# POTS deep-phenotyping facet vocabulary.
#
# A facet is a labelled axis of evidence, NOT a mutually exclusive subtype.
# Angeli et al. (Sci Rep 2024) classified 352 patients and found 42% met two
# mechanistic definitions and 11% met all three; symptoms alone did not separate
# them. The vocabulary is therefore built as overlapping evidence flags that a
# patient (or a paper) can carry in any combination.
#
# Every facet carries:
#   pubmed_query  - AND-ed with the corpus query to tag which papers discuss it.
#   mesh_terms    - descriptor names for a second, indexing-based tag path.
#   concepts      - search terms handed to the OMOP concept resolver. These are
#                   SEARCH TERMS, not asserted codes: no concept_id or code is
#                   hand-written in this repo. The resolver looks them up and
#                   records provenance, and every mapping lands as
#                   mapping_status='unreviewed' until a human signs it off.
#                   fallback_gap: true marks a term that is correct against full
#                   SNOMED but that the public fallback service cannot resolve,
#                   because the EBI Ontology Lookup Service carries only a subset
#                   of SNOMED. Such a term is kept deliberately: it is the right
#                   thing to look up once an ATHENA bundle is available, and the
#                   validation report lists it as a known fallback gap rather
#                   than as a vocabulary error.
#
# groups: mechanism | measurement | comorbidity | treatment

groups:
  mechanism:
    label: Mechanistic evidence flag
    definition: >
      A pathophysiological process proposed to produce or sustain orthostatic
      tachycardia. These are the flags intended to become OMOP-computable
      phenotype outputs.
  measurement:
    label: Objective test or measurement
    definition: >
      A procedure or laboratory measurement that supplies objective evidence for
      one or more mechanism flags. These are what an OMOP phenotype can actually
      observe, in the Measurement and Procedure domains.
  comorbidity:
    label: Comorbidity, etiology or differential
    definition: >
      A co-occurring condition, a triggering exposure, or a competing diagnosis
      that changes the interpretation of a mechanism flag.
  treatment:
    label: Treatment whose use implies a phenotype
    definition: >
      An intervention whose prescription is itself weak evidence of a clinician's
      mechanistic hypothesis, usable as a Drug- or Procedure-domain proxy.

facets:

  # ---------------------------------------------------------------- mechanism
  - id: hyperadrenergic_evidence
    group: mechanism
    label: Hyperadrenergic evidence
    definition: >
      Excess sympathetic outflow or impaired noradrenaline clearance: upright
      plasma noradrenaline elevation, marked orthostatic hypertension, tremor and
      cold sweaty extremities, or a noradrenaline transporter deficiency.
    pubmed_query: 'hyperadrenergic[tiab] OR "hyper-adrenergic"[tiab] OR ("norepinephrine"[tiab] OR "noradrenaline"[tiab] OR catecholamine*[tiab] OR "sympathetic activation"[tiab] OR "sympathetic overactivity"[tiab] OR "muscle sympathetic nerve activity"[tiab] OR "norepinephrine transporter"[tiab] OR SLC6A2[tiab])'
    mesh_terms: ['Norepinephrine', 'Catecholamines', 'Sympathetic Nervous System', 'Epinephrine', 'Norepinephrine Plasma Membrane Transport Proteins']
    concepts:
      - {vocabulary: SNOMED, search_term: 'increased sympathetic activity', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'orthostatic hypertension', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'standing blood pressure'}
      - {vocabulary: LOINC,  search_term: 'norepinephrine plasma'}
      - {vocabulary: LOINC,  search_term: 'norepinephrine standing'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013, zhang2022, larsen2025]

  - id: neuropathic_evidence
    group: mechanism
    label: Neuropathic evidence
    definition: >
      Peripheral autonomic denervation: a small-fibre and sudomotor deficit,
      often patchy rather than length-dependent, that impairs lower-limb
      vasoconstriction and lets blood pool in the legs.
    pubmed_query: '"small fiber"[tiab] OR "small-fibre"[tiab] OR "small fibre"[tiab] OR neuropathic[tiab] OR neuropathy[tiab] OR denervation[tiab] OR "sudomotor"[tiab] OR "nerve fiber density"[tiab] OR "nerve fibre density"[tiab] OR "venous pooling"[tiab] OR "acral"[tiab]'
    mesh_terms: ['Peripheral Nervous System Diseases', 'Small Fiber Neuropathy', 'Sweat Glands', 'Nerve Fibers, Unmyelinated', 'Autonomic Nervous System Diseases']
    concepts:
      - {vocabulary: SNOMED, search_term: 'small fibre neuropathy'}
      - {vocabulary: SNOMED, search_term: 'autonomic neuropathy'}
      - {vocabulary: SNOMED, search_term: 'anhidrosis'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013, zhang2022, larsen2025]

  - id: hypovolemic_evidence
    group: mechanism
    label: Hypovolemic evidence
    definition: >
      Reduced plasma or red-cell volume, frequently with a paradoxically low
      plasma renin activity and aldosterone for the degree of volume depletion.
    pubmed_query: 'hypovolemi*[tiab] OR hypovolaemi*[tiab] OR "plasma volume"[tiab] OR "blood volume"[tiab] OR "red cell volume"[tiab] OR "renin"[tiab] OR "aldosterone"[tiab] OR "angiotensin"[tiab] OR "volume depletion"[tiab] OR "volume expansion"[tiab]'
    mesh_terms: ['Hypovolemia', 'Plasma Volume', 'Blood Volume', 'Renin', 'Aldosterone', 'Renin-Angiotensin System']
    concepts:
      - {vocabulary: SNOMED, search_term: 'hypovolaemia'}
      - {vocabulary: LOINC,  search_term: 'plasma volume'}
      - {vocabulary: LOINC,  search_term: 'renin activity plasma'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013, zhang2022]

  - id: deconditioning_evidence
    group: mechanism
    label: Deconditioning evidence
    definition: >
      Reduced cardiac mass and stroke volume with low peak oxygen uptake, whether
      as primary cause or as a secondary consequence of activity avoidance. Its
      causal direction is contested, which is exactly why it is a flag and not a
      subtype.
    pubmed_query: 'deconditioning[tiab] OR deconditioned[tiab] OR "physical inactivity"[tiab] OR "bed rest"[tiab] OR "exercise capacity"[tiab] OR "peak oxygen"[tiab] OR VO2[tiab] OR "cardiac atrophy"[tiab] OR "stroke volume"[tiab] OR "cardiac mass"[tiab]'
    mesh_terms: ['Bed Rest', 'Exercise Tolerance', 'Oxygen Consumption', 'Cardiomegaly', 'Sedentary Behavior', 'Stroke Volume']
    concepts:
      - {vocabulary: SNOMED, search_term: 'physical deconditioning'}
      - {vocabulary: LOINC,  search_term: 'oxygen consumption'}
    source_refs: [lau2026, chung2026, low2009, gibbons2013]

  - id: autoimmune_evidence
    group: mechanism
    label: Autoimmune evidence
    definition: >
      Autoantibodies against autonomic targets (ganglionic acetylcholine
      receptor, adrenergic and muscarinic receptors) or a coexisting systemic
      autoimmune disease.
    pubmed_query: 'autoimmun*[tiab] OR autoantibod*[tiab] OR "antibodies"[tiab] OR "acetylcholine receptor"[tiab] OR "adrenergic receptor antibod*"[tiab] OR "muscarinic receptor antibod*"[tiab] OR "ganglionic"[tiab] OR immunotherapy[tiab] OR "molecular mimicry"[tiab]'
    mesh_terms: ['Autoantibodies', 'Autoimmune Diseases', 'Autoimmunity', 'Receptors, Adrenergic', 'Receptors, Muscarinic', 'Receptors, Nicotinic']
    concepts:
      - {vocabulary: SNOMED, search_term: 'autoimmune autonomic ganglionopathy', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'autonomic ganglionopathy'}
      - {vocabulary: SNOMED, search_term: 'autoimmune disorder of autonomic nervous system'}
      - {vocabulary: LOINC,  search_term: 'acetylcholine receptor ganglionic antibody'}
    source_refs: [lau2026, chung2026, low2009, gibbons2013, zhang2022]

