heor-agent-mcp 0.2.0 → 0.3.0

package/dist/formatters/comparisonMarkdown.d.ts

@@ -0,0 +1,3 @@
+import type { IndirectComparisonResult } from "../network/types.js";
+export declare function comparisonToMarkdown(result: IndirectComparisonResult): string;
+//# sourceMappingURL=comparisonMarkdown.d.ts.map

package/dist/formatters/comparisonMarkdown.d.ts.map

@@ -0,0 +1 @@
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package/dist/formatters/comparisonMarkdown.js

@@ -0,0 +1,68 @@
+function formatNum(n, decimals = 2) {
+    return n.toFixed(decimals);
+}
+function formatP(p) {
+    if (p < 0.001)
+        return "<0.001";
+    if (p < 0.01)
+        return formatNum(p, 3);
+    return formatNum(p, 3);
+}
+export function comparisonToMarkdown(result) {
+    const lines = [];
+    lines.push("## Indirect Treatment Comparisons");
+    lines.push("");
+    const methodLabel = result.method === "bucher"
+        ? "Bucher Method"
+        : result.method === "frequentist_nma"
+            ? "Frequentist Network Meta-Analysis"
+            : "Mixed Methods";
+    lines.push(`**Method:** ${methodLabel}`);
+    lines.push(`**Comparisons:** ${result.estimates.length}`);
+    lines.push("");
+    if (result.estimates.length === 0) {
+        lines.push("No indirect comparisons could be computed. Check that comparisons share a common comparator and measure the same outcome.");
+        return lines.join("\n");
+    }
+    // Group by outcome
+    const outcomes = new Map();
+    for (const e of result.estimates) {
+        if (!outcomes.has(e.outcome))
+            outcomes.set(e.outcome, []);
+        outcomes.get(e.outcome).push(e);
+    }
+    for (const [outcome, estimates] of outcomes) {
+        lines.push(`### ${outcome}`);
+        lines.push("");
+        const measure = estimates[0].measure;
+        const label = measure === "MD" ? "MD" : measure;
+        lines.push(`| Comparison | ${label} | 95% CI | p-value | Via | Method |`);
+        lines.push("|------------|---------|--------|---------|-----|--------|");
+        for (const e of estimates) {
+            const est = measure === "MD"
+                ? formatNum(e.estimate)
+                : formatNum(e.estimate);
+            const ci = `[${formatNum(e.ci_lower)}, ${formatNum(e.ci_upper)}]`;
+            const p = formatP(e.p_value);
+            const via = e.commonComparator;
+            const method = e.method === "bucher" ? "Bucher" : "Freq. NMA";
+            lines.push(`| ${e.intervention} vs ${e.comparator} | ${est} | ${ci} | ${p} | ${via} | ${method} |`);
+        }
+        lines.push("");
+    }
+    // Warnings
+    if (result.warnings.length > 0) {
+        lines.push("### Warnings");
+        for (const w of result.warnings) {
+            lines.push(`- ⚠️ ${w}`);
+        }
+        lines.push("");
+    }
+    // Limitations
+    lines.push("### Limitations");
+    for (const l of result.limitations) {
+        lines.push(`- ${l}`);
+    }
+    return lines.join("\n");
+}
+//# sourceMappingURL=comparisonMarkdown.js.map

