/**
 * Special Populations Oncology Module
 *
 * ╔═══════════════════════════════════════════════════════════════════════════════╗
 * ║  SPECIAL POPULATIONS - COMPREHENSIVE PROTOCOLS FOR ALL PATIENTS              ║
 * ╠═══════════════════════════════════════════════════════════════════════════════╣
 * ║  This module provides:                                                        ║
 * ║  - Pediatric dosing calculations and protocols                               ║
 * ║  - Geriatric assessment and dose modifications                               ║
 * ║  - Pregnancy-specific management by trimester                                ║
 * ║  - Organ dysfunction dosing adjustments                                      ║
 * ║  - HIV/AIDS oncology protocols                                               ║
 * ║  - Drug interaction safety checking                                          ║
 * ╚═══════════════════════════════════════════════════════════════════════════════╝
 */

// ═══════════════════════════════════════════════════════════════════════════════
// PEDIATRIC ONCOLOGY DOSING
// ═══════════════════════════════════════════════════════════════════════════════

export interface PediatricDosingProtocol {
  drug: string;
  indication: string[];
  dosingMethod: 'BSA' | 'Weight' | 'Age-based' | 'Fixed';
  standardDose: string;
  maxDose: string;
  ageAdjustments: AgeAdjustment[];
  organFunctionAdjustments: string[];
  formulations: string[];
  administrationNotes: string[];
  monitoringRequirements: string[];
}

export interface AgeAdjustment {
  ageGroup: 'Neonate (<1 mo)' | 'Infant (1-12 mo)' | 'Toddler (1-3 yr)' | 'Child (3-12 yr)' | 'Adolescent (12-18 yr)';
  adjustment: string;
  rationale: string;
}

export function calculateBSA(weight: number, height: number): number {
  // Mosteller formula: BSA (m²) = √((height cm × weight kg) / 3600)
  return Math.sqrt((height * weight) / 3600);
}

export function calculatePediatricDose(
  adultDose: number,
  patientBSA: number,
  dosingMethod: 'BSA' | 'Weight' | 'Fixed',
  weight?: number
): { dose: number; unit: string; notes: string[] } {
  const notes: string[] = [];

  if (dosingMethod === 'BSA') {
    const dose = adultDose * patientBSA;
    notes.push(`Calculated using BSA ${patientBSA.toFixed(2)} m²`);
    return { dose: Math.round(dose * 10) / 10, unit: 'mg', notes };
  } else if (dosingMethod === 'Weight' && weight) {
    notes.push(`Calculated using weight ${weight} kg`);
    return { dose: Math.round(adultDose * weight * 10) / 10, unit: 'mg', notes };
  }