  - id: postinfectious_evidence
    group: mechanism
    label: Post-infectious evidence
    definition: >
      Symptom onset temporally linked to an infection, including SARS-CoV-2,
      Epstein-Barr virus, influenza and Lyme disease.
    pubmed_query: 'post-infectious[tiab] OR postinfectious[tiab] OR "post infectious"[tiab] OR postviral[tiab] OR "post-viral"[tiab] OR COVID*[tiab] OR "SARS-CoV-2"[tiab] OR "Epstein-Barr"[tiab] OR mononucleosis[tiab] OR influenza[tiab] OR "Lyme"[tiab] OR sepsis[tiab] OR "viral illness"[tiab]'
    mesh_terms: ['COVID-19', 'SARS-CoV-2', 'Post-Acute COVID-19 Syndrome', 'Epstein-Barr Virus Infections', 'Virus Diseases', 'Lyme Disease']
    concepts:
      - {vocabulary: SNOMED, search_term: 'post-viral syndrome', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'Postviral fatigue syndrome'}
      - {vocabulary: SNOMED, search_term: 'Chronic post-COVID-19 syndrome'}
    source_refs: [lau2026, chung2026, low2009, gibbons2013, larsen2025]


  - id: cerebral_hypoperfusion_evidence
    group: mechanism
    label: Cerebral hypoperfusion evidence
    definition: >
      Reduced cerebral blood flow on standing, often with orthostatic
      hyperventilation and hypocapnia that further constrict cerebral vessels,
      proposed as a driver of brain fog and of the orthostatic symptoms. Named as
      a proposed mechanism by Chung 2026 and Lau 2026; Larsen 2025 found
      cerebrovascular measures did not correlate with symptoms.
    pubmed_query: '"cerebral hypoperfusion"[tiab] OR "cerebral blood flow"[tiab] OR "cerebral perfusion"[tiab] OR "cerebrovascular"[tiab] OR hypocapnia[tiab] OR hypocapnic[tiab] OR "orthostatic hyperventilation"[tiab] OR "end-tidal CO2"[tiab] OR "brain fog"[tiab]'
    mesh_terms: ['Cerebrovascular Circulation', 'Hypocapnia', 'Hyperventilation', 'Cognitive Dysfunction']
    concepts:
      - {vocabulary: SNOMED, search_term: 'cerebral hypoperfusion'}
      - {vocabulary: SNOMED, search_term: 'hypocapnia'}
    source_refs: [chung2026]

  # -------------------------------------------------------------- measurement
  - id: head_up_tilt_test
    group: measurement
    label: Head-up tilt table test
    definition: >
      Passive 60-70 degree head-up tilt with continuous heart rate and blood
      pressure. Supplies the diagnostic heart-rate increment itself.
    pubmed_query: '"tilt table"[tiab] OR "tilt-table"[tiab] OR "head-up tilt"[tiab] OR "head up tilt"[tiab] OR HUTT[tiab] OR "tilt testing"[tiab] OR "orthostatic challenge"[tiab]'
    mesh_terms: ['Tilt-Table Test']
    concepts:
      - {vocabulary: SNOMED, search_term: 'tilt table test'}
      - {vocabulary: LOINC,  search_term: 'tilt table study'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013, zhang2022, larsen2025]

  - id: active_stand_test
    group: measurement
    label: Active stand test
    definition: >
      Ten-minute active standing with serial heart rate and blood pressure, the
      pragmatic clinic alternative to tilt. Yields a different heart-rate
      increment than tilt, which matters for phenotype threshold portability.
    pubmed_query: '"active stand"[tiab] OR "standing test"[tiab] OR "stand test"[tiab] OR "10-minute stand"[tiab] OR "orthostatic vital signs"[tiab] OR "NASA lean test"[tiab]'
    mesh_terms: ['Standing Position', 'Posture']
    concepts:
      - {vocabulary: SNOMED, search_term: 'measurement of orthostatic blood pressure'}
      - {vocabulary: SNOMED, search_term: 'standing blood pressure'}
      - {vocabulary: LOINC,  search_term: 'heart rate standing'}
    source_refs: [lau2026, chung2026, angeli2024]

  - id: qsart_sudomotor_testing
    group: measurement
    label: QSART and sudomotor testing
    definition: >
      Quantitative sudomotor axon reflex test and related sympathetic sweat
      measures. Zhang et al. found reduced sweat output in about a third of 356
      patients tested.
    pubmed_query: 'QSART[tiab] OR "quantitative sudomotor"[tiab] OR "sudomotor axon reflex"[tiab] OR "sweat output"[tiab] OR "sympathetic skin response"[tiab] OR sudoscan[tiab] OR "electrochemical skin conductance"[tiab] OR "silastic sweat imprint"[tiab]'
    mesh_terms: ['Sweating', 'Galvanic Skin Response', 'Sweat Glands']
    concepts:
      - {vocabulary: SNOMED, search_term: 'quantitative sudomotor axon reflex test', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'sweat test'}
      - {vocabulary: SNOMED, search_term: 'sweat measure'}
    source_refs: [chung2026, angeli2024, low2009, gibbons2013, zhang2022, larsen2025]

  - id: thermoregulatory_sweat_test
    group: measurement
    label: Thermoregulatory sweat test
    definition: >
      Whole-body sweat distribution under controlled heating, localising
      anhidrosis and distinguishing pre- from post-ganglionic lesions when read
      against QSART.
    pubmed_query: '"thermoregulatory sweat test"[tiab] OR TST[tiab] OR anhidrosis[tiab] OR hypohidrosis[tiab] OR "sweat distribution"[tiab]'
    mesh_terms: ['Hypohidrosis', 'Body Temperature Regulation']
    concepts:
      - {vocabulary: SNOMED, search_term: 'thermoregulatory sweat test', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'sweat measure'}
      - {vocabulary: SNOMED, search_term: 'sweat test'}
    source_refs: [angeli2024, low2009]

  - id: skin_biopsy_ienfd
    group: measurement
    label: Skin biopsy and intraepidermal nerve fibre density
    definition: >
      Punch biopsy with PGP 9.5 immunostaining and nerve-fibre density
      quantification, the structural counterpart to sudomotor testing. Reduced
      density is reported in about 24% (Zhang 2022) to 45-53% (Chung 2026) of
      patients biopsied.
    pubmed_query: '"skin biopsy"[tiab] OR "punch biopsy"[tiab] OR "intraepidermal nerve fiber"[tiab] OR "intraepidermal nerve fibre"[tiab] OR IENFD[tiab] OR "nerve fiber density"[tiab] OR "PGP 9.5"[tiab] OR "PGP9.5"[tiab] OR "sweat gland nerve fiber density"[tiab]'
    mesh_terms: ['Biopsy', 'Skin', 'Nerve Fibers', 'Ubiquitin Thiolesterase']
    concepts:
      - {vocabulary: SNOMED, search_term: 'skin biopsy'}
      - {vocabulary: SNOMED, search_term: 'punch biopsy of skin'}
    source_refs: [chung2026, angeli2024, gibbons2013, zhang2022, larsen2025]

  - id: plasma_catecholamine_assay
    group: measurement
    label: Supine and upright plasma catecholamines
    definition: >
      Paired supine and standing noradrenaline and adrenaline. An upright
      noradrenaline above roughly 600 pg/mL is the most-cited hyperadrenergic
      criterion, and the paired design is what makes it interpretable.
    pubmed_query: '"plasma norepinephrine"[tiab] OR "plasma noradrenaline"[tiab] OR "plasma catecholamine*"[tiab] OR "upright norepinephrine"[tiab] OR "standing norepinephrine"[tiab] OR "supine norepinephrine"[tiab] OR "24-hour urinary catecholamine*"[tiab] OR metanephrine*[tiab]'
    mesh_terms: ['Norepinephrine', 'Catecholamines', 'Epinephrine', 'Metanephrine']
    concepts:
      - {vocabulary: LOINC, search_term: 'norepinephrine plasma'}
      - {vocabulary: LOINC, search_term: 'epinephrine plasma'}
      - {vocabulary: LOINC, search_term: 'metanephrine plasma'}
    source_refs: [chung2026, angeli2024, low2009, larsen2025]

