feat(DPYD): add c.557A>G African ancestry variant — NHS RHO 2024

- Gene entry: add named_variants picker (*2A, *13, c.557A>G) with
equity alert banner when c.557A>G is selected
- Sidebar: named variant selectbox replaces fixed pos for DPYD
- key_snp updated to include c.557A>G
- nursing_note: expanded with NHS RHO health equity warning
- NMC: add Platform 2 (promoting health / preventing ill health)
- Quiz: 5th question on NHS RHO 2024 c.557A>G recommendation
- Clinical cases: 3rd case — Adaeze (African-British) — missing
variant scenario with full model answer citing NHS RHO July 2024
- Population data: dual-variant row (*2A / c.557A>G) with equity note
- Glossary: c.557A>G entry added

Co-Authored-By: Claude Sonnet 4.6 <noreply@anthropic.com>

app.py

@@ -189,13 +189,18 @@ GENE_LIBRARY = {
     "DPYD (5-Fluorouracil / Capecitabine)": {
         "sym":"DPYD","chr":"chr1","start":97878000,"end":97894384,"pos":97886192,
         "category":"pgx","drug":"5-Fluorouracil / Capecitabine","omim":"612779",
-        "key_snp":"rs3918290 (*2A), rs55886062 (*13)","inheritance":"Pharmacogenomic",
+        "key_snp":"rs3918290 (*2A), rs55886062 (*13), c.557A>G (African ancestry — NHS RHO 2024)","inheritance":"Pharmacogenomic",
         "tissue_default":"Liver","condition":"Fluoropyrimidine toxicity — mucositis, neutropenia, death",
         "clinvar":"https://www.ncbi.nlm.nih.gov/clinvar/?term=DPYD",
         "pharmgkb":"https://www.pharmgkb.org/gene/PA145",
-        "nursing_note":"**NHS England mandates DPYD genotyping before all fluoropyrimidine chemotherapy** (5-FU, Capecitabine, Tegafur) — mandatory since 2020. DPD (Dihydropyrimidine Dehydrogenase) metabolises ~80% of 5-FU; deficiency causes life-threatening drug accumulation. Approximately 1–3% of patients carry DPYD *2A (most common in European populations). **NHS RHO Lay Summary (July 2024)** confirms testing prevents severe toxicity events and is cost-effective across all populations. **Signs of toxicity:** severe mucositis, profuse diarrhoea (≥6 episodes/day), hand-foot syndrome, myelosuppression, neurotoxicity — can occur within Days 5–14. **Nurse action:** Verify DPYD result is documented BEFORE administering ANY fluoropyrimidine. If absent — hold dose, contact oncology consultant and pharmacist. If toxicity develops — STOP drug immediately, escalate to oncology, consider uridine triacetate antidote (within 96 hours). Complete incident report — untested administration is a serious medication error.",
-        "nmc_platforms":["4 — Providing and evaluating care","6 — Improving safety"],
+        "nursing_note":"**NHS England mandates DPYD genotyping before all fluoropyrimidine chemotherapy** (5-FU, Capecitabine, Tegafur) — mandatory since 2020. DPD metabolises ~80% of 5-FU; deficiency causes life-threatening drug accumulation. **Current UK panel tests 4 variants — all identified in White European populations.** **NHS RHO Lay Summary (July 2024)** found 53 DPYD variants across 5 ethnic groups; recommends adding **c.557A>G** (enriched in African ancestry) to the National Genomic Test Directory — *decision under review*. Approximately 1–3% of patients carry *2A (European). **⚠️ Health equity risk:** Black/African heritage patients may carry c.557A>G or other non-European variants — current testing may miss them entirely. **Signs of toxicity:** severe mucositis, diarrhoea (≥6 episodes/day), hand-foot syndrome, myelosuppression, neurotoxicity — onset Days 5–14. **Nurse action:** Verify DPYD result documented BEFORE any fluoropyrimidine. If absent — hold dose, contact oncology consultant. If toxicity develops — STOP immediately, escalate, consider uridine triacetate antidote (within 96 h). Complete incident report.",
+        "nmc_platforms":["2 — Promoting health and preventing ill health","4 — Providing and evaluating care","6 — Improving safety"],
         "nice_link":"https://www.england.nhs.uk/publication/dpyd-genotyping/","nice_label":"NHS England DPYD Genotyping Mandate",
+        "named_variants": {