  return { dose: adultDose, unit: 'mg', notes: ['Fixed dose used'] };
}

export const PEDIATRIC_DOSING_PROTOCOLS: PediatricDosingProtocol[] = [
  {
    drug: 'Vincristine',
    indication: ['ALL', 'Lymphoma', 'Wilms tumor', 'Neuroblastoma'],
    dosingMethod: 'BSA',
    standardDose: '1.5 mg/m² IV (max 2 mg)',
    maxDose: '2 mg absolute',
    ageAdjustments: [
      { ageGroup: 'Infant (1-12 mo)', adjustment: 'Reduce by 50%', rationale: 'Immature hepatic metabolism' },
      { ageGroup: 'Neonate (<1 mo)', adjustment: 'Use with extreme caution, 75% reduction', rationale: 'Limited clearance' }
    ],
    organFunctionAdjustments: ['Reduce dose 50% for bilirubin >3', 'Reduce 75% for bilirubin >5'],
    formulations: ['1 mg/mL solution for injection'],
    administrationNotes: ['Vesicant - ensure good IV access', 'Fatal if given intrathecally', 'Must be in minibag, not syringe'],
    monitoringRequirements: ['Neuro exam for neuropathy', 'Bowel function (constipation)', 'Jaw pain (first-dose)']
  },
  {
    drug: 'Doxorubicin',
    indication: ['Osteosarcoma', 'Ewing sarcoma', 'Lymphoma', 'Solid tumors'],
    dosingMethod: 'BSA',
    standardDose: '30-75 mg/m² IV per cycle (protocol-dependent)',
    maxDose: 'Cumulative lifetime max: 450-550 mg/m²',
    ageAdjustments: [
      { ageGroup: 'Infant (1-12 mo)', adjustment: 'Use with caution; increased cardiac risk', rationale: 'Developing myocardium' },
      { ageGroup: 'Adolescent (12-18 yr)', adjustment: 'Standard dosing; monitor cumulative dose', rationale: 'Long survival means late effects matter' }
    ],
    organFunctionAdjustments: ['Bilirubin 1.2-3: reduce 50%', 'Bilirubin 3-5: reduce 75%', 'Bilirubin >5: hold'],
    formulations: ['2 mg/mL solution'],
    administrationNotes: ['Vesicant', 'Infuse over 15-60 minutes', 'Red urine is expected'],
    monitoringRequirements: ['Echocardiogram at baseline, q3-6 months during, and annually after', 'CBC before each dose', 'LFTs']
  },
  {
    drug: 'Methotrexate (High-dose)',
    indication: ['ALL', 'Osteosarcoma', 'Lymphoma'],
    dosingMethod: 'BSA',
    standardDose: '1-12 g/m² IV (protocol-dependent)',
    maxDose: 'Protocol-specific',
    ageAdjustments: [
      { ageGroup: 'Infant (1-12 mo)', adjustment: 'Reduce by 30-50%; prolonged clearance', rationale: 'Immature renal function' },
      { ageGroup: 'Child (3-12 yr)', adjustment: 'Standard protocol dosing', rationale: 'Adequate clearance' }
    ],
    organFunctionAdjustments: ['Contraindicated if CrCl <60', 'Third-spacing prolongs clearance', 'Hold if effusions present'],
    formulations: ['Various concentrations for IV'],
    administrationNotes: ['Aggressive hydration required', 'Urine alkalinization (pH ≥7)', 'Leucovorin rescue per protocol'],
    monitoringRequirements: ['MTX levels per protocol', 'Creatinine daily', 'CBC', 'Continue leucovorin until MTX <0.1']
  },
  {
    drug: 'Cisplatin',
    indication: ['Osteosarcoma', 'Hepatoblastoma', 'Germ cell tumors', 'Brain tumors'],
    dosingMethod: 'BSA',
    standardDose: '60-100 mg/m² IV (protocol-dependent)',
    maxDose: 'Protocol-specific; watch cumulative nephrotoxicity/ototoxicity',
    ageAdjustments: [
      { ageGroup: 'Infant (1-12 mo)', adjustment: 'Reduce dose; higher ototoxicity risk', rationale: 'Developing auditory system' },
      { ageGroup: 'Neonate (<1 mo)', adjustment: 'Avoid if possible', rationale: 'Extreme ototoxicity risk' }
    ],
    organFunctionAdjustments: ['CrCl 10-50: reduce 25-50%', 'CrCl <10: avoid'],
    formulations: ['1 mg/mL solution'],
    administrationNotes: ['Vigorous hydration pre/post', 'Mannitol diuresis in some protocols', 'Antiemetics required'],
    monitoringRequirements: ['Audiometry at baseline and after each cycle', 'Creatinine/BUN', 'Electrolytes (Mg, K)', 'CBC']
  },
  {
    drug: 'Cyclophosphamide',
    indication: ['ALL', 'Lymphoma', 'Solid tumors', 'Conditioning for HSCT'],
    dosingMethod: 'BSA',
    standardDose: '500-1800 mg/m² (protocol-dependent)',
    maxDose: 'Protocol-specific',
    ageAdjustments: [
      { ageGroup: 'Infant (1-12 mo)', adjustment: 'Standard dosing per BSA; monitor closely', rationale: 'Adequate metabolism' }
    ],
    organFunctionAdjustments: ['Reduce 25% for CrCl 10-50', 'Reduce 50% for CrCl <10'],
    formulations: ['Lyophilized powder for reconstitution', 'Oral tablets'],
    administrationNotes: ['Hydrate to prevent hemorrhagic cystitis', 'Mesna for high doses (>1g/m²)'],
    monitoringRequirements: ['CBC', 'Urinalysis', 'Fluid balance', 'Fertility counseling']
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// GERIATRIC ONCOLOGY
// ═══════════════════════════════════════════════════════════════════════════════

export interface GeriatricAssessment {
  domain: string;
  tool: string;
  interpretation: AssessmentInterpretation[];
  treatmentImplications: string[];
}

export interface AssessmentInterpretation {
  score: string;
  category: string;
  meaning: string;
}