  - id: plasma_blood_volume_assay
    group: measurement
    label: Plasma and blood volume measurement
    definition: >
      Direct volume quantification by carbon monoxide rebreathing, indocyanine
      green, or iodinated-albumin dilution. The only way to make the hypovolemic
      flag objective rather than inferred.
    pubmed_query: '"plasma volume"[tiab] OR "blood volume"[tiab] OR "red cell mass"[tiab] OR "carbon monoxide rebreathing"[tiab] OR "indocyanine green"[tiab] OR "iodinated albumin"[tiab] OR "volume status"[tiab] OR hematocrit[tiab]'
    mesh_terms: ['Plasma Volume', 'Blood Volume Determination', 'Blood Volume', 'Hematocrit']
    concepts:
      - {vocabulary: LOINC, search_term: 'plasma volume'}
      - {vocabulary: LOINC, search_term: 'blood volume'}
      - {vocabulary: LOINC, search_term: 'hematocrit'}
    source_refs: [chung2026]

  - id: cerebral_blood_flow_measurement
    group: measurement
    label: Cerebral blood flow velocity
    definition: >
      Transcranial Doppler middle-cerebral-artery velocity, near-infrared
      spectroscopy, or cerebral oximetry during orthostasis. Explains symptoms
      that the heart-rate criterion does not.
    pubmed_query: '"cerebral blood flow"[tiab] OR "transcranial Doppler"[tiab] OR "middle cerebral artery"[tiab] OR "cerebral oximetry"[tiab] OR "near-infrared spectroscopy"[tiab] OR "cerebral autoregulation"[tiab] OR "cerebral perfusion"[tiab] OR "cerebral hypoperfusion"[tiab]'
    mesh_terms: ['Cerebrovascular Circulation', 'Ultrasonography, Doppler, Transcranial', 'Spectroscopy, Near-Infrared', 'Middle Cerebral Artery']
    concepts:
      - {vocabulary: SNOMED, search_term: 'transcranial Doppler ultrasonography'}
      - {vocabulary: SNOMED, search_term: 'cerebral blood flow'}
    source_refs: [chung2026, larsen2025]

  - id: heart_rate_variability
    group: measurement
    label: Heart rate variability and baroreflex sensitivity
    definition: >
      Spectral and time-domain heart-rate variability, deep-breathing
      respiratory sinus arrhythmia, and baroreflex gain: the cardiovagal side of
      autonomic testing.
    pubmed_query: '"heart rate variability"[tiab] OR HRV[tiab] OR baroreflex[tiab] OR "baroreceptor"[tiab] OR "deep breathing"[tiab] OR "respiratory sinus arrhythmia"[tiab] OR "vagal tone"[tiab] OR "cardiovagal"[tiab] OR "spectral analysis"[tiab]'
    mesh_terms: ['Heart Rate', 'Baroreflex', 'Vagus Nerve', 'Autonomic Nervous System']
    concepts:
      - {vocabulary: SNOMED, search_term: 'heart rate variability'}
      - {vocabulary: LOINC,  search_term: 'heart rate'}
    source_refs: [chung2026, angeli2024, gibbons2013, zhang2022, larsen2025]

  - id: valsalva_maneuver
    group: measurement
    label: Valsalva manoeuvre
    definition: >
      Valsalva ratio and phase II/IV blood-pressure response, separating
      adrenergic from cardiovagal failure. Part of the standard autonomic reflex
      screen alongside deep breathing and QSART.
    pubmed_query: 'Valsalva[tiab] OR "Valsalva ratio"[tiab] OR "adrenergic baroreflex"[tiab] OR "phase IV"[tiab] OR "composite autonomic severity"[tiab] OR CASS[tiab] OR "autonomic reflex screen"[tiab]'
    mesh_terms: ['Valsalva Maneuver', 'Blood Pressure']
    concepts:
      - {vocabulary: SNOMED, search_term: 'Valsalva manoeuvre'}
      - {vocabulary: SNOMED, search_term: 'autonomic function studies'}
    source_refs: [chung2026, low2009, gibbons2013, zhang2022, larsen2025]

  - id: cardiopulmonary_exercise_test
    group: measurement
    label: Cardiopulmonary exercise testing
    definition: >
      Peak oxygen uptake, chronotropic response and ventilatory efficiency, the
      objective substrate for the deconditioning flag and for post-exertional
      malaise phenotyping.
    pubmed_query: '"cardiopulmonary exercise"[tiab] OR CPET[tiab] OR "exercise testing"[tiab] OR "peak VO2"[tiab] OR "VO2 max"[tiab] OR "maximal oxygen uptake"[tiab] OR "anaerobic threshold"[tiab] OR "2-day CPET"[tiab] OR "invasive cardiopulmonary"[tiab]'
    mesh_terms: ['Exercise Test', 'Oxygen Consumption', 'Exercise Tolerance']
    concepts:
      - {vocabulary: SNOMED, search_term: 'cardiopulmonary exercise test'}
      - {vocabulary: LOINC,  search_term: 'oxygen consumption'}
    source_refs: [lau2026, chung2026, low2009]

  - id: autonomic_autoantibody_assay
    group: measurement
    label: Autonomic autoantibody assay
    definition: >
      Ganglionic acetylcholine receptor antibody, and adrenergic and muscarinic
      receptor antibody panels including functional cell-based assays.
    pubmed_query: '"ganglionic acetylcholine receptor"[tiab] OR "alpha-1 adrenergic receptor antibod*"[tiab] OR "beta-1 adrenergic receptor antibod*"[tiab] OR "beta-2 adrenergic"[tiab] OR "muscarinic acetylcholine receptor antibod*"[tiab] OR "angiotensin II type 1 receptor antibod*"[tiab] OR "functional autoantibod*"[tiab] OR "G-protein coupled receptor autoantibod*"[tiab]'
    mesh_terms: ['Autoantibodies', 'Receptors, Nicotinic', 'Receptors, Adrenergic, beta-1', 'Receptors, Muscarinic']
    concepts:
      - {vocabulary: LOINC,  search_term: 'acetylcholine receptor antibody'}
      - {vocabulary: SNOMED, search_term: 'autoantibody measurement'}
    source_refs: [lau2026, chung2026, low2009, zhang2022]

  - id: ambulatory_monitoring
    group: measurement
    label: Ambulatory heart rate and blood pressure monitoring
    definition: >
      Holter, patch electrocardiography, wearable heart-rate and 24-hour
      ambulatory blood pressure. The realistic source of a heart-rate criterion
      in routine electronic health record data, as opposed to a formal lab.
    pubmed_query: 'Holter[tiab] OR "ambulatory blood pressure"[tiab] OR "ambulatory monitoring"[tiab] OR "wearable"[tiab] OR "24-hour heart rate"[tiab] OR actigraphy[tiab] OR "implantable loop"[tiab] OR "patch monitor"[tiab]'
    mesh_terms: ['Electrocardiography, Ambulatory', 'Blood Pressure Monitoring, Ambulatory', 'Wearable Electronic Devices', 'Actigraphy']
    concepts:
      - {vocabulary: SNOMED, search_term: 'ambulatory electrocardiographic monitoring'}
      - {vocabulary: SNOMED, search_term: 'electrocardiographic monitoring'}
      - {vocabulary: SNOMED, search_term: 'ambulatory blood pressure monitoring'}
    source_refs: [lau2026, chung2026, low2009]

  - id: genetic_testing
    group: measurement
    label: Genetic testing
    definition: >
      Variant testing relevant to POTS and its comorbidities: noradrenaline
      transporter (SLC6A2), mast-cell and tryptase loci, and connective-tissue
      genes.
    pubmed_query: '"genetic"[tiab] OR genotyp*[tiab] OR polymorphism*[tiab] OR variant*[tiab] OR SLC6A2[tiab] OR TPSAB1[tiab] OR "whole exome"[tiab] OR "genome-wide"[tiab] OR heritab*[tiab] OR familial[tiab]'
    mesh_terms: ['Genetic Testing', 'Polymorphism, Single Nucleotide', 'Genetic Predisposition to Disease', 'Exome Sequencing']
    concepts:
      - {vocabulary: SNOMED, search_term: 'genetic test'}
    source_refs: [low2009]


