Medical Policy

Policy Num:      11.003.096
Policy Name:    Miscellaneous Genetic and Molecular Diagnostic Tests

Policy ID:          [11.003.096]  [Ac / B / M- / P-]  [2.04.121]

Last Review:       August 12, 2024
Next Review:      August 20, 2025
 

Related Policies:

11.003.028 - Genetic Testing for Lynch Syndrome and Other Inherited Colon Cancer Syndromes
11.001.007 - Identification of Microorganisms Using Nucleic Acid Probes
11.003.090 - Gene Expression Profiling for Uveal Melanoma

11.003.097- Gene Expression Profiling for Cutaneous Melanoma

11.003.133- Serologic Genetic and Molecular Screening for Colorectal Cancer
11.003.004 - Somatic Biomarker Testing (Including Liquid Biopsy) for Targeted Treatment and Immunotherapy in Metastatic Colorectal Cancer (KRAS, NRAF, BRAF, MMR/MSI, HER2, and TMB) 
11.003.073- Laboratory and Genetic Testing for Use of 5-Fluorouracil inPatients With Cancer
11.003.062 - General Approach to Genetic Testing
11.003.023 - General Approach to Evaluating the Utility of Genetic Panels

  Miscellaneous Genetic and Molecular Diagnostic Tests

Summary

There are numerous commercially available genetic and molecular diagnostic, prognostic, and therapeutic tests for individuals with certain diseases or asymptomatic individuals with future risk. This evidence review evaluates miscellaneous genetic and molecular diagnostic tests not addressed in a separate review. If a separate evidence review exists, then conclusions reached there supersede conclusions here. The main criterion for inclusion in this review is the limited evidence on the clinical validity for the test. As a result, these tests do not have clinical utility, and the evidence is insufficient to determine the effect on health outcomes.

Summary of Evidence

For each test addressed, a literature review was conducted. The literature review was not comprehensive, but sufficient to establish lack of clinical utility. If it is determined that enough evidence has accumulated to reevaluate its potential clinical utility, the test will be removed from this evidence review and addressed separately. The lack of demonstrated clinical utility of these tests is based on the following factors: (1) there is no or extremely limited published data addressing the test; and/or (2) there is insufficient evidence demonstrating the clinical validity of the test.

Diagnostic Testing

For individuals with symptoms of various conditions thought to be hereditary or with a known genetic component who receive diagnostic testing with a miscellaneous genetic or molecular test (eg, DNA Methylation Pathway Profile, Know Error, Celiac PLUS, GI Effects [Stool], IBD sgi Diagnostic), the evidence is limited. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The evidence is insufficient to determine the effects of the technologies on health outcomes

Prognostic Testing

For individuals who are diagnosed with various conditions who receive prognostic testing with a miscellaneous genetic or molecular test (eg, Crohn's Prognostic), there are no published studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The evidence is insufficient to determine the effects of the technologies on health outcomes.

Additional Information

Not applicable

OBJECTIVE

The objective of this evidence review is to determine whether diagnostic, prognostic, therapeutic, or future risk assessment testing using one of several miscellaneous genetic or molecular diagnostic tests improves the net health outcome in individuals with or with a risk of one of the various genetic conditions.

Policy Statements

All tests listed in this policy are considered investigational and grouped according to the categories of genetic testing outlined in evidence review 2.04.91:

• Testing of an affected (symptomatic) individual's germline to benefit the individual (excluding reproductive testing)
• Diagnostic testing
• Prognostic testing
• Therapeutic testing
• Testing an asymptomatic individual to determine future risk of disease.

Policy Guidelines

Genetic testing is considered investigational when BCBSA criteria are not met, including when there is insufficient evidence to determine whether the technology improves the net health outcome.

Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

Please see the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Tests Addressed in This Evidence Review

Table 1 lists tests assessed in this evidence review. Three types of tests are related to testing of an affected (symptomatic) individual's germline to benefit the individual (excluding reproductive testing): diagnostic testing, prognostic testing, and therapeutic testing. The fourth type of test reviewed is testing of an asymptomatic individual to determine future risk of disease.