export interface GeriatricDosingAdjustment {
  drug: string;
  standardDose: string;
  geriatricConsiderations: string[];
  doseModification: string;
  alternativeAgents?: string[];
  monitoringIntensification: string[];
}

export const COMPREHENSIVE_GERIATRIC_ASSESSMENT: GeriatricAssessment[] = [
  {
    domain: 'Functional Status',
    tool: 'Activities of Daily Living (ADL)',
    interpretation: [
      { score: '6/6', category: 'Independent', meaning: 'No functional impairment' },
      { score: '4-5/6', category: 'Mild impairment', meaning: 'May need some assistance' },
      { score: '<4/6', category: 'Dependent', meaning: 'Significant functional limitation' }
    ],
    treatmentImplications: ['Independent: standard treatment', 'Mild impairment: consider dose reduction', 'Dependent: palliative-focused care often appropriate']
  },
  {
    domain: 'Functional Status',
    tool: 'Instrumental ADL (IADL)',
    interpretation: [
      { score: '8/8', category: 'Independent', meaning: 'Can manage complex tasks' },
      { score: '5-7/8', category: 'Some limitation', meaning: 'May need support for some tasks' },
      { score: '<5/8', category: 'Significant limitation', meaning: 'Needs substantial support' }
    ],
    treatmentImplications: ['IADL impairment predicts chemotherapy toxicity', 'Consider treatment simplification']
  },
  {
    domain: 'Comorbidity',
    tool: 'Charlson Comorbidity Index',
    interpretation: [
      { score: '0', category: 'No comorbidity', meaning: 'Low competing mortality' },
      { score: '1-2', category: 'Mild comorbidity', meaning: 'Moderate competing mortality' },
      { score: '≥3', category: 'Severe comorbidity', meaning: 'High competing mortality' }
    ],
    treatmentImplications: ['High CCI: balance cancer treatment benefit vs comorbidity burden', 'Consider life expectancy from comorbidities']
  },
  {
    domain: 'Cognition',
    tool: 'Mini-Cog',
    interpretation: [
      { score: '4-5', category: 'Normal', meaning: 'No cognitive impairment detected' },
      { score: '0-3', category: 'Abnormal', meaning: 'Possible cognitive impairment; needs further evaluation' }
    ],
    treatmentImplications: ['Cognitive impairment affects treatment adherence', 'Need caregiver involvement', 'Simplify oral regimens']
  },
  {
    domain: 'Nutrition',
    tool: 'Mini Nutritional Assessment - Short Form (MNA-SF)',
    interpretation: [
      { score: '12-14', category: 'Normal', meaning: 'No malnutrition risk' },
      { score: '8-11', category: 'At risk', meaning: 'Malnutrition risk' },
      { score: '0-7', category: 'Malnourished', meaning: 'Malnutrition present' }
    ],
    treatmentImplications: ['Malnutrition increases toxicity', 'Consider nutritional support before chemotherapy', 'May need dose reduction']
  },
  {
    domain: 'Mood',
    tool: 'Geriatric Depression Scale (GDS-4)',
    interpretation: [
      { score: '0', category: 'Normal', meaning: 'No depression' },
      { score: '≥1', category: 'Possible depression', meaning: 'Screen further with GDS-15' }
    ],
    treatmentImplications: ['Depression affects QoL and adherence', 'Consider psychiatry/psychology referral']
  },
  {
    domain: 'Falls',
    tool: 'Falls in past 6 months',
    interpretation: [
      { score: '0 falls', category: 'Low risk', meaning: 'No recent falls' },
      { score: '1+ falls', category: 'High risk', meaning: 'Fall risk present' }
    ],
    treatmentImplications: ['Falls risk with neurotoxic agents (taxanes, platinum)', 'Physical therapy evaluation', 'Home safety assessment']
  },
  {
    domain: 'Polypharmacy',
    tool: 'Number of medications',
    interpretation: [
      { score: '<5', category: 'Normal', meaning: 'Acceptable' },
      { score: '5-9', category: 'Polypharmacy', meaning: 'Moderate drug burden' },
      { score: '≥10', category: 'Excessive polypharmacy', meaning: 'High interaction risk' }
    ],
    treatmentImplications: ['Review for deprescribing', 'Drug-drug interaction check critical', 'Simplify regimens']
  }
];