  - id: urine_sodium_24h
    group: measurement
    label: 24-hour urine sodium
    definition: >
      Sodium excreted over 24 hours, a proxy for salt intake and volume status;
      below 100 mmol/24 h marks the hypovolemic phenotype in Angeli 2024.
    pubmed_query: '"urine sodium"[tiab] OR "urinary sodium"[tiab] OR "sodium excretion"[tiab] OR "24-hour urine"[tiab] OR "24-h urine"[tiab]'
    mesh_terms: ['Natriuresis', 'Sodium, Dietary']
    concepts:
      - {vocabulary: LOINC, search_term: 'sodium 24 hour urine'}
    source_refs: [angeli2024, low2009]
  - id: renin_aldosterone_assay
    group: measurement
    label: Plasma renin and aldosterone
    definition: >
      Plasma renin activity and aldosterone, inappropriately low for the degree
      of hypovolaemia in some patients (the renin-angiotensin-aldosterone paradox).
    pubmed_query: '"plasma renin"[tiab] OR "renin activity"[tiab] OR aldosterone[tiab] OR "renin-angiotensin"[tiab]'
    mesh_terms: ['Renin', 'Aldosterone', 'Renin-Angiotensin System']
    concepts:
      - {vocabulary: LOINC, search_term: 'renin activity plasma'}
      - {vocabulary: LOINC, search_term: 'aldosterone serum'}
    source_refs: [chung2026]
  - id: regional_norepinephrine_spillover
    group: measurement
    label: Regional norepinephrine spillover
    definition: >
      Research measurement of noradrenaline released into the venous drainage
      of a limb; reduced in the legs in neuropathic POTS.
    pubmed_query: '"norepinephrine spillover"[tiab] OR "noradrenaline spillover"[tiab] OR "norepinephrine release"[tiab]'
    mesh_terms: ['Norepinephrine']
    concepts:
      - {vocabulary: LOINC, search_term: 'norepinephrine plasma'}
    source_refs: [chung2026, low2009]
  - id: muscle_sympathetic_nerve_activity
    group: measurement
    label: Muscle sympathetic nerve activity (microneurography)
    definition: >
      Direct recording of sympathetic outflow to muscle; blunted in the legs of
      a subset of patients, supporting patchy sympathetic denervation.
    pubmed_query: '"muscle sympathetic nerve activity"[tiab] OR MSNA[tiab] OR microneurography[tiab]'
    mesh_terms: ['Sympathetic Nervous System']
    concepts:
      - {vocabulary: SNOMED, search_term: 'autonomic nervous system function'}
    source_refs: [chung2026]
  - id: cardiac_mri
    group: measurement
    label: Cardiac MRI (left ventricular mass)
    definition: >
      Cardiac magnetic resonance imaging; a smaller left ventricular mass in POTS
      is taken as evidence of cardiac deconditioning.
    pubmed_query: '"cardiac magnetic resonance"[tiab] OR "cardiac MRI"[tiab] OR "left ventricular mass"[tiab] OR "cardiac mass"[tiab]'
    mesh_terms: ['Magnetic Resonance Imaging, Cine', 'Heart Ventricles']
    concepts:
      - {vocabulary: SNOMED, search_term: 'magnetic resonance imaging of heart'}
    source_refs: [chung2026]
  - id: quantitative_sensory_testing
    group: measurement
    label: Quantitative sensory testing
    definition: >
      Thermal and vibration threshold testing of small and large sensory
      fibres; one of the three criteria for neuropathic POTS in Gibbons 2013.
    pubmed_query: '"quantitative sensory testing"[tiab] OR "thermal threshold"[tiab] OR "thermal thresholds"[tiab] OR "cold detection"[tiab] OR "heat pain threshold"[tiab]'
    mesh_terms: ['Sensory Thresholds', 'Thermosensing']
    concepts:
      - {vocabulary: SNOMED, search_term: 'quantitative sensory testing'}
    source_refs: [gibbons2013]
  - id: end_tidal_co2
    group: measurement
    label: End-tidal CO2 on tilt
    definition: >
      Capnography during orthostatic challenge; low end-tidal CO2 at end-tilt
      shows orthostatic hypocapnia.
    pubmed_query: '"end-tidal CO2"[tiab] OR "end-tidal carbon dioxide"[tiab] OR ETCO2[tiab] OR capnography[tiab] OR hypocapnia[tiab]'
    mesh_terms: ['Capnography', 'Hypocapnia']
    concepts:
      - {vocabulary: LOINC, search_term: 'carbon dioxide end tidal'}
    source_refs: [larsen2025]

  # -------------------------------------------------------------- comorbidity
  - id: hypermobility_heds
    group: comorbidity
    label: Joint hypermobility and hypermobile Ehlers-Danlos syndrome
    definition: >
      Generalised joint hypermobility or hypermobile Ehlers-Danlos syndrome,
      offered as a mechanism for increased venous compliance and pooling.
    pubmed_query: '"Ehlers-Danlos"[tiab] OR EDS[tiab] OR hEDS[tiab] OR hypermobil*[tiab] OR "Beighton"[tiab] OR "joint laxity"[tiab] OR "connective tissue disorder"[tiab] OR "hypermobility spectrum"[tiab]'
    mesh_terms: ['Ehlers-Danlos Syndrome', 'Joint Instability', 'Connective Tissue Diseases']
    concepts:
      - {vocabulary: SNOMED, search_term: 'hypermobile Ehlers-Danlos syndrome'}
      - {vocabulary: SNOMED, search_term: 'joint hypermobility'}
    source_refs: [lau2026, chung2026, angeli2024, zhang2022]

  - id: mast_cell_activation
    group: comorbidity
    label: Mast cell activation syndrome
    definition: >
      Mast cell activation disorder with flushing, and raised tryptase or urinary
      methylhistamine, which can mimic or amplify a hyperadrenergic picture.
    pubmed_query: '"mast cell"[tiab] OR MCAS[tiab] OR mastocytosis[tiab] OR tryptase[tiab] OR "methylhistamine"[tiab] OR flushing[tiab] OR "prostaglandin D2"[tiab] OR histamine[tiab]'
    mesh_terms: ['Mastocytosis', 'Mast Cells', 'Tryptases', 'Histamine']
    concepts:
      - {vocabulary: SNOMED, search_term: 'mast cell activation syndrome'}
      - {vocabulary: LOINC,  search_term: 'tryptase serum'}
    source_refs: [lau2026, chung2026]

  - id: me_cfs
    group: comorbidity
    label: ME/CFS and post-exertional malaise
    definition: >
      Myalgic encephalomyelitis / chronic fatigue syndrome, sharing orthostatic
      intolerance and post-exertional malaise with POTS.
    pubmed_query: '"chronic fatigue"[tiab] OR "myalgic encephalomyelitis"[tiab] OR ME/CFS[tiab] OR "post-exertional"[tiab] OR "postexertional"[tiab] OR "systemic exertion intolerance"[tiab] OR fatigue[tiab]'
    mesh_terms: ['Fatigue Syndrome, Chronic', 'Fatigue']
    concepts:
      - {vocabulary: SNOMED, search_term: 'chronic fatigue syndrome'}
      - {vocabulary: SNOMED, search_term: 'post-exertional malaise', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'malaise and fatigue'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013]

  - id: long_covid
    group: comorbidity
    label: Long COVID and post-acute sequelae of SARS-CoV-2
    definition: >
      POTS arising after SARS-CoV-2 infection. The subject of the Larsen deep
      phenotyping study, and the reason the modern incident cohort exists.
    pubmed_query: '"long COVID"[tiab] OR "long-COVID"[tiab] OR PASC[tiab] OR "post-acute sequelae"[tiab] OR "post COVID"[tiab] OR "post-COVID"[tiab] OR "COVID-19"[tiab] OR "SARS-CoV-2"[tiab]'
    mesh_terms: ['Post-Acute COVID-19 Syndrome', 'COVID-19', 'SARS-CoV-2']
    concepts:
      - {vocabulary: SNOMED, search_term: 'post COVID-19 condition', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'Chronic post-COVID-19 syndrome'}
    source_refs: [lau2026, chung2026, larsen2025]

