Coverage Policy Manual
Policy #: 2015008
Category: Laboratory
Initiated: March 2015
Last Review: June 2022
  Genetic Test: Miscellaneous Genetic and Molecular Diagnostic Tests

Description:
Miscellaneous Genetic and Molecular Diagnostic Tests
There are numerous commercially available genetic and molecular diagnostic tests. This policy evaluates the clinical utility of many miscellaneous genetic and molecular diagnostic tests that are not addressed in a separate coverage policy. If a separate policy does exist, criteria in that policy, supersedes criteria in this policy.
 
Criteria by which it is determined that a test will be included in the miscellaneous genetic and molecular diagnostic tests policy includes:
 
      • There is no or extremely limited published data addressing the test
      • There is insufficient evidence demonstrating clinical validity of the test.
 
For each of the tests addressed in this policy, a literature review will be conducted. The literature review will not be comprehensive, but sufficient to establish lack of clinical utility. A test will be removed from this policy and addressed in a separate policy if it is determined that enough evidence has accumulated that the test needs to be reevaluated for potential clinical utility.
 
Coding
 
According to laboratory websites, the following CPT codes are used to report some of the listed tests:
 
Prometheus CeliacPlus - 81382 (x2), 82784, 83520 (x3), and 86255.
 
Prometheus Crohn’s Prognostic - 81479, 83520 (x3), 86021 (x2), and 86255 (x2).
 
Genova GI Effects – 87045, 87046 (x3), 87075, 87798 (x20), 87177, 87209, 87328, 87336, 87329, 87102
 
Prometheus IBD sgi Diagnostic - 81229, 82397 (x3), 83520 (x7), 86021, 86255 (x2), 86140
 
SEPT9 methylated DNA - 81401
 
TransPredict Fc gamma 3a – 81479
 
OncoTarget/OncoTreat-0019U
 
Prometheus IBcause Diagnostic Test- 82784, 83520 (X2), 83993, 86141, 87507, 88346
 
Prometheus Monitr Crohn’s Disease - 83520(x12) and 86141 (x1)
 
BeScreened™-CRC – 0163U
 
 
If any component of the test has been codified in CPT, that specific code would be reported for that component of the test. One unit of the unlisted molecular pathology code 81479 or unlisted chemistry code 84999 is likely used for the remaining components or the entire test.

Policy/
Coverage:
Effective January 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The following miscellaneous genetic and molecular diagnostic tests, including but not limited to the following tests, do not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
        • BeScreened™-CRC test (added 05/2020)
        • Celiac Plus, Celiac Genetics and Celiac Serology
        • ColonSentry (Added 12/2015)
        • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
        • Crohn’s Prognostic
        • DecisionDx-Melanoma
        • DecisionDx-Thymoma
        • DNA Methylation Pathway Profile
        • GI Effects® (Stool)
        • IBD sgi Diagnostic™
        • ImmunoGenomic Profile (added 12/2015)
        • Moleculera Cunningham Panel (added 09/2016)
        • OncoTarget/OncoTreat (added 03/2018)
        • Prometheus IBcause Diagnostic Test (added 04/19/2018)
        • Prometheus Monitr Crohn’s Disease (added 6/5/2018)
        • ResponseDX Colon
        • SEPT9 methylated DNA, Colovantage, Epi proColon
        • TransPredict Fc gamma 3A
        • PanGIA Prostate (added 1/1/2021)
 
For members with contracts without primary coverage criteria, these tests are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
  
Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Genetic Testing for CCND1/IGH (t(11;14)) translocation analysis does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, genetic testing for CCND1/IGH (t(11;14)) translocation analysis is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Gene expression profiling for cutaneous melanoma (81529) by real time RT PCR does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, gene expression profiling for cutaneous melanoma (81529) by real time RT PCR is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to January 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The following miscellaneous genetic and molecular diagnostic tests, including but not limited to the following tests, do not meet primary coverage criteria that there be scientific evidence of effectiveness:
 