export const GERIATRIC_DOSING_ADJUSTMENTS: GeriatricDosingAdjustment[] = [
  {
    drug: 'Capecitabine',
    standardDose: '1000-1250 mg/m² BID D1-14 q21d',
    geriatricConsiderations: ['Higher toxicity in elderly', 'Diarrhea more severe', 'Hand-foot syndrome'],
    doseModification: 'Start at 75% dose (750-1000 mg/m² BID); reduce further if toxicity',
    alternativeAgents: ['5-FU infusional if poor compliance'],
    monitoringIntensification: ['Weekly calls/visits first cycle', 'Aggressive antidiarrheal education']
  },
  {
    drug: 'Docetaxel',
    standardDose: '75-100 mg/m² q3w',
    geriatricConsiderations: ['Higher neutropenia risk', 'Fluid retention', 'Neuropathy'],
    doseModification: 'Consider 60-75 mg/m² in frail elderly; weekly dosing (35 mg/m²) as alternative',
    alternativeAgents: ['Paclitaxel weekly may be better tolerated'],
    monitoringIntensification: ['G-CSF support recommended', 'Weekly CBC first cycle', 'Daily weights for edema']
  },
  {
    drug: 'Cisplatin',
    standardDose: '75-100 mg/m² q3w',
    geriatricConsiderations: ['Nephrotoxicity', 'Ototoxicity', 'Neuropathy', 'Requires aggressive hydration'],
    doseModification: 'Consider carboplatin substitution (AUC 5-6) in elderly; if cisplatin required, reduce to 60-75 mg/m²',
    alternativeAgents: ['Carboplatin preferred in elderly', 'Oxaliplatin for GI cancers'],
    monitoringIntensification: ['CrCl before each cycle', 'Hearing assessment', 'Hydration status']
  },
  {
    drug: 'Doxorubicin',
    standardDose: '60-75 mg/m² q3w',
    geriatricConsiderations: ['Cardiotoxicity risk higher', 'Age-related decrease in cardiac reserve'],
    doseModification: 'Consider liposomal doxorubicin or dose reduction to 50 mg/m²; lower cumulative max (400 mg/m²)',
    alternativeAgents: ['Pegylated liposomal doxorubicin (lower cardiotoxicity)', 'Epirubicin'],
    monitoringIntensification: ['ECHO before treatment and q2-3 cycles', 'BNP/troponin monitoring']
  },
  {
    drug: 'Pembrolizumab/Nivolumab',
    standardDose: 'Standard dosing (fixed or weight-based)',
    geriatricConsiderations: ['Similar efficacy in elderly', 'irAE profile similar but monitoring important'],
    doseModification: 'No dose adjustment for age; monitor closely for irAEs',
    monitoringIntensification: ['Lower threshold for steroid initiation', 'Close symptom monitoring', 'Thyroid function each cycle']
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// PREGNANCY AND CANCER
// ═══════════════════════════════════════════════════════════════════════════════

export interface PregnancyCancerProtocol {
  trimester: 'First' | 'Second' | 'Third';
  generalPrinciples: string[];
  allowedTreatments: TreatmentSafety[];
  contraindicated: string[];
  fetalMonitoring: string[];
  deliveryConsiderations: string[];
}

export interface TreatmentSafety {
  modality: string;
  safety: 'Generally Safe' | 'Use with Caution' | 'Limited Data' | 'Contraindicated';
  evidence: string;
  specificAgents?: string[];
}