  - id: post_vaccination_onset
    group: comorbidity
    label: Post-vaccination onset
    definition: >
      Symptom onset temporally associated with vaccination, principally human
      papillomavirus and SARS-CoV-2 vaccines. Recorded because it appears in the
      literature as a claimed trigger and any phenotype must be able to identify
      and stratify these reports rather than silently absorb them.
    pubmed_query: 'vaccin*[tiab] OR immunization[tiab] OR immunisation[tiab] OR HPV[tiab] OR Gardasil[tiab] OR "adverse event following immunization"[tiab] OR AEFI[tiab]'
    mesh_terms: ['Vaccination', 'Papillomavirus Vaccines', 'COVID-19 Vaccines', 'Vaccines']
    concepts:
      - {vocabulary: SNOMED, search_term: 'adverse reaction to vaccine'}
    source_refs: [lau2026, chung2026]

  - id: systemic_autoimmune_disease
    group: comorbidity
    label: Sjogren and other systemic autoimmune disease
    definition: >
      Coexisting systemic autoimmune disease: Sjogren syndrome, systemic lupus
      erythematosus, coeliac disease, autoimmune thyroiditis.
    pubmed_query: '"Sjogren"[tiab] OR "Sjögren"[tiab] OR lupus[tiab] OR SLE[tiab] OR "celiac"[tiab] OR "coeliac"[tiab] OR "Hashimoto"[tiab] OR thyroiditis[tiab] OR "rheumatoid"[tiab] OR "antiphospholipid"[tiab] OR "antinuclear antibod*"[tiab]'
    mesh_terms: ['Sjogren''s Syndrome', 'Lupus Erythematosus, Systemic', 'Celiac Disease', 'Thyroiditis, Autoimmune', 'Autoimmune Diseases']
    concepts:
      - {vocabulary: SNOMED, search_term: 'Sjogren syndrome'}
      - {vocabulary: SNOMED, search_term: 'systemic lupus erythematosus'}
    source_refs: [lau2026, chung2026, zhang2022]

  - id: small_fiber_neuropathy_dx
    group: comorbidity
    label: Small fibre neuropathy diagnosis
    definition: >
      Small fibre neuropathy as a recorded diagnosis rather than as a test
      result. Held separately from the neuropathic mechanism flag because in
      electronic health record data the diagnosis code and the biopsy result are
      different observations with different reliability.
    pubmed_query: '"small fiber neuropathy"[tiab] OR "small fibre neuropathy"[tiab] OR SFN[tiab] OR "sensory neuropathy"[tiab] OR "painful neuropathy"[tiab] OR "burning feet"[tiab] OR allodynia[tiab]'
    mesh_terms: ['Small Fiber Neuropathy', 'Peripheral Nervous System Diseases']
    concepts:
      - {vocabulary: SNOMED, search_term: 'small fibre neuropathy'}
    source_refs: [lau2026, chung2026, zhang2022]

  - id: gi_dysmotility
    group: comorbidity
    label: Gastrointestinal dysmotility and functional GI disorders
    definition: >
      Gastroparesis, chronic constipation, rapid gastric emptying, irritable
      bowel syndrome and other functional gastrointestinal symptoms.
    pubmed_query: 'gastroparesis[tiab] OR dysmotility[tiab] OR "gastric emptying"[tiab] OR constipation[tiab] OR "irritable bowel"[tiab] OR nausea[tiab] OR "gastrointestinal symptom*"[tiab] OR "enteric nervous system"[tiab]'
    mesh_terms: ['Gastroparesis', 'Gastrointestinal Motility', 'Constipation', 'Irritable Bowel Syndrome', 'Enteric Nervous System']
    concepts:
      - {vocabulary: SNOMED, search_term: 'gastroparesis'}
      - {vocabulary: SNOMED, search_term: 'gastrointestinal dysmotility', fallback_gap: true}
      - {vocabulary: SNOMED, search_term: 'intestinal dysmotility'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013]

  - id: chronic_migraine
    group: comorbidity
    label: Migraine and chronic headache
    definition: >
      Migraine, chronic daily headache and their overlap with orthostatic
      headache from cerebral hypoperfusion or cerebrospinal fluid leak.
    pubmed_query: 'migraine[tiab] OR headache*[tiab] OR "orthostatic headache"[tiab] OR "cerebrospinal fluid leak"[tiab] OR "intracranial hypotension"[tiab]'
    mesh_terms: ['Migraine Disorders', 'Headache', 'Intracranial Hypotension']
    concepts:
      - {vocabulary: SNOMED, search_term: 'migraine'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, zhang2022]

  - id: differential_syncope_oh
    group: comorbidity
    label: Competing orthostatic diagnoses
    definition: >
      Orthostatic hypotension, vasovagal and other reflex syncope, pure
      autonomic failure and multiple system atrophy. The absence of orthostatic
      hypotension is part of the POTS definition, so a computable phenotype
      needs these explicitly. Other causes of sinus tachycardia and arrhythmias
      are separate facets.
    pubmed_query: '"vasovagal"[tiab] OR "orthostatic hypotension"[tiab] OR "pure autonomic failure"[tiab] OR "multiple system atrophy"[tiab] OR "neurally mediated syncope"[tiab] OR "reflex syncope"[tiab]'
    mesh_terms: ['Syncope, Vasovagal', 'Hypotension, Orthostatic', 'Pure Autonomic Failure', 'Multiple System Atrophy']
    concepts:
      - {vocabulary: SNOMED, search_term: 'vasovagal syncope'}
      - {vocabulary: SNOMED, search_term: 'orthostatic hypotension'}
      - {vocabulary: SNOMED, search_term: 'inappropriate sinus tachycardia'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, zhang2022]