    • BeScreened™-CRC test (added 05/2020)
    • Celiac Plus, Celiac Genetics and Celiac Serology
    • ColonSentry (Added 12/2015)
    • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
    • Crohn’s Prognostic
    • DecisionDx-Melanoma
    • DecisionDx-Thymoma
    • DNA Methylation Pathway Profile
    • GI Effects® (Stool)
    • IBD sgi Diagnostic™
    • ImmunoGenomic Profile (added 12/2015)
    • Moleculera Cunningham Panel (added 09/2016)
    • OncoTarget/OncoTreat (added 03/2018)
    • Prometheus IBcause Diagnostic Test (added 04/19/2018)
    • Prometheus Monitr Crohn’s Disease (added 6/5/2018)
    • ResponseDX Colon
    • SEPT9 methylated DNA, Colovantage, Epi proColon
    • TransPredict Fc gamma 3A
 
For members with contracts without primary coverage criteria, these tests are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
  
Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective July 2020
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
        • BeScreened™-CRC test (added 05/2020)
        • Celiac Plus, Celiac Genetics and Celiac Serology
        • ColonSentry (Added 12/2015)
        • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
        • Crohn’s Prognostic
        • DecisionDx-Melanoma
        • DecisionDx-Thymoma
        • DNA Methylation Pathway Profile
        • GI Effects® (Stool)
        • IBD sgi Diagnostic™
        • ImmunoGenomic Profile (added 12/2015)
        • Moleculera Cunningham Panel (added 09/2016)
        • OncoTarget/OncoTreat (added 03/2018)
        • Prometheus IBcause Diagnostic Test (added 04/19/2018)
        • Prometheus Monitr Crohn’s Disease (added 6/5/2018)
        • ResponseDX Colon
        • SEPT9 methylated DNA, Colovantage, Epi proColon
        • TransPredict Fc gamma 3A
 
For members with contracts without primary coverage criteria, these tests are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
  
Gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, gastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti-CdtB and anti-vinculin antibodies is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to July 2020
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
    • BeScreened™-CRC test (added 05/2020)
    • Celiac Plus, Celiac Genetics and Celiac Serology
    • ColonSentry (Added 12/2015)
    • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
    • Crohn’s Prognostic
    • DecisionDx-Melanoma
    • DecisionDx-Thymoma
    • DNA Methylation Pathway Profile
    • GI Effects® (Stool)
    • IBD sgi Diagnostic™
    • ImmunoGenomic Profile (added 12/2015)
    • Moleculera Cunningham Panel (added 09/2016)
    • OncoTarget/OncoTreat (added 03/2018)
    • Prometheus IBcause Diagnostic Test (added 04/19/2018)
    • Prometheus Monitr Crohn’s Disease (added 6/5/2018)
    • ResponseDX Colon
    • SEPT9 methylated DNA, Colovantage, Epi proColon
    • TransPredict Fc gamma 3A
 
For members with contracts without primary coverage criteria, these tests are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective June 2018 to April 2020
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
    • Celiac Plus, Celiac Genetics and Celiac Serology
    • ColonSentry (Added 12/2015)
    • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
    • Crohn’s Prognostic
    • DecisionDx-Melanoma
    • DecisionDx-Thymoma
    • DNA Methylation Pathway Profile
    • GI Effects® (Stool)
    • IBD sgi Diagnostic™
    • ImmunoGenomic Profile (added 12/2015)
    • Moleculera Cunningham Panel (added 09/2016)
    • OncoTarget/OncoTreat (added 03/2018)
    • Prometheus IBcause Diagnostic Test (added 04/19/2018)
    • Prometheus Monitr Crohn’s Disease (added 6/5/2018)
    • ResponseDX Colon
    • SEPT9 methylated DNA, Colovantage, Epi proColon
    • TransPredict Fc gamma 3A
 
For members with contracts without primary coverage criteria, these tests are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to June 2018
 
The following tests do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness, or are investigational (for those members with contracts without primary coverage criteria):
 
    • Celiac Plus, Celiac Genetics and Celiac Serology
    • Crohn’s Prognostic
    • DecisionDx-Melanoma
    • DecisionDx-Thymoma
    • DNA Methylation Pathway Profile
    • GI Effects® (Stool)
    • IBD sgi Diagnostic™
    • ResponseDX Colon
    • SEPT9 methylated DNA, Colovantage, Epi proColon
    • TransPredict Fc gamma 3A
    • ColonSentry (Added 12/2015)
    • ImmunoGenomic Profile (added 12/2015)
    • Moleculera Cunningham Panel (added 09/2016)
    • Courtagen Spotlight Panels (any spotlight panel unless the indication is specifically addressed in separate policy) (Added 03/2017)
    • OncoTarget/OncoTreat (added 03/2018)
    • Prometheus IBcause Diagnostic Test (added 04/19/2018)

