/**
 * Retrospective Validation Framework
 *
 * Provides tools for validating the treatment recommendation system against
 * real patient outcomes. Essential for:
 * - Model performance assessment
 * - Calibration checking
 * - Concordance analysis with actual treatments
 * - Outcome correlation studies
 * - Continuous quality improvement
 *
 * IMPORTANT: All patient data used for validation must be properly de-identified
 * or used with appropriate IRB approval and patient consent.
 */
import { EventEmitter } from 'events';
export interface ValidationPatient {
    id: string;
    demographics: {
        ageAtDiagnosis: number;
        gender: 'male' | 'female';
        ethnicity?: string;
    };
    diagnosis: {
        cancerType: string;
        histology?: string;
        stage: string;
        diagnosisDate: Date;
        biomarkers?: {
            name: string;
            value: string | number;
            status?: string;
        }[];
        genomicAlterations?: {
            gene: string;
            alteration: string;
        }[];
        msiStatus?: 'MSI-H' | 'MSI-L' | 'MSS';
        tmbValue?: number;
        pdl1Score?: number;
        hrdStatus?: boolean;
    };
    treatment: {
        regimen: string;
        drugs: string[];
        setting: string;
        startDate: Date;
        endDate?: Date;
        cycles?: number;
        doseModifications?: boolean;
    };
    outcomes: {
        bestResponse?: 'CR' | 'PR' | 'SD' | 'PD' | 'NE';
        responseDate?: Date;
        progressionDate?: Date;
        deathDate?: Date;
        lastFollowUpDate: Date;
        causeOfDeath?: 'disease' | 'treatment' | 'other' | 'unknown';
        toxicities?: {
            name: string;
            grade: number;
            date?: Date;
        }[];
    };
    ecogAtBaseline?: number;
    priorLines?: number;
}
export interface SystemRecommendation {
    patientId: string;
    recommendedRegimen: string;
    recommendedDrugs: string[];
    predictions: {
        responseRate: number;
        pfsMonths: number;
        osMonths: number;
        toxicityRisk: number;
    };
    matchingBiomarkers: string[];
    confidenceScore: number;
    timestamp: Date;
}
export interface ValidationResult {
    patientId: string;
    concordance: {
        regimenMatch: boolean;
        partialMatch: boolean;
        matchedDrugs: string[];
    };
    outcomeComparison: {
        predictedResponse: number;
        actualResponse?: 'CR' | 'PR' | 'SD' | 'PD' | 'NE';
        responseCorrect?: boolean;
        predictedPFS: number;
        actualPFS?: number;
        pfsDifference?: number;
        predictedOS: number;
        actualOS?: number;
        osDifference?: number;
        predictedToxicityRisk: number;
        actualGrade3PlusToxicity: boolean;
    };
    clinicalBenefit: {
        objectiveResponse: boolean;
        diseaseControl: boolean;
        durableBenefit: boolean;
    };
}
export interface CohortAnalysis {
    cohortId: string;
    description: string;
    patientCount: number;
    dateRange: {
        start: Date;
        end: Date;
    };
    demographics: {
        medianAge: number;
        ageRange: [number, number];
        genderDistribution: {
            male: number;
            female: number;
        };
        stageDistribution: Record<string, number>;
    };
    concordance: {
        fullConcordance: number;
        partialConcordance: number;
        noConcordance: number;
        concordanceByBiomarker: Record<string, number>;
    };
    predictionAccuracy: {
        responseAccuracy: number;
        responseSensitivity: number;
        responseSpecificity: number;
        responseAUC?: number;
        pfsCIndex: number;
        pfsCalibration: number;
        osCIndex: number;
        osCalibration: number;
        toxicityAccuracy: number;
        toxicityAUC?: number;
    };
    clinicalImpact: {
        objectiveResponseRate: number;
        diseaseControlRate: number;
        medianPFS: number;
        medianOS: number;
        concordantVsDiscordant: {
            concordantORR: number;
            discordantORR: number;
            concordantMedianPFS: number;
            discordantMedianPFS: number;
            pValue?: number;
        };
    };
    subgroupAnalyses: {
        subgroup: string;
        patientCount: number;
        concordance: number;
        responseAccuracy: number;
        medianPFS: number;
    }[];
}
export declare class RetrospectiveValidationService extends EventEmitter {
    private validationCohorts;
    private systemRecommendations;
    private validationResults;
    constructor();
    /**
     * Load a validation cohort
     */
    loadCohort(cohortId: string, patients: ValidationPatient[]): void;
    /**
     * Load system recommendations for comparison
     */
    loadRecommendations(recommendations: SystemRecommendation[]): void;
    /**
     * Run validation for a cohort
     */
    runValidation(cohortId: string): Promise<CohortAnalysis>;
    /**
     * Validate a single patient
     */
    private validatePatient;
    /**
     * Assess concordance between recommendation and actual treatment
     */
    private assessConcordance;
    /**
     * Check if two drug names refer to the same drug
     */
    private drugsMatch;
    /**
     * Calculate PFS in months
     */
    private calculatePFS;
    /**
     * Calculate OS in months
     */
    private calculateOS;
    /**
     * Assess if response prediction was accurate
     */
    private assessResponseAccuracy;
    /**
     * Compute cohort-level analysis
     */
    private computeCohortAnalysis;
    /**
     * Calculate concordance index (C-index)
     */
    private calculateCIndex;
    /**
     * Calculate calibration score (0-1, higher is better)
     */
    private calculateCalibration;
    /**
     * Calculate median of an array
     */
    private calculateMedian;
    /**
     * Calculate concordance by biomarker subgroup
     */
    private calculateConcordanceByBiomarker;
    /**
     * Perform subgroup analyses
     */
    private performSubgroupAnalyses;
    /**
     * Calculate response accuracy for a subgroup
     */
    private calculateSubgroupResponseAccuracy;
    /**
     * Validate and de-identify patient data
     */
    private validateAndDeidentify;
    /**
     * Generate validation report
     */
    generateReport(analysis: CohortAnalysis): string;
    /**
     * Export validation results
     */
    exportResults(cohortId: string, format: 'json' | 'csv'): string;
}
export default RetrospectiveValidationService;
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