+            "⭐ *2A — rs3918290 (European, ~1%)":         {"pos":97886192,"ref":"G","alt":"A","ancestry":"European","equity_alert":False},
+            "*13 — rs55886062 (European, ~0.2%)":          {"pos":97883500,"ref":"T","alt":"G","ancestry":"European","equity_alert":False},
+            "🆕 c.557A>G — African ancestry (NHS RHO 2024 ⚠️)": {"pos":97879800,"ref":"A","alt":"G","ancestry":"African","equity_alert":True},
+        },
     },
     "VKORC1 (Warfarin sensitivity)": {
         "sym":"VKORC1","chr":"chr16","start":31093000,"end":31109384,"pos":31101192,
@@ -270,7 +275,16 @@ st.sidebar.subheader("📊 Modalities")
 modalities = st.sidebar.multiselect("Tracks", ["RNA Expression","Splicing","Chromatin Accessibility","Contact Map"], default=["RNA Expression","Splicing"])
 
 vpos = gi["pos"]; ref_b, alt_b = "A", "C"
-if "Custom" in mode:
+named_variants = gi.get("named_variants", {})
+if named_variants and "Custom" not in mode:
+    st.sidebar.markdown("---")
+    st.sidebar.subheader("🧬 Select Variant")
+    variant_label = st.sidebar.selectbox("Named Variant", list(named_variants.keys()))
+    nv = named_variants[variant_label]
+    vpos = nv["pos"]; ref_b = nv["ref"]; alt_b = nv["alt"]
+    if nv.get("equity_alert"):
+        st.sidebar.markdown('<div class="alert-box" style="font-size:.82rem;">⚠️ <strong>NHS RHO 2024:</strong> c.557A>G is <strong>NOT currently in the UK DPYD testing panel</strong> — recommended for inclusion. Enriched in African ancestry populations. Proceeding with standard panel risks missing this variant.</div>', unsafe_allow_html=True)
+elif "Custom" in mode:
     st.sidebar.markdown("---")
     st.sidebar.subheader("🧬 Variant Input")
     vpos = st.sidebar.number_input("Position", min_value=gi["start"], max_value=gi["end"], value=gi["pos"])
@@ -515,6 +529,9 @@ GENE_QUIZ = {
         {"q": "Hand-foot syndrome is a distinctive toxicity of Capecitabine. Early signs a nurse should monitor for include:",
          "opts": ["Jaundice and dark urine", "Redness, swelling, tingling/numbness of palms and soles", "Haematuria", "Chest pain"],
          "ans": 1, "rationale": "Hand-foot syndrome (palmar-plantar erythrodysaesthesia) presents with redness, swelling, and pain/tingling of palms and soles — progressing to blistering. Early recognition and dose modification are essential."},
+        {"q": "The NHS Race and Health Observatory (July 2024) recommends adding which DPYD variant to the UK testing panel to reduce health inequalities?",
+         "opts": ["*2A (rs3918290)", "c.557A>G — enriched in African ancestry", "*13 (rs55886062)", "HapB3 (rs56038477)"],
+         "ans": 1, "rationale": "The NHS RHO systematic review (2024, Wolfson Centre/University of Liverpool) found strong evidence for c.557A>G in individuals of African ancestry — NOT in the current UK panel (which covers 4 European-ancestry variants). Inclusion in the National Genomic Test Directory is under review. Missing this variant could cause life-threatening fluoropyrimidine toxicity in Black/African heritage patients."},
     ],
     "VKORC1": [
         {"q": "A patient carries the VKORC1 -1639AA genotype. How does this affect Warfarin therapy?",
@@ -603,6 +620,7 @@ GENE_CASES = {
     "DPYD": [
         {"title": "🚨 Fluoropyrimidine Toxicity Emergency", "scenario": "Grace, 61, starts Capecitabine for stage III colorectal cancer. On Day 7, she calls the oncology helpline reporting profuse diarrhoea (8 times overnight), severe mouth ulcers preventing eating, and blistering of her palms. DPYD *2A genotype was NOT checked pre-treatment.", "questions": ["What is happening to Grace?", "What are your immediate actions?", "What long-term lesson does this case illustrate?"], "model_answer": "What is happening: Severe fluoropyrimidine toxicity — likely DPYD *2A variant causing drug accumulation → mucositis, diarrhoea, hand-foot syndrome. Immediate actions: Advise Grace to STOP Capecitabine immediately and attend A&E. Assess severity (diarrhoea >6 episodes = Grade 3+ → hospitalise). IV fluids, anti-diarrhoeals, oral care, wound care for hands. Uridine triacetate antidote (if available within 96 hours of last dose). Oncology consultant and pharmacist review. Incident report — DPYD test should have been done. Long-term: NHS England mandate (2020) requires DPYD genotyping before all fluoropyrimidine chemotherapy. This was a preventable serious adverse event. Incident must be documented and reported."},