Rationale:
Evaluation of genetic tests focuses on 3 main principles:
 
(1) Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
 
(2) Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
 
(3) Clinical utility (how results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
 
Evidence Review
 
Diagnostic Tests
 
Celiac Plus (Prometheus®, San Diego, CA)
Celiac disease (previously called sprue, celiac sprue, gluten-sensitive enteropathy, gluten intolerance, nontropical sprue, idiopathic steatorrhea) 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 (HLA) DQ2 or DQ8 allele; negative predictive value (NPV) of having neither allele exceeds 98% (Pallav, 2014). Serum antibodies to tissue transglutaminase (TTG), endomysium (EMA), and deamidated gliadin peptide (DGP) support a diagnosis of celiac disease, but diagnostic confirmation requires duodenal biopsy taken when patients are on a gluten-containing diet (Ludvigsson, 2013).
 
Description
Celiac Plus is a panel of 2 genetic and 5 serologic markers associated with celiac disease. Per the manufacturer, Celiac Plus is a diagnostic test that also stratifies future risk of celiac disease (Prometheus, 2011). Genetic markers, HLA DQ2 and DQ8, are considered predictive of the risk of developing celiac disease (Pietzak, 2009); serologic  markers, immunoglobulin A (IgA) anti-TTG antibody, IgA anti-endomysial antibodies (EMA), IgA anti-DGP antibodies, IgG anti-DGP, and total IgA, are considered diagnostic for celiac disease. Celiac Plus isintended for use in patients at risk for disease (eg, with an affected first-degree relative) or with symptoms suggestive of disease.
 
Literature Review
In 2013, the American College of Gastroenterology published an evidence-based diagnostic algorithm for patients with high (>5%) or low (<5%) probability of disease (Rubio-Tapia, 2013). In both groups of patients, IgA anti-TTG antibody is “the preferred single test for detection of celiac disease in individuals over the age of 2 years” (strong recommendation based on a high level of evidence); sensitivity and specificity of anti-TTG IgA are both approximately 95% (Lewis, 2010). For patients with high probability of disease, initial diagnostic work-up comprises duodenal biopsy and anti-TTG IgA. If both tests are negative, celiac disease is unlikely; if both are positive, celiac disease is diagnosed. If results are discrepant, further work-up including HLA DQ2 and DQ8 genotyping and total IgA level to rule out IgA deficiency is recommended. For patients with low probability of disease, initial diagnostic work-up comprises anti-TTG IgA level and total IgA level. With 1 exception, combining several serologic tests rather than obtaining IgA anti-TTG alone is not recommended due to substantially reduced specificity for only marginally increased sensitivity (weak recommendation based on moderate evidence). In children younger than 2 years of age, however, combination testing with IgA anti-TTG and anti-DGP (both IgA and IgG) is recommended due to reduced test performance in this age group (strong recommendation based on moderate evidence). A strong recommendation (based on moderate evidence) against routine HLA DQ2 and DQ8 testing in the initial diagnostic work-up of celiac disease is made; targeted HLA DQ2 and DQ8 testing is recommended for select clinical situations, eg, discrepant serology and biopsy results (strong recommendation based on moderate evidence).
 
No studies of the combined serologic and genetic Celiac Plus test were identified.
 
Summary of Clinical Validity
Celiac Plus tests for genetic and serologic factors that are known to be associated with celiac disease. All 7 test components are included in an evidence-based diagnostic algorithm developed by a professional medical society (Rubio-Tapia, 2013). However, algorithmic testing is individualized according to baseline risk of disease and is done sequentially, rather than simultaneously as in Celiac Plus. 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.
 
Summary of Clinical Utility
No studies examining the clinical utility of Celiac Plus were identified. Factors that support an indirect chain of evidence for prognostic or diagnostic utility are lacking. A comparison of clinical and/or histopathologic outcomes using either Celiac Plus or the American College of Gastroenterology’s published diagnostic algorithm would be required to demonstrate improved health outcomes with Celiac Plus.
 