package/dist/formatters/comparisonMarkdown.js.map

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

@@ -0,0 +1,230 @@
+import { seFromCI, pValueFromZ, poolFixedEffect } from "./bucher.js";
+function isLogScale(measure) {
+    return measure === "OR" || measure === "RR" || measure === "HR";
+}
+function toWorkingScale(d) {
+    const log = isLogScale(d.measure);
+    const se = log
+        ? (Math.log(d.ci_upper) - Math.log(d.ci_lower)) / 3.92
+        : seFromCI(d.ci_lower, d.ci_upper);
+    const value = log ? Math.log(d.estimate) : d.estimate;
+    return { value, se };
+}
+/**
+ * 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 function frequentistNMA(comparisons, outcome, measure) {
+    // Filter to the specified outcome
+    const relevant = comparisons.filter((c) => c.outcome === outcome && c.measure === measure);
+    if (relevant.length === 0)
+        return [];
+    // Pool direct comparisons by edge (intervention-comparator pair)
+    const edgeKey = (a, b) => [a, b].sort().join("↔");
+    const edgeMap = new Map();
+    for (const d of relevant) {
+        const ws = toWorkingScale(d);
+        const key = edgeKey(d.intervention, d.comparator);
+        if (!edgeMap.has(key)) {
+            edgeMap.set(key, { a: d.intervention, b: d.comparator, studies: [] });
+        }
+        const edge = edgeMap.get(key);
+        // Ensure consistent direction: if stored as B-A but input is A-B
+        if (edge.a === d.comparator && edge.b === d.intervention) {
+            ws.value = -ws.value; // flip direction
+        }
+        edge.studies.push(ws);
+    }
+    // Pool each edge
+    const contrasts = [];
+    for (const edge of edgeMap.values()) {
+        const pooled = poolFixedEffect(edge.studies);
+        contrasts.push({
+            a: edge.a,
+            b: edge.b,
+            value: pooled.value,
+            se: pooled.se,
+            n_studies: pooled.n_studies,
+        });
+    }
+    // Collect all treatment names
+    const treatments = new Set();
+    for (const c of contrasts) {
+        treatments.add(c.a);
+        treatments.add(c.b);
+    }
+    const treatmentList = Array.from(treatments).sort();
+    const n = treatmentList.length;
+    const idx = new Map(treatmentList.map((t, i) => [t, i]));
+    if (n < 2)
+        return [];
+    // Reference treatment = first alphabetically
+    const ref = treatmentList[0];
+    // Build design matrix and weight matrix
+    // Each contrast gives one equation: effect_a - effect_b = observed_value
+    // Parameters: treatment effects relative to reference (n-1 params)
+    const m = contrasts.length; // number of equations
+    const p = n - 1; // number of parameters
+    // X: m x p design matrix
+    // W: m x m diagonal weight matrix (1/se^2)
+    // y: m x 1 observation vector
+    const X = Array.from({ length: m }, () => Array(p).fill(0));
+    const W = new Array(m);
+    const y = new Array(m);
+    for (let i = 0; i < m; i++) {
+        const c = contrasts[i];
+        const ia = idx.get(c.a);
+        const ib = idx.get(c.b);
+        // effect_a - effect_b (relative to reference, which has effect = 0)
+        if (ia > 0)
+            X[i][ia - 1] = 1; // a is not reference
+        if (ib > 0)
+            X[i][ib - 1] = -1; // b is not reference
+        W[i] = 1 / (c.se * c.se);
+        y[i] = c.value;
+    }
+    // Solve: beta = (X'WX)^-1 X'Wy
+    // X'WX is p x p
+    const XtWX = Array.from({ length: p }, () => Array(p).fill(0));
+    const XtWy = Array(p).fill(0);
+    for (let i = 0; i < m; i++) {
+        for (let j = 0; j < p; j++) {
+            XtWy[j] += X[i][j] * W[i] * y[i];
+            for (let k = 0; k < p; k++) {
+                XtWX[j][k] += X[i][j] * W[i] * X[i][k];
+            }
+        }
+    }
+    // Invert XtWX using Gaussian elimination
+    const invXtWX = invertMatrix(XtWX);
+    if (!invXtWX) {
+        // Singular — network is disconnected or underdetermined
+        return [];
+    }
+    // beta = invXtWX * XtWy
+    const beta = Array(p).fill(0);
+    for (let j = 0; j < p; j++) {
+        for (let k = 0; k < p; k++) {
+            beta[j] += invXtWX[j][k] * XtWy[k];
+        }
+    }
+    // SE of each beta: sqrt(diag(invXtWX))
+    const seBeta = Array(p).fill(0);
+    for (let j = 0; j < p; j++) {
+        seBeta[j] = Math.sqrt(invXtWX[j][j]);
+    }
+    // Generate all pairwise comparisons
+    const estimates = [];
+    for (let i = 0; i < n; i++) {
+        for (let j = i + 1; j < n; j++) {
+            const tA = treatmentList[i];
+            const tB = treatmentList[j];
+            // Effect A vs B = effect_A - effect_B (relative to ref)
+            let value;
+            let variance;
+            if (i === 0) {
+                // A is reference: effect = -beta_B
+                value = -beta[j - 1];
+                variance = invXtWX[j - 1][j - 1];
+            }
+            else if (j === 0) {
+                // B is reference: effect = beta_A
+                value = beta[i - 1];
+                variance = invXtWX[i - 1][i - 1];
+            }
+            else {
+                // Neither is reference: effect = beta_A - beta_B
+                value = beta[i - 1] - beta[j - 1];
+                variance =
+                    invXtWX[i - 1][i - 1] +
+                        invXtWX[j - 1][j - 1] -
+                        2 * invXtWX[i - 1][j - 1];
+            }
+            const se = Math.sqrt(Math.max(0, variance));
+            const z = se > 0 ? value / se : 0;
+            const p_value = pValueFromZ(z);
+            let estimate;
+            let ci_lower;
+            let ci_upper;
+            if (isLogScale(measure)) {
+                estimate = Math.exp(value);
+                ci_lower = Math.exp(value - 1.96 * se);
+                ci_upper = Math.exp(value + 1.96 * se);
+            }
+            else {
+                estimate = value;
+                ci_lower = value - 1.96 * se;
+                ci_upper = value + 1.96 * se;
+            }
+            // Check if this is a direct or indirect comparison
+            const directKey = edgeKey(tA, tB);
+            const isDirect = edgeMap.has(directKey);
+            estimates.push({
+                intervention: tA,
+                comparator: tB,
+                commonComparator: isDirect ? "(direct)" : ref,
+                outcome,
+                measure,
+                method: "frequentist_nma",
+                estimate,
+                se,
+                ci_lower,
+                ci_upper,
+                z,
+                p_value,
+                pooled_ab: { value: beta[Math.max(0, i - 1)] ?? 0, se: seBeta[Math.max(0, i - 1)] ?? 0, n_studies: 0 },
+                pooled_bc: { value: beta[Math.max(0, j - 1)] ?? 0, se: seBeta[Math.max(0, j - 1)] ?? 0, n_studies: 0 },
+            });
+        }
+    }
+    return estimates;
+}
+/** Gaussian elimination matrix inversion for small matrices */
+function invertMatrix(matrix) {
+    const n = matrix.length;
+    // Augmented matrix [A | I]
+    const aug = matrix.map((row, i) => {
+        const augRow = [...row];
+        for (let j = 0; j < n; j++) {
+            augRow.push(i === j ? 1 : 0);
+        }
+        return augRow;
+    });
+    for (let col = 0; col < n; col++) {
+        // Find pivot
+        let maxRow = col;
+        let maxVal = Math.abs(aug[col][col]);
+        for (let row = col + 1; row < n; row++) {
+            if (Math.abs(aug[row][col]) > maxVal) {
+                maxVal = Math.abs(aug[row][col]);
+                maxRow = row;
+            }
+        }
+        if (maxVal < 1e-12)
+            return null; // Singular
+        // Swap rows
+        [aug[col], aug[maxRow]] = [aug[maxRow], aug[col]];
+        // Scale pivot row
+        const pivot = aug[col][col];
+        for (let j = 0; j < 2 * n; j++) {
+            aug[col][j] /= pivot;
+        }
+        // Eliminate column
+        for (let row = 0; row < n; row++) {
+            if (row === col)
+                continue;
+            const factor = aug[row][col];
+            for (let j = 0; j < 2 * n; j++) {
+                aug[row][j] -= factor * aug[col][j];
+            }
+        }
+    }
+    // Extract inverse
+    return aug.map((row) => row.slice(n));
+}
+//# sourceMappingURL=frequentistNma.js.map

package/dist/network/frequentistNma.js.map

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

@@ -1,4 +1,7 @@
 export { extractComparatorPairs, normalizeDrugName } from "./extractor.js";
 export { buildEvidenceNetwork } from "./builder.js";
-export type { EvidenceNode, EvidenceEdge, EvidenceNetwork, NMAFeasibility, NetworkGap, ComparatorPair, } from "./types.js";
+export { computeIndirectComparison, poolFixedEffect } from "./bucher.js";
+export { frequentistNMA } from "./frequentistNma.js";
+export { findIndirectPaths } from "./pathfinder.js";
+export type { EvidenceNode, EvidenceEdge, EvidenceNetwork, NMAFeasibility, NetworkGap, ComparatorPair, DirectComparison, IndirectEstimate, IndirectComparisonResult, IndirectPath, EffectMeasure, PooledEstimate, } from "./types.js";
 //# sourceMappingURL=index.d.ts.map

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

@@ -1 +1 @@
-{"version":3,"file":"index.d.ts","sourceRoot":"","sources":["../../src/network/index.ts"],"names":[],"mappings":"AAAA,OAAO,EAAE,sBAAsB,EAAE,iBAAiB,EAAE,MAAM,gBAAgB,CAAC;AAC3E,OAAO,EAAE,oBAAoB,EAAE,MAAM,cAAc,CAAC;AACpD,YAAY,EACV,YAAY,EACZ,YAAY,EACZ,eAAe,EACf,cAAc,EACd,UAAU,EACV,cAAc,GACf,MAAM,YAAY,CAAC"}
+{"version":3,"file":"index.d.ts","sourceRoot":"","sources":["../../src/network/index.ts"],"names":[],"mappings":"AAAA,OAAO,EAAE,sBAAsB,EAAE,iBAAiB,EAAE,MAAM,gBAAgB,CAAC;AAC3E,OAAO,EAAE,oBAAoB,EAAE,MAAM,cAAc,CAAC;AACpD,OAAO,EAAE,yBAAyB,EAAE,eAAe,EAAE,MAAM,aAAa,CAAC;AACzE,OAAO,EAAE,cAAc,EAAE,MAAM,qBAAqB,CAAC;AACrD,OAAO,EAAE,iBAAiB,EAAE,MAAM,iBAAiB,CAAC;AACpD,YAAY,EACV,YAAY,EACZ,YAAY,EACZ,eAAe,EACf,cAAc,EACd,UAAU,EACV,cAAc,EACd,gBAAgB,EAChB,gBAAgB,EAChB,wBAAwB,EACxB,YAAY,EACZ,aAAa,EACb,cAAc,GACf,MAAM,YAAY,CAAC"}

package/dist/network/index.js

@@ -1,3 +1,6 @@
 export { extractComparatorPairs, normalizeDrugName } from "./extractor.js";
 export { buildEvidenceNetwork } from "./builder.js";
+export { computeIndirectComparison, poolFixedEffect } from "./bucher.js";
+export { frequentistNMA } from "./frequentistNma.js";
+export { findIndirectPaths } from "./pathfinder.js";
 //# sourceMappingURL=index.js.map

package/dist/network/index.js.map

@@ -1 +1 @@
-{"version":3,"file":"index.js","sourceRoot":"","sources":["../../src/network/index.ts"],"names":[],"mappings":"AAAA,OAAO,EAAE,sBAAsB,EAAE,iBAAiB,EAAE,MAAM,gBAAgB,CAAC;AAC3E,OAAO,EAAE,oBAAoB,EAAE,MAAM,cAAc,CAAC"}
+{"version":3,"file":"index.js","sourceRoot":"","sources":["../../src/network/index.ts"],"names":[],"mappings":"AAAA,OAAO,EAAE,sBAAsB,EAAE,iBAAiB,EAAE,MAAM,gBAAgB,CAAC;AAC3E,OAAO,EAAE,oBAAoB,EAAE,MAAM,cAAc,CAAC;AACpD,OAAO,EAAE,yBAAyB,EAAE,eAAe,EAAE,MAAM,aAAa,CAAC;AACzE,OAAO,EAAE,cAAc,EAAE,MAAM,qBAAqB,CAAC;AACrD,OAAO,EAAE,iBAAiB,EAAE,MAAM,iBAAiB,CAAC"}

package/dist/network/pathfinder.d.ts

@@ -0,0 +1,14 @@
+import type { DirectComparison, IndirectPath } from "./types.js";
+/**
+ * Find all indirect comparison paths through a single common comparator.
+ *
+ * Given comparisons A-B and B-C, returns the path A→B→C allowing
+ * indirect estimation of A vs C.
+ *
+ * If `target` is specified, only returns paths for that specific comparison.
+ */
+export declare function findIndirectPaths(comparisons: DirectComparison[], target?: {
+    intervention: string;
+    comparator: string;
+}): IndirectPath[];
+//# sourceMappingURL=pathfinder.d.ts.map

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

@@ -0,0 +1 @@
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