Table1. Genetic and Molecular Diagnostic Tests Assessed This Evidence Review

 Dxcs: Diagnostics; Gxcs: Genetics.a. For example, ColoVantage® and Epi proColon®.b. ARUP, Quest, Clinical Genomics and Epigenomics.

Diagnostic Tests

Multiple Conditions

Single nucleotide variants (SNVs) are the most common type of genetic variation, and each SNV represents a difference in a single nucleotide in the DNA sequence. Most commonly, SNVs are found in the DNA between genes and can act as biologic markers of genes and disease association. When SNVs occur within a gene or a gene regulatory region, they can play a more direct role in disease by affecting the gene's function. SNVs may predict an individual's response to certain drugs, susceptibility to environmental factors, and the risk of developing certain diseases.

DNA specimen provenance assays can be used to confirm that tissue specimens are correctly matched to the patient of origin. Specimen provenance errors may occur in up to 1% to 2% of pathology tissue specimens^1,and have serious negative implications for patient care if the error is not corrected.^2,Analysis of DNA microsatellites from tissue specimens can be performed by analyzing long tandem repeats (LTR) and comparing the LTRs of the tissue specimen with LTRs from a patient sample.

Test Description: DNA Methylation Pathway Profile

The DNA Methylation Pathway Profile (Great Plains Laboratory) analyzes SNVs associated with certain biochemical processes, including methionine metabolism, detoxification, hormone imbalances, and vitamin D function. Intended uses for the test include clarification of a diagnosis suggested by other testing and as an indication for supplements and diet modifications.

Test Description: Know Error DNA Specimen Provenance Assay

The Know Error test (Strand Diagnostics) compares the LTRs of tissue samples with LTRs from a buccal swab of the patient. The intended use of the test is to confirm tissue of origin and avoid specimen provenance errors due to switching of patient samples, mislabeling, or sample contamination.

Celiac Disease

Previously called sprue, celiac sprue, gluten-sensitive enteropathy, gluten intolerance, nontropical sprue, or idiopathic steatorrhea, celiac disease is an immune-based reaction to gluten (water-insoluble proteins in wheat, barley, rye) that primarily affects the small intestine. Celiac disease occurs almost exclusively in patients who carry at least 1 human leukocyte antigen DQ2 or DQ8; the negative predictive value of having neither allele exceeds 98%.^3, Serum antibodies to tissue transglutaminase, endomysium, and deamidated gliadin peptide support a diagnosis of celiac disease but diagnostic confirmation requires duodenal biopsy taken when patients are on a gluten-containing diet.^4,

Test Description: Celiac PLUS

Celiac PLUS (Prometheus Therapeutics & Diagnostics) is a panel of two genetic and five serologic markers associated with celiac disease. Per the manufacturer, Celiac PLUS is a diagnostic test that also stratifies the future risk of celiac disease.^5, Genetic markers (human leukocyte antigen DQ2 and DQ8) are considered predictive of the risk of developing celiac disease^6,; serologic markers (immunoglobulin A [IgA] anti-tissue transglutaminase antibody, IgA anti-endomysial antibodies, IgA anti-deamidated gliadin peptide antibodies, IgG anti-deamidated gliadin peptide, and total IgA) are considered diagnostic for celiac disease. Celiac PLUS is intended for patients at risk for the disease (eg, with an affected first-degree relative) or with symptoms suggestive of the disease.