  - id: secondary_sinus_tachycardia
    group: comorbidity
    label: Other causes of sinus tachycardia (rule out)
    definition: >
      Conditions that raise heart rate and must be excluded before POTS is
      diagnosed: anaemia, dehydration, infection, hyperthyroidism, adrenal
      insufficiency, pheochromocytoma, pain, anorexia nervosa and other
      transient states.
    pubmed_query: 'anemia[tiab] OR anaemia[tiab] OR dehydration[tiab] OR hyperthyroidism[tiab] OR thyrotoxicosis[tiab] OR pheochromocytoma[tiab] OR "adrenal insufficiency"[tiab] OR "anorexia nervosa"[tiab]'
    mesh_terms: ['Anemia', 'Dehydration', 'Hyperthyroidism', 'Pheochromocytoma', 'Adrenal Insufficiency', 'Anorexia Nervosa']
    concepts:
      - {vocabulary: SNOMED, search_term: 'anemia'}
      - {vocabulary: SNOMED, search_term: 'hyperthyroidism'}
      - {vocabulary: SNOMED, search_term: 'pheochromocytoma'}
    source_refs: [lau2026, chung2026, gibbons2013]
  - id: arrhythmia_differential
    group: comorbidity
    label: Arrhythmias and inappropriate sinus tachycardia (rule out)
    definition: >
      Supraventricular tachycardias and inappropriate sinus tachycardia, which
      can resemble POTS and are excluded with ECG, Holter or electrophysiology.
    pubmed_query: '"supraventricular tachycardia"[tiab] OR "inappropriate sinus tachycardia"[tiab] OR "atrial tachycardia"[tiab] OR "sinus node reentr*"[tiab] OR arrhythmia[tiab]'
    mesh_terms: ['Tachycardia, Supraventricular', 'Tachycardia, Sinus', 'Arrhythmias, Cardiac']
    concepts:
      - {vocabulary: SNOMED, search_term: 'supraventricular tachycardia'}
      - {vocabulary: SNOMED, search_term: 'inappropriate sinus tachycardia'}
    source_refs: [chung2026, low2009]
  - id: structural_cardiopulmonary_disease
    group: comorbidity
    label: Structural heart and chronic lung disease (rule out)
    definition: >
      Cardiomyopathy, valvular and congenital heart disease, and chronic lung
      disease, which must be excluded as causes of tachycardia and dyspnoea.
    pubmed_query: 'cardiomyopathy[tiab] OR "valvular heart disease"[tiab] OR "congenital heart disease"[tiab] OR "structural heart"[tiab] OR "chronic lung disease"[tiab] OR COPD[tiab]'
    mesh_terms: ['Cardiomyopathies', 'Heart Valve Diseases', 'Heart Defects, Congenital', 'Lung Diseases']
    concepts:
      - {vocabulary: SNOMED, search_term: 'cardiomyopathy'}
      - {vocabulary: SNOMED, search_term: 'chronic lung disease'}
    source_refs: [chung2026, angeli2024]
  - id: medication_induced_tachycardia
    group: comorbidity
    label: Medication-induced tachycardia (rule out)
    definition: >
      Tachycardia caused or worsened by drugs: stimulants, sympathomimetics,
      norepinephrine reuptake inhibitors, SNRIs, diuretics, alpha-1 blockers,
      vasodilators and anticholinergics.
    pubmed_query: '"drug-induced"[tiab] OR "medication-induced"[tiab] OR stimulant*[tiab] OR atomoxetine[tiab] OR amphetamine*[tiab] OR methylphenidate[tiab] OR diuretic*[tiab]'
    mesh_terms: ['Central Nervous System Stimulants', 'Diuretics', 'Adrenergic alpha-1 Receptor Antagonists']
    concepts:
      - {vocabulary: SNOMED, search_term: 'adverse reaction to drug'}
      - {vocabulary: SNOMED, search_term: 'sinus tachycardia'}
    source_refs: [lau2026, chung2026]
  - id: anxiety_depression
    group: comorbidity
    label: Anxiety and depression
    definition: >
      Anxiety, panic and depressive disorders and somatic hypervigilance. Common
      in POTS and a frequent misdiagnosis, though anxiety does not cause the
      orthostatic tachycardia.
    pubmed_query: 'anxiety[tiab] OR depression[tiab] OR depressive[tiab] OR "panic disorder"[tiab] OR hypervigilance[tiab]'
    mesh_terms: ['Anxiety', 'Anxiety Disorders', 'Depression', 'Depressive Disorder', 'Panic Disorder']
    concepts:
      - {vocabulary: SNOMED, search_term: 'anxiety disorder'}
      - {vocabulary: SNOMED, search_term: 'depressive disorder'}
    source_refs: [lau2026, low2009, gibbons2013]
  - id: fibromyalgia
    group: comorbidity
    label: Fibromyalgia
    definition: Chronic widespread pain syndrome reported to co-occur with POTS.
    pubmed_query: 'fibromyalgia[tiab]'
    mesh_terms: ['Fibromyalgia']
    concepts:
      - {vocabulary: SNOMED, search_term: 'fibromyalgia'}
    source_refs: [lau2026, chung2026, low2009]
  - id: sleep_disturbance
    group: comorbidity
    label: Sleep disturbance
    definition: Insomnia, unrefreshing sleep and other sleep disorders in POTS.
    pubmed_query: '"sleep disturbance"[tiab] OR "sleep disorder"[tiab] OR "sleep disorders"[tiab] OR insomnia[tiab] OR "sleep quality"[tiab]'
    mesh_terms: ['Sleep Wake Disorders', 'Sleep Initiation and Maintenance Disorders']
    concepts:
      - {vocabulary: SNOMED, search_term: 'sleep disorder'}
    source_refs: [chung2026, low2009]
  - id: iron_deficiency
    group: comorbidity
    label: Iron deficiency
    definition: Low iron stores (ferritin), reported in some patients with POTS.
    pubmed_query: '"iron deficiency"[tiab] OR ferritin[tiab] OR "low iron"[tiab]'
    mesh_terms: ['Iron Deficiencies', 'Anemia, Iron-Deficiency', 'Ferritins']
    concepts:
      - {vocabulary: SNOMED, search_term: 'iron deficiency'}
      - {vocabulary: LOINC, search_term: 'ferritin serum'}
    source_refs: [lau2026]
  - id: neurodevelopmental_disorder
    group: comorbidity
    label: Autism and ADHD
    definition: Neurodevelopmental conditions reported to co-occur with POTS.
    pubmed_query: 'autism[tiab] OR autistic[tiab] OR ADHD[tiab] OR "attention deficit"[tiab] OR neurodevelopmental[tiab] OR neurodivergen*[tiab]'
    mesh_terms: ['Autism Spectrum Disorder', 'Attention Deficit Disorder with Hyperactivity', 'Neurodevelopmental Disorders']
    concepts:
      - {vocabulary: SNOMED, search_term: 'autism spectrum disorder'}
      - {vocabulary: SNOMED, search_term: 'attention deficit hyperactivity disorder'}
    source_refs: [lau2026]
  - id: endometriosis
    group: comorbidity
    label: Endometriosis
    definition: Endometriosis, reported to co-occur with POTS.
    pubmed_query: 'endometriosis[tiab]'
    mesh_terms: ['Endometriosis']
    concepts:
      - {vocabulary: SNOMED, search_term: 'endometriosis'}
    source_refs: [lau2026]
  - id: functional_neurological_disorder
    group: comorbidity
    label: Functional neurological disorder
    definition: Functional neurological symptom disorder, reported alongside POTS.
    pubmed_query: '"functional neurological"[tiab] OR "conversion disorder"[tiab] OR "psychogenic non-epileptic"[tiab]'
    mesh_terms: ['Conversion Disorder']
    concepts:
      - {vocabulary: SNOMED, search_term: 'functional neurological disorder'}
    source_refs: [lau2026]
  - id: physical_trauma_onset
    group: comorbidity
    label: Onset after trauma or concussion
    definition: POTS beginning after physical trauma, including concussion.
    pubmed_query: 'concussion[tiab] OR "traumatic brain injury"[tiab] OR "physical trauma"[tiab] OR "after trauma"[tiab]'
    mesh_terms: ['Brain Concussion', 'Brain Injuries, Traumatic', 'Wounds and Injuries']
    concepts:
      - {vocabulary: SNOMED, search_term: 'concussion'}
    source_refs: [lau2026, chung2026]
  - id: surgery_onset
    group: comorbidity
    label: Onset after surgery
    definition: POTS beginning after a surgical procedure.
    pubmed_query: 'surgery[tiab] OR surgical[tiab] OR postoperative[tiab] OR "post-operative"[tiab]'
    mesh_terms: ['Surgical Procedures, Operative', 'Postoperative Period']
    concepts:
      - {vocabulary: SNOMED, search_term: 'surgical procedure'}
    source_refs: [lau2026, chung2026]
  - id: hormonal_transition_onset
    group: comorbidity
    label: Onset with hormonal change
    definition: POTS beginning or worsening around menarche, pregnancy or menopause.
    pubmed_query: 'pregnancy[tiab] OR pregnant[tiab] OR menarche[tiab] OR menopause[tiab] OR perimenopause[tiab] OR puberty[tiab]'
    mesh_terms: ['Pregnancy', 'Menarche', 'Menopause', 'Puberty']
    concepts:
      - {vocabulary: SNOMED, search_term: 'pregnancy'}
      - {vocabulary: SNOMED, search_term: 'menopause'}
    source_refs: [lau2026, chung2026]
  - id: adolescent_growth_spurt
    group: comorbidity
    label: Onset with adolescent growth spurt
    definition: POTS beginning during the adolescent growth spurt.
    pubmed_query: '"growth spurt"[tiab] OR "pubertal growth"[tiab] OR "rapid growth"[tiab]'
    mesh_terms: ['Adolescent Development']
    concepts:
      - {vocabulary: SNOMED, search_term: 'puberty'}
    source_refs: [lau2026]
  - id: prolonged_bed_rest
    group: comorbidity
    label: Prolonged bed rest
    definition: Extended bed rest or immobility, which produces deconditioning.
    pubmed_query: '"bed rest"[tiab] OR "bedrest"[tiab] OR immobili*[tiab] OR "head-down tilt bed rest"[tiab] OR spaceflight[tiab]'
    mesh_terms: ['Bed Rest', 'Immobilization', 'Space Flight']
    concepts:
      - {vocabulary: SNOMED, search_term: 'bed rest'}
    source_refs: [low2009]