Practice Guidelines and Position Statements
In 2013, the American College of Gastroenterology published an evidence-based consensus algorithm for the diagnosis and management of celiac disease (Rubio-Tapia, 2013). A recommendation for genetic testing using a mutligene panel test (eg, Celiac Plus) was not included.
 
Section Summary
No studies examining the clinical utility of Celiac Plus were identified. Factors that support an indirect chain of evidence for prognostic or diagnostic utility are lacking. A comparison of clinical and/or histopathologic outcomes using either Celiac Plus or the American College of Gastroenterology’s published diagnostic algorithm would be required to demonstrate improved health outcomes with Celiac Plus.
 
DNA Methylation Pathway Profile (Great Plains Laboratory)
 
Description of Disease
Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation, and each SNP represents a difference in a single nucleotide in the DNA sequence. Most commonly, SNPs are found in the DNA between genes and can act as biological markers of genes and disease association. When SNPs occur within a gene or a gene regulatory region, they can play a more direct role in disease by affecting the gene’s function. SNPs may predict an individual’s response to certain drugs, susceptibility to environmental factors, and the risk of developing certain diseases.
 
Description of Test
The DNA Methylation Pathway Profile analyses SNPs that are 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.
 
Literature Review
No full-length, peer-reviewed studies of DNA Methylation Pathway Profile were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
No guidelines were identified that address the use of SNP testing for DNA methylation.
 
Section Summary
No studies examining the clinical validity or clinical utility of the DNA Methylation Pathway Profile were identified.
 
GI Effects® Comprehensive Stool Profile (Genova Diagnostics®, Asheville, NC)
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder that affects 10% to 20% of the general population in the United States and worldwide (NICE, 2008; McKenzie, 2012; Trinkley, 2011). Symptoms include abdominal pain and/or bloating associated with disordered bowel habit (constipation, diarrhea, or both) (ROME Foundation, 2006). Pathophysiology is poorly understood but may be related to chronic low-grade mucosal inflammation and disturbances in GI flora (Ford, 2014). Recommended treatments comprise dietary restriction and pharmacologic symptom control (NICE, 2008; McKenzie, 2012; Weinberg, 2014). Probiotics, living microorganisms that promote health when administered to a host in therapeutic doses (Hill, 2014), are being investigated as a treatment for IBS. Several systematic reviews of randomized controlled trials (RCTs) have found evidence to support efficacy (McKenzie, 2012; Trinkley, 2011; Ford, 2014; Hungin, 2013; Ortiz-Lucas, 2013; Whelan, 2011), but results from recent
RCTs have been mixed.17-22 This discrepancy may be due in part to differential effects of different probiotic strains and doses (McKenzie, 2012).
 
Description
The GI Effects Comprehensive Stool Profile is a multianalyte stool assay (Genova Diagnostics, 2014). 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).
 
Literature Review
Two manufacturer-sponsored studies were published in 2014. Goepp et al conducted a retrospective cohort study to determine the frequency of abnormal fecal biomarkers among patients with IBS symptoms (Goepp, 2014). Records from Genova Diagnostics were reviewed to identify patients with ICD-9 codes for at least 1 of 13 IBS symptoms who had available results of a fecal biomarker panel (N=2256).
 
Quantitative
stool culture for Lactobacillus and Bifidobacterium (“beneficial bacteria”) indicated low growth in 73% of patients, parasites were detected in 8%, and biochemical analyses showed elevated eosinophil protein X, elevated calprotectin, and low pancreatic elastase in 14%, 12%, and 7%, respectively. The authors interpreted these biochemical findings to support diagnoses of food allergies, inflammation, and exocrine pancreatic insufficiency, respectively.
 
