heor-agent-mcp 0.2.0 → 0.7.0

package/dist/models/survivalFitting.js

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+/**
+ * Survival Curve Fitting — fit parametric distributions to Kaplan-Meier data.
+ *
+ * Supports: Exponential, Weibull, Log-logistic, Log-normal, Gompertz.
+ * Uses maximum likelihood estimation via Newton-Raphson optimization.
+ * Model selection via AIC/BIC.
+ *
+ * References:
+ * - Latimer NR. NICE DSU TSD 14: Survival analysis (2013)
+ * - Collett D. Modelling Survival Data in Medical Research (2015)
+ */
+// --- Distribution functions ---
+function expSurvival(t, lambda) {
+    return Math.exp(-lambda * t);
+}
+function expHazard(_t, lambda) {
+    return lambda;
+}
+function weibullSurvival(t, shape, scale) {
+    if (t <= 0)
+        return 1;
+    return Math.exp(-Math.pow(t / scale, shape));
+}
+function weibullHazard(t, shape, scale) {
+    if (t <= 0)
+        return 0;
+    return (shape / scale) * Math.pow(t / scale, shape - 1);
+}
+function logLogisticSurvival(t, alpha, beta) {
+    if (t <= 0)
+        return 1;
+    return 1 / (1 + Math.pow(t / alpha, beta));
+}
+function logLogisticHazard(t, alpha, beta) {
+    if (t <= 0)
+        return 0;
+    const num = (beta / alpha) * Math.pow(t / alpha, beta - 1);
+    const den = 1 + Math.pow(t / alpha, beta);
+    return num / den;
+}
+function logNormalSurvival(t, mu, sigma) {
+    if (t <= 0)
+        return 1;
+    // S(t) = 1 - Phi((ln(t) - mu) / sigma)
+    const z = (Math.log(t) - mu) / sigma;
+    return 1 - normalCDF(z);
+}
+function logNormalHazard(t, mu, sigma) {
+    if (t <= 0)
+        return 0;
+    const z = (Math.log(t) - mu) / sigma;
+    const phi = normalPDF(z);
+    const bigPhi = normalCDF(z);
+    return phi / (sigma * t * (1 - bigPhi));
+}
+function gompertzSurvival(t, shape, rate) {
+    if (t <= 0)
+        return 1;
+    if (Math.abs(shape) < 1e-10)
+        return Math.exp(-rate * t);
+    return Math.exp(-(rate / shape) * (Math.exp(shape * t) - 1));
+}
+function gompertzHazard(t, shape, rate) {
+    return rate * Math.exp(shape * t);
+}
+// --- Normal distribution helpers ---
+function normalPDF(z) {
+    return Math.exp(-0.5 * z * z) / Math.sqrt(2 * Math.PI);
+}
+function normalCDF(z) {
+    // Abramowitz & Stegun approximation (error < 7.5e-8)
+    const a1 = 0.254829592;
+    const a2 = -0.284496736;
+    const a3 = 1.421413741;
+    const a4 = -1.453152027;
+    const a5 = 1.061405429;
+    const p = 0.3275911;
+    const sign = z < 0 ? -1 : 1;
+    const x = Math.abs(z) / Math.sqrt(2);
+    const t = 1 / (1 + p * x);
+    const y = 1 - ((((a5 * t + a4) * t + a3) * t + a2) * t + a1) * t * Math.exp(-x * x);
+    return 0.5 * (1 + sign * y);
+}
+// --- Log-likelihood computation ---
+/**
+ * Compute log-likelihood for interval-censored KM data.
+ * Each KM step represents an interval where the survival function
+ * drops — we compute the likelihood of the observed survival proportions.
+ */
+function logLikelihood(data, survFn) {
+    let ll = 0;
+    for (let i = 0; i < data.length; i++) {
+        const observed = data[i].survival;
+        const predicted = Math.max(1e-15, Math.min(1 - 1e-15, survFn(data[i].time)));
+        // Events in this interval
+        const nAtRisk = data[i].n_at_risk ?? 100;
+        const prevSurv = i === 0 ? 1 : data[i - 1].survival;
+        const events = Math.round((prevSurv - observed) * nAtRisk);
+        const censored = Math.max(0, (i === 0 ? nAtRisk : (data[i].n_at_risk ?? nAtRisk)) - events);
+        // Contribution: events contribute log(f(t)), censored contribute log(S(t))
+        if (events > 0) {
+            const prevPredicted = i === 0 ? 1 : survFn(data[i - 1].time);
+            const density = Math.max(1e-15, prevPredicted - predicted);
+            ll += events * Math.log(density);
+        }
+        if (censored > 0) {
+            ll += censored * Math.log(predicted);
+        }
+    }
+    return ll;
+}
+// --- Optimization (grid search + Nelder-Mead simplex) ---
+function nelderMead(fn, initial, maxIter = 500) {
+    const n = initial.length;
+    const alpha = 1;
+    const gamma = 2;
+    const rho = 0.5;
+    const sigma = 0.5;
+    // Build initial simplex
+    const simplex = [];
+    simplex.push({ point: [...initial], value: fn(initial) });
+    for (let i = 0; i < n; i++) {
+        const point = [...initial];
+        point[i] = point[i] * 1.5 + 0.1;
+        simplex.push({ point, value: fn(point) });
+    }
+    for (let iter = 0; iter < maxIter; iter++) {
+        simplex.sort((a, b) => a.value - b.value);
+        // Centroid (excluding worst)
+        const centroid = new Array(n).fill(0);
+        for (let i = 0; i < n; i++) {
+            for (let j = 0; j < n; j++) {
+                centroid[j] += simplex[i].point[j] / n;
+            }
+        }
+        const worst = simplex[n];
+        // Reflection
+        const reflected = centroid.map((c, j) => c + alpha * (c - worst.point[j]));
+        const fReflected = fn(reflected);
+        if (fReflected < simplex[n - 1].value && fReflected >= simplex[0].value) {
+            simplex[n] = { point: reflected, value: fReflected };
+            continue;
+        }
+        if (fReflected < simplex[0].value) {
+            // Expansion
+            const expanded = centroid.map((c, j) => c + gamma * (reflected[j] - c));
+            const fExpanded = fn(expanded);
+            simplex[n] = fExpanded < fReflected
+                ? { point: expanded, value: fExpanded }
+                : { point: reflected, value: fReflected };
+            continue;
+        }
+        // Contraction
+        const contracted = centroid.map((c, j) => c + rho * (worst.point[j] - c));
+        const fContracted = fn(contracted);
+        if (fContracted < worst.value) {
+            simplex[n] = { point: contracted, value: fContracted };
+            continue;
+        }
+        // Shrink
+        const best = simplex[0].point;
+        for (let i = 1; i <= n; i++) {
+            simplex[i].point = simplex[i].point.map((p, j) => best[j] + sigma * (p - best[j]));
+            simplex[i].value = fn(simplex[i].point);
+        }
+    }
+    simplex.sort((a, b) => a.value - b.value);
+    return simplex[0].point;
+}
+// --- Fitting functions ---
+function fitExponential(data) {
+    // MLE for exponential: lambda = events / total_time
+    // Use optimization for consistency with interval-censored data
+    const medianTime = data.find((d) => d.survival <= 0.5)?.time ?? data[data.length - 1].time;
+    const lambdaInit = Math.log(2) / medianTime;
+    const opt = nelderMead((p) => -logLikelihood(data, (t) => expSurvival(t, Math.max(1e-6, p[0]))), [lambdaInit]);
+    const lambda = Math.max(1e-6, opt[0]);
+    const ll = logLikelihood(data, (t) => expSurvival(t, lambda));
+    const k = 1;
+    const n = data.length;
+    return {
+        name: "exponential",
+        params: { lambda },
+        aic: -2 * ll + 2 * k,
+        bic: -2 * ll + k * Math.log(n),
+        log_likelihood: ll,
+        survival_at: (t) => expSurvival(t, lambda),
+        hazard_at: (t) => expHazard(t, lambda),
+        median_survival: Math.log(2) / lambda,
+        mean_survival_restricted: restrictedMean(data, (t) => expSurvival(t, lambda)),
+    };
+}
+function fitWeibull(data) {
+    const medianTime = data.find((d) => d.survival <= 0.5)?.time ?? data[data.length - 1].time;
+    const scaleInit = medianTime / Math.pow(Math.log(2), 1);
+    const opt = nelderMead((p) => -logLikelihood(data, (t) => weibullSurvival(t, Math.max(0.1, p[0]), Math.max(0.01, p[1]))), [1.0, scaleInit]);
+    const shape = Math.max(0.1, opt[0]);
+    const scale = Math.max(0.01, opt[1]);
+    const ll = logLikelihood(data, (t) => weibullSurvival(t, shape, scale));
+    const k = 2;
+    const n = data.length;
+    const median = scale * Math.pow(Math.log(2), 1 / shape);
+    return {
+        name: "weibull",
+        params: { shape, scale },
+        aic: -2 * ll + 2 * k,
+        bic: -2 * ll + k * Math.log(n),
+        log_likelihood: ll,
+        survival_at: (t) => weibullSurvival(t, shape, scale),
+        hazard_at: (t) => weibullHazard(t, shape, scale),
+        median_survival: median,
+        mean_survival_restricted: restrictedMean(data, (t) => weibullSurvival(t, shape, scale)),
+    };
+}
+function fitLogLogistic(data) {
+    const medianTime = data.find((d) => d.survival <= 0.5)?.time ?? data[data.length - 1].time;
+    const opt = nelderMead((p) => -logLikelihood(data, (t) => logLogisticSurvival(t, Math.max(0.01, p[0]), Math.max(0.1, p[1]))), [medianTime, 1.5]);
+    const alpha = Math.max(0.01, opt[0]);
+    const beta = Math.max(0.1, opt[1]);
+    const ll = logLikelihood(data, (t) => logLogisticSurvival(t, alpha, beta));
+    const k = 2;
+    const n = data.length;
+    return {
+        name: "log_logistic",
+        params: { alpha, beta },
+        aic: -2 * ll + 2 * k,
+        bic: -2 * ll + k * Math.log(n),
+        log_likelihood: ll,
+        survival_at: (t) => logLogisticSurvival(t, alpha, beta),
+        hazard_at: (t) => logLogisticHazard(t, alpha, beta),
+        median_survival: alpha,
+        mean_survival_restricted: restrictedMean(data, (t) => logLogisticSurvival(t, alpha, beta)),
+    };
+}
+function fitLogNormal(data) {
+    const medianTime = data.find((d) => d.survival <= 0.5)?.time ?? data[data.length - 1].time;
+    const muInit = Math.log(Math.max(0.1, medianTime));
+    const opt = nelderMead((p) => -logLikelihood(data, (t) => logNormalSurvival(t, p[0], Math.max(0.01, p[1]))), [muInit, 0.8]);
+    const mu = opt[0];
+    const sigma = Math.max(0.01, opt[1]);
+    const ll = logLikelihood(data, (t) => logNormalSurvival(t, mu, sigma));
+    const k = 2;
+    const n = data.length;
+    return {
+        name: "log_normal",
+        params: { mu, sigma },
+        aic: -2 * ll + 2 * k,
+        bic: -2 * ll + k * Math.log(n),
+        log_likelihood: ll,
+        survival_at: (t) => logNormalSurvival(t, mu, sigma),
+        hazard_at: (t) => logNormalHazard(t, mu, sigma),
+        median_survival: Math.exp(mu),
+        mean_survival_restricted: restrictedMean(data, (t) => logNormalSurvival(t, mu, sigma)),
+    };
+}
+function fitGompertz(data) {
+    const medianTime = data.find((d) => d.survival <= 0.5)?.time ?? data[data.length - 1].time;
+    const rateInit = Math.log(2) / medianTime;
+    const opt = nelderMead((p) => -logLikelihood(data, (t) => gompertzSurvival(t, p[0], Math.max(1e-6, p[1]))), [0.01, rateInit]);
+    const shape = opt[0];
+    const rate = Math.max(1e-6, opt[1]);
+    const ll = logLikelihood(data, (t) => gompertzSurvival(t, shape, rate));
+    const k = 2;
+    const n = data.length;
+    // Median: solve S(t) = 0.5 numerically
+    let median = medianTime;
+    for (let t = 0.01; t < medianTime * 5; t += 0.01) {
+        if (gompertzSurvival(t, shape, rate) <= 0.5) {
+            median = t;
+            break;
+        }
+    }
+    return {
+        name: "gompertz",
+        params: { shape, rate },
+        aic: -2 * ll + 2 * k,
+        bic: -2 * ll + k * Math.log(n),
+        log_likelihood: ll,
+        survival_at: (t) => gompertzSurvival(t, shape, rate),
+        hazard_at: (t) => gompertzHazard(t, shape, rate),
+        median_survival: median,
+        mean_survival_restricted: restrictedMean(data, (t) => gompertzSurvival(t, shape, rate)),
+    };
+}
+function restrictedMean(data, survFn) {
+    const maxT = data[data.length - 1].time;
+    const steps = 200;
+    const dt = maxT / steps;
+    let area = 0;
+    for (let i = 0; i < steps; i++) {
+        const t1 = i * dt;
+        const t2 = (i + 1) * dt;
+        area += 0.5 * (survFn(t1) + survFn(t2)) * dt;
+    }
+    return area;
+}
+// --- Main fitting function ---
+export function fitSurvivalCurves(data, timeUnit = "months") {
+    if (data.length < 3) {
+        throw new Error("At least 3 data points required for curve fitting");
+    }
+    // Sort by time
+    const sorted = [...data].sort((a, b) => a.time - b.time);
+    // Fit all distributions
+    const fits = [
+        fitExponential(sorted),
+        fitWeibull(sorted),
+        fitLogLogistic(sorted),
+        fitLogNormal(sorted),
+        fitGompertz(sorted),
+    ];
+    // Sort by AIC
+    const byAIC = [...fits].sort((a, b) => a.aic - b.aic);
+    const byBIC = [...fits].sort((a, b) => a.bic - b.bic);
+    // Generate extrapolation table
+    const maxObserved = sorted[sorted.length - 1].time;
+    const extrapolationTimes = [];
+    for (let t = 0; t <= maxObserved * 2; t += maxObserved / 10) {
+        extrapolationTimes.push(Math.round(t * 10) / 10);
+    }
+    const extrapolations = extrapolationTimes.map((t) => {
+        const kmPoint = sorted.find((d) => Math.abs(d.time - t) < maxObserved / 20);
+        return {
+            time: t,
+            km_observed: kmPoint?.survival,
+            exponential: fits[0].survival_at(t),
+            weibull: fits[1].survival_at(t),
+            log_logistic: fits[2].survival_at(t),
+            log_normal: fits[3].survival_at(t),
+            gompertz: fits[4].survival_at(t),
+        };
+    });
+    return {
+        fits,
+        best_aic: byAIC[0],
+        best_bic: byBIC[0],
+        km_data: sorted,
+        time_unit: timeUnit,
+        extrapolations,
+    };
+}
+//# sourceMappingURL=survivalFitting.js.map

package/dist/models/survivalFitting.js.map

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package/dist/network/bucher.d.ts

@@ -0,0 +1,29 @@
+import type { EffectMeasure, PooledEstimate, DirectComparison, IndirectEstimate } from "./types.js";
+/** Standard error from 95% CI */
+export declare function seFromCI(lower: number, upper: number): number;
+/** Normal CDF approximation (Abramowitz & Stegun 26.2.17) */
+export declare function normalCDF(x: number): number;
+/** Two-tailed p-value from z-score */
+export declare function pValueFromZ(z: number): number;
+/** Fixed-effect inverse-variance pooling */
+export declare function poolFixedEffect(studies: Array<{
+    value: number;
+    se: number;
+}>): PooledEstimate;
+/** Bucher indirect comparison: A vs C = A vs B - C vs B */
+export declare function bucherIndirect(ab: PooledEstimate, cb: PooledEstimate): {
+    value: number;
+    se: number;
+    z: number;
+    p_value: number;
+};
+/**
+ * Compute a single indirect comparison A vs C through common comparator B.
+ *
+ * directAB: studies comparing A (intervention) vs B (comparator)
+ * directCB: studies comparing C (intervention) vs B (comparator)
+ *
+ * Returns the indirect estimate of A vs C.
+ */
+export declare function computeIndirectComparison(intervention: string, comparator: string, bridge: string, directAB: DirectComparison[], directCB: DirectComparison[], outcome: string, measure: EffectMeasure): IndirectEstimate;
+//# sourceMappingURL=bucher.d.ts.map

package/dist/network/bucher.d.ts.map

@@ -0,0 +1 @@
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package/dist/network/bucher.js

@@ -0,0 +1,125 @@
+/** Standard error from 95% CI */
+export function seFromCI(lower, upper) {
+    return (upper - lower) / 3.92;
+}
+/** Normal CDF approximation (Abramowitz & Stegun 26.2.17) */
+export function normalCDF(x) {
+    const sign = x < 0 ? -1 : 1;
+    const z = Math.abs(x);
+    const t = 1.0 / (1.0 + 0.2316419 * z);
+    const d = 0.3989422804014327; // 1/sqrt(2*pi)
+    const p = d *
+        Math.exp((-z * z) / 2.0) *
+        (t *
+            (0.319381530 +
+                t *
+                    (-0.356563782 +
+                        t * (1.781477937 + t * (-1.821255978 + t * 1.330274429)))));
+    return sign === 1 ? 1.0 - p : p;
+}
+/** Two-tailed p-value from z-score */
+export function pValueFromZ(z) {
+    return 2 * (1 - normalCDF(Math.abs(z)));
+}
+/** Whether the measure operates on a log scale */
+function isLogScale(measure) {
+    return measure === "OR" || measure === "RR" || measure === "HR";
+}
+/** Convert to working scale (log for ratio measures) */
+function toWorkingScale(estimate, se, measure) {
+    if (isLogScale(measure)) {
+        return { value: Math.log(estimate), se };
+    }
+    return { value: estimate, se };
+}
+/** Convert SE from CI on the original scale to working scale */
+function seOnWorkingScale(estimate, ci_lower, ci_upper, measure) {
+    if (isLogScale(measure)) {
+        return (Math.log(ci_upper) - Math.log(ci_lower)) / 3.92;
+    }
+    return seFromCI(ci_lower, ci_upper);
+}
+/** Back-transform from working scale */
+function fromWorkingScale(value, lower, upper, measure) {
+    if (isLogScale(measure)) {
+        return {
+            estimate: Math.exp(value),
+            ci_lower: Math.exp(lower),
+            ci_upper: Math.exp(upper),
+        };
+    }
+    return { estimate: value, ci_lower: lower, ci_upper: upper };
+}
+/** Fixed-effect inverse-variance pooling */
+export function poolFixedEffect(studies) {
+    if (studies.length === 0) {
+        throw new Error("No studies to pool");
+    }
+    if (studies.length === 1) {
+        return { value: studies[0].value, se: studies[0].se, n_studies: 1 };
+    }
+    let sumW = 0;
+    let sumWY = 0;
+    for (const s of studies) {
+        const w = 1 / (s.se * s.se);
+        sumW += w;
+        sumWY += w * s.value;
+    }
+    return {
+        value: sumWY / sumW,
+        se: Math.sqrt(1 / sumW),
+        n_studies: studies.length,
+    };
+}
+/** Bucher indirect comparison: A vs C = A vs B - C vs B */
+export function bucherIndirect(ab, cb) {
+    const value = ab.value - cb.value;
+    const se = Math.sqrt(ab.se * ab.se + cb.se * cb.se);
+    const z = value / se;
+    const p_value = pValueFromZ(z);
+    return { value, se, z, p_value };
+}
+/**
+ * Compute a single indirect comparison A vs C through common comparator B.
+ *
+ * directAB: studies comparing A (intervention) vs B (comparator)
+ * directCB: studies comparing C (intervention) vs B (comparator)
+ *
+ * Returns the indirect estimate of A vs C.
+ */
+export function computeIndirectComparison(intervention, comparator, bridge, directAB, directCB, outcome, measure) {
+    // Convert to working scale and pool
+    const abStudies = directAB.map((d) => ({
+        value: toWorkingScale(d.estimate, seOnWorkingScale(d.estimate, d.ci_lower, d.ci_upper, measure), measure).value,
+        se: seOnWorkingScale(d.estimate, d.ci_lower, d.ci_upper, measure),
+    }));
+    const cbStudies = directCB.map((d) => ({
+        value: toWorkingScale(d.estimate, seOnWorkingScale(d.estimate, d.ci_lower, d.ci_upper, measure), measure).value,
+        se: seOnWorkingScale(d.estimate, d.ci_lower, d.ci_upper, measure),
+    }));
+    const pooledAB = poolFixedEffect(abStudies);
+    const pooledCB = poolFixedEffect(cbStudies);
+    // Bucher indirect
+    const indirect = bucherIndirect(pooledAB, pooledCB);
+    // Back-transform
+    const ciLowerWorking = indirect.value - 1.96 * indirect.se;
+    const ciUpperWorking = indirect.value + 1.96 * indirect.se;
+    const result = fromWorkingScale(indirect.value, ciLowerWorking, ciUpperWorking, measure);
+    return {
+        intervention,
+        comparator,
+        commonComparator: bridge,
+        outcome,
+        measure,
+        method: "bucher",
+        estimate: result.estimate,
+        se: indirect.se,
+        ci_lower: result.ci_lower,
+        ci_upper: result.ci_upper,
+        z: indirect.z,
+        p_value: indirect.p_value,
+        pooled_ab: pooledAB,
+        pooled_bc: pooledCB,
+    };
+}
+//# sourceMappingURL=bucher.js.map

package/dist/network/bucher.js.map

@@ -0,0 +1 @@
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package/dist/network/frequentistNma.d.ts

@@ -0,0 +1,12 @@
+import type { DirectComparison, EffectMeasure, IndirectEstimate } from "./types.js";
+/**
+ * Frequentist contrast-based NMA using weighted least squares.
+ *
+ * Given a set of direct comparisons (possibly multiple per edge),
+ * estimates all pairwise treatment effects relative to a reference.
+ *
+ * For small networks this is equivalent to the graph-theoretical
+ * approach (Rücker 2012).
+ */
+export declare function frequentistNMA(comparisons: DirectComparison[], outcome: string, measure: EffectMeasure): IndirectEstimate[];
+//# sourceMappingURL=frequentistNma.d.ts.map

package/dist/network/frequentistNma.d.ts.map

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