  # ---------------------------------------------------------------- treatment
  - id: volume_expansion_therapy
    group: treatment
    label: Volume expansion therapy
    definition: >
      Fludrocortisone, salt and fluid loading, desmopressin, and intravenous
      saline. Prescription implies a clinician's hypovolemic hypothesis.
    pubmed_query: 'fludrocortisone[tiab] OR "salt loading"[tiab] OR "sodium chloride"[tiab] OR "salt tablet*"[tiab] OR desmopressin[tiab] OR DDAVP[tiab] OR "intravenous saline"[tiab] OR "IV saline"[tiab] OR "IV fluid*"[tiab] OR "volume loading"[tiab] OR erythropoietin[tiab]'
    mesh_terms: ['Fludrocortisone', 'Deamino Arginine Vasopressin', 'Sodium Chloride', 'Fluid Therapy', 'Erythropoietin']
    concepts:
      - {vocabulary: RxNorm, search_term: 'fludrocortisone'}
      - {vocabulary: RxNorm, search_term: 'desmopressin'}
    source_refs: [lau2026, chung2026, angeli2024, low2009]

  - id: midodrine_therapy
    group: treatment
    label: Midodrine
    definition: >
      Alpha-1 agonist vasoconstrictor, used where venous pooling or neuropathic
      vasoconstrictor failure is suspected.
    pubmed_query: 'midodrine[tiab] OR "alpha-1 agonist"[tiab] OR "alpha agonist"[tiab] OR ProAmatine[tiab]'
    mesh_terms: ['Midodrine']
    concepts:
      - {vocabulary: RxNorm, search_term: 'midodrine'}
    source_refs: [lau2026, chung2026, angeli2024, low2009]

  - id: droxidopa_therapy
    group: treatment
    label: Droxidopa
    definition: >
      Noradrenaline prodrug used where a peripheral noradrenergic deficit is
      suspected.
    pubmed_query: 'droxidopa[tiab] OR L-DOPS[tiab] OR "L-threo-DOPS"[tiab] OR Northera[tiab]'
    mesh_terms: ['Droxidopa']
    concepts:
      - {vocabulary: RxNorm, search_term: 'droxidopa'}
    source_refs: [low2009]

  - id: ivabradine_therapy
    group: treatment
    label: Ivabradine
    definition: >
      Selective sinoatrial funny-current inhibitor, lowering heart rate without
      lowering blood pressure. Signals a rate-centred rather than volume-centred
      hypothesis.
    pubmed_query: 'ivabradine[tiab] OR "I(f) current"[tiab] OR "funny current"[tiab] OR "sinus node"[tiab] OR Corlanor[tiab]'
    mesh_terms: ['Ivabradine']
    concepts:
      - {vocabulary: RxNorm, search_term: 'ivabradine'}
    source_refs: [lau2026, chung2026, angeli2024]

  - id: beta_blocker_therapy
    group: treatment
    label: Beta blockade
    definition: >
      Propranolol, metoprolol, bisoprolol and related agents, most often given
      on a hyperadrenergic rationale.
    pubmed_query: '"beta blocker*"[tiab] OR "beta-blocker*"[tiab] OR "beta-adrenergic block*"[tiab] OR propranolol[tiab] OR metoprolol[tiab] OR bisoprolol[tiab] OR atenolol[tiab] OR nadolol[tiab] OR labetalol[tiab] OR carvedilol[tiab]'
    mesh_terms: ['Adrenergic beta-Antagonists', 'Propranolol', 'Metoprolol', 'Bisoprolol', 'Atenolol']
    concepts:
      - {vocabulary: RxNorm, search_term: 'propranolol'}
      - {vocabulary: RxNorm, search_term: 'metoprolol'}
    source_refs: [lau2026, chung2026, angeli2024, low2009]

  - id: pyridostigmine_therapy
    group: treatment
    label: Pyridostigmine
    definition: >
      Peripheral acetylcholinesterase inhibitor enhancing ganglionic
      transmission, used on a neuropathic or autoimmune rationale.
    pubmed_query: 'pyridostigmine[tiab] OR "acetylcholinesterase inhibitor"[tiab] OR "cholinesterase inhibitor"[tiab] OR Mestinon[tiab]'
    mesh_terms: ['Pyridostigmine Bromide', 'Cholinesterase Inhibitors']
    concepts:
      - {vocabulary: RxNorm, search_term: 'pyridostigmine'}
    source_refs: [lau2026, chung2026, angeli2024, low2009]

  - id: central_sympatholytic_therapy
    group: treatment
    label: Central sympatholytics
    definition: >
      Clonidine, guanfacine and methyldopa, alpha-2 agonists that lower central
      sympathetic tone; used mainly for a hyperadrenergic presentation.
    pubmed_query: 'clonidine[tiab] OR methyldopa[tiab] OR guanfacine[tiab] OR "central sympatholytic"[tiab] OR "alpha-2 agonist"[tiab]'
    mesh_terms: ['Clonidine', 'Methyldopa', 'Guanfacine', 'Sympatholytics']
    concepts:
      - {vocabulary: RxNorm, search_term: 'clonidine'}
      - {vocabulary: RxNorm, search_term: 'methyldopa'}
    source_refs: [lau2026, chung2026, low2009]

  - id: immunomodulatory_therapy
    group: treatment
    label: Immunomodulation
    definition: >
      Intravenous immunoglobulin, rituximab, plasma exchange and corticosteroids
      given for a presumed autoimmune mechanism.
    pubmed_query: '"intravenous immunoglobulin"[tiab] OR IVIG[tiab] OR IVIg[tiab] OR rituximab[tiab] OR "plasma exchange"[tiab] OR plasmapheresis[tiab] OR "immunoadsorption"[tiab] OR immunosuppress*[tiab] OR immunomodulat*[tiab] OR corticosteroid*[tiab]'
    mesh_terms: ['Immunoglobulins, Intravenous', 'Rituximab', 'Plasma Exchange', 'Immunomodulating Agents', 'Immunosuppressive Agents']
    concepts:
      - {vocabulary: RxNorm, search_term: 'immune globulin'}
      - {vocabulary: RxNorm, search_term: 'rituximab'}
    source_refs: [lau2026]

  - id: exercise_reconditioning
    group: treatment
    label: Exercise reconditioning
    definition: >
      Structured recumbent-to-upright exercise programmes such as the Levine and
      CHOP protocols, prescribed against a deconditioning hypothesis.
    pubmed_query: '"exercise training"[tiab] OR "exercise program*"[tiab] OR reconditioning[tiab] OR rehabilitation[tiab] OR "recumbent"[tiab] OR "Levine protocol"[tiab] OR "CHOP protocol"[tiab] OR "physical therapy"[tiab] OR "aerobic training"[tiab]'
    mesh_terms: ['Exercise Therapy', 'Exercise', 'Physical Therapy Modalities', 'Rehabilitation']
    concepts:
      - {vocabulary: SNOMED, search_term: 'exercise therapy'}
      - {vocabulary: SNOMED, search_term: 'cardiac rehabilitation'}
    source_refs: [lau2026, chung2026, angeli2024, low2009, gibbons2013]

  - id: compression_therapy
    group: treatment
    label: Compression garments
    definition: >
      Abdominal binders and lower-limb compression that mechanically oppose
      venous pooling, targeting the neuropathic and hypovolemic flags.
    pubmed_query: 'compression[tiab] OR "compression stocking*"[tiab] OR "abdominal binder"[tiab] OR "abdominal compression"[tiab] OR "waist-high"[tiab] OR "counter-manoeuvre*"[tiab] OR "countermaneuver*"[tiab]'
    mesh_terms: ['Stockings, Compression', 'Compression Bandages']
    concepts:
      - {vocabulary: SNOMED, search_term: 'compression stockings'}
    source_refs: [lau2026, chung2026, angeli2024, low2009]

  - id: serotonergic_therapy
    group: treatment
    label: Serotonergic and other central agents
    definition: >
      Serotonin reuptake inhibitors, serotonin-noradrenaline reuptake
      inhibitors and modafinil. Low specificity: these are mostly prescribed for
      coexisting depression, anxiety or fatigue, and SNRIs can worsen
      orthostatic tachycardia (Lau 2026, Chung 2026).
    pubmed_query: 'SSRI[tiab] OR SNRI[tiab] OR fluoxetine[tiab] OR sertraline[tiab] OR venlafaxine[tiab] OR duloxetine[tiab] OR modafinil[tiab] OR "serotonin reuptake"[tiab] OR "tricyclic"[tiab]'
    mesh_terms: ['Selective Serotonin Reuptake Inhibitors', 'Modafinil', 'Serotonin and Noradrenaline Reuptake Inhibitors']
    concepts:
      - {vocabulary: RxNorm, search_term: 'sertraline'}
      - {vocabulary: RxNorm, search_term: 'venlafaxine'}
    source_refs: [chung2026]