Irritable Bowel Syndrome

IBS is a functional gastrointestinal (GI) disorder that affects 10% to 20% of the general population in the U. S. and worldwide. Symptoms include abdominal pain and/or bloating associated with disordered bowel habit (constipation, diarrhea, or both). Pathophysiology is poorly understood but may be related to chronic low-grade mucosal inflammation and disturbances in GI flora.^7, Recommended treatments include dietary restriction and pharmacologic symptom control.^8,9,10, As living microorganisms that promote health when administered to a host in therapeutic doses,^11, probiotics are being investigated as a treatment for IBS. Several systematic reviews of randomized controlled trials have found evidence to support efficacy,^{7,12,13,14,15,} but results from recent randomized controlled trials have been mixed.^{16,17,18,19,20,21,} This discrepancy may be due in part to the differential effects of different probiotic strains and doses.

Test Description: GI Effects Comprehensive Stool Profile

The GI Effects Comprehensive Stool Profile (Genova Diagnostics) is a multianalyte stool assay.^22, The test uses polymerase chain reaction (PCR) to quantify 26 commensal gut bacteria and standard biochemical and culture methods to measure levels of other stool components (eg, lipids, fecal occult blood) and potential pathogens (ova and parasites, opportunistic bacteria, yeast). The test is purported to optimize management of gut health and to differentiate IBS from inflammatory bowel disease (IBD).

Inflammatory Bowel Disease

IBD is an autoimmune condition characterized by inflammation of the bowel wall and has clinical symptoms of abdominal pain, diarrhea, and associated symptoms. Crohn disease (CD) and ulcerative colitis are the two main entities under the category of IBD. The diagnosis is typically made by endoscopy or colonoscopy with biopsy and histologic analysis. This requires a semi-invasive procedure; as a result, a blood test to diagnose IBD could avoid the need for the procedures.

Test Description: IBD sgi Diagnostic

IBD sgi Diagnostic (Prometheus Therapeutics & Diagnostics) is a panel of 17 serologic (n=8), genetic (n=4), and inflammatory (n=5) biomarkers. A proprietary algorithm produces an IBD score; results are reported as consistent with IBD (consistent with ulcerative colitis, consistent with CD, or inconclusive for ulcerative colitisvs CD) or not consistent with IBD. The test is intended for use in patients with clinical suspicion of IBD.

Therapeutic Tests

Previously reviewed therapeutic tests are no longer commercially available; no commercially available therapeutic test is reviewed in this policy.

Prognostic Tests

Crohn Disease

Recent studies have identified serologic^23, and genetic^24,25, correlates of aggressive CD that is characterized by fistula formation, fibrostenosis, and the need for surgical intervention. Prometheus has developed a blood test that aims to identify patients with CD who are likely to experience an aggressive disease course.

Test Description: Crohn's Prognostic

Crohn's Prognostic (Prometheus Therapeutics & Diagnostics) is a panel of six serologic (n=3) and genetic (n=3) biomarkers. Limited information about the test is available on the manufacturer's website.

Regulatory Status

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Genetic tests evaluated in this evidence review are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the Food and Drug Administration has chosen not to require any regulatory review of these tests.

The ImmunoGenomic Profile (Genova Diagnostics) was a buccal swab test that evaluated SNVs in 6 genes associated with immune function and inflammation: interleukin (IL)-10, IL-13, IL-1b, IL-4, IL-6, and tumor necrosis factor α.]^26, The test was intended to uncover potential genetic susceptibility to: asthma, autoimmune disorders, certain cancers, allergy, infectious diseases, bone inflammation, arthritis, inflammatory bowel disease, heart disease, osteopenia, and Helicobacter pylori infection. Due to low testing volume, this test was discontinued in February 2022.

Rationale

This evidence review was created in October 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through May 20, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Diagnostic Testing

Clinical Context and Test Purpose

The purpose of diagnostic testing in patients for heritable or genetic pathogenic variants in a symptomatic individual is to establish a molecular diagnosis defined by the presence of known pathologic variant(s). For genetic testing, a symptomatic individual is defined as an individual with a clinical phenotype that correlates with a known pathologic variant.

The specific clinical context of each test is described briefly in the following sections. The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients with symptoms of a particular disease for which a definitive diagnosis cannot be made using other diagnostic methods.

Interventions

The interventions of interest are miscellaneous genetic or molecular diagnostic tests, specifically: DNA Methylation Pathway Profile, Know Error, Celiac PLUS, GI Effects (Stool), and IBD sgi Diagnostic.

Comparators

The comparator of interest is standard care without genetic or molecular diagnostic testing.

Outcomes

The outcomes of interest are overall survival (OS), disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The timing of follow-up for irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and celiac disease ranges from weeks for the diagnosis to years for assessment of health outcomes.

Study Selection Criteria

For the evaluation of clinical validity of miscellaneous genetic or molecular tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Clinically Useful

A test is clinically useful if the use of the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No studies examining clinical utility were identified.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

It is not possible to construct a chain of evidence for clinical utility due to the lack of evidence on clinical validity.

Diagnostic Testing for Multiple Conditions: DNA Methylation Pathway Profile

Review of Evidence

No full-length, peer-reviewed studies of the DNA Methylation Pathway Profile were identified.

Section Summary: DNA Methylation Pathway Profile

No studies were identified that evaluated this test.

Diagnostic Testing for Multiple Conditions: Know Error Specimen Provenance Assay

Review of Evidence

Evidence for the clinical validity of the Know Error Specimen Provenance Assay is lacking. There is some evidence on the application of short tandem repeat testing for specimen provenance assays in general,^27, but these data are not specific to the Know Error test.

Section Summary: Know Error Specimen Provenance Assays

There is a lack of published evidence on the use of the Know Error test to confirm the tissue of origin. Studies are needed that compare the use of Know Error with standard laboratory quality measures and that demonstrate a reduction in specimen provenance errors associated with the use of Know Error.

Diagnostic Testing for Celiac Disease: Celiac PLUS

Review of Evidence

Celiac PLUS tests for genetic and serologic factors known to be associated with celiac disease. All 7 test components are included in an evidence-based diagnostic algorithm developed by the American College of Gastroenterology.^28, However, algorithmic testing is individualized according to the baseline risk of disease and is done sequentially, rather than simultaneously as in Celiac PLUS.

No studies of the combined serologic and genetic Celiac PLUS test were identified. Information about clinical validity of obtaining several serologic and genetic tests at once (ie, Celiac PLUS) is lacking; improved sensitivity and reduced specificity may be expected.

Section Summary: Celiac Disease

No studies examining the clinical validity or clinical utility of Celiac PLUS were identified. Factors that support a chain of evidence for prognostic or diagnostic utility are lacking.

Diagnostic Testing for Irritable Bowel Syndrome: GI Effects Comprehensive Stool Profile

Review of Evidence

No studies were identified that assessed the accuracy of the GI Effects fecal panel for diagnosing IBS or for documenting "gut health," a concept that may be difficult to define given large interindividual variability in gut flora.^29,

Section Summary: Diagnostic Testing for Irritable Bowel Syndrome

Evidence for the clinical validity and utility of the GI Effects Comprehensive Stool Profile is lacking. Because probiotics are not currently a standard treatment of IBS, the impact of test results on disease management is uncertain; ie, a chain of evidence for clinical utility of the test cannot be established.

Diagnostic Testing for Inflammatory Bowel Disease: IBD sgi Diagnostic

Review of Evidence

The IBD sgi Diagnostic product monograph includes an extensive bibliography that documents associations of the 18 component markers, individually and in combination, with ulcerative colitis and/or Crohn disease (CD). ^30,

In a review of the monograph, Shirts et al (2012)^31, observed that serologic tests for ASCA-IgA, ASCA-IgG, and atypical perinuclear anti-neutrophil cytoplasmic antibody are standard of care in the diagnostic workup of IBD,^32,33, although not all investigators include these tests in recommended diagnostic strategies.^34,35,36,37, These 3 markers are included in the 18-marker panel. Based on a 2006 meta-analysis of 60 studies (N=11,608 patients), Reese et al (2006) reported that pooled sensitivity and specificity of the 3-test panel were 63% and 93%, respectively, for diagnosing IBD.^38, Because the product monograph did not compare the 18-marker panel with the 3-marker panel, incremental improvement in diagnosis with the 18-marker panel is unknown. Shirts et al (2012) calculated an area under the curve for the 3-marker panel of 0.899.

Published evidence supports associations of each marker in the 18-marker panel, alone and in combination, with IBD diagnosis. Based on manufacturer data, the accuracy for IBD diagnosis of the 18-marker panel exceeds that of each component marker, but the relevant comparison with a panel of 3 markers that has good discrimination for IBD was not included; subsequent analysis has suggested that the panels may perform similarly. Performance characteristics for the 18-marker panel to distinguish ulcerative colitis from CD were not provided.

Section Summary: IBD sgi Diagnostic

No studies examining the clinical utility of IBD sgi Diagnostic were identified. Although manufacturer data supported the clinical validity of the test for diagnosing IBD, this evidence is insufficient to support a chain of evidence for clinical utility. For distinguishing ulcerative colitis from CD, clinical validity has not been established; therefore, a chain of evidence for clinical utility for this purpose cannot be established.

For individuals with symptoms of various conditions thought to be hereditary or with a known genetic component who receive diagnostic testing with a miscellaneous genetic or molecular test (eg, DNA Methylation Pathway Profile, Know Error, Celiac PLUS, GI Effects [Stool], IBD sgi Diagnostic), the evidence is limited. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The evidence is insufficient to determine the effects of the technologies on health outcomes.

Population Reference No. 2

Prognostic Testing

Clinical Context and Test Purpose

The purpose of prognostic testing of diagnosed disease is to predict natural disease course (eg, aggressiveness, the risk of recurrence, death). This type of testing uses gene expression of affected tissue to predict the course of the disease.

The specific clinical context of each test is described briefly in the following sections. The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is patients diagnosed with a disease (eg, CD).

Interventions

The interventions of interest are miscellaneous prognostic tests, specifically Crohn's Prognostic for CD.

Comparators

The comparator of interest is standard care without prognostic testing.

Outcomes

The outcomes of interest are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The timing of follow-up ranges from months for the aggressiveness of the disease to years for risk of recurrence or death.

Study Selection Criteria

For the evaluation of clinical validity of miscellaneous genetic or molecular tests, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Prognostic Testing for Crohn Disease With Crohn's Prognostic

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

No studies of the 6-marker Crohn's Prognostic test were identified.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, more effective therapy, or avoid unnecessary therapy or testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Direct evidence for clinical utility is lacking.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

It is not possible to construct a chain of evidence for clinical utility due to the lack of clinical validity.

Section Summary: Crohn's Prognostic

Direct and indirect evidence for clinical utility of the Crohn's Prognostic test to identify individuals likely to have an aggressive disease course are currently lacking.

For individuals who are diagnosed with various conditions who receive prognostic testing with a miscellaneous genetic or molecular test (eg, Crohn's Prognostic), there are no published studies. Relevant outcomes are OS, disease-specific survival, test accuracy and validity, change in disease status, and morbid events. The evidence is insufficient to determine the effects of the technologies on health outcomes.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The NCCN (v.2.2024 ) guidelines for colon cancer state that it has "not been established if molecular markers are useful in treatment determination (predictive markers) and prognosis."^39,

American Gastroenterological Association

Celiac Disease

In 2023, the American Gastroenterological Association published a clinical practice update for the diagnosis and management of celiac disease.^40, A recommendation for genetic testing using a multigene panel test (eg, Celiac PLUS) was not included.

American College of Gastroenterology

Inflammatory Bowel Disease

The 2018 American College of Gastroenterology practice guidelines on Crohn's disease ^41,states that genetic and routine serologic testing is not indicated to establish the diagnosis of Crohn's disease.

Medicare National Coverage

There is no national coverage determination for the tests in this review. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov did not identify any currently ongoing or unpublished trials that might influence this review.

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