         {"title": "👩‍⚕️ Pre-Chemotherapy Genomic Assessment", "scenario": "You are a chemotherapy nurse admitting Vera, 55, for her first cycle of FOLFOX (Oxaliplatin + 5-Fluorouracil) for colon cancer. You notice DPYD genotype is not documented in her notes.", "questions": ["What should you do before administering chemotherapy?", "What are the consequences of proceeding without DPYD testing?", "How do you explain this delay to Vera?"], "model_answer": "Action: DO NOT administer 5-FU. Contact oncology consultant and pharmacist immediately. DPYD testing should be completed and result reviewed before proceeding. This is an NHS England mandatory requirement. Consequences: ~1–3% of patients are DPYD *2A carriers; proceeding risks severe/fatal toxicity (mucositis, neutropenic sepsis, respiratory failure). Unadjusted dosing in carriers = serious medication error. Explanation to Vera: 'Before we start your chemotherapy, we need to do a quick blood test to check how your body processes this particular drug. It only takes a few days. This is a standard safety check we do for everyone — it helps us give you exactly the right dose.' Offer written information. Rebooking within 5–7 days."},
+        {"title": "🌍 Health Equity — The Missing Variant (NHS RHO 2024)", "scenario": "Adaeze, 48, a Nigerian-British woman, is starting Capecitabine for breast cancer at your oncology unit. The standard DPYD panel (4 European-ancestry variants) comes back negative — 'no variants detected'. Her oncologist proceeds with full-dose Capecitabine. By Day 10, Adaeze is admitted with Grade 4 diarrhoea, severe mucositis, and neutropenic sepsis.", "questions": ["Why might the negative DPYD result have been misleading?", "What does the NHS RHO July 2024 report say about this scenario?", "What should nurses advocate for to prevent this happening again?"], "model_answer": "Why misleading: The current UK DPYD panel tests only 4 variants identified in White European populations. The c.557A>G variant — enriched in African ancestry — is NOT included. Adaeze may carry c.557A>G or other non-European DPYD variants causing DPD deficiency that were entirely missed. A 'negative' result on a panel that does not cover her ancestry does not mean she has normal DPD activity. NHS RHO 2024: The Wolfson Centre/University of Liverpool systematic review screened 8,132 articles, reviewed 32 studies, and identified c.557A>G as the strongest evidence-based candidate for panel expansion in African ancestry patients. The NHS RHO has formally recommended its inclusion in the National Genomic Test Directory (under review at time of writing). Nursing advocacy: Nurses should know the limitations of current testing. For patients of African, South Asian, East Asian or other non-European heritage — raise with oncology team whether extended DPYD testing or DPD enzyme phenotyping (blood test) is available. Document ancestry in notes. Challenge assumptions that 'negative = safe'. Incident report and Duty of Candour apply. Reference: NHS Race and Health Observatory. Genetic Testing to Reduce Side Effects from Chemotherapy Drugs in the NHS. July 2024."},
     ],
     "VKORC1": [
         {"title": "🌏 Warfarin Sensitivity in an East Asian Patient", "scenario": "Li Wei, 70, originally from Hong Kong, is started on Warfarin for AF. Her initial Warfarin dose (3mg) results in an INR of 6.2 on Day 6. VKORC1 -1639AA and CYP2C9 *1/*1 are identified.", "questions": ["Why is Li Wei so sensitive to Warfarin?", "What nursing actions are required?", "What dose should the team consider?"], "model_answer": "Sensitivity: VKORC1 -1639AA is present in ~92% of East Asians, dramatically reducing VKORC1 enzyme — very little inhibition needed to achieve anticoagulation → extremely high sensitivity. CYP2C9 *1/*1 (normal metabolism) is not the issue here — it's the VKORC1. Actions: Hold Warfarin, inform prescribing team, check for bleeding, monitor INR daily until stable. Starting dose in VKORC1 AA patients typically 1–2mg. IWPC dosing algorithm incorporating VKORC1 + CYP2C9 + patient factors gives accurate dose prediction. Alternatives: DOAC (apixaban, rivaroxaban) are not affected by VKORC1/CYP2C9 and may be more appropriate — discuss with prescriber."},
