ActionableBiomarkerGateChecker

Actionable Biomarker Gate

Liquid Biopsy жидкостная биопсия cfDNA ctDNA CTC exosomes NGS qPCR

Utility description: Actionable Biomarker Gate

Actionable Biomarker Gate Checker — Clinically Actionable Biomarker Filter

ℹ️ Utility performs automatic validation of identified genetic variants for clinical actionability according to AMP/ASCO/CAP and FDA guidelines:
• Tier Classification: Separation of variants into levels of evidence (Tier I: FDA-approved, Tier II: Standard care, Tier III: Clinical trials, Tier IV: Preclinical/Benign).
• Therapy Check: Presence of approved drug or recommendation in clinical guidelines (NCCN, ESMO).
• VUS Filtering: Exclusion of Variants of Uncertain Significance from "Recommendations" section.
• Gating: Decision making on inclusion of biomarker in final physician report.

⚠️ IMPORTANT:
• Mutation detection does not always mean treatment possibility.
• Error in tier interpretation may lead to prescription of ineffective therapy.

Usage:
ActionableBiomarkerGateChecker.exe → demo mode (console output)
ActionableBiomarkerGateChecker.exe input.csv output.json → evaluate your data

Input format:
SampleID,Gene,Variant,VariantType,VAF_Percent,ClinicalTier,FDA_Approved_Drug,Guideline

Example:
NGS-001,EGFR,L858R,SNV,15.5,Tier I,Osimertinib,NCCN

📍 Scope of Application (Usage Where):
• Molecular Oncology: Interpretation of NGS panel results.
• Tumor Boards: Preparation of targeted therapy options lists.
• Clinical Trials: Patient selection by specific biomarkers.
• Laboratory Diagnostics: Automation of pre-analytical reporting stage.

— WHY IS THIS NEEDED?
NGS data volume is huge, and it is difficult for physician to manually filter out irrelevant findings.
Automated "gate" guarantees that only variants with real clinical application enter the report.
This improves quality of medical decision making and complies with Precision Medicine principles.

⚠️ CRITICAL:
• Tier I/II: Only these levels are basis for standard therapy.
• VUS (Tier IV): Should not be interpreted as driver mutations without additional studies.
• Database Actuality: Data on approved drugs changes rapidly, knowledge bases must be updated.
• VAF: Low Variant Allele Frequency may require confirmation by another method.

Key features:
• Automatic sorting by levels of evidence
• Verification of FDA-approved drugs presence
• Filtering of variants of uncertain significance
• Structured report generation for physician
• Compliance with AMP/ASCO/CAP standards

Critical parameters:
• Clinical Tier: I or II for action
• FDA Approved Drug: Presence of specific drug
• Guideline: Confirmation by recommendations
• VAF: Sufficient for confident call

💡 Usage tips:
1. Database Update: Regularly synchronize tier directories with OncoKB or CIViC.
2. Multidisciplinary: Utility results must be verified by molecular pathologist.
3. Context: Consider tissue of origin when assessing actionability.
4. Documentation: Save version of knowledge base used for analysis.
5. Training: Physicians must understand difference between Tier I and Tier II.

⚠️ Note: This utility is a Clinical Decision Support System (CDSS) tool. It does not replace physician's clinical judgment but ensures strict data filtering based on current scientific evidence.
```

input.csv

SampleID,Gene,Variant,VariantType,VAF_Percent,ClinicalTier,FDA_Approved_Drug,Guideline
NGS-2026-001,EGFR,L858R,SNV,15.5,Tier I,Osimertinib,NCCN
NGS-2026-002,BRCA1,K1183N,SNV,45.0,Tier IV,None,None
NGS-2026-003,MET,Exon 14 Skipping,Indel,8.2,Tier II,Capmatinib,NCCN
NGS-2026-004,KRAS,G12C,SNV,22.1,Tier I,Sotorasib,NCCN

URS & FS — User Requirements and Functional Specification

This document describes the controlled interface and behaviour of ActionableBiomarkerGateChecker for Actionable Biomarker Gate Checker.

Domain limits URS input.csv FS IQ/OQ/PQ

Domain limits and critical parameters

Key fragments from the source description are shown below. Before production use, limits must be verified against the approved specification, registration dossier and local SOPs.

⚠️ CRITICAL:
• Database Actuality: Data on approved drugs changes rapidly, knowledge bases must be updated.
Critical parameters:
2. Multidisciplinary: Utility results must be verified by molecular pathologist.
5. Training: Physicians must understand difference between Tier I and Tier II.

URS — User Requirements Specification

ID	Requirement	Criticality	Acceptance criterion
URS-001	The utility shall accept an input.csv file for Actionable Biomarker Gate Checker with headers defined in the data contract.	High	The file is processed without manual header editing.
URS-002	The utility shall perform deterministic QC evaluation without machine learning and without probabilistic conformance decisions.	High	Identical input data, rule version and configuration produce reproducible results.
URS-003	The utility shall validate mandatory fields, data types, ranges, units and domain plausibility.	High	Schema, conversion and range errors are explicitly reported.
URS-004	The utility shall apply domain limits and rules from the description, approved specification, registration dossier and local SOPs.	High	Each check has PASS/WARNING/FAIL and a clear message.
URS-005	The utility shall generate output.json with machine-readable results, source values, warnings, failures and critical findings.	High	JSON is suitable for LIMS/ELN/MES integration and QA/QC review.
URS-006	The utility shall preserve traceability between batch/sample, input file, applied rules and final status.	High	Output contains identifiers, checked parameters and audit metadata.
URS-007	The documentation shall support IQ/OQ/PQ, CSV/CSA and review by internal QA or inspectors.	Medium	URS, FS, input/output contract and test scenarios are supplied with the utility.
URS-008	The utility shall be used as a QC decision-support tool and not as a substitute for approved specifications and QA/QP release decision.	Medium	Documentation states change control and limit-verification expectations.

input.csv contract

#	Field	Type	Sample	Purpose
1	`SampleID`	string / controlled vocabulary	`NGS-2026-001`	Sample or laboratory specimen identifier.
2	`Gene`	string / controlled vocabulary	`EGFR`	Controlled input parameter for deterministic QC rules.
3	`Variant`	string / controlled vocabulary	`L858R`	Controlled input parameter for deterministic QC rules.
4	`VariantType`	string / controlled vocabulary	`SNV`	Controlled input parameter for deterministic QC rules.
5	`VAF_Percent`	decimal	`15.5`	Controlled input parameter for deterministic QC rules.
6	`ClinicalTier`	string / controlled vocabulary	`Tier I`	Controlled input parameter for deterministic QC rules.
7	`FDA_Approved_Drug`	string / controlled vocabulary	`Osimertinib`	Controlled input parameter for deterministic QC rules.
8	`Guideline`	string / controlled vocabulary	`NCCN`	Controlled input parameter for deterministic QC rules.

SampleID,Gene,Variant,VariantType,VAF_Percent,ClinicalTier,FDA_Approved_Drug,Guideline
NGS-2026-001,EGFR,L858R,SNV,15.5,Tier I,Osimertinib,NCCN
NGS-2026-002,BRCA1,K1183N,SNV,45.0,Tier IV,None,None
NGS-2026-003,MET,Exon 14 Skipping,Indel,8.2,Tier II,Capmatinib,NCCN

Input validation rules

ID	Field	Rule	Criticality
VR-001	`SampleID`	The field shall match an approved dictionary or accepted string representation.	High
VR-002	`Gene`	The field shall match an approved dictionary or accepted string representation.	High
VR-003	`Variant`	The field shall match an approved dictionary or accepted string representation.	High
VR-004	`VariantType`	The field shall match an approved dictionary or accepted string representation.	Medium
VR-005	`VAF_Percent`	The field shall match an approved dictionary or accepted string representation.	Medium
VR-006	`ClinicalTier`	The field shall match an approved dictionary or accepted string representation.	Medium
VR-007	`FDA_Approved_Drug`	The field shall match an approved dictionary or accepted string representation.	Medium
VR-008	`Guideline`	The field shall match an approved dictionary or accepted string representation.	Medium

FS — Functional Specification

ID	Function	Implementation