export const PREGNANCY_CANCER_PROTOCOLS: PregnancyCancerProtocol[] = [
  {
    trimester: 'First',
    generalPrinciples: [
      'Organogenesis occurs - highest teratogenic risk',
      'Delay chemotherapy until second trimester if possible',
      'Surgery can be performed with caution',
      'Radiation generally contraindicated near fetus'
    ],
    allowedTreatments: [
      { modality: 'Surgery', safety: 'Use with Caution', evidence: 'Second trimester preferred but first trimester acceptable for urgent cases' },
      { modality: 'Breast surgery', safety: 'Generally Safe', evidence: 'Can proceed; avoid supine hypotension' },
      { modality: 'Sentinel node biopsy', safety: 'Use with Caution', evidence: 'Technetium safe; blue dye avoided by some' }
    ],
    contraindicated: [
      'All chemotherapy (teratogenic risk 10-20%)',
      'Radiation therapy near pelvis',
      'Endocrine therapy (tamoxifen, AIs)',
      'Methotrexate (abortifacient)',
      'All targeted therapies'
    ],
    fetalMonitoring: ['First trimester ultrasound', 'Nuchal translucency if indicated', 'Cell-free DNA screening'],
    deliveryConsiderations: ['Plan for second trimester treatment initiation']
  },
  {
    trimester: 'Second',
    generalPrinciples: [
      'Chemotherapy can be given after week 14',
      'Organogenesis complete - lower malformation risk',
      'Surgery remains feasible',
      'Goal: deliver at term if possible'
    ],
    allowedTreatments: [
      { modality: 'Anthracyclines', safety: 'Generally Safe', evidence: 'Extensive data; doxorubicin, epirubicin acceptable', specificAgents: ['Doxorubicin', 'Epirubicin'] },
      { modality: 'Taxanes', safety: 'Generally Safe', evidence: 'Growing safety data', specificAgents: ['Paclitaxel', 'Docetaxel'] },
      { modality: 'Platinum agents', safety: 'Use with Caution', evidence: 'Carboplatin preferred; cisplatin with caution', specificAgents: ['Carboplatin'] },
      { modality: 'Alkylating agents', safety: 'Use with Caution', evidence: 'Cyclophosphamide used in FAC/FEC', specificAgents: ['Cyclophosphamide'] },
      { modality: 'Surgery', safety: 'Generally Safe', evidence: 'Optimal timing 14-28 weeks' },
      { modality: 'Radiation (non-pelvic)', safety: 'Use with Caution', evidence: 'Fetal shielding; keep dose <100 mGy to fetus' }
    ],
    contraindicated: [
      'Methotrexate',
      'Endocrine therapy',
      'Targeted therapies (trastuzumab - oligohydramnios)',
      'Immunotherapy (limited data, potential fetal harm)',
      'Radiation to pelvis'
    ],
    fetalMonitoring: ['Anatomy scan at 18-20 weeks', 'Growth ultrasound after chemotherapy', 'Fetal echocardiogram if anthracyclines used'],
    deliveryConsiderations: ['Allow 3 weeks between last chemo and delivery', 'Avoid delivery during nadir', 'Term delivery preferred (≥37 weeks)']
  },
  {
    trimester: 'Third',
    generalPrinciples: [
      'Continue chemotherapy until 35-37 weeks',
      'Plan delivery around treatment',
      'Allow 3 weeks between last chemo and delivery',
      'Delivery at term preferred'
    ],
    allowedTreatments: [
      { modality: 'Anthracyclines', safety: 'Generally Safe', evidence: 'Continue if started', specificAgents: ['Doxorubicin'] },
      { modality: 'Taxanes', safety: 'Generally Safe', evidence: 'Continue if started', specificAgents: ['Paclitaxel'] },
      { modality: 'Surgery', safety: 'Use with Caution', evidence: 'Possible but fetus approaching term' }
    ],
    contraindicated: [
      'Same as second trimester',
      'Avoid new regimen initiation if delivery imminent'
    ],
    fetalMonitoring: ['Weekly NST after 32 weeks', 'Growth ultrasound', 'Biophysical profile if concerns'],
    deliveryConsiderations: [
      'Stop chemotherapy at 35-37 weeks',
      'Delivery at ≥37 weeks if possible',
      'Cesarean only for obstetric indications',
      'Breastfeeding contraindicated during chemotherapy'
    ]
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// ORGAN DYSFUNCTION DOSING
// ═══════════════════════════════════════════════════════════════════════════════

export interface OrganDysfunctionDosing {
  drug: string;
  renalDosing: RenalDosing[];
  hepaticDosing: HepaticDosing[];
  dialysisGuidance?: string;
}

export interface RenalDosing {
  crclRange: string;
  adjustment: string;
}

export interface HepaticDosing {
  bilirubinRange: string;
  astAltRange: string;
  adjustment: string;
}

export const ORGAN_DYSFUNCTION_DOSING: OrganDysfunctionDosing[] = [
  {
    drug: 'Carboplatin',
    renalDosing: [
      { crclRange: '≥60', adjustment: 'Standard AUC dosing (Calvert formula)' },
      { crclRange: '15-59', adjustment: 'Calvert formula accounts for renal function; dose automatically reduced' },
      { crclRange: '<15', adjustment: 'Use with extreme caution; AUC 2-4' }
    ],
    hepaticDosing: [
      { bilirubinRange: 'Any', astAltRange: 'Any', adjustment: 'No adjustment needed (not hepatically cleared)' }
    ],
    dialysisGuidance: 'Dialyzable; give after dialysis'
  },
  {
    drug: 'Cisplatin',
    renalDosing: [
      { crclRange: '≥60', adjustment: 'Full dose with aggressive hydration' },
      { crclRange: '40-59', adjustment: 'Reduce by 25% or consider carboplatin substitution' },
      { crclRange: '<40', adjustment: 'Avoid; use carboplatin' }
    ],
    hepaticDosing: [
      { bilirubinRange: 'Any', astAltRange: 'Any', adjustment: 'No adjustment needed' }
    ]
  },
  {
    drug: 'Methotrexate',
    renalDosing: [
      { crclRange: '≥60', adjustment: 'Full dose' },
      { crclRange: '30-59', adjustment: 'Reduce by 50%' },
      { crclRange: '<30', adjustment: 'Contraindicated for high-dose; low-dose with caution' }
    ],
    hepaticDosing: [
      { bilirubinRange: '>3x ULN', astAltRange: 'Any', adjustment: 'Hold until resolved; hepatotoxic' }
    ],
    dialysisGuidance: 'High-flux dialysis can remove methotrexate in toxicity'
  },
  {
    drug: 'Doxorubicin',
    renalDosing: [
      { crclRange: 'Any', adjustment: 'No adjustment (not renally cleared)' }
    ],
    hepaticDosing: [
      { bilirubinRange: '1.2-3.0', astAltRange: 'Any', adjustment: '50% dose reduction' },
      { bilirubinRange: '3.1-5.0', astAltRange: 'Any', adjustment: '75% dose reduction' },
      { bilirubinRange: '>5.0', astAltRange: 'Any', adjustment: 'Contraindicated' }
    ]
  },
  {
    drug: 'Paclitaxel',
    renalDosing: [
      { crclRange: 'Any', adjustment: 'No adjustment needed' }
    ],
    hepaticDosing: [
      { bilirubinRange: '≤1.5x ULN', astAltRange: '≤10x ULN', adjustment: 'Full dose' },
      { bilirubinRange: '1.6-3x ULN', astAltRange: 'Any', adjustment: 'Reduce by 20%' },
      { bilirubinRange: '>3x ULN', astAltRange: 'Any', adjustment: 'Avoid' }
    ]
  },
  {
    drug: 'Docetaxel',
    renalDosing: [
      { crclRange: 'Any', adjustment: 'No adjustment needed' }
    ],
    hepaticDosing: [
      { bilirubinRange: '>ULN', astAltRange: '>1.5x ULN + Alk phos >2.5x ULN', adjustment: 'Contraindicated' }
    ]
  },
  {
    drug: 'Capecitabine',
    renalDosing: [
      { crclRange: '≥50', adjustment: 'Full dose' },
      { crclRange: '30-49', adjustment: '75% dose' },
      { crclRange: '<30', adjustment: 'Contraindicated' }
    ],
    hepaticDosing: [
      { bilirubinRange: 'Mild-moderate', astAltRange: 'Any', adjustment: 'Use with caution' },
      { bilirubinRange: 'Severe', astAltRange: 'Any', adjustment: 'Contraindicated' }
    ]
  },
  {
    drug: 'Pembrolizumab',
    renalDosing: [
      { crclRange: 'Any', adjustment: 'No adjustment needed' }
    ],
    hepaticDosing: [
      { bilirubinRange: '1-1.5x ULN', astAltRange: 'Any', adjustment: 'No adjustment' },
      { bilirubinRange: '>1.5x ULN', astAltRange: 'Any', adjustment: 'Limited data; use with caution' }
    ]
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// HIV/AIDS ONCOLOGY
// ═══════════════════════════════════════════════════════════════════════════════

export interface HIVOncologyProtocol {
  cancerType: string;
  artInteractions: ARTInteraction[];
  treatmentModifications: string[];
  prophylaxisRequirements: string[];
  monitoringIntensification: string[];
  prognosticConsiderations: string;
}

export interface ARTInteraction {
  artClass: string;
  interaction: string;
  management: string;
}

export const HIV_ONCOLOGY_PROTOCOLS: HIVOncologyProtocol[] = [
  {
    cancerType: 'Kaposi Sarcoma',
    artInteractions: [
      { artClass: 'All ART', interaction: 'ART is primary treatment for limited disease', management: 'Optimize ART first' },
      { artClass: 'PIs', interaction: 'CYP3A4 interactions with taxanes, vinca alkaloids', management: 'Consider INSTI-based regimen during chemo' }
    ],
    treatmentModifications: [
      'Limited/stable KS: ART alone may induce remission',
      'Advanced/visceral: Liposomal doxorubicin + ART',
      'Paclitaxel for refractory disease'
    ],
    prophylaxisRequirements: ['PCP prophylaxis if CD4 <200', 'MAC prophylaxis if CD4 <50', 'CMV monitoring'],
    monitoringIntensification: ['CD4/viral load monthly during chemo', 'Watch for immune reconstitution inflammatory syndrome (IRIS)'],
    prognosticConsiderations: 'CD4 >150 and undetectable VL associated with better outcomes'
  },
  {
    cancerType: 'Non-Hodgkin Lymphoma (AIDS-related)',
    artInteractions: [
      { artClass: 'Protease inhibitors', interaction: 'Increase vincristine/doxorubicin toxicity', management: 'Switch to INSTI-based ART' },
      { artClass: 'NNRTIs (efavirenz)', interaction: 'CYP inducer; may reduce chemo levels', management: 'Consider dose adjustment or switch' }
    ],
    treatmentModifications: [
      'R-EPOCH preferred for DLBCL (infusional, less myelosuppressive)',
      'DA-EPOCH-R with dose adjustments',
      'R-CHOP for patients with good PS and CD4'
    ],
    prophylaxisRequirements: ['G-CSF support routinely', 'PCP prophylaxis regardless of CD4 during chemo', 'Consider antifungal prophylaxis'],
    monitoringIntensification: ['CD4/VL monthly', 'Close monitoring for opportunistic infections', 'Tumor lysis prophylaxis'],
    prognosticConsiderations: 'IPI + CD4 count; ART era outcomes approaching HIV-negative patients'
  },
  {
    cancerType: 'Cervical Cancer (AIDS-defining)',
    artInteractions: [
      { artClass: 'All ART', interaction: 'Continue ART during treatment', management: 'Optimize regimen for minimal interactions' }
    ],
    treatmentModifications: [
      'Standard treatment per stage',
      'Cisplatin-based chemoradiation for locally advanced',
      'May have higher toxicity rates'
    ],
    prophylaxisRequirements: ['Standard prophylaxis per CD4', 'Aggressive supportive care'],
    monitoringIntensification: ['CD4/VL q3 months', 'Close monitoring for treatment toxicity'],
    prognosticConsiderations: 'Outcomes improving with ART but still worse than HIV-negative'
  },
  {
    cancerType: 'Lung Cancer (non-AIDS-defining)',
    artInteractions: [
      { artClass: 'PIs/Cobicistat', interaction: 'CYP3A4 interactions with TKIs (osimertinib, crizotinib)', management: 'Use INSTI-based ART; consider TKI dose adjustment' }
    ],
    treatmentModifications: [
      'Standard treatment per stage and histology',
      'Immunotherapy appears safe and effective',
      'Watch for increased autoimmune manifestations'
    ],
    prophylaxisRequirements: ['Continue standard prophylaxis', 'G-CSF as needed'],
    monitoringIntensification: ['CD4/VL monitoring', 'Watch for irAEs with immunotherapy'],
    prognosticConsiderations: 'Outcomes similar to HIV-negative in ART era with controlled HIV'
  }
];

// ═══════════════════════════════════════════════════════════════════════════════
// SPECIAL POPULATIONS ENGINE
// ═══════════════════════════════════════════════════════════════════════════════

export class SpecialPopulationsEngine {
  calculatePediatricDose(
    drug: string,
    weight: number,
    height: number,
    age: number
  ): { dose: string; adjustments: string[]; monitoring: string[] } {
    const bsa = calculateBSA(weight, height);
    const protocol = PEDIATRIC_DOSING_PROTOCOLS.find(p => p.drug.toLowerCase() === drug.toLowerCase());

    if (!protocol) {
      return { dose: 'Protocol not found', adjustments: [], monitoring: [] };
    }

    const adjustments: string[] = [];

    // Check age-specific adjustments
    let ageGroup: AgeAdjustment['ageGroup'];
    if (age < 1/12) ageGroup = 'Neonate (<1 mo)';
    else if (age < 1) ageGroup = 'Infant (1-12 mo)';
    else if (age < 3) ageGroup = 'Toddler (1-3 yr)';
    else if (age < 12) ageGroup = 'Child (3-12 yr)';
    else ageGroup = 'Adolescent (12-18 yr)';

    const ageAdj = protocol.ageAdjustments.find(a => a.ageGroup === ageGroup);
    if (ageAdj) {
      adjustments.push(`${ageGroup}: ${ageAdj.adjustment} - ${ageAdj.rationale}`);
    }

    return {
      dose: `${protocol.standardDose} (BSA: ${bsa.toFixed(2)} m²)`,
      adjustments,
      monitoring: protocol.monitoringRequirements
    };
  }

  performGeriatricAssessment(scores: Record<string, number>): {
    riskCategory: 'Fit' | 'Vulnerable' | 'Frail';
    recommendations: string[];
    treatmentImplications: string[];
  } {
    let fitCount = 0;
    let vulnerableCount = 0;
    let frailCount = 0;
    const recommendations: string[] = [];

    // Simple scoring based on key domains
    if (scores['adl'] >= 5) fitCount++; else if (scores['adl'] >= 3) vulnerableCount++; else frailCount++;
    if (scores['iadl'] >= 7) fitCount++; else if (scores['iadl'] >= 4) vulnerableCount++; else frailCount++;
    if (scores['comorbidity'] <= 1) fitCount++; else if (scores['comorbidity'] <= 3) vulnerableCount++; else frailCount++;

    let riskCategory: 'Fit' | 'Vulnerable' | 'Frail';
    if (frailCount >= 2) {
      riskCategory = 'Frail';
      recommendations.push('Consider palliative-focused or modified-intensity treatment');
      recommendations.push('Prioritize quality of life');
    } else if (vulnerableCount >= 2 || frailCount === 1) {
      riskCategory = 'Vulnerable';
      recommendations.push('Consider dose reductions');
      recommendations.push('Close monitoring for toxicity');
      recommendations.push('Geriatric co-management recommended');
    } else {
      riskCategory = 'Fit';
      recommendations.push('Standard treatment appropriate');
      recommendations.push('Continue routine monitoring');
    }

    return {
      riskCategory,
      recommendations,
      treatmentImplications: COMPREHENSIVE_GERIATRIC_ASSESSMENT.flatMap(a => a.treatmentImplications)
    };
  }

  getPregnancyGuidelines(trimester: PregnancyCancerProtocol['trimester']): PregnancyCancerProtocol | undefined {
    return PREGNANCY_CANCER_PROTOCOLS.find(p => p.trimester === trimester);
  }

  getOrganDysfunctionDosing(drug: string, crcl?: number, bilirubin?: number): {
    renalAdjustment: string;
    hepaticAdjustment: string;
  } {
    const protocol = ORGAN_DYSFUNCTION_DOSING.find(p => p.drug.toLowerCase() === drug.toLowerCase());

    if (!protocol) {
      return { renalAdjustment: 'No data available', hepaticAdjustment: 'No data available' };
    }

    let renalAdjustment = 'Check CrCl';
    if (crcl !== undefined) {
      for (const rd of protocol.renalDosing) {
        if (rd.crclRange === 'Any' ||
            (rd.crclRange.includes('≥') && crcl >= parseInt(rd.crclRange.replace('≥', ''))) ||
            (rd.crclRange.includes('<') && crcl < parseInt(rd.crclRange.replace('<', '')))) {
          renalAdjustment = rd.adjustment;
          break;
        }
      }
    }

    let hepaticAdjustment = 'Check bilirubin/LFTs';
    if (bilirubin !== undefined) {
      for (const hd of protocol.hepaticDosing) {
        if (hd.bilirubinRange === 'Any') {
          hepaticAdjustment = hd.adjustment;
          break;
        }
      }
    }

    return { renalAdjustment, hepaticAdjustment };
  }

  getHIVOncologyProtocol(cancerType: string): HIVOncologyProtocol | undefined {
    return HIV_ONCOLOGY_PROTOCOLS.find(p =>
      p.cancerType.toLowerCase().includes(cancerType.toLowerCase())
    );
  }

  getGeriatricDosingAdjustment(drug: string): GeriatricDosingAdjustment | undefined {
    return GERIATRIC_DOSING_ADJUSTMENTS.find(g =>
      g.drug.toLowerCase() === drug.toLowerCase()
    );
  }
}

// Export singleton
export const specialPopulationsEngine = new SpecialPopulationsEngine();