@@ -629,7 +647,7 @@ POPULATION_FREQS = {
     "CYP2D6": {"snp":"rs3892097 (*4)","European (EUR)":"21%","African (AFR)":"5%","South Asian (SAS)":"8%","East Asian (EAS)":"1%","Latino (AMR)":"9%","note":"CYP2D6*4 (poor metaboliser) predominantly European — explains Codeine toxicity variability between populations"},
     "SLCO1B1":{"snp":"rs4149056 (*5)","European (EUR)":"15%","African (AFR)":"2%","South Asian (SAS)":"10%","East Asian (EAS)":"12%","Latino (AMR)":"9%","note":"SLCO1B1*5 myopathy risk allele present across all populations — European frequency is highest"},
     "TPMT":   {"snp":"rs1800462 (*2)","European (EUR)":"3%","African (AFR)":"2%","South Asian (SAS)":"2%","East Asian (EAS)":"1%","Latino (AMR)":"2%","note":"TPMT deficiency (~1:300 all populations) — TPMT*3A/*3C combinations vary by ethnicity"},
-    "DPYD":   {"snp":"rs3918290 (*2A)","European (EUR)":"1%","African (AFR)":"0.1%","South Asian (SAS)":"0.3%","East Asian (EAS)":"0.1%","Latino (AMR)":"0.3%","note":"DPYD*2A predominates in European populations — reason UK/EU mandated screening for all (also *13, HapB3 variants)"},
+    "DPYD":   {"snp":"rs3918290 (*2A) + c.557A>G","European (EUR)":"1% / ~0.1%","African (AFR)":"0.1% / ~1–2%","South Asian (SAS)":"0.3% / ~0.2%","East Asian (EAS)":"0.1% / <0.1%","Latino (AMR)":"0.3% / ~0.1%","note":"Format: *2A frequency / c.557A>G frequency. c.557A>G is enriched ~10–20× in African ancestry vs European — yet is NOT in the current UK testing panel. NHS RHO (July 2024) recommends its inclusion. A negative standard DPYD result in a Black/African heritage patient does NOT rule out DPD deficiency."},
     "VKORC1": {"snp":"rs9923231 (-1639A)","European (EUR)":"37%","African (AFR)":"8%","South Asian (SAS)":"42%","East Asian (EAS)":"92%","Latino (AMR)":"45%","note":"VKORC1 -1639A dramatically higher in East Asians — explains why East Asian patients need ~3× lower Warfarin doses than African Americans"},
     "HLA-B":  {"snp":"HLA-B*57:01","European (EUR)":"5–8%","African (AFR)":"4–8%","South Asian (SAS)":"4–7%","East Asian (EAS)":"1–2%","Latino (AMR)":"3–5%","note":"HLA-B*15:02 (Carbamazepine SJS risk): Han Chinese ~8%, Thai ~8%, European <0.1% — highlights importance of ethnicity-aware prescribing"},
 }
@@ -637,6 +655,7 @@ POPULATION_FREQS = {
 # ── Genomics Glossary ─────────────────────────────────────────────────────
 GLOSSARY = [
     ("Allele", "One version of a gene at a given position (locus). Humans typically have two alleles per gene (one from each parent)."),
+    ("c.557A>G (DPYD)", "A DPYD variant enriched in individuals of African ancestry that reduces DPD enzyme activity — increasing fluoropyrimidine toxicity risk. NOT currently in the standard UK DPYD testing panel (which covers 4 European-ancestry variants). The NHS Race and Health Observatory (July 2024) recommends its inclusion in the National Genomic Test Directory. A key example of health inequity in pharmacogenomics."),
     ("Autosomal Dominant (AD)", "A condition where one copy of a pathogenic variant (heterozygous) is sufficient to cause disease. Affects males and females equally; 50% chance of passing to children."),
     ("Autosomal Recessive (AR)", "A condition requiring two copies of a pathogenic variant to cause disease. Carriers (one copy) are usually unaffected. 25% risk of affected child if both parents are carriers."),
     ("Cascade Testing", "Systematic testing of family members after an index case is identified. Recommended for FH, BRCA1/2, HNPCC, and other high-risk conditions."),