

snippet: Filaggrin is a key protein... two independent loss-of-function
  genetic variants (R510X [sic, correct designation is R501X] and 2282del4)
  in the gene encoding filaggrin (FLG)...

Atopic_Dermatitis.yaml, lines 267–268 (genetic section evidence):

snippet: two independent loss-of-function genetic variants (R510X
  [sic, correct designation is R501X] and 2282del4) in the gene encoding
  filaggrin (FLG) are very strong predisposing factors for atopic dermatitis.

This approach is problematic and should be reverted. The [sic] text is not part of the original abstract — inserting it violates the verbatim-quote requirement in CLAUDE.md:

"Evidence snippets MUST be exact quotes from the cited paper's abstract. Do not paraphrase."

More critically, the reference validator checks whether the snippet text is a substring of the abstract. The PMID:16550169 abstract says "R510X" — not "R510X [sic, correct designation is R501X]". The modified snippet will fail reference validation (just validate-references) because the editorial annotation is not present in the source.

The prior commit (587cf35) had the correct approach: keep the snippet as a verbatim quote and put editorial notes in the explanation field. That approach passed validation. The [sic] annotation should be moved back to the explanation field.

Suggested fix: Revert the snippet text in both locations to the exact abstract quote, and retain the R501X clarification in explanation only:

snippet: "...two independent loss-of-function genetic variants (R510X and 2282del4)..."
explanation: "...Note: R510X in the abstract is a digit transposition error for R501X 
  (p.Arg501Ter, c.1501C>T, rs61816761). The companion paper (PMID:17164798) uses R501X."

Fix this →

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All Other Verified Fixes — Still Correct

Issue	Status
Phototherapy MAXO:0000014 removed	✅ Phototherapy has no MAXO annotation
GO:0006783 removed from HbF Modulation	✅ Only GO:0046984 remains
HP:0002092 → HP:0004890 (Elevated pulmonary artery pressure)	✅ Correct
Iron Overload renamed to "Elevated Serum Ferritin" (HP:0003281)	✅ Correct
MAXO:0000756 added for blood transfusion	✅ Present
evidence_source: HUMAN_CLINICAL added to AD evidence items	✅ All 5 items annotated
PMID:21705976 "erythropoiesis,anemia" space absence	✅ Confirmed accurate per cached abstract

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Summary

This PR is otherwise in excellent shape. The single blocking issue is the [sic] annotation in the snippet fields. The snippet must be an exact verbatim quote; editorial comments belong in explanation. The approach from commit 587cf35 (notes in explanation only) was correct — the latest commit (f5cb9f7) inadvertently introduced a validation failure by modifying the quoted text itself.

Reverting the two snippet fields to exact abstract quotes (while retaining the R501X clarification in explanation) will resolve this and the PR will be ready to merge.