@erosolaraijs/cure 1.0.1 → 1.0.3

package/dist/ml/outcomePredictor.js

@@ -0,0 +1,823 @@
+/**
+ * Machine Learning Outcome Prediction Infrastructure
+ *
+ * Provides ML-based prediction models for:
+ * - Treatment response prediction
+ * - Survival probability estimation
+ * - Toxicity risk assessment
+ * - Resistance prediction
+ * - Optimal therapy selection
+ *
+ * This module provides the infrastructure for training and deploying
+ * ML models. In production, models would be trained on real patient cohorts
+ * with proper validation and FDA clearance.
+ */
+import { EventEmitter } from 'events';
+import { createHash } from 'crypto';
+// ═══════════════════════════════════════════════════════════════════════════════
+// OUTCOME PREDICTOR SERVICE
+// ═══════════════════════════════════════════════════════════════════════════════
+export class OutcomePredictorService extends EventEmitter {
+    modelRegistry = new Map();
+    featureEncoders = new Map();
+    predictionCache = new Map();
+    cacheDuration = 3600000; // 1 hour
+    constructor() {
+        super();
+        this.initializeDefaultModels();
+        this.initializeFeatureEncoders();
+    }
+    /**
+     * Predict treatment response
+     */
+    async predictResponse(patient, treatment) {
+        const cacheKey = this.getCacheKey('response', patient, treatment);
+        const cached = this.getFromCache(cacheKey);
+        if (cached)
+            return cached;
+        // Get appropriate model
+        const model = this.getBestModel('response', patient.cancerType);
+        // Encode features
+        const features = this.encodeFeatures(patient, treatment);
+        // Make prediction (in production, this would call a trained model)
+        const prediction = this.computeResponsePrediction(features, patient, treatment, model);
+        this.setCache(cacheKey, prediction);
+        this.emit('prediction-made', { type: 'response', patient, treatment, prediction });
+        return prediction;
+    }
+    /**
+     * Predict survival outcomes
+     */
+    async predictSurvival(patient, treatment) {
+        const cacheKey = this.getCacheKey('survival', patient, treatment);
+        const cached = this.getFromCache(cacheKey);
+        if (cached)
+            return cached;
+        const model = this.getBestModel('pfs', patient.cancerType);
+        const features = this.encodeFeatures(patient, treatment);
+        const prediction = this.computeSurvivalPrediction(features, patient, treatment, model);
+        this.setCache(cacheKey, prediction);
+        this.emit('prediction-made', { type: 'survival', patient, treatment, prediction });
+        return prediction;
+    }
+    /**
+     * Predict toxicity risk
+     */
+    async predictToxicity(patient, treatment) {
+        const cacheKey = this.getCacheKey('toxicity', patient, treatment);
+        const cached = this.getFromCache(cacheKey);
+        if (cached)
+            return cached;
+        const model = this.getBestModel('toxicity', patient.cancerType);
+        const features = this.encodeFeatures(patient, treatment);
+        const prediction = this.computeToxicityPrediction(features, patient, treatment, model);
+        this.setCache(cacheKey, prediction);
+        this.emit('prediction-made', { type: 'toxicity', patient, treatment, prediction });
+        return prediction;
+    }
+    /**
+     * Predict resistance development
+     */
+    async predictResistance(patient, treatment) {
+        const cacheKey = this.getCacheKey('resistance', patient, treatment);
+        const cached = this.getFromCache(cacheKey);
+        if (cached)
+            return cached;
+        const model = this.getBestModel('resistance', patient.cancerType);
+        const features = this.encodeFeatures(patient, treatment);
+        const prediction = this.computeResistancePrediction(features, patient, treatment, model);
+        this.setCache(cacheKey, prediction);
+        this.emit('prediction-made', { type: 'resistance', patient, treatment, prediction });
+        return prediction;
+    }
+    /**
+     * Rank treatment options
+     */
+    async rankTherapies(patient, treatmentOptions, preferences) {
+        const rankings = [];
+        // Get predictions for each treatment option
+        for (const treatment of treatmentOptions) {
+            const [response, survival, toxicity] = await Promise.all([
+                this.predictResponse(patient, treatment),
+                this.predictSurvival(patient, treatment),
+                this.predictToxicity(patient, treatment)
+            ]);
+            // Calculate overall score based on preferences
+            const weights = {
+                efficacy: preferences?.prioritizeEfficacy ? 0.5 : 0.35,
+                toxicity: preferences?.prioritizeToxicity ? 0.3 : 0.25,
+                qol: preferences?.prioritizeQoL ? 0.3 : 0.2,
+                survival: 0.2
+            };
+            const efficacyScore = response.objectiveResponseRate;
+            const toxicityScore = 1 - toxicity.grade3PlusRisk;
+            const survivalScore = survival.pfs.twelveMonth;
+            const qolScore = this.estimateQoLScore(toxicity);
+            const overallScore = efficacyScore * weights.efficacy +
+                toxicityScore * weights.toxicity +
+                survivalScore * weights.survival +
+                qolScore * weights.qol;
+            rankings.push({
+                regimen: treatment.regimen,
+                drugs: treatment.drugs,
+                rank: 0, // Will be set after sorting
+                predictions: {
+                    responseRate: response.objectiveResponseRate,
+                    pfsSurvival: survival.pfs.median,
+                    osSurvival: survival.os.median,
+                    toxicityRisk: toxicity.grade3PlusRisk,
+                    qualityOfLifeScore: qolScore
+                },
+                overallScore,
+                confidence: (response.confidence + survival.pfs.confidence) / 2,
+                matchingBiomarkers: this.getMatchingBiomarkers(patient, treatment),
+                fdaApproved: this.checkFDAApproval(treatment, patient.cancerType),
+                nccnRecommended: this.checkNCCNRecommendation(treatment, patient.cancerType, patient.stage),
+                considerations: this.getConsiderations(patient, treatment)
+            });
+        }
+        // Sort by overall score
+        rankings.sort((a, b) => b.overallScore - a.overallScore);
+        // Assign ranks
+        rankings.forEach((r, i) => r.rank = i + 1);
+        const bestChoice = rankings[0];
+        return {
+            therapies: rankings,
+            bestChoice: {
+                regimen: bestChoice.regimen,
+                rationale: [
+                    `Highest overall score (${(bestChoice.overallScore * 100).toFixed(1)}%)`,
+                    `Expected response rate: ${(bestChoice.predictions.responseRate * 100).toFixed(1)}%`,
+                    `Expected median PFS: ${bestChoice.predictions.pfsSurvival.toFixed(1)} months`,
+                    bestChoice.fdaApproved ? 'FDA approved for this indication' : '',
+                    bestChoice.nccnRecommended ? 'NCCN recommended' : '',
+                    ...bestChoice.matchingBiomarkers.map(b => `Matches biomarker: ${b}`)
+                ].filter(Boolean)
+            }
+        };
+    }
+    /**
+     * Get comprehensive prediction report
+     */
+    async getComprehensivePrediction(patient, treatment) {
+        const [response, survival, toxicity, resistance] = await Promise.all([
+            this.predictResponse(patient, treatment),
+            this.predictSurvival(patient, treatment),
+            this.predictToxicity(patient, treatment),
+            this.predictResistance(patient, treatment)
+        ]);
+        // Generate overall assessment
+        const overallAssessment = this.generateOverallAssessment(patient, treatment, response, survival, toxicity, resistance);
+        return {
+            response,
+            survival,
+            toxicity,
+            resistance,
+            overallAssessment
+        };
+    }
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // PREDICTION COMPUTATION (Placeholder implementations)
+    // In production, these would use trained ML models
+    // ═══════════════════════════════════════════════════════════════════════════════
+    computeResponsePrediction(features, patient, treatment, model) {
+        // Base probabilities based on treatment type and cancer
+        let baseCR = 0.15;
+        let basePR = 0.30;
+        let baseSD = 0.30;
+        // Adjust based on biomarkers
+        if (this.hasBiomarkerMatch(patient, treatment)) {
+            baseCR += 0.15;
+            basePR += 0.15;
+        }
+        // Adjust based on stage
+        const stageModifiers = {
+            'I': 1.3, 'IA': 1.3, 'IB': 1.25,
+            'II': 1.15, 'IIA': 1.15, 'IIB': 1.1,
+            'III': 0.9, 'IIIA': 0.95, 'IIIB': 0.85, 'IIIC': 0.8,
+            'IV': 0.7, 'IVA': 0.75, 'IVB': 0.65
+        };
+        const stageMod = stageModifiers[patient.stage] || 1.0;
+        // Adjust based on ECOG
+        const ecogModifiers = [1.0, 0.9, 0.75, 0.5, 0.25];
+        const ecogMod = ecogModifiers[patient.ecogStatus];
+        // Adjust based on treatment setting
+        const settingModifiers = {
+            'first-line': 1.0,
+            'second-line': 0.75,
+            'third-line-plus': 0.5,
+            'neoadjuvant': 1.1,
+            'adjuvant': 1.05,
+            'maintenance': 0.9
+        };
+        const settingMod = settingModifiers[treatment.setting] || 1.0;
+        // Apply modifiers
+        const modifier = stageMod * ecogMod * settingMod;
+        const crProb = Math.min(baseCR * modifier, 0.6);
+        const prProb = Math.min(basePR * modifier, 0.5);
+        const sdProb = Math.min(baseSD * modifier, 0.4);
+        const pdProb = Math.max(1 - crProb - prProb - sdProb, 0.05);
+        // Normalize
+        const total = crProb + prProb + sdProb + pdProb;
+        const probabilities = {
+            completeResponse: crProb / total,
+            partialResponse: prProb / total,
+            stableDisease: sdProb / total,
+            progressiveDisease: pdProb / total
+        };
+        // Determine best response
+        const maxProb = Math.max(...Object.values(probabilities));
+        let predictedResponse = 'SD';
+        if (probabilities.completeResponse === maxProb)
+            predictedResponse = 'CR';
+        else if (probabilities.partialResponse === maxProb)
+            predictedResponse = 'PR';
+        else if (probabilities.progressiveDisease === maxProb)
+            predictedResponse = 'PD';
+        return {
+            predictedResponse,
+            probabilities,
+            confidence: model ? model.performance.auc || 0.75 : 0.70,
+            objectiveResponseRate: probabilities.completeResponse + probabilities.partialResponse,
+            diseaseControlRate: probabilities.completeResponse + probabilities.partialResponse + probabilities.stableDisease,
+            timeToResponse: {
+                median: 8,
+                range: [4, 16]
+            }
+        };
+    }
+    computeSurvivalPrediction(features, patient, treatment, model) {
+        // Base survival estimates (in months)
+        let basePFS = 12;
+        let baseOS = 24;
+        // Cancer type adjustments
+        const cancerPFSModifiers = {
+            'NSCLC': 1.0, 'SCLC': 0.5, 'Breast': 1.5, 'Colorectal': 1.0,
+            'Melanoma': 1.2, 'RCC': 1.3, 'Ovarian': 0.8, 'Pancreatic': 0.4,
+            'Glioblastoma': 0.3, 'AML': 0.6, 'Multiple Myeloma': 1.5
+        };
+        const cancerMod = cancerPFSModifiers[patient.cancerType] || 1.0;
+        basePFS *= cancerMod;
+        baseOS *= cancerMod;
+        // Stage adjustments
+        const stageModifiers = {
+            'I': 3.0, 'IA': 3.5, 'IB': 2.8,
+            'II': 2.0, 'IIA': 2.2, 'IIB': 1.8,
+            'III': 1.0, 'IIIA': 1.2, 'IIIB': 0.9, 'IIIC': 0.7,
+            'IV': 0.5, 'IVA': 0.55, 'IVB': 0.4
+        };
+        const stageMod = stageModifiers[patient.stage] || 1.0;
+        basePFS *= stageMod;
+        baseOS *= stageMod;
+        // Biomarker-driven therapy boost
+        if (this.hasBiomarkerMatch(patient, treatment)) {
+            basePFS *= 1.5;
+            baseOS *= 1.3;
+        }
+        // ECOG adjustment
+        const ecogMultipliers = [1.0, 0.85, 0.65, 0.4, 0.2];
+        basePFS *= ecogMultipliers[patient.ecogStatus];
+        baseOS *= ecogMultipliers[patient.ecogStatus];
+        // Calculate probabilities using exponential survival model
+        const lambda_pfs = 1 / basePFS;
+        const lambda_os = 1 / baseOS;
+        const pfs = {
+            median: basePFS,
+            sixMonth: Math.exp(-lambda_pfs * 6),
+            twelveMonth: Math.exp(-lambda_pfs * 12),
+            twentyFourMonth: Math.exp(-lambda_pfs * 24),
+            confidence: model ? model.performance.cIndex || 0.72 : 0.68
+        };
+        const os = {
+            median: baseOS,
+            twelveMonth: Math.exp(-lambda_os * 12),
+            twentyFourMonth: Math.exp(-lambda_os * 24),
+            fiveYear: Math.exp(-lambda_os * 60),
+            confidence: model ? model.performance.cIndex || 0.72 : 0.68
+        };
+        // Calculate risk score (0-100)
+        const riskFactors = [
+            patient.stage.startsWith('IV') ? 25 : patient.stage.startsWith('III') ? 15 : 5,
+            patient.ecogStatus >= 2 ? 20 : patient.ecogStatus === 1 ? 10 : 0,
+            (patient.priorLines || 0) >= 2 ? 15 : (patient.priorLines || 0) >= 1 ? 8 : 0,
+            patient.ldh && patient.ldh > 250 ? 10 : 0,
+            patient.metastaticSites && patient.metastaticSites.length > 2 ? 15 : 0,
+            patient.age > 75 ? 10 : patient.age > 65 ? 5 : 0
+        ];
+        const riskScore = Math.min(riskFactors.reduce((a, b) => a + b, 0), 100);
+        let riskGroup;
+        if (riskScore < 25)
+            riskGroup = 'low';
+        else if (riskScore < 50)
+            riskGroup = 'intermediate-low';
+        else if (riskScore < 75)
+            riskGroup = 'intermediate-high';
+        else
+            riskGroup = 'high';
+        return { pfs, os, riskGroup, riskScore };
+    }
+    computeToxicityPrediction(features, patient, treatment, model) {
+        const specificRisks = [];
+        let grade3PlusRisk = 0;
+        // Define toxicity profiles by drug class
+        const drugToxicities = this.getDrugToxicityProfiles(treatment.drugs);
+        for (const tox of drugToxicities) {
+            // Adjust risk based on patient factors
+            let adjustedRisk = tox.baseRisk;
+            // Age adjustment
+            if (patient.age > 70)
+                adjustedRisk *= 1.2;
+            if (patient.age > 80)
+                adjustedRisk *= 1.4;
+            // Organ function adjustment
+            if (tox.affectedOrgan === 'hepatic' && patient.organFunction?.hepatic === 'impaired') {
+                adjustedRisk *= 1.5;
+            }
+            if (tox.affectedOrgan === 'renal' && patient.organFunction?.renal === 'impaired') {
+                adjustedRisk *= 1.5;
+            }
+            if (tox.affectedOrgan === 'cardiac' && patient.organFunction?.cardiac === 'impaired') {
+                adjustedRisk *= 1.5;
+            }
+            // ECOG adjustment
+            adjustedRisk *= (1 + patient.ecogStatus * 0.1);
+            adjustedRisk = Math.min(adjustedRisk, 0.95);
+            specificRisks.push({
+                toxicity: tox.name,
+                grade: tox.typicalGrade,
+                probability: adjustedRisk,
+                timeToOnset: tox.timeToOnset,
+                reversible: tox.reversible,
+                management: tox.management
+            });
+            if (tox.typicalGrade >= 3) {
+                grade3PlusRisk += adjustedRisk * 0.3; // Weighted contribution
+            }
+        }
+        grade3PlusRisk = Math.min(grade3PlusRisk, 0.9);
+        // Immunotherapy-specific irAE prediction
+        let iraeRisk;
+        if (treatment.treatmentType === 'immunotherapy' || this.hasImmunotherapyDrug(treatment.drugs)) {
+            iraeRisk = {
+                any: 0.60,
+                grade3Plus: 0.15,
+                specificOrgans: [
+                    { organ: 'skin', risk: 0.35 },
+                    { organ: 'GI', risk: 0.20 },
+                    { organ: 'endocrine', risk: 0.15 },
+                    { organ: 'hepatic', risk: 0.10 },
+                    { organ: 'pulmonary', risk: 0.08 }
+                ]
+            };
+        }
+        // Dose modification recommendation
+        let doseModification;
+        if (patient.age > 75 || patient.ecogStatus >= 2 || patient.organFunction?.renal === 'impaired') {
+            doseModification = {
+                recommended: true,
+                reduction: 20,
+                reason: patient.age > 75 ? 'Advanced age' :
+                    patient.ecogStatus >= 2 ? 'Poor performance status' :
+                        'Impaired organ function'
+            };
+        }
+        return {
+            overallRisk: grade3PlusRisk > 0.4 ? 'high' : grade3PlusRisk > 0.2 ? 'moderate' : 'low',
+            grade3PlusRisk,
+            specificRisks,
+            iraeRisk,
+            doseModification
+        };
+    }
+    computeResistancePrediction(features, patient, treatment, model) {
+        let intrinsicRisk = 0.2;
+        let acquiredRisk = 0.6;
+        // Adjust based on prior treatments
+        if (patient.priorLines && patient.priorLines > 0) {
+            intrinsicRisk += 0.1 * patient.priorLines;
+            acquiredRisk += 0.05 * patient.priorLines;
+        }
+        // Adjust based on prior response
+        if (patient.priorResponse === 'PD') {
+            intrinsicRisk += 0.2;
+        }
+        else if (patient.priorResponse === 'CR') {
+            intrinsicRisk -= 0.1;
+        }
+        // Get resistance mechanisms based on treatment and mutations
+        const mechanisms = this.getResistanceMechanisms(patient, treatment);
+        // Calculate time to resistance
+        const baseTimeToResistance = this.hasBiomarkerMatch(patient, treatment) ? 18 : 9;
+        const timeModifier = patient.priorLines ? 1 - (patient.priorLines * 0.15) : 1;
+        // Get next line options
+        const nextLineOptions = this.getNextLineOptions(patient, treatment, mechanisms);
+        return {
+            intrinsicResistanceRisk: Math.min(intrinsicRisk, 0.9),
+            acquiredResistanceRisk: Math.min(acquiredRisk, 0.95),
+            predictedMechanisms: mechanisms,
+            timeToResistance: {
+                median: baseTimeToResistance * timeModifier,
+                range: [baseTimeToResistance * timeModifier * 0.5, baseTimeToResistance * timeModifier * 2]
+            },
+            nextLineOptions
+        };
+    }
+    // ═══════════════════════════════════════════════════════════════════════════════
+    // HELPER METHODS
+    // ═══════════════════════════════════════════════════════════════════════════════
+    initializeDefaultModels() {
+        // Register placeholder models
+        const defaultModels = [
+            {
+                id: 'response-nsclc-v1',
+                name: 'NSCLC Response Predictor',
+                version: '1.0',
+                type: 'classification',
+                target: 'response',
+                cancerTypes: ['NSCLC'],
+                performance: { auc: 0.78, accuracy: 0.72 },
+                validation: { method: 'cross-validation', cohortSize: 1500, testSetSize: 300, validationDate: new Date() },
+                features: ['age', 'stage', 'ecog', 'pdl1', 'tmb', 'egfr', 'alk', 'kras'],
+                importantFeatures: [
+                    { feature: 'pdl1', importance: 0.25 },
+                    { feature: 'tmb', importance: 0.20 },
+                    { feature: 'egfr', importance: 0.18 }
+                ],
+                status: 'validation'
+            },
+            {
+                id: 'survival-pan-cancer-v1',
+                name: 'Pan-Cancer Survival Model',
+                version: '1.0',
+                type: 'survival',
+                target: 'os',
+                cancerTypes: ['all'],
+                performance: { cIndex: 0.72 },
+                validation: { method: 'cross-validation', cohortSize: 10000, testSetSize: 2000, validationDate: new Date() },
+                features: ['age', 'stage', 'ecog', 'cancerType', 'priorLines', 'ldh'],
+                importantFeatures: [
+                    { feature: 'stage', importance: 0.30 },
+                    { feature: 'ecog', importance: 0.25 },
+                    { feature: 'priorLines', importance: 0.15 }
+                ],
+                status: 'validation'
+            }
+        ];
+        for (const model of defaultModels) {
+            this.modelRegistry.set(model.id, model);
+        }
+    }
+    initializeFeatureEncoders() {
+        // Initialize encoders for categorical variables
+        this.featureEncoders.set('stage', new FeatureEncoder({
+            'I': 1, 'IA': 1, 'IB': 1.5,
+            'II': 2, 'IIA': 2, 'IIB': 2.5,
+            'III': 3, 'IIIA': 3, 'IIIB': 3.5, 'IIIC': 3.8,
+            'IV': 4, 'IVA': 4, 'IVB': 4.5
+        }));
+        this.featureEncoders.set('cancerType', new FeatureEncoder({
+            'NSCLC': 1, 'SCLC': 2, 'Breast': 3, 'Colorectal': 4,
+            'Melanoma': 5, 'RCC': 6, 'Ovarian': 7, 'Pancreatic': 8
+        }));
+    }
+    encodeFeatures(patient, treatment) {
+        const features = [];
+        // Numeric features (normalized)
+        features.push(patient.age / 100);
+        features.push(patient.ecogStatus / 4);
+        features.push(patient.gender === 'male' ? 1 : 0);
+        // Encoded categorical features
+        const stageEncoder = this.featureEncoders.get('stage');
+        features.push((stageEncoder?.encode(patient.stage) || 2) / 5);
+        // Biomarker features
+        features.push((patient.pdl1Score || 0) / 100);
+        features.push((patient.tmbValue || 0) / 50);
+        features.push(patient.msiStatus === 'MSI-H' ? 1 : 0);
+        features.push(patient.hrdStatus === 'positive' ? 1 : 0);
+        // Prior treatment features
+        features.push((patient.priorLines || 0) / 5);
+        // Treatment features
+        features.push(treatment.treatmentType === 'immunotherapy' ? 1 : 0);
+        features.push(treatment.treatmentType === 'targeted' ? 1 : 0);
+        return features;
+    }
+    getBestModel(target, cancerType) {
+        const models = Array.from(this.modelRegistry.values())
+            .filter(m => m.target === target &&
+            (m.cancerTypes.includes(cancerType) || m.cancerTypes.includes('all')) &&
+            m.status !== 'deprecated')
+            .sort((a, b) => (b.performance.auc || b.performance.cIndex || 0) - (a.performance.auc || a.performance.cIndex || 0));
+        return models[0];
+    }
+    hasBiomarkerMatch(patient, treatment) {
+        // Check for biomarker-drug matches
+        const matches = [
+            { biomarker: 'EGFR', drugs: ['osimertinib', 'erlotinib', 'gefitinib', 'afatinib'] },
+            { biomarker: 'ALK', drugs: ['alectinib', 'crizotinib', 'brigatinib', 'lorlatinib'] },
+            { biomarker: 'BRAF V600', drugs: ['dabrafenib', 'vemurafenib', 'encorafenib'] },
+            { biomarker: 'HER2', drugs: ['trastuzumab', 'pertuzumab', 't-dxd'] },
+            { biomarker: 'BRCA', drugs: ['olaparib', 'rucaparib', 'niraparib', 'talazoparib'] },
+            { biomarker: 'KRAS G12C', drugs: ['sotorasib', 'adagrasib'] }
+        ];
+        for (const match of matches) {
+            const hasBiomarker = patient.genomicAlterations.some(g => g.gene.toUpperCase().includes(match.biomarker) ||
+                g.alteration.toUpperCase().includes(match.biomarker));
+            const hasDrug = treatment.drugs.some(d => match.drugs.some(md => d.toLowerCase().includes(md)));
+            if (hasBiomarker && hasDrug)
+                return true;
+        }
+        // Check immunotherapy eligibility
+        if (treatment.treatmentType === 'immunotherapy' || this.hasImmunotherapyDrug(treatment.drugs)) {
+            if (patient.msiStatus === 'MSI-H')
+                return true;
+            if (patient.tmbStatus === 'high')
+                return true;
+            if (patient.pdl1Score && patient.pdl1Score >= 50)
+                return true;
+        }
+        return false;
+    }
+    hasImmunotherapyDrug(drugs) {
+        const immunoDrugs = ['pembrolizumab', 'nivolumab', 'ipilimumab', 'atezolizumab', 'durvalumab', 'avelumab'];
+        return drugs.some(d => immunoDrugs.some(id => d.toLowerCase().includes(id)));
+    }
+    getDrugToxicityProfiles(drugs) {
+        const profiles = [];
+        // Check for common drug classes and their toxicities
+        for (const drug of drugs) {
+            const lower = drug.toLowerCase();
+            // Checkpoint inhibitors
+            if (['pembrolizumab', 'nivolumab', 'ipilimumab', 'atezolizumab'].some(d => lower.includes(d))) {
+                profiles.push({ name: 'Immune-related dermatitis', baseRisk: 0.35, typicalGrade: 2, affectedOrgan: 'skin', reversible: true }, { name: 'Immune-related colitis', baseRisk: 0.15, typicalGrade: 3, affectedOrgan: 'GI', reversible: true, management: 'Corticosteroids' }, { name: 'Immune-related pneumonitis', baseRisk: 0.05, typicalGrade: 3, affectedOrgan: 'pulmonary', reversible: true, management: 'Hold treatment, corticosteroids' }, { name: 'Immune-related hepatitis', baseRisk: 0.08, typicalGrade: 3, affectedOrgan: 'hepatic', reversible: true }, { name: 'Immune-related thyroiditis', baseRisk: 0.15, typicalGrade: 2, affectedOrgan: 'endocrine', reversible: false });
+            }
+            // Platinum agents
+            if (['carboplatin', 'cisplatin', 'oxaliplatin'].some(d => lower.includes(d))) {
+                profiles.push({ name: 'Nausea/Vomiting', baseRisk: 0.60, typicalGrade: 2, affectedOrgan: 'GI', reversible: true }, { name: 'Nephrotoxicity', baseRisk: lower.includes('cisplatin') ? 0.25 : 0.08, typicalGrade: 2, affectedOrgan: 'renal', reversible: true }, { name: 'Myelosuppression', baseRisk: 0.40, typicalGrade: 3, affectedOrgan: 'hematologic', reversible: true }, { name: 'Peripheral neuropathy', baseRisk: 0.30, typicalGrade: 2, affectedOrgan: 'neurologic', reversible: false });
+            }
+            // EGFR TKIs
+            if (['osimertinib', 'erlotinib', 'gefitinib', 'afatinib'].some(d => lower.includes(d))) {
+                profiles.push({ name: 'Rash', baseRisk: 0.45, typicalGrade: 2, affectedOrgan: 'skin', reversible: true }, { name: 'Diarrhea', baseRisk: 0.50, typicalGrade: 2, affectedOrgan: 'GI', reversible: true }, { name: 'Interstitial lung disease', baseRisk: 0.03, typicalGrade: 4, affectedOrgan: 'pulmonary', reversible: false });
+            }
+            // CDK4/6 inhibitors
+            if (['palbociclib', 'ribociclib', 'abemaciclib'].some(d => lower.includes(d))) {
+                profiles.push({ name: 'Neutropenia', baseRisk: 0.70, typicalGrade: 3, affectedOrgan: 'hematologic', reversible: true }, { name: 'Fatigue', baseRisk: 0.40, typicalGrade: 2, reversible: true }, { name: 'Diarrhea', baseRisk: lower.includes('abemaciclib') ? 0.80 : 0.20, typicalGrade: 2, affectedOrgan: 'GI', reversible: true });
+            }
+        }
+        return profiles;
+    }
+    getResistanceMechanisms(patient, treatment) {
+        const mechanisms = [];
+        // EGFR TKI resistance mechanisms
+        if (treatment.drugs.some(d => ['osimertinib', 'erlotinib', 'gefitinib'].some(e => d.toLowerCase().includes(e)))) {
+            mechanisms.push({ mechanism: 'MET amplification', probability: 0.20, monitoringBiomarker: 'MET FISH/NGS' }, { mechanism: 'EGFR C797S mutation', probability: 0.15, monitoringBiomarker: 'ctDNA EGFR' }, { mechanism: 'Histologic transformation (SCLC)', probability: 0.05, monitoringBiomarker: 'Tissue biopsy' }, { mechanism: 'HER2 amplification', probability: 0.10, monitoringBiomarker: 'HER2 NGS/FISH' });
+        }
+        // Immunotherapy resistance
+        if (this.hasImmunotherapyDrug(treatment.drugs)) {
+            mechanisms.push({ mechanism: 'Beta-2 microglobulin loss', probability: 0.10, monitoringBiomarker: 'B2M NGS' }, { mechanism: 'JAK1/2 mutations', probability: 0.08, monitoringBiomarker: 'JAK1/2 NGS' }, { mechanism: 'Immunosuppressive TME', probability: 0.25, monitoringBiomarker: 'Tissue biopsy + IHC' }, { mechanism: 'Antigen loss', probability: 0.15 });
+        }
+        // BRAF inhibitor resistance
+        if (treatment.drugs.some(d => ['dabrafenib', 'vemurafenib', 'encorafenib'].some(b => d.toLowerCase().includes(b)))) {
+            mechanisms.push({ mechanism: 'MAPK reactivation', probability: 0.30, monitoringBiomarker: 'NRAS/MEK NGS' }, { mechanism: 'BRAF amplification', probability: 0.15, monitoringBiomarker: 'BRAF CNV' }, { mechanism: 'RTK bypass (EGFR, MET)', probability: 0.20, monitoringBiomarker: 'Comprehensive NGS' });
+        }
+        return mechanisms;
+    }
+    getNextLineOptions(patient, treatment, mechanisms) {
+        const options = [];
+        // Based on predicted resistance mechanisms
+        for (const mech of mechanisms.slice(0, 3)) {
+            if (mech.mechanism === 'MET amplification') {
+                options.push({
+                    therapy: 'Osimertinib + Savolitinib',
+                    rationale: 'Targets MET bypass pathway',
+                    expectedBenefit: 8
+                });
+            }
+            if (mech.mechanism === 'EGFR C797S mutation') {
+                options.push({
+                    therapy: 'First-generation EGFR TKI + Third-generation EGFR TKI',
+                    rationale: 'C797S may restore sensitivity to 1st-gen TKI',
+                    expectedBenefit: 6
+                });
+            }
+            if (mech.mechanism === 'Histologic transformation (SCLC)') {
+                options.push({
+                    therapy: 'Platinum-etoposide chemotherapy',
+                    rationale: 'Standard SCLC treatment',
+                    expectedBenefit: 4
+                });
+            }
+        }
+        // Add general next-line options
+        if (treatment.treatmentType !== 'immunotherapy' && !this.hasImmunotherapyDrug(treatment.drugs)) {
+            options.push({
+                therapy: 'Immunotherapy (if PD-L1+/TMB-H)',
+                rationale: 'Different mechanism of action',
+                expectedBenefit: 10
+            });
+        }
+        // Clinical trial option
+        options.push({
+            therapy: 'Clinical trial enrollment',
+            rationale: 'Access to novel agents',
+            expectedBenefit: 8
+        });
+        return options;
+    }
+    estimateQoLScore(toxicity) {
+        let score = 0.85; // Base quality of life
+        // Reduce based on toxicity severity
+        score -= toxicity.grade3PlusRisk * 0.3;
+        // Specific high-impact toxicities
+        for (const tox of toxicity.specificRisks) {
+            if (tox.toxicity.toLowerCase().includes('neuropathy') && tox.grade >= 2) {
+                score -= 0.1;
+            }
+            if (tox.toxicity.toLowerCase().includes('fatigue') && tox.grade >= 2) {
+                score -= 0.08;
+            }
+            if (tox.toxicity.toLowerCase().includes('nausea') && tox.grade >= 2) {
+                score -= 0.05;
+            }
+        }
+        return Math.max(score, 0.3);
+    }
+    getMatchingBiomarkers(patient, treatment) {
+        const matches = [];
+        for (const alt of patient.genomicAlterations) {
+            if (this.isBiomarkerRelevant(alt.gene, alt.alteration, treatment)) {
+                matches.push(`${alt.gene} ${alt.alteration}`);
+            }
+        }
+        if (patient.msiStatus === 'MSI-H' && this.hasImmunotherapyDrug(treatment.drugs)) {
+            matches.push('MSI-H');
+        }
+        if (patient.tmbStatus === 'high' && this.hasImmunotherapyDrug(treatment.drugs)) {
+            matches.push('TMB-High');
+        }
+        if (patient.hrdStatus === 'positive' && treatment.drugs.some(d => ['olaparib', 'rucaparib', 'niraparib', 'talazoparib'].some(p => d.toLowerCase().includes(p)))) {
+            matches.push('HRD-positive');
+        }
+        return matches;
+    }
+    isBiomarkerRelevant(gene, alteration, treatment) {
+        const relevantPairs = {
+            'EGFR': ['osimertinib', 'erlotinib', 'gefitinib', 'afatinib'],
+            'ALK': ['alectinib', 'crizotinib', 'brigatinib', 'lorlatinib'],
+            'ROS1': ['crizotinib', 'entrectinib'],
+            'BRAF': ['dabrafenib', 'vemurafenib', 'encorafenib'],
+            'HER2': ['trastuzumab', 'pertuzumab', 't-dxd'],
+            'BRCA': ['olaparib', 'rucaparib', 'niraparib', 'talazoparib'],
+            'KRAS': ['sotorasib', 'adagrasib'],
+            'NTRK': ['larotrectinib', 'entrectinib'],
+            'RET': ['selpercatinib', 'pralsetinib'],
+            'MET': ['capmatinib', 'tepotinib']
+        };
+        const drugs = relevantPairs[gene.toUpperCase()];
+        if (!drugs)
+            return false;
+        return treatment.drugs.some(d => drugs.some(rd => d.toLowerCase().includes(rd)));
+    }
+    checkFDAApproval(treatment, cancerType) {
+        // Simplified FDA approval check - would reference actual database in production
+        const approvedCombinations = {
+            'NSCLC': ['osimertinib', 'pembrolizumab', 'alectinib', 'sotorasib'],
+            'Breast': ['palbociclib', 'trastuzumab', 'olaparib', 'sacituzumab'],
+            'Melanoma': ['pembrolizumab', 'nivolumab', 'ipilimumab', 'dabrafenib'],
+            'Colorectal': ['pembrolizumab', 'cetuximab', 'bevacizumab'],
+            'RCC': ['pembrolizumab', 'nivolumab', 'cabozantinib']
+        };
+        const approvedDrugs = approvedCombinations[cancerType] || [];
+        return treatment.drugs.some(d => approvedDrugs.some(ad => d.toLowerCase().includes(ad)));
+    }
+    checkNCCNRecommendation(treatment, cancerType, stage) {
+        // Simplified NCCN check - would reference actual guidelines in production
+        return this.checkFDAApproval(treatment, cancerType);
+    }
+    getConsiderations(patient, treatment) {
+        const considerations = [];
+        if (patient.age > 75) {
+            considerations.push('Consider dose reduction for elderly patient');
+        }
+        if (patient.ecogStatus >= 2) {
+            considerations.push('Poor performance status may limit tolerability');
+        }
+        if (patient.organFunction?.renal === 'impaired') {
+            considerations.push('Dose adjustment may be needed for renal impairment');
+        }
+        if (patient.priorLines && patient.priorLines >= 2) {
+            considerations.push('Heavily pretreated - consider clinical trial');
+        }
+        return considerations;
+    }
+    generateOverallAssessment(patient, treatment, response, survival, toxicity, resistance) {
+        const rationale = [];
+        const caveats = [];
+        const alternativeOptions = [];
+        // Calculate recommendation score
+        let score = 50;
+        // Response contribution
+        if (response.objectiveResponseRate >= 0.6) {
+            score += 20;
+            rationale.push('High expected response rate');
+        }
+        else if (response.objectiveResponseRate >= 0.4) {
+            score += 10;
+        }
+        else if (response.objectiveResponseRate < 0.2) {
+            score -= 20;
+            caveats.push('Low expected response rate');
+        }
+        // Survival contribution
+        if (survival.pfs.twelveMonth >= 0.6) {
+            score += 15;
+            rationale.push('Favorable survival outlook');
+        }
+        else if (survival.pfs.twelveMonth < 0.3) {
+            score -= 15;
+            caveats.push('Limited expected duration of benefit');
+        }
+        // Toxicity contribution
+        if (toxicity.grade3PlusRisk < 0.2) {
+            score += 10;
+            rationale.push('Favorable toxicity profile');
+        }
+        else if (toxicity.grade3PlusRisk > 0.5) {
+            score -= 20;
+            caveats.push('High risk of severe toxicity');
+        }
+        // Biomarker match
+        if (this.hasBiomarkerMatch(patient, treatment)) {
+            score += 15;
+            rationale.push('Biomarker-matched therapy');
+        }
+        // FDA approval and guidelines
+        if (this.checkFDAApproval(treatment, patient.cancerType)) {
+            score += 10;
+            rationale.push('FDA approved for indication');
+        }
+        // Add alternatives
+        if (resistance.nextLineOptions.length > 0) {
+            alternativeOptions.push(...resistance.nextLineOptions.slice(0, 2).map(o => o.therapy));
+        }
+        // Determine recommendation
+        let recommendation;
+        if (score >= 80)
+            recommendation = 'strongly-recommended';
+        else if (score >= 60)
+            recommendation = 'recommended';
+        else if (score >= 40)
+            recommendation = 'consider';
+        else if (score >= 20)
+            recommendation = 'caution';
+        else
+            recommendation = 'not-recommended';
+        return { recommendation, rationale, caveats, alternativeOptions };
+    }
+    getCacheKey(type, patient, treatment) {
+        const data = JSON.stringify({ type, patient, treatment });
+        return createHash('sha256').update(data).digest('hex').substring(0, 16);
+    }
+    getFromCache(key) {
+        const cached = this.predictionCache.get(key);
+        if (cached && Date.now() - cached.timestamp.getTime() < this.cacheDuration) {
+            return cached.prediction;
+        }
+        return null;
+    }
+    setCache(key, prediction) {
+        this.predictionCache.set(key, { prediction, timestamp: new Date() });
+    }
+    /**
+     * Register a new model
+     */
+    registerModel(model) {
+        this.modelRegistry.set(model.id, model);
+        this.emit('model-registered', model);
+    }
+    /**
+     * Get model performance metrics
+     */
+    getModelMetrics(modelId) {
+        return this.modelRegistry.get(modelId)?.performance;
+    }
+    /**
+     * List all available models
+     */
+    listModels() {
+        return Array.from(this.modelRegistry.values());
+    }
+}
+// ═══════════════════════════════════════════════════════════════════════════════
+// FEATURE ENCODER
+// ═══════════════════════════════════════════════════════════════════════════════
+class FeatureEncoder {
+    mapping;
+    constructor(mapping) {
+        this.mapping = mapping;
+    }
+    encode(value) {
+        return this.mapping[value] ?? 0;
+    }
+}
+export default OutcomePredictorService;
+//# sourceMappingURL=outcomePredictor.js.map