# Seed references, used by the validation report to check that the corpus
# actually contains the papers the vocabulary was built from.
# Resolution is by title match, not by taking esearch's first hit: PubMed treats
# an unquoted [Title] search as a bag of words ordered by relevance, so the first
# hit for a title query is regularly a different paper. expected_pmid is checked
# independently against the corpus, so a drifting lookup query is detected
# without the check becoming circular.
  - id: physical_countermaneuvers
    group: treatment
    label: Physical countermaneuvers
    definition: >
      Leg crossing, muscle tensing, squatting and similar manoeuvres that push
      blood back from the legs on standing.
    pubmed_query: 'countermaneuver*[tiab] OR "counter-maneuver*"[tiab] OR "counter maneuver*"[tiab] OR "physical counterpressure"[tiab] OR "leg crossing"[tiab] OR "muscle tensing"[tiab]'
    mesh_terms: ['Exercise Therapy']
    concepts:
      - {vocabulary: SNOMED, search_term: 'isometric exercise'}
    source_refs: [chung2026, angeli2024, low2009]
  - id: lifestyle_modification
    group: treatment
    label: Behavioural and dietary measures
    definition: >
      Avoiding heat, prolonged standing, alcohol and large carbohydrate-rich
      meals; small frequent meals; head-up sleeping and similar measures.
    pubmed_query: '"lifestyle"[tiab] OR "small meals"[tiab] OR "avoid heat"[tiab] OR "head-up sleeping"[tiab] OR "dietary modification"[tiab] OR "behavioral modification"[tiab]'
    mesh_terms: ['Life Style', 'Health Behavior']
    concepts:
      - {vocabulary: SNOMED, search_term: 'lifestyle education'}
    source_refs: [chung2026]
  - id: offending_medication_withdrawal
    group: treatment
    label: Stopping drugs that worsen POTS
    definition: Withdrawing or replacing medications that worsen orthostatic tachycardia.
    pubmed_query: '"deprescribing"[tiab] OR "medication review"[tiab] OR "drug withdrawal"[tiab] OR "medication withdrawal"[tiab]'
    mesh_terms: ['Deprescriptions', 'Withholding Treatment']
    concepts:
      - {vocabulary: SNOMED, search_term: 'medication review'}
    source_refs: [chung2026]
  - id: auricular_vagus_nerve_stimulation
    group: treatment
    label: Auricular vagus nerve stimulation
    definition: Non-invasive stimulation of the auricular branch of the vagus nerve.
    pubmed_query: '"vagus nerve stimulation"[tiab] OR "vagal nerve stimulation"[tiab] OR tVNS[tiab] OR taVNS[tiab] OR "auricular stimulation"[tiab]'
    mesh_terms: ['Vagus Nerve Stimulation', 'Transcutaneous Electric Nerve Stimulation']
    concepts:
      - {vocabulary: SNOMED, search_term: 'vagus nerve stimulation'}
    source_refs: [lau2026]
  - id: antihistamine_therapy
    group: treatment
    label: Antihistamines and mast cell stabilisers
    definition: H1 and H2 antihistamines and mast cell stabilisers, used when mast cell activation is suspected.
    pubmed_query: 'antihistamine*[tiab] OR "H1 blocker*"[tiab] OR "H2 blocker*"[tiab] OR famotidine[tiab] OR cetirizine[tiab] OR "cromolyn"[tiab] OR "mast cell stabili*"[tiab]'
    mesh_terms: ['Histamine Antagonists', 'Histamine H1 Antagonists', 'Histamine H2 Antagonists', 'Cromolyn Sodium']
    concepts:
      - {vocabulary: RxNorm, search_term: 'cetirizine'}
      - {vocabulary: RxNorm, search_term: 'famotidine'}
    source_refs: [lau2026]
  - id: prokinetic_therapy
    group: treatment
    label: Prokinetic agents
    definition: Drugs that promote gastrointestinal motility, used for gut dysmotility in POTS.
    pubmed_query: 'prokinetic*[tiab] OR metoclopramide[tiab] OR domperidone[tiab] OR prucalopride[tiab] OR erythromycin[tiab]'
    mesh_terms: ['Gastrointestinal Agents', 'Metoclopramide', 'Domperidone']
    concepts:
      - {vocabulary: RxNorm, search_term: 'metoclopramide'}
    source_refs: [lau2026]
  - id: phenobarbital_therapy
    group: treatment
    label: Phenobarbital
    definition: Low-dose phenobarbital, used by Low 2009 for unstable hypertensive tilt responses.
    pubmed_query: 'phenobarbital[tiab] OR phenobarbitone[tiab] OR barbiturate*[tiab]'
    mesh_terms: ['Phenobarbital']
    concepts:
      - {vocabulary: RxNorm, search_term: 'phenobarbital'}
    source_refs: [low2009]


seed_references:
  angeli2024:
    citation: 'Angeli et al. Symptom presentation by phenotype of postural orthostatic tachycardia syndrome. Scientific Reports, 2024.'
    pubmed_lookup: 'Angeli[Author] AND "postural orthostatic tachycardia"[Title] AND 2024[PDAT]'
    expected_title: 'Symptom presentation by phenotype of postural orthostatic tachycardia syndrome.'
    expected_pmid: '38168762'
  gibbons2013:
    citation: 'Gibbons et al. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS ONE, 2013.'
    pubmed_lookup: 'small fiber abnormalities in the neuropathic postural tachycardia syndrome[Title]'
    expected_title: 'Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.'
    expected_pmid: '24386408'
  zhang2022:
    citation: 'Zhang et al. Skin biopsy and QSART testing in patients with postural orthostatic tachycardia syndrome. Cureus, 2022.'
    pubmed_lookup: 'Skin Biopsy and Quantitative Sudomotor Axon Reflex Testing[Title]'
    expected_title: 'Skin Biopsy and Quantitative Sudomotor Axon Reflex Testing in Patients With Postural Orthostatic Tachycardia Syndrome.'
    expected_pmid: '36349067'
  larsen2025:
    citation: 'Larsen et al. Long-COVID POTS: a deep phenotyping study. medRxiv preprint, 2025.'
    pubmed_lookup: 'long COVID postural orthostatic tachycardia deep phenotyping[Title/Abstract]'
    note: >
      medRxiv preprint. PubMed does not index medRxiv, so this seed is expected
      to be absent from a PubMed-only corpus. The validation report treats its
      absence as expected rather than as a defect.
  lau2026:
    citation: 'Lau DH, Fedorowski A, Raj SR, et al. Postural orthostatic tachycardia syndrome: a state-of-the-art review. Heart, Lung and Circulation, 2026;35:171-185.'
    pubmed_lookup: 'Postural Orthostatic Tachycardia Syndrome State-of-the-Art Review[Title] AND Lau DH[Author]'
    expected_title: 'Postural Orthostatic Tachycardia Syndrome: A State-of-the-Art Review.'
    expected_pmid: '41519610'
  chung2026:
    citation: 'Chung TH, Raj SR. Postural orthostatic tachycardia syndrome (POTS): a review. JAMA, 2026.'
    pubmed_lookup: 'Chung TH[Author] AND Raj SR[Author] AND "postural orthostatic tachycardia"[Title] AND 2026[PDAT]'
    expected_title: 'Postural Orthostatic Tachycardia Syndrome (POTS): A Review.'
    expected_pmid: '42635998'
  low2009:
    citation: 'Low et al. Postural tachycardia syndrome (POTS). Journal of Cardiovascular Electrophysiology / review, 2009.'
    pubmed_lookup: 'Postural tachycardia syndrome (POTS)[Title] AND Low PA[Author]'
    expected_title: 'Postural tachycardia syndrome (POTS).'
    expected_pmid: '19207771'