CurrentRegence BlueCross BlueShieldPolicy 77

Investigational Gene Expression, Biomarker, and Multianalyte Testing

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This policy governs coverage of gene expression, biomarker, and multianalyte assays used for diagnosis, prognosis, risk assessment, treatment selection, or disease monitoring. The listed tests are considered investigational because current evidence is insufficient to demonstrate improved health outcomes.

Policy Summary

PayerRegence BlueCross BlueShield

PolicyInvestigational Gene Expression, Biomarker, and Multianalyte Testing

Policy CodePolicy N/A

Change TypeNo material change

Effective DateSeptember 1, 2026

Last ReviewJul 1, 2026

Next Review DateNovember 1, 2026

Key ActionTreat the listed gene-expression, biomarker, DNA-methylation, molecular, and multianalyte testing procedures as investigational when submitting claims.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

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CurrentRegence BlueCross BlueShieldPolicy 77

Investigational Gene Expression, Biomarker, and Multianalyte Testing

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Policy Summary

PayerRegence BlueCross BlueShield

PolicyInvestigational Gene Expression, Biomarker, and Multianalyte Testing

Policy CodePolicy N/A

Change TypeNo material change

Effective DateSeptember 1, 2026

Last ReviewJul 1, 2026

Next Review DateNovember 1, 2026

Key ActionTreat the listed gene-expression, biomarker, DNA-methylation, molecular, and multianalyte testing procedures as investigational when submitting claims.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

Coverage Criteria

Investigational gene expression, biomarker, and multianalyte tests

The following tests are considered investigational because current scientific evidence is not yet sufficient to establish their impact on health outcomes.

Investigational listed tests: Each gene expression, biomarker, and multianalyte test named in the policy is considered investigational.

Named tests include AdvanceAD-Tx; aiSLE DX Disease Activity Index and Flare Risk Index; Auria; Avise Lupus; DecisionDx-SCC; DiviTum TKa; EndoSign Barrett's Esophagus Test; EpiSwitch Checkpoint-inhibitor Response Test; ESOPREDICT; FebriDx; FRAT; HART CADhs, HART CVE, and HART KD; HeproDx; IGoCheck; IMMray PanCan-d; IntelliSep; KawasakiDx; KidneyIntelX.dkd; Liposcale; LungOI; MammoCheck; MeMed BV; Mind.Px; MindX Blood Tests; M-inSight; mRNA CancerDetect; myOLARIS-KTdx; NaviDKD; NETest; NPDX ASD Test Panels I, II, and III; PancreaSeq Genomic Classifier; PancreaSure; PreciseDx Breast Biopsy Test; PrismRA; Promarker D; PurIST SM; RiskReveal; Salivary Melatonin Profile; SmartVascular DX; SOMAmer; SAAmplify-aSYN; Tempus p-MSI; Tempus p-Prostate; Thyroid GuidePx; and TruD MDS Tests, including the listed Alzheimer's and MCI, ASCVD, bipolar, COPD, hepatocellular carcinoma, Lyme disease, major depressive disorder, multiple sclerosis, NASH, osteoporosis, Parkinson's, and schizophrenia tests.

Investigational testing

The listed procedures are identified within the policy as investigational gene expression, biomarker, and multianalyte testing.

Investigational laboratory testing: The service is one of the gene-expression, biomarker, DNA-methylation, molecular, or multianalyte assays listed in this policy section, or is billed under an identified unlisted molecular or multianalyte assay code.

This includes mRNA expression profiling, RNA or next-generation sequencing, PCR and RT-PCR expression analysis, proteomic and metabolomic testing, algorithmic risk classification or predictive scoring, DNA-methylation and epigenetic marker profiling, multianalyte biomarker and protein assays, augmentative algorithmic analysis of digitized whole-slide imaging, molecular pathology procedures, and unlisted codes 81479 and 81599. The policy does not state a covered exception or separate medical-necessity pathway for these services.

Coverage is determined under the applicable contract. Services or procedures considered investigational or cosmetic are excluded from coverage, and providers may bill members for these services when permitted by the contract. Providers should inform members before performing an investigational or cosmetic service that they may be financially responsible for the cost.

The listed gene expression, biomarker, and multianalyte tests are considered investigational because they remain in a developmental phase and have limited evidence of clinical utility for diagnosis, prognosis, or risk assessment. Current research is insufficient to show that these tests improve patient health outcomes.

Investigational Testing Codes

Investigational gene expression, biomarker, and multianalyte testing codesCPTExperimental

0006M	Oncology (hepatic), mRNA expression levels of 161 genes, utilizing fresh hepatocellular carcinoma tumor tissue, with alpha-fetoprotein level, algorithm reported as a risk classifier
0007M	Oncology (gastrointestinal neuroendocrine tumors), real-time PCR expression analysis of 51 genes, utilizing whole peripheral blood, algorithm reported as a nomogram of tumor disease index
0019M	Cardiovascular disease, plasma, analysis of protein biomarkers by aptamer-based microarray and algorithm reported as 4-year likelihood of coronary event in high-risk populations
0063U	Neurology (autism), 32 amines by LCMS/MS, using plasma, algorithm reported as metabolic signature associated with autism spectrum disorder
0258U	Neurology (autism spectrum disorder [ASD]), RNA, next-generation sequencing, saliva, algorithmic analysis, and results reported as predictive probability of ASD diagnosis
0263U	Neurology (autism spectrum disorder [ASD]), quantitative measurements of 16 central carbon metabolites by LC-MS/MS, plasma, algorithmic analysis with result reported as negative or positive, with metabolic subtypes of ASD
0288U	Oncology (lung), mRNA, quantitative PCR analysis of 11 genes and 3 reference genes, FFPE tumor tissue, algorithmic interpretation reported as a recurrence risk score
0289U	Neurology (Alzheimer disease), mRNA, gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score
0290U	Pain management, mRNA, gene expression profiling by RNA sequencing of 36 genes, whole blood, algorithm reported as predictive risk score
0294U	Longevity and mortality risk, mRNA, gene expression profiling by RNA sequencing of 18 genes, whole blood, algorithm reported as predictive risk score

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Investigational gene expression, biomarker, and multianalyte testing codesCPTExperimental

0289U	Neurology (Alzheimer disease), mRNA gene expression profiling by RNA sequencing of 24 genes, whole blood, algorithm reported as predictive risk score.
0290U	Pain management, mRNA gene expression profiling by RNA sequencing of 36 genes, whole blood, algorithm reported as predictive risk score.
0290U	Psychiatry (mood disorders), mRNA gene expression profiling by RNA sequencing of 144 genes, whole blood, algorithm reported as predictive risk score.
0290U	Psychiatry (stress disorders), mRNA gene expression profiling by RNA sequencing of 72 genes, whole blood, algorithm reported as predictive risk score.
0290U	Psychiatry (suicidal ideation), mRNA gene expression profiling by RNA sequencing of 54 genes, whole blood, algorithm reported as predictive risk score.
0294U	Longevity and mortality risk, mRNA gene expression profiling by RNA sequencing of 18 genes, whole blood, algorithm reported as predictive risk score.
0294U	Oncology (oral and/or oropharyngeal cancer), gene expression profiling by RNA sequencing of at least 20 molecular features, including human and/or microbial mRNA, saliva, algorithm reported as positive or negative for a signature associated with malignancy.
0308U	Cardiology (coronary artery disease), analysis of high-sensitivity troponin, adiponectin, and kidney injury molecule-1 with age, sex, and history of cardiac intervention, plasma, algorithm reported as a risk score for obstructive CAD.
0309U	Cardiology (cardiovascular disease), analysis of NT-proBNP, osteopontin, TIMP-1, and KIM-1, plasma, algorithm reported as a risk score for major adverse cardiac event.
0310U	Pediatrics (vasculitis, Kawasaki disease), analysis of NT-proBNP, C-reactive protein, and T-uptake, plasma, algorithm reported as a risk score for Kawasaki disease.

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Provider and Billing Implications

Denial Risk

Inform members before billing for listed investigational tests

Claims for the gene expression, biomarker, and multianalyte tests listed in this policy are at risk of denial because the tests are considered investigational and current evidence is insufficient to establish that they improve health outcomes. Contracts exclude services or procedures considered investigational; providers may bill members for these services when permitted by the applicable contract and should inform members before rendering them that they are likely to be financially responsible.

Denial Risk

Expect denial for identified investigational procedures

Do not assume coverage for the listed gene-expression, biomarker, DNA-methylation, molecular, or multianalyte assays, or for unlisted molecular pathology and multianalyte assay codes. The policy identifies these procedures as investigational, including codes 0289U, 0290U, 0294U, 0296U, 0308U, 0309U, 0310U, 0312U, 0313U, 0315U, 0322U, 0332U, 0342U, 0351U, 0362U, 0377U, 0384U, 0385U, 0389U, 0393U, 0398U, 0399U, 0404U, 0407U, 0414U, 0415U, 0418U, 0437U, 0441U, 0442U, 0446U, 0447U, 0458U, 0462U, 0506U, 0510U, 0558U, 0559U, 0579U, 0616U–0627U, 0635U, 81479, and 81599; claims are therefore at risk of denial.

Background

Gene expression testing measures the relative transcription levels of selected genes and may use methods such as PCR, microarray, immunohistochemistry, or RNA sequencing. Results may be reported as a score, risk percentage, predictive probability, or categorical classification. Related multianalyte assays measure patterns of biochemical and molecular analytes, such as metabolites, peptides, proteins, and genetic biomarkers. Multianalyte assays with algorithmic analysis combine these measurements—and sometimes clinical or demographic information—to generate a classification or risk score.

Definitions

Gene expression tests

DefinitionTests that measure the relative levels of gene transcription for selected genes.

PurposeIndicate how much a gene is expressed or active in a particular tissue.

MethodsMay be performed using PCR, microarray, immunohistochemistry, or RNA sequencing.

Reported resultsResults are usually expressed as a score, risk percentage, or classification, such as positive or high risk.

Multianalyte assays

DefinitionTests that measure multiple biochemical and molecular analytes.

Analyte types

Not Covered

The gene expression, biomarker, multianalyte, DNA-methylation, and other molecular assays listed in this policy are not covered because they are considered investigational. The policy does not establish coverage based solely on a test being offered by a CLIA-licensed laboratory or on whether the test has FDA marketing clearance. Unlisted molecular pathology procedure code 81479 and unlisted multianalyte assay with algorithmic analysis code 81599 are also included among the investigational services.