FS-001	CLI execution	Support execution modes: demo mode without arguments and production mode input.csv output.json.
FS-002	CSV import	Read input.csv in UTF-8/CSV-compatible format and validate header and expected columns.
FS-003	Schema validation	Check mandatory fields, column count, unknown key fields and empty mandatory values.
FS-004	Type conversion	Convert numeric, flag and text values; invalid format is recorded as a row-level error.
FS-005	Domain rule engine	Apply rules for Actionable Biomarker Gate Checker, including critical limits from the description and approved specification.
FS-006	Status aggregation	Produce final status: FAIL for critical failure, WARNING for non-critical deviation, PASS for conformance.
FS-007	JSON export	Write output.json with detailed checks, source values, warnings, failures and critical findings.
FS-008	Audit support	Keep result structure suitable for review, deviation investigation and calculation reproduction.
FS-009	Integration contract	Support the scenario LIMS/ELN/MES → input.csv → utility → output.json → portal/admin review.
FS-010	Error handling	Return explicit messages for missing file, empty CSV, invalid schema, output write failure and invalid format.

Example output.json

{
  "utilityId": "actionablebiomarkergatechecker",
  "utilityFolder": "ActionableBiomarkerGateChecker",
  "package": "LiquidBiopsy",
  "overallStatus": "PASS|WARNING|FAIL",
  "sourceFile": "input.csv",
  "processedAtUtc": "2026-06-10T00:00:00Z",
  "checks": [
    {
      "parameter": "SampleID",
      "value": "NGS-2026-001",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-001"
    },
    {
      "parameter": "Gene",
      "value": "EGFR",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-002"
    },
    {
      "parameter": "Variant",
      "value": "L858R",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-003"
    },
    {
      "parameter": "VariantType",
      "value": "SNV",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-004"
    },
    {
      "parameter": "VAF_Percent",
      "value": "15.5",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-005"
    },
    {
      "parameter": "ClinicalTier",
      "value": "Tier I",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-006"
    },
    {
      "parameter": "FDA_Approved_Drug",
      "value": "Osimertinib",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-007"
    },
    {
      "parameter": "Guideline",
      "value": "NCCN",
      "status": "PASS|WARNING|FAIL",
      "message": "Deterministic rule-based check result",
      "ruleReference": "FS-RULE-008"
    }
  ],
  "criticalFindings": [],
  "warnings": [],
  "audit": {
    "inputHash": "sha256:<calculated at runtime>",
    "rulesVersion": "<utility executable version>",
    "documentation": "ActionableBiomarkerGateChecker.documentation.html"
  }
}

Traceability matrix

URS	FS	Test	Evidence
URS-001	FS-001, FS-002	OQ-001	Verify execution and import of valid input.csv.
URS-002	FS-005, FS-006	OQ-004	Repeat the same dataset and compare output.json.
URS-003	FS-003, FS-004, FS-010	OQ-002, OQ-003	Verify missing columns and invalid types.
URS-004	FS-005, FS-006	OQ-004, PQ-001	Verify critical deviations on real/boundary data.
URS-005	FS-007, FS-009	OQ-005	Verify JSON schema and downstream-system suitability.
URS-006	FS-008	OQ-006	Verify identifiers and audit metadata.
URS-007	FS-008, FS-010	IQ-001, OQ-007	Verify documentation completeness and control evidence.
URS-008	FS-005, FS-008	PQ-002	Verify review workflow and no replacement of QA decision.

IQ/OQ/PQ test scenarios

ID	Scenario	Expected result
IQ-001	Verify executable, input.csv, documentation and checksum availability.	Delivery set is complete; version is recorded.
OQ-001	Valid sample row from input.csv.	PASS or acceptable WARNING according to rules.
OQ-002	Remove a mandatory CSV column.	Schema error or FAIL with missing-column reference.
OQ-003	Place a non-numeric value into a numeric field.	Type-conversion error with row/field reference.
OQ-004	Set a critical parameter outside the limit.	FAIL and critical finding.
OQ-005	Verify output.json structure.	All mandatory sections are present and JSON is valid.
OQ-006	Verify batch/sample traceability.	Input and result identifiers match.
PQ-001	Verify 3–5 real user batches/samples.	Result is confirmed by QC/QA review.
PQ-002	Verify deviation workflow and manual QA decision.	Utility supports review but does not replace approved decision.

QA/QC and change control

Do not rename columns without updating validator, documentation and test set.
Retain input.csv, output.json, executable version and checksum.
Before production use, perform IQ/OQ/PQ or equivalent CSV/CSA verification.
Critical limits shall be verified against the approved specification, registration dossier and local SOPs.
The utility provides structured QC decision support; final release decision remains with QA/QP and approved procedures.

Included in packages

Liquid Biopsy QC Suite

QC and pre-analytical control package for liquid biopsy workflows: cfDNA/ctDNA, CTC, EV/exosomes, methylation, NGS/qPCR/ddPCR, sample quality, contamination, sensitivity and reporting checks.

Open