Parsons et al (2014) conducted a retrospective matched cohort study to compare direct medical costs of care for patients with IBS who underwent fecal biomarker testing with those of matched controls (Parsons, 2014). Investigators searched medical and pharmacy claims from a national pharmacy benefits manager for IBS related diagnosis codes; patients who also had fecal panel test codes and data for up to 1 year after testing (n=132) were compared with propensity-matched (for age, sex, diagnosis code[s], and baseline medical and pharmacy utilization) controls from the same database who had IBS-related diagnosis codes but no fecal test codes. Outcomes of interest were diagnostic and medical service costs determined from claims data. At baseline, laboratory costs were higher in tested groups compared with controls. At 30, 90, and 365 days after testing, total medical costs, GI procedural costs including imaging, and laboratory costs were higher in controls. For example, at 90 days after testing, GI procedural costs were $26 less than baseline utilization in the tested cohort and $165 more than baseline in the control cohort.
 
Summary of Clinical Validity
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 inter-individual variability in gut flora (Hanaway, 2006).
 
Summary of Clinical Utility
Clinical trials demonstrating net health benefit with the GI Effects fecal panel were not identified. Because probiotics are not currently a standard treatment of IBS, impacts of test results on disease management are uncertain; that is, an indirect chain of evidence for clinical utility of the test cannot be established.
 
Practice Guidelines and Position Statements
 
    • American Gastroenterological Association (AGA): A 2014 evidence-based AGA guideline for pharmacologic management of IBS does not review probiotic treatment (Weinberg, 2014).
    • British Dietetic Association: A 2012 evidence-based British Dietetic Association guideline for dietary management of IBS in adults recommends consideration of probiotics “secondary to other second-line advanced dietary interventions,” such as reduced intake of fermentable carbohydrates (Grade of recommendation: B [based on 5 studies (4 RCTs and 1 observational study) with high risk of bias]) (McKenzie, 2012).
    • National Institute for Health and Care Excellence: A 2008 evidence-based National Institute for Health and Care Excellence guideline for diagnosis and management of IBS in primary care states that testing for fecal ova and parasites is unnecessary to confirm the diagnosis in patients who meet IBS diagnostic criteria (NICE, 2008). The guideline also states, “People with IBS who choose to try probiotics should be advised to take the product for at least 4 weeks while monitoring the effect. Probiotics should be taken at the dose recommended by the manufacturer.” This guideline is currently being updated (NICE, 2014).
 
Section Summary
Evidence for clinical validity and clinical utility of the GI Effects Comprehensive Stool Profile is lacking. Two claims-based, retrospective studies evaluated abnormal fecal marker prevalence and costs associated with use of the test. This evidence is not sufficient to demonstrate net health benefit with use of the test.
 
IBD sgi Diagnostic™ (Prometheus®, San Diego, CA)
Current approaches to diagnosing IBD include endoscopy, mucosal biopsy, serology, and radiology (Conrad, 2014; Ordas, 2012; Kornbluth, 2010; Laass, 2014; Baumgart, 2012; Lichtenstein, 2009). Differential diagnosis includes other GI inflammatory disorders and infectious etiologies. Differentiating ulcerative colitis (UC) from Crohn disease (CD) is necessary for appropriate treatment planning; in cases with atypical presentations, this differentiation can be difficult. Prometheus® laboratories has developed a blood test that aims to more accurately diagnose IBD and differentiate UC from CD.
 
Description
IBD sgi Diagnostic™ is a panel of 17 serologic (n=8), genetic (n=4), and inflammatory biomarkers (n=5). A proprietary algorithm produces an IBD score; results are reported as consistent with IBD (consistent with UC, consistent with CD, or inconclusive for UC versus CD) or not consistent with IBD. The test is intended for use in patients with clinical suspicion of IBD.
 
Literature Review
The IBD sgi Diagnostic™ product monograph includes an extensive bibliography that documents associations of the 17 component markers, individually and in combination, with UC and/or CD (Prometheus, 2011).Development and performance characteristics of the 17-marker panel are described without citation, and it is unclear what standard criterion was used for diagnosis. Overall sensitivity for IBD, UC, and CD is reported as 74%, 98%, and 89%, respectively; specificity is reported as 90%, 84%, and 81%, respectively; receiver operating characteristic (ROC) analysis showed greater discrimination with the 17-marker panel (area under the curve [AUC], 0.871) compared with any individual marker (greatest AUC, 0.690 for IgA anti-Saccharomyces cerevisiae antibodies [ASCA]). Test performance characteristics for distinguishing UC from CD were not provided.
 
In a 2012 review of the monograph, Shirts et al (Shirts, 2012) observed that serