{
  "schema": "oncoref.normal-tissue-taxonomy",
  "schema_version": 1,
  "policy_version": "2026-10-20.5",
  "taxon_ids": [
    9606,
    9615,
    10090
  ],
  "references": {
    "blagosklonny2003": {
      "title": "Tissue-selective therapy of cancer",
      "url": "https://doi.org/10.1038/sj.bjc.6601256",
      "kind": "conceptual_minireview",
      "scope": "Proposed examples: melanocytes, prostate, testis, breast, ovary; not an exhaustive or clinically validated whitelist."
    },
    "openstax_female": {
      "title": "Anatomy and Physiology: Female Reproductive System",
      "url": "https://openstax.org/books/anatomy-and-physiology/pages/27-2-anatomy-and-physiology-of-the-female-reproductive-system",
      "kind": "anatomy",
      "scope": "Reproductive organs, ovarian compartments, and mammary glands as accessory reproductive organs."
    },
    "openstax_male": {
      "title": "Anatomy and Physiology: Male Reproductive System",
      "url": "https://openstax.org/books/anatomy-and-physiology/pages/27-1-anatomy-and-physiology-of-the-male-reproductive-system",
      "kind": "anatomy",
      "scope": "Testis, excurrent ducts, accessory glands and external genitalia."
    },
    "mouse_anatomy": {
      "title": "The Anatomy of the Laboratory Mouse, Margaret J. Cook",
      "url": "https://www.informatics.jax.org/cookbook/chapters/contents2.shtml",
      "kind": "comparative_anatomy",
      "scope": "Mouse reproductive anatomy; anatomical applicability does not establish therapeutic tolerability."
    },
    "dog_anatomy": {
      "title": "Male reproductive pelvic and external genitalia, ICAR-IVRI",
      "url": "https://veterinaryanatomy.com/atlas/hindlimb-pelvis/splanchnology/male-reproductive-pelvic-and-external-genitalia/",
      "kind": "comparative_anatomy",
      "scope": "Dog lacks seminal vesicles and bulbourethral glands; prostate is its principal accessory sex gland."
    },
    "hpa_tissues": {
      "title": "Human Protein Atlas tissue and cell-type definitions",
      "url": "https://www.proteinatlas.org/humanproteome/tissue/data",
      "kind": "source_documentation",
      "scope": "Source tissue and cell-type labels; version-specific mapping rows refer to the v23 files."
    },
    "hpa_skin": {
      "title": "Human Protein Atlas: skin histology",
      "url": "https://www.proteinatlas.org/learn/dictionary/normal/skin",
      "kind": "source_documentation",
      "scope": "Skin melanocytes and hair follicles are separate compartments from other skin cells."
    },
    "hpa_pigment": {
      "title": "Human Protein Atlas: pigment cells",
      "url": "https://www.proteinatlas.org/humanproteome/single%2Bcell/single%2Bcell%2Btype/pigment%2Bcells",
      "kind": "source_documentation",
      "scope": "Skin melanocytes distinct from retinal pigment epithelial cells."
    },
    "johnson2009": {
      "title": "Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC2929689/",
      "kind": "clinical_study",
      "scope": "Melanocyte-antigen targeting can affect skin, eye and ear; a cutaneous exception must not include ocular or inner-ear compartments."
    },
    "purba2019": {
      "title": "CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia",
      "url": "https://pubmed.ncbi.nlm.nih.gov/31512803/",
      "kind": "human_ex_vivo_study",
      "scope": "Follicular matrix and stem-cell injury differ; follicular toxicity can cause persistent alopecia. Supports compartment distinction, not safety of immune ablation."
    },
    "nci_alopecia": {
      "title": "Hair Loss (Alopecia) and Cancer Treatment",
      "url": "https://www.cancer.gov/about-cancer/treatment/side-effects/hair-loss",
      "kind": "clinical_information",
      "scope": "Alopecia is a recognized cancer-treatment toxicity; regrowth and permanence depend on treatment."
    },
    "barkbase2019": {
      "title": "BarkBase: Epigenomic Annotation of Canine Genomes",
      "url": "https://doi.org/10.3390/genes10060433",
      "kind": "primary_atlas",
      "scope": "Canine adult and embryonic tissues; retain source developmental-stage terminology."
    },
    "fetal_atlas2020": {
      "title": "A human cell atlas of fetal gene expression",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33184181/",
      "kind": "primary_atlas",
      "scope": "Fetal organ and cell identities are stage-specific and must not stand for adult-organ evidence."
    },
    "hpa_tissue_specificity": {
      "title": "Human Protein Atlas v23 tissue specificity definitions",
      "url": "https://v23.proteinatlas.org/humanproteome/tissue/tissue%2Bspecific",
      "kind": "primary_atlas",
      "scope": "HPA tissue enrichment compares expression against other tissues. This is a conceptual specificity precedent, not validation of the project maximum reproductive reference, selectivity grid, or therapeutic safety limits."
    },
    "project_policy": {
      "title": "oncoref normal-tissue scope policy, version 1",
      "url": "https://github.com/pirl-unc/oncoref/blob/main/docs/normal-tissue-scopes.md",
      "kind": "project_definition",
      "scope": "Reproductive includes reproductive organs, mammary tissue, placenta, extraembryonic, embryonic and fetal contexts. Disposable normal is a conditional research scope, not a clinical safety claim. The permitted scope includes cutaneous melanocytes, follicles, tonsil, appendix and gallbladder. Manageable separates skin, spleen, thymus, thyroid and adipose from Protected tissues. Tiered RNA ceilings are project screening parameters; IHC detections outside the permitted scope remain exclusions."
    },
    "nci_organ_inflammation": {
      "title": "Immunotherapy and Organ-Related Inflammation",
      "url": "https://www.cancer.gov/about-cancer/treatment/side-effects/organ-inflammation",
      "kind": "clinical_information",
      "scope": "Organ-specific immune injury supports conservative review of normal expression. Does not validate this project's tissue tiers or numerical cutoffs."
    },
    "niddk_adrenal": {
      "title": "Definition and Facts of Adrenal Insufficiency and Addison's Disease",
      "url": "https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/definition-facts",
      "kind": "clinical_information",
      "scope": "Adrenal crisis can be life-threatening. Supports including adrenal and pituitary contexts in the conservative vital tier; not an RNA threshold validation."
    },
    "mouse_coagulating": {
      "title": "MGI Adult Mouse Anatomy: coagulating gland (MA:0000402)",
      "url": "https://www.informatics.jax.org/vocab/gxd/ma_ontology/MA%3A0000402",
      "kind": "anatomy_ontology",
      "scope": "Mouse male reproductive gland, synonym prostate gland anterior lobe."
    },
    "mouse_lymphoid": {
      "title": "Janeway Immunobiology: Organization of the mucosal immune system",
      "url": "https://nerd.wwnorton.com/ebooks/epub/janeway10/EPUB/content/12.1-chapter12.xhtml",
      "kind": "comparative_anatomy",
      "scope": "Mouse nasal-associated lymphoid tissue is not anatomically a tonsil."
    },
    "nhs_tonsillectomy": {
      "title": "Making a decision about recurrent tonsillitis in children and adults",
      "url": "https://www.england.nhs.uk/wp-content/uploads/2023/10/decision-support-tool-making-a-decision-about-recurrent-tonsillitis-in-children-and-adults.pdf",
      "kind": "clinical_information",
      "scope": "Tonsillectomy is an established intervention; other tissues also provide immune functions. Surgical tolerability does not validate systemic immune ablation."
    },
    "cdc_asplenia": {
      "title": "Risk Factors for Meningococcal Disease",
      "url": "https://www.cdc.gov/meningococcal/risk-factors/index.html",
      "kind": "clinical_information",
      "scope": "Anatomic or functional asplenia increases serious infection risk. Spleen allowance requires an infection-risk and mitigation assessment."
    },
    "nci_lymph_nodes": {
      "title": "Sentinel Lymph Node Biopsy",
      "url": "https://www.cancer.gov/about-cancer/diagnosis-staging/staging/sentinel-node-biopsy-fact-sheet",
      "kind": "clinical_information",
      "scope": "Lymph nodes contain mobile immune cells. More extensive removal increases lymphedema and infection risks; regional surgery does not validate systemic injury."
    },
    "nei_retina": {
      "title": "National Plan for Eye and Vision Research",
      "url": "https://www.nei.nih.gov/sites/default/files/nei-pdfs/nationalplan1.pdf",
      "kind": "clinical_information",
      "scope": "Retinal injury can cause severe irreversible visual disability. Supports critical-function protection independently of immediate mortality."
    },
    "bradley2020": {
      "title": "Vestigial-like 1 is a shared targetable cancer-placenta antigen expressed by pancreatic and basal-like breast cancers",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7577998/",
      "kind": "primary_target_selection_study",
      "scope": "Supplementary Table 2 specifies danger, hazard, caution and non-essential tissue groups with GTEx TPM screening thresholds. These are study parameters, not validated organ-injury limits or transferable HPA nTPM thresholds."
    },
    "kaufmann2019": {
      "title": "Large-scale in-silico identification of a tumor-specific antigen pool for targeted immunotherapy in triple-negative breast cancer",
      "url": "https://www.oncotarget.com/article/26808/text/",
      "kind": "primary_target_selection_study",
      "scope": "Essential brain/heart/lung and graded predicted adverse events in other tissues support relative protection priorities, not these numerical ceilings."
    },
    "kooshesh2023": {
      "title": "Health Consequences of Thymus Removal in Adults",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC10557034/",
      "kind": "observational_clinical_study",
      "scope": "Adult thymectomy was associated with higher mortality and cancer incidence. Observational association does not establish causality or immune-injury risk."
    },
    "kristinsson2014": {
      "title": "Long-term risks after splenectomy among 8149 cancer-free American veterans",
      "url": "https://haematologica.org/article/view/6942",
      "kind": "observational_clinical_study",
      "scope": "Increased long-term infection and thromboembolic risks support screening spleen expression rather than treating spleen as a default disposable organ."
    },
    "heinemeier2016": {
      "title": "Radiocarbon dating reveals minimal collagen turnover in both healthy and osteoarthritic human cartilage",
      "url": "https://pubmed.ncbi.nlm.nih.gov/27384346/",
      "kind": "primary_human_tissue_study",
      "scope": "Minimal replacement of mature articular cartilage collagen supports concern about lasting structural damage; not direct evidence of immune toxicity."
    },
    "braaten2020": {
      "title": "Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC7031780/",
      "kind": "prospective_observational_clinical_study",
      "scope": "Persistent inflammatory arthritis supports concern about chronic joint injury; arthritis is not equivalent to selective chondrocyte targeting."
    },
    "warner2019": {
      "title": "Sicca Syndrome Associated with Immune Checkpoint Inhibitor Therapy",
      "url": "https://pubmed.ncbi.nlm.nih.gov/30996010/",
      "kind": "clinical_series",
      "scope": "In 20 patients, symptoms often improved with treatment but salivary secretion remained very low. Does not support reliable local-steroid rescue."
    },
    "sitc2021": {
      "title": "SITC clinical practice guideline on immune checkpoint inhibitor-related adverse events",
      "url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC8237720/",
      "kind": "clinical_guideline",
      "scope": "Skin and other organ toxicities are graded by manifestation and severity. Local treatment for selected skin events does not establish controllability of extensive antigen-directed cell killing."
    },
    "nhs_appendix": {
      "title": "Appendicitis",
      "url": "https://www.nhs.uk/conditions/appendicitis/",
      "kind": "clinical_information",
      "scope": "Appendix removal is compatible with normal life; surgical outcomes do not establish the consequences of in-situ immune inflammation or perforation."
    },
    "niddk_gallbladder": {
      "title": "Treatment for Gallstones",
      "url": "https://www.niddk.nih.gov/health-information/digestive-diseases/gallstones/treatment",
      "kind": "clinical_information",
      "scope": "Normal life is possible without a gallbladder; post-removal digestive effects can occur. No allowance for liver or bile ducts is implied."
    },
    "fetal_gonads2007": {
      "title": "MAGE-A1, GAGE and NY-ESO-1 cancer/testis antigen expression during human gonadal development",
      "url": "https://pubmed.ncbi.nlm.nih.gov/17208940/",
      "kind": "primary_developmental_expression_study",
      "scope": "CTA expression in fetal testes and ovaries demonstrates why adult male restriction does not establish maternal or fetal exclusion."
    }
  },
  "concepts": {
    "testis": {
      "label": "testis",
      "parents": [],
      "aliases": [
        "testes"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ]
    },
    "spermatogonium": {
      "label": "spermatogonium",
      "parents": [
        "testis"
      ],
      "aliases": [
        "spermatogonia",
        "spermatogonia cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "spermatocyte": {
      "label": "spermatocyte",
      "parents": [
        "testis"
      ],
      "aliases": [
        "spermatocytes",
        "pachytene spermatocytes",
        "preleptotene spermatocytes"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "spermatid": {
      "label": "spermatid",
      "parents": [
        "testis"
      ],
      "aliases": [
        "spermatids",
        "early spermatids",
        "late spermatids",
        "round or early spermatids",
        "elongated or late spermatids"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "spermatozoon": {
      "label": "spermatozoon",
      "parents": [],
      "aliases": [
        "spermatozoa",
        "sperm"
      ],
      "references": [
        "hpa_tissues"
      ],
      "notes": "Male germ cells without an inferred anatomical site; a sperm observation alone does not establish testis restriction."
    },
    "sertoli_cell": {
      "label": "sertoli cell",
      "parents": [
        "testis"
      ],
      "aliases": [
        "sertoli cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "leydig_cell": {
      "label": "leydig cell",
      "parents": [
        "testis"
      ],
      "aliases": [
        "leydig cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "testicular_peritubular_cell": {
      "label": "testicular peritubular cell",
      "parents": [
        "testis"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "seminiferous_tubule": {
      "label": "seminiferous tubule",
      "parents": [
        "testis"
      ],
      "aliases": [
        "seminiferous tubules",
        "cells in seminiferous ducts"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "ovary": {
      "label": "ovary",
      "parents": [],
      "aliases": [
        "ovaries"
      ],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "oocyte": {
      "label": "oocyte",
      "parents": [
        "ovary"
      ],
      "aliases": [
        "oocytes",
        "ovum",
        "ova"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "ovarian_follicle": {
      "label": "ovarian follicle",
      "parents": [
        "ovary"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "granulosa_cell": {
      "label": "granulosa cell",
      "parents": [
        "ovarian_follicle"
      ],
      "aliases": [
        "granulosa cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "ovarian_stromal_cell": {
      "label": "ovarian stromal cell",
      "parents": [
        "ovary"
      ],
      "aliases": [
        "ovarian stromal cells",
        "ovarian stroma cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "theca_cell": {
      "label": "theca cell",
      "parents": [
        "ovary"
      ],
      "aliases": [
        "theca cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "corpus_luteum": {
      "label": "corpus luteum",
      "parents": [
        "ovary"
      ],
      "aliases": [
        "corpora lutea"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "epididymis": {
      "label": "epididymis",
      "parents": [],
      "aliases": [
        "epididymides"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ]
    },
    "vas_deferens": {
      "label": "vas deferens",
      "parents": [],
      "aliases": [
        "ductus deferens",
        "deferent duct"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ]
    },
    "prostate": {
      "label": "prostate",
      "parents": [],
      "aliases": [
        "prostate gland"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ]
    },
    "penis": {
      "label": "penis",
      "parents": [],
      "aliases": [],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ]
    },
    "seminal_vesicle": {
      "label": "seminal vesicle",
      "parents": [],
      "aliases": [
        "seminal vesicles",
        "vesicular gland"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ],
      "taxon_ids": [
        9606,
        10090
      ]
    },
    "bulbourethral_gland": {
      "label": "bulbourethral gland",
      "parents": [],
      "aliases": [
        "bulbourethral glands",
        "cowper gland"
      ],
      "references": [
        "openstax_male",
        "mouse_anatomy",
        "dog_anatomy"
      ],
      "taxon_ids": [
        9606,
        10090
      ]
    },
    "coagulating_gland": {
      "label": "coagulating gland",
      "parents": [
        "prostate"
      ],
      "aliases": [],
      "references": [
        "mouse_anatomy",
        "mouse_coagulating"
      ],
      "taxon_ids": [
        10090
      ],
      "notes": "Mouse anterior prostate/coagulating gland; no dog counterpart is assigned."
    },
    "fallopian_tube": {
      "label": "fallopian tube",
      "parents": [],
      "aliases": [
        "fallopian tubes",
        "oviduct",
        "oviducts",
        "uterine tube"
      ],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "uterus": {
      "label": "uterus",
      "parents": [],
      "aliases": [
        "uterine corpus"
      ],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "vagina": {
      "label": "vagina",
      "parents": [],
      "aliases": [],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "vulva": {
      "label": "vulva",
      "parents": [],
      "aliases": [],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "clitoris": {
      "label": "clitoris",
      "parents": [],
      "aliases": [],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "endometrium": {
      "label": "endometrium",
      "parents": [
        "uterus"
      ],
      "aliases": [
        "endometrium 1",
        "endometrium 2",
        "uterine endometrium"
      ],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "myometrium": {
      "label": "myometrium",
      "parents": [
        "uterus"
      ],
      "aliases": [],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "cervix": {
      "label": "cervix",
      "parents": [
        "uterus"
      ],
      "aliases": [
        "cervix uteri",
        "uterine cervix"
      ],
      "references": [
        "openstax_female",
        "mouse_anatomy"
      ]
    },
    "uterine_horn": {
      "label": "uterine horn",
      "parents": [
        "uterus"
      ],
      "aliases": [
        "uterine horns"
      ],
      "references": [
        "mouse_anatomy",
        "barkbase2019"
      ],
      "taxon_ids": [
        9615,
        10090
      ]
    },
    "mammary_tissue": {
      "label": "Mammary tissue (whole breast or mammary gland)",
      "parents": [],
      "aliases": [
        "breast",
        "mammary gland",
        "mammary glands",
        "mammary tissue",
        "lactating breast"
      ],
      "references": [
        "openstax_female",
        "blagosklonny2003",
        "mouse_anatomy"
      ],
      "notes": "Whole-organ observation includes stroma; it does not establish glandular-cell restriction. Source sex and lactation state remain separate metadata."
    },
    "mammary_glandular": {
      "label": "Mammary glandular epithelium",
      "parents": [
        "mammary_tissue"
      ],
      "aliases": [
        "mammary glandular tissue",
        "breast glandular cells",
        "breast myoepithelial cells"
      ],
      "references": [
        "openstax_female",
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "placenta": {
      "label": "placenta",
      "parents": [],
      "aliases": [
        "placental tissue"
      ],
      "references": [
        "hpa_tissues",
        "project_policy"
      ],
      "notes": "Placenta-specific evidence qualifies directly; maternal/fetal compartment resolution is not required."
    },
    "trophoblast": {
      "label": "trophoblast",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "trophoblasts",
        "trophoblastic cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "cytotrophoblast": {
      "label": "cytotrophoblast",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "cytotrophoblasts"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "syncytiotrophoblast": {
      "label": "syncytiotrophoblast",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "syncytiotrophoblasts"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "extravillous_trophoblast": {
      "label": "extravillous trophoblast",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "extravillous trophoblasts"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "placental_decidua": {
      "label": "placental decidua",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "placental decidual cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "hofbauer_cell": {
      "label": "hofbauer cell",
      "parents": [
        "placenta"
      ],
      "aliases": [
        "hofbauer cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "amnion": {
      "label": "amnion",
      "parents": [],
      "aliases": [
        "amniotic membrane"
      ],
      "references": [
        "project_policy",
        "fetal_atlas2020"
      ]
    },
    "chorion": {
      "label": "chorion",
      "parents": [],
      "aliases": [
        "chorionic membrane"
      ],
      "references": [
        "project_policy",
        "fetal_atlas2020"
      ]
    },
    "yolk_sac": {
      "label": "yolk sac",
      "parents": [],
      "aliases": [],
      "references": [
        "project_policy",
        "fetal_atlas2020"
      ]
    },
    "allantois": {
      "label": "allantois",
      "parents": [],
      "aliases": [],
      "references": [
        "project_policy",
        "fetal_atlas2020"
      ]
    },
    "umbilical_cord": {
      "label": "umbilical cord",
      "parents": [],
      "aliases": [],
      "references": [
        "project_policy",
        "fetal_atlas2020"
      ]
    },
    "embryo": {
      "label": "embryo",
      "parents": [],
      "aliases": [
        "whole embryo",
        "embryonic tissue"
      ],
      "references": [
        "barkbase2019",
        "project_policy"
      ]
    },
    "fetus": {
      "label": "fetus",
      "parents": [],
      "aliases": [
        "foetus",
        "whole fetus",
        "fetal tissue",
        "foetal tissue"
      ],
      "references": [
        "fetal_atlas2020",
        "project_policy"
      ]
    },
    "skin": {
      "label": "skin",
      "parents": [],
      "aliases": [
        "skin 1",
        "skin 2",
        "zone of skin"
      ],
      "references": [
        "hpa_skin"
      ]
    },
    "cutaneous_melanocyte": {
      "label": "Cutaneous melanocytes",
      "parents": [
        "skin"
      ],
      "aliases": [
        "skin melanocytes",
        "cutaneous melanocytes",
        "epidermal melanocytes"
      ],
      "references": [
        "blagosklonny2003",
        "johnson2009",
        "hpa_skin"
      ],
      "notes": "Only cutaneous melanocytes; an unsited melanocyte label, eye, retina and inner ear do not qualify."
    },
    "hair_follicle": {
      "label": "Hair follicle compartment",
      "parents": [
        "skin"
      ],
      "aliases": [
        "hair follicles",
        "hair follicle epithelium",
        "follicular keratinocytes"
      ],
      "references": [
        "nci_alopecia",
        "purba2019",
        "hpa_skin"
      ],
      "notes": "Conditional acceptance of alopecia; includes follicular epithelial compartments. A bulk follicle does not resolve matrix versus bulge/stem-cell involvement or reversibility."
    },
    "adipose_tissue": {
      "label": "adipose tissue",
      "parents": [],
      "aliases": [
        "adipose"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "adrenal_gland": {
      "label": "adrenal gland",
      "parents": [],
      "aliases": [
        "adrenal"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "brain": {
      "label": "brain",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "amygdala": {
      "label": "amygdala",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "basal_ganglia": {
      "label": "basal ganglia",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "cerebellum": {
      "label": "cerebellum",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "cerebral_cortex": {
      "label": "cerebral cortex",
      "parents": [
        "cerebrum"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "choroid_plexus": {
      "label": "choroid plexus",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "hippocampus": {
      "label": "hippocampus",
      "parents": [
        "hippocampal_formation"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "hypothalamus": {
      "label": "hypothalamus",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "midbrain": {
      "label": "midbrain",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "dorsal_raphe": {
      "label": "dorsal raphe",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "substantia_nigra": {
      "label": "substantia nigra",
      "parents": [
        "brain"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "spinal_cord": {
      "label": "spinal cord",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "retina": {
      "label": "retina",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues",
        "nei_retina"
      ]
    },
    "eye": {
      "label": "eye",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues",
        "nei_retina",
        "johnson2009"
      ]
    },
    "inner_ear": {
      "label": "inner ear",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues",
        "johnson2009"
      ]
    },
    "heart": {
      "label": "heart",
      "parents": [],
      "aliases": [
        "heart muscle"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "kidney": {
      "label": "kidney",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "liver": {
      "label": "liver",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "lung": {
      "label": "lung",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "pancreas": {
      "label": "pancreas",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "thyroid_gland": {
      "label": "thyroid gland",
      "parents": [],
      "aliases": [
        "thyroid"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "parathyroid_gland": {
      "label": "parathyroid gland",
      "parents": [],
      "aliases": [
        "parathyroid"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "pituitary_gland": {
      "label": "pituitary gland",
      "parents": [],
      "aliases": [
        "pituitary"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "salivary_gland": {
      "label": "salivary gland",
      "parents": [],
      "aliases": [
        "salivary"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "bone_marrow": {
      "label": "bone marrow",
      "parents": [],
      "aliases": [
        "bonemarrow"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "blood": {
      "label": "blood",
      "parents": [],
      "aliases": [
        "white blood cells",
        "peripheral blood mononuclear cells"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "lymph_node": {
      "label": "lymph node",
      "parents": [],
      "aliases": [
        "lymphnode"
      ],
      "references": [
        "hpa_tissues",
        "nci_lymph_nodes"
      ],
      "notes": "Distributed lymphatic and immune organ. Limited regional excision does not justify allowing expression across the entire lymph-node system."
    },
    "spleen": {
      "label": "spleen",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues",
        "cdc_asplenia",
        "nci_lymph_nodes"
      ],
      "notes": "Conditional project allowance. Organ loss requires infection-risk management; expression in shared immune cells needs separate distribution review."
    },
    "thymus": {
      "label": "thymus",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "tonsil": {
      "label": "tonsil",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues",
        "mouse_lymphoid",
        "nhs_tonsillectomy",
        "nci_lymph_nodes"
      ],
      "taxon_ids": [
        9606,
        9615
      ],
      "notes": "Native tonsil samples, with palatine tonsillectomy as the human rationale. Does not include adenoids, all mucosal lymphoid tissue or mouse NALT. Bulk source labels do not establish cell-type confinement."
    },
    "appendix": {
      "label": "appendix",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ],
      "taxon_ids": [
        9606
      ],
      "notes": "Human appendix label only; animal caecal lymphoid tissue is not mapped to vermiform appendix."
    },
    "esophagus": {
      "label": "esophagus",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "stomach": {
      "label": "stomach",
      "parents": [],
      "aliases": [
        "stomach 1",
        "stomach 2"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "colon": {
      "label": "colon",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "rectum": {
      "label": "rectum",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "small_intestine": {
      "label": "small intestine",
      "parents": [],
      "aliases": [
        "smallintestine"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "gallbladder": {
      "label": "gallbladder",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "urinary_bladder": {
      "label": "urinary bladder",
      "parents": [],
      "aliases": [
        "bladder"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "ureter": {
      "label": "ureter",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "skeletal_muscle": {
      "label": "skeletal muscle",
      "parents": [],
      "aliases": [
        "skeletalmuscle",
        "muscle tissue"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "smooth_muscle": {
      "label": "smooth muscle",
      "parents": [],
      "aliases": [
        "smooth muscle tissue"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "cartilage": {
      "label": "cartilage",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "soft_tissue": {
      "label": "soft tissue",
      "parents": [],
      "aliases": [
        "soft tissue 1",
        "soft tissue 2"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "peripheral_nerve": {
      "label": "peripheral nerve",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "endothelium": {
      "label": "endothelium",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "oral_mucosa": {
      "label": "oral mucosa",
      "parents": [],
      "aliases": [
        "buccal oral mucosa"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "nasopharynx": {
      "label": "nasopharynx",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "tongue": {
      "label": "tongue",
      "parents": [],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "head": {
      "label": "head",
      "parents": [],
      "aliases": [
        "heads"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "nail_bed": {
      "label": "nail bed",
      "parents": [
        "skin"
      ],
      "aliases": [],
      "references": [
        "hpa_tissues"
      ]
    },
    "foot": {
      "label": "foot",
      "parents": [],
      "aliases": [
        "sole of foot"
      ],
      "references": [
        "hpa_tissues"
      ]
    },
    "cerebrum": {
      "label": "cerebrum",
      "parents": [
        "brain"
      ],
      "aliases": [
        "cerebrum"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "caudate": {
      "label": "caudate",
      "parents": [
        "basal_ganglia"
      ],
      "aliases": [
        "caudate"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "hippocampal_formation": {
      "label": "hippocampal formation",
      "parents": [
        "brain"
      ],
      "aliases": [
        "hippocampal formation"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "frontal_cortex": {
      "label": "frontal cortex",
      "parents": [
        "cerebral_cortex"
      ],
      "aliases": [
        "frontalcortex"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "occipital_cortex": {
      "label": "occipital cortex",
      "parents": [
        "cerebral_cortex"
      ],
      "aliases": [
        "occipitalcortex"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "renal_cortex": {
      "label": "renal cortex",
      "parents": [
        "kidney"
      ],
      "aliases": [
        "kidneycortex"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "renal_medulla": {
      "label": "renal medulla",
      "parents": [
        "kidney"
      ],
      "aliases": [
        "kidneymedulla"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "left_atrium": {
      "label": "left atrium",
      "parents": [
        "heart"
      ],
      "aliases": [
        "leftatrium"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "right_atrium": {
      "label": "right atrium",
      "parents": [
        "heart"
      ],
      "aliases": [
        "rightatrium"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "left_ventricle": {
      "label": "left ventricle",
      "parents": [
        "heart"
      ],
      "aliases": [
        "leftventricle"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "right_ventricle": {
      "label": "right ventricle",
      "parents": [
        "heart"
      ],
      "aliases": [
        "rightventricle"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "duodenum": {
      "label": "duodenum",
      "parents": [
        "small_intestine"
      ],
      "aliases": [
        "duodenum"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "ileum": {
      "label": "ileum",
      "parents": [
        "small_intestine"
      ],
      "aliases": [
        "ileum"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "jejunum": {
      "label": "jejunum",
      "parents": [
        "small_intestine"
      ],
      "aliases": [
        "jejunum"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "bronchus": {
      "label": "bronchus",
      "parents": [],
      "aliases": [
        "bronchus"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "parotid_gland": {
      "label": "parotid gland",
      "parents": [
        "salivary_gland"
      ],
      "aliases": [
        "parotid gland"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    },
    "retinal_pigment_epithelium": {
      "label": "retinal pigment epithelium",
      "parents": [
        "retina"
      ],
      "aliases": [
        "retinal pigment epithelium"
      ],
      "references": [
        "hpa_tissues",
        "mouse_anatomy"
      ]
    }
  },
  "scopes": {
    "testis": {
      "roots": [
        "testis"
      ],
      "union": [],
      "aliases": [
        "male_strict"
      ],
      "description": "Testis and its explicitly mapped subcompartments."
    },
    "oocyte": {
      "roots": [
        "oocyte"
      ],
      "union": [],
      "aliases": [
        "female_strict"
      ],
      "description": "Oocytes only; bulk ovary and follicle cells do not imply oocyte expression."
    },
    "ovary": {
      "roots": [
        "ovary"
      ],
      "union": [],
      "aliases": [],
      "description": "Whole ovary and ovarian subcompartments, including oocytes."
    },
    "mammary_glandular": {
      "roots": [
        "mammary_glandular"
      ],
      "union": [],
      "aliases": [],
      "description": "Explicit mammary glandular epithelium; bulk breast/mammary samples are broader."
    },
    "mammary": {
      "roots": [
        "mammary_tissue"
      ],
      "union": [],
      "aliases": [],
      "description": "Mammary organ and its mapped subcompartments; lactation and sex retained separately."
    },
    "male_reproductive": {
      "roots": [
        "epididymis",
        "vas_deferens",
        "prostate",
        "seminal_vesicle",
        "bulbourethral_gland",
        "penis",
        "spermatozoon"
      ],
      "union": [
        "testis"
      ],
      "aliases": [
        "male_extended"
      ],
      "description": "Testis, spermatozoa, and species-applicable male reproductive ducts, accessory glands and penis."
    },
    "female_reproductive": {
      "roots": [
        "fallopian_tube",
        "uterus",
        "vagina",
        "vulva",
        "clitoris"
      ],
      "union": [
        "ovary",
        "mammary"
      ],
      "aliases": [
        "female_extended"
      ],
      "description": "Ovary, reproductive tract and mammary tissue; this anatomical grouping does not infer sample sex."
    },
    "placental": {
      "roots": [
        "placenta"
      ],
      "union": [],
      "aliases": [],
      "description": "Placenta, with or without further compartment annotation."
    },
    "extraembryonic": {
      "roots": [
        "amnion",
        "chorion",
        "yolk_sac",
        "allantois",
        "umbilical_cord"
      ],
      "union": [
        "placental"
      ],
      "aliases": [],
      "description": "Placenta and other extraembryonic tissues."
    },
    "embryonic": {
      "roots": [
        "embryo"
      ],
      "union": [],
      "aliases": [],
      "description": "Whole embryo or tissue explicitly sampled at an embryonic stage; source organ is retained."
    },
    "fetal": {
      "roots": [
        "fetus"
      ],
      "union": [],
      "aliases": [],
      "description": "Whole fetus or tissue explicitly sampled at a fetal stage; source organ is retained."
    },
    "reproductive_core": {
      "roots": [],
      "union": [
        "testis",
        "ovary",
        "placental"
      ],
      "aliases": [
        "core"
      ],
      "description": "Historical core anatomical union: testis, ovary and placenta."
    },
    "reproductive": {
      "roots": [],
      "union": [
        "male_reproductive",
        "female_reproductive",
        "extraembryonic",
        "embryonic",
        "fetal"
      ],
      "aliases": [
        "extended",
        "permissive"
      ],
      "description": "Project union across all reproductive-organ and developmental contexts."
    },
    "disposable_normal": {
      "roots": [
        "cutaneous_melanocyte",
        "hair_follicle"
      ],
      "union": [],
      "aliases": [],
      "description": "Conditional research exception for cutaneous melanocytes and hair follicles. Not all skin, pigment cells or normal tissues. Human rationale; animal tolerability is unvalidated."
    },
    "reproductive_or_disposable": {
      "roots": [],
      "union": [
        "reproductive",
        "disposable_normal"
      ],
      "aliases": [],
      "description": "Union of reproductive and conditionally disposable normal tissue contexts."
    },
    "permitted_normal": {
      "roots": [
        "tonsil",
        "appendix",
        "gallbladder"
      ],
      "union": [
        "disposable_normal"
      ],
      "aliases": [
        "acceptable_normal"
      ],
      "description": "Conditionally acceptable normal contexts comprising tonsil, appendix and gallbladder, plus cutaneous melanocytes and follicles. Tonsil requires review of immune-cell distribution, age and immune reserve. Whole skin, salivary glands, thymus and spleen no longer receive a default allowance. Permission applies only to the sampled organ, not the same cell type elsewhere."
    },
    "reproductive_or_permitted_normal": {
      "roots": [],
      "union": [
        "reproductive",
        "permitted_normal"
      ],
      "aliases": [
        "reproductive_or_acceptable_normal"
      ],
      "description": "Expanded project union of reproductive contexts and permitted normal tissues. Heart, lung, CNS, liver, pancreas, retina and muscle are outside."
    }
  },
  "screening_policies": {
    "tiered_cta": {
      "policy_id": "oncoref.cta-permitted-screen.2026-10-20.5",
      "permitted_scope": "reproductive_or_permitted_normal",
      "required_positive_scope": "reproductive",
      "minimum_reproductive_rna": 1.0,
      "tier_labels": {
        "permitted": "Permitted",
        "vital": "Vital",
        "protected": "Protected",
        "manageable": "Manageable",
        "unresolved": "Unresolved"
      },
      "rna_source": "hpa_rna_consensus",
      "rna_source_version": "v23",
      "rna_species": "human",
      "rna_unit": "nTPM",
      "minimum_permitted_rna": 1.0,
      "positive_ihc_levels": [
        "Low",
        "Medium",
        "High",
        "Ascending",
        "Descending"
      ],
      "vital": {
        "maximum_rna": 1.0,
        "minimum_reproductive_selectivity": 0.99,
        "roots": [
          "heart",
          "lung",
          "bronchus",
          "brain",
          "spinal_cord",
          "liver",
          "kidney",
          "bone_marrow",
          "blood",
          "adrenal_gland",
          "pituitary_gland",
          "pancreas",
          "small_intestine",
          "skeletal_muscle",
          "smooth_muscle",
          "peripheral_nerve",
          "endothelium",
          "retina",
          "eye",
          "inner_ear"
        ],
        "description": "Strictest project tier for organs whose extensive injury can threaten life or cause major irreversible neurological or sensory loss. Includes all mapped descendants. Vital is the stable machine identifier; the full meaning is vital or critical function."
      },
      "protected": {
        "maximum_rna": 2.0,
        "minimum_reproductive_selectivity": 0.97,
        "roots": [
          "salivary_gland",
          "parathyroid_gland",
          "lymph_node",
          "esophagus",
          "stomach",
          "colon",
          "rectum",
          "urinary_bladder",
          "ureter",
          "cartilage",
          "oral_mucosa",
          "nasopharynx",
          "tongue"
        ],
        "description": "Higher protection priority for persistent functional or structural injury and important mucosal or distributed-organ function. Any positive IHC excludes. Injury can be severe or fatal; this is a relative research priority."
      },
      "manageable": {
        "maximum_rna": 5.0,
        "minimum_reproductive_selectivity": 0.95,
        "roots": [
          "skin",
          "spleen",
          "thymus",
          "thyroid_gland",
          "adipose_tissue"
        ],
        "description": "Conditional manageability is a relative project priority, informed by published caution/non-essential groups and organ-specific evidence. These tissues remain screened and any positive IHC excludes. The name describes potential management or compensation for selected injuries, not established control of every injury. It does not imply reversibility, local-steroid control or dispensability. Explicit permitted cutaneous compartments take precedence over skin."
      },
      "context_reviews": {
        "removable_digestive_organs": {
          "roots": [
            "appendix",
            "gallbladder"
          ],
          "flags": [
            "in_situ_inflammation_review"
          ],
          "references": [
            "nhs_appendix",
            "niddk_gallbladder"
          ],
          "rationale": "Organ removal can be tolerated, but in-situ immune injury may cause inflammation, leakage or obstruction. The allowance does not extend to adjacent intestine, liver, bile ducts or shared immune populations.",
          "allowance_basis": "organ_removal",
          "local_steroid_control": "not_established"
        },
        "skin_injury_extent": {
          "roots": [
            "skin"
          ],
          "flags": [
            "skin_compartment_and_extent_review",
            "local_control_not_guaranteed"
          ],
          "references": [
            "sitc2021",
            "johnson2009",
            "bradley2020"
          ],
          "rationale": "Whole skin is Manageable and remains subject to RNA and IHC gates. Distinguish permitted cutaneous pigment or follicular loss from extensive epithelial, blistering or mucosal injury. Local corticosteroid use for selected toxicities is not guaranteed rescue from persistent antigen-directed T cells.",
          "allowance_basis": "no_whole_skin_allowance",
          "local_steroid_control": "supported_for_selected_manifestations_not_general_ablation"
        },
        "salivary_function": {
          "roots": [
            "salivary_gland"
          ],
          "flags": [
            "persistent_salivary_dysfunction_review",
            "local_control_not_established"
          ],
          "references": [
            "warner2019",
            "bradley2020"
          ],
          "rationale": "Salivary glands are Protected. Published immune-mediated injury can cause persistent low salivary secretion despite symptom improvement. Minor-gland expression does not establish restriction to one removable gland.",
          "allowance_basis": "no_default_allowance",
          "local_steroid_control": "not_established_with_persistent_dysfunction_reported"
        },
        "lymphoid_organ_review": {
          "roots": [
            "tonsil",
            "spleen",
            "thymus"
          ],
          "flags": [
            "immune_cell_distribution_review",
            "age_and_immune_reserve_review"
          ],
          "references": [
            "nhs_tonsillectomy",
            "cdc_asplenia",
            "nci_lymph_nodes",
            "project_policy"
          ],
          "rationale": "Only tonsil retains a conditional allowance; spleen and thymus are Manageable and must pass RNA and IHC gates. Identify the expressing cell population and its distribution in blood, marrow and other organs. Assess age and immune reserve. Surgery is not a model of systemic antigen-directed injury. Bulk tissue cannot establish organ confinement.",
          "allowance_basis": "tonsil_only_conditional_allowance",
          "local_steroid_control": "not_established"
        },
        "spleen_infection_risk": {
          "roots": [
            "spleen"
          ],
          "flags": [
            "asplenia_infection_risk_review"
          ],
          "references": [
            "cdc_asplenia",
            "kristinsson2014"
          ],
          "rationale": "Assess consequences of functional asplenia and an appropriate infection-prevention and management strategy before therapeutic acceptance.",
          "local_steroid_control": "not_established"
        },
        "thymus_long_term_function": {
          "roots": [
            "thymus"
          ],
          "flags": [
            "thymic_function_review",
            "age_and_immune_reserve_review"
          ],
          "references": [
            "kooshesh2023"
          ],
          "rationale": "Adult thymectomy has observational associations with mortality and cancer. Thymus is Manageable, not disposable; pediatric consequences need separate review. Surgery does not quantify antigen-directed injury.",
          "local_steroid_control": "not_established"
        },
        "cartilage_structural_function": {
          "roots": [
            "cartilage"
          ],
          "flags": [
            "persistent_structural_injury_review",
            "cartilage_site_review"
          ],
          "references": [
            "heinemeier2016",
            "braaten2020"
          ],
          "rationale": "Cartilage is Protected because structural injury may persist. Articular-collagen turnover and inflammatory-arthritis studies provide indirect support, not direct chondrocyte-targeting safety evidence. A generic cartilage label does not locate a joint or exclude airway cartilage.",
          "local_steroid_control": "symptom_control_does_not_establish_structural_repair"
        },
        "distributed_lymph_nodes": {
          "roots": [
            "lymph_node"
          ],
          "flags": [
            "lymphatic_and_immune_function_review"
          ],
          "references": [
            "nci_lymph_nodes"
          ],
          "rationale": "Remains Protected. Regional removal does not justify whole-system depletion or injury to lymphatic stroma. Lineage-specific exceptions require a separately defined policy and evidence."
        }
      },
      "unresolved_roots": [
        "head",
        "foot",
        "soft_tissue"
      ],
      "references": [
        "project_policy",
        "hpa_tissue_specificity",
        "hpa_tissues",
        "nci_organ_inflammation",
        "niddk_adrenal",
        "nhs_tonsillectomy",
        "cdc_asplenia",
        "nci_lymph_nodes",
        "nei_retina",
        "johnson2009",
        "bradley2020",
        "kaufmann2019",
        "kooshesh2023",
        "kristinsson2014",
        "heinemeier2016",
        "braaten2020",
        "warner2019",
        "sitc2021"
      ],
      "review_semantics": "Review annotations do not add numerical tiers or establish clinical acceptability. Positive observations in flagged contexts remain visible even when a candidate passes the research expression screen.",
      "coverage": "Complete routine bulk RNA is required. Missing or partial IHC is reported explicitly and cannot establish protein absence. Unresolved positive anatomy, unusable measurements and reviewed unreliable IHC block retention.",
      "species_note": "Anatomical tiers apply to human, dog and mouse. The numerical policy is calibrated only as a project screen for human HPA v23 nTPM; numerical thresholds and clinical tolerability do not transfer to other species."
    },
    "ihc_adaptive_cta": {
      "policy_id": "oncoref.cta-ihc-adaptive-screen.2026-10-20.5",
      "permitted_scope": "reproductive_or_permitted_normal",
      "required_positive_scope": "reproductive",
      "minimum_reproductive_rna": 1.0,
      "tier_labels": {
        "permitted": "Permitted",
        "vital": "Vital",
        "protected": "Protected",
        "manageable": "Manageable",
        "unresolved": "Unresolved"
      },
      "rna_source": "hpa_rna_consensus",
      "rna_source_version": "v23",
      "rna_species": "human",
      "rna_unit": "nTPM",
      "minimum_permitted_rna": 1.0,
      "positive_ihc_levels": [
        "Low",
        "Medium",
        "High",
        "Ascending",
        "Descending"
      ],
      "vital": {
        "maximum_rna": 1.0,
        "minimum_reproductive_selectivity": 0.99,
        "roots": [
          "heart",
          "lung",
          "bronchus",
          "brain",
          "spinal_cord",
          "liver",
          "kidney",
          "bone_marrow",
          "blood",
          "adrenal_gland",
          "pituitary_gland",
          "pancreas",
          "small_intestine",
          "skeletal_muscle",
          "smooth_muscle",
          "peripheral_nerve",
          "endothelium",
          "retina",
          "eye",
          "inner_ear"
        ],
        "description": "Strictest project tier for organs whose extensive injury can threaten life or cause major irreversible neurological or sensory loss. Includes all mapped descendants. Vital is the stable machine identifier; the full meaning is vital or critical function."
      },
      "protected": {
        "maximum_rna": 2.0,
        "minimum_reproductive_selectivity": 0.97,
        "roots": [
          "salivary_gland",
          "parathyroid_gland",
          "lymph_node",
          "esophagus",
          "stomach",
          "colon",
          "rectum",
          "urinary_bladder",
          "ureter",
          "cartilage",
          "oral_mucosa",
          "nasopharynx",
          "tongue"
        ],
        "description": "Higher protection priority for persistent functional or structural injury and important mucosal or distributed-organ function. Any positive IHC excludes. Injury can be severe or fatal; this is a relative research priority."
      },
      "manageable": {
        "maximum_rna": 5.0,
        "minimum_reproductive_selectivity": 0.95,
        "roots": [
          "skin",
          "spleen",
          "thymus",
          "thyroid_gland",
          "adipose_tissue"
        ],
        "description": "Conditional manageability is a relative project priority, informed by published caution/non-essential groups and organ-specific evidence. These tissues remain screened and any positive IHC excludes. The name describes potential management or compensation for selected injuries, not established control of every injury. It does not imply reversibility, local-steroid control or dispensability. Explicit permitted cutaneous compartments take precedence over skin."
      },
      "context_reviews": {
        "removable_digestive_organs": {
          "roots": [
            "appendix",
            "gallbladder"
          ],
          "flags": [
            "in_situ_inflammation_review"
          ],
          "references": [
            "nhs_appendix",
            "niddk_gallbladder"
          ],
          "rationale": "Organ removal can be tolerated, but in-situ immune injury may cause inflammation, leakage or obstruction. The allowance does not extend to adjacent intestine, liver, bile ducts or shared immune populations.",
          "allowance_basis": "organ_removal",
          "local_steroid_control": "not_established"
        },
        "skin_injury_extent": {
          "roots": [
            "skin"
          ],
          "flags": [
            "skin_compartment_and_extent_review",
            "local_control_not_guaranteed"
          ],
          "references": [
            "sitc2021",
            "johnson2009",
            "bradley2020"
          ],
          "rationale": "Whole skin is Manageable and remains subject to RNA and IHC gates. Distinguish permitted cutaneous pigment or follicular loss from extensive epithelial, blistering or mucosal injury. Local corticosteroid use for selected toxicities is not guaranteed rescue from persistent antigen-directed T cells.",
          "allowance_basis": "no_whole_skin_allowance",
          "local_steroid_control": "supported_for_selected_manifestations_not_general_ablation"
        },
        "salivary_function": {
          "roots": [
            "salivary_gland"
          ],
          "flags": [
            "persistent_salivary_dysfunction_review",
            "local_control_not_established"
          ],
          "references": [
            "warner2019",
            "bradley2020"
          ],
          "rationale": "Salivary glands are Protected. Published immune-mediated injury can cause persistent low salivary secretion despite symptom improvement. Minor-gland expression does not establish restriction to one removable gland.",
          "allowance_basis": "no_default_allowance",
          "local_steroid_control": "not_established_with_persistent_dysfunction_reported"
        },
        "lymphoid_organ_review": {
          "roots": [
            "tonsil",
            "spleen",
            "thymus"
          ],
          "flags": [
            "immune_cell_distribution_review",
            "age_and_immune_reserve_review"
          ],
          "references": [
            "nhs_tonsillectomy",
            "cdc_asplenia",
            "nci_lymph_nodes",
            "project_policy"
          ],
          "rationale": "Only tonsil retains a conditional allowance; spleen and thymus are Manageable and must pass RNA and IHC gates. Identify the expressing cell population and its distribution in blood, marrow and other organs. Assess age and immune reserve. Surgery is not a model of systemic antigen-directed injury. Bulk tissue cannot establish organ confinement.",
          "allowance_basis": "tonsil_only_conditional_allowance",
          "local_steroid_control": "not_established"
        },
        "spleen_infection_risk": {
          "roots": [
            "spleen"
          ],
          "flags": [
            "asplenia_infection_risk_review"
          ],
          "references": [
            "cdc_asplenia",
            "kristinsson2014"
          ],
          "rationale": "Assess consequences of functional asplenia and an appropriate infection-prevention and management strategy before therapeutic acceptance.",
          "local_steroid_control": "not_established"
        },
        "thymus_long_term_function": {
          "roots": [
            "thymus"
          ],
          "flags": [
            "thymic_function_review",
            "age_and_immune_reserve_review"
          ],
          "references": [
            "kooshesh2023"
          ],
          "rationale": "Adult thymectomy has observational associations with mortality and cancer. Thymus is Manageable, not disposable; pediatric consequences need separate review. Surgery does not quantify antigen-directed injury.",
          "local_steroid_control": "not_established"
        },
        "cartilage_structural_function": {
          "roots": [
            "cartilage"
          ],
          "flags": [
            "persistent_structural_injury_review",
            "cartilage_site_review"
          ],
          "references": [
            "heinemeier2016",
            "braaten2020"
          ],
          "rationale": "Cartilage is Protected because structural injury may persist. Articular-collagen turnover and inflammatory-arthritis studies provide indirect support, not direct chondrocyte-targeting safety evidence. A generic cartilage label does not locate a joint or exclude airway cartilage.",
          "local_steroid_control": "symptom_control_does_not_establish_structural_repair"
        },
        "distributed_lymph_nodes": {
          "roots": [
            "lymph_node"
          ],
          "flags": [
            "lymphatic_and_immune_function_review"
          ],
          "references": [
            "nci_lymph_nodes"
          ],
          "rationale": "Remains Protected. Regional removal does not justify whole-system depletion or injury to lymphatic stroma. Lineage-specific exceptions require a separately defined policy and evidence."
        }
      },
      "unresolved_roots": [
        "head",
        "foot",
        "soft_tissue"
      ],
      "references": [
        "project_policy",
        "hpa_tissue_specificity",
        "hpa_tissues",
        "nci_organ_inflammation",
        "niddk_adrenal",
        "nhs_tonsillectomy",
        "cdc_asplenia",
        "nci_lymph_nodes",
        "nei_retina",
        "johnson2009",
        "bradley2020",
        "kaufmann2019",
        "kooshesh2023",
        "kristinsson2014",
        "heinemeier2016",
        "braaten2020",
        "warner2019",
        "sitc2021"
      ],
      "review_semantics": "Review annotations do not add numerical tiers or establish clinical acceptability. Positive observations in flagged contexts remain visible even when a candidate passes the research expression screen.",
      "coverage": "Complete routine bulk RNA is required. Missing or partial IHC is reported explicitly and cannot establish protein absence. Unresolved positive anatomy, unusable measurements and reviewed unreliable IHC block retention.",
      "species_note": "Anatomical tiers apply to human, dog and mouse. The numerical policy is calibrated only as a project screen for human HPA v23 nTPM; numerical thresholds and clinical tolerability do not transfer to other species.",
      "ihc_source": "hpa_normal_tissue",
      "ihc_source_version": "v23",
      "negative_ihc_rna_limits": {
        "Missing": {
          "vital": 1.0,
          "protected": 2.0,
          "manageable": 5.0
        },
        "Uncertain": {
          "vital": 1.0,
          "protected": 2.0,
          "manageable": 5.0
        },
        "Approved": {
          "vital": 2.0,
          "protected": 4.0,
          "manageable": 10.0
        },
        "Supported": {
          "vital": 3.0,
          "protected": 6.0,
          "manageable": 15.0
        },
        "Enhanced": {
          "vital": 6.0,
          "protected": 12.0,
          "manageable": 30.0
        }
      },
      "negative_ihc_rule": "Relax only with valid Not detected observations in every routine IHC tissue/cell context mapping to the same anatomical tissue as the RNA measurement. Use the weakest reliability among all observations in that tissue. Missing contexts, unknown reliability, invalid observations, positive staining or reviewed-unreliable IHC cannot earn relaxation. A narrower region cannot clear a broader organ; other organs cannot supply negative evidence. Enhanced describes source validation, not a guaranteed limit of detection for a negative stain or for peptide-HLA presentation.",
      "negative_ihc_minimum_reproductive_selectivity": {
        "Missing": {
          "vital": 0.99,
          "protected": 0.97,
          "manageable": 0.95
        },
        "Uncertain": {
          "vital": 0.99,
          "protected": 0.97,
          "manageable": 0.95
        },
        "Approved": {
          "vital": 0.98,
          "protected": 0.95,
          "manageable": 0.9
        },
        "Supported": {
          "vital": 0.97,
          "protected": 0.9,
          "manageable": 0.8
        },
        "Enhanced": {
          "vital": 0.95,
          "protected": 0.8,
          "manageable": 0.6
        }
      },
      "reproductive_selectivity": {
        "formula": "Rmax / (Rmax + tissue_rna_ntpm)",
        "reference": "Maximum valid raw RNA across mapped Reproductive tissues for the same gene, species, source and version. Disposable does not enter the reference.",
        "minimum_reference": "Strictly positive; a zero or missing reference is unresolved.",
        "comparison": "Inclusive minimum per screened RNA observation. The same local negative-IHC evidence chooses both the RNA ceiling and selectivity threshold.",
        "aggregation": "Every screened tissue must pass both gates. Category summaries report the worst margin against its own threshold, not a pooled category score.",
        "meaning": "Pairwise expression selectivity, not percent of total-body RNA or protein. Uses raw nTPM without deflation, averaging, tissue sums or rounding before gating.",
        "provenance": "User-approved project grid. Protected reuses the numerical ladder of the legacy global deflated score, but this new metric has different semantics and is not calibrated to the same pass rate. Neither grid is clinically validated."
      },
      "threshold_provenance": "Project starting grid specified for the requested category by IHC-evidence screen on 2026-10-20. Vital 1/2/3/6 and Protected 2/4/6/12 follow the user's earlier proposed sensitivity values; Manageable 5/10/15/30 extends that grid. The user approved all three ladders. Literature supports graded priorities, not these HPA nTPM values or a conversion from GTEx TPM. These are not clinically validated or estimated from outcomes. Missing/Uncertain equals the fixed baseline. HPA reliability labels are evidence strata, not calibrated probabilities of a negative stain or peptide-HLA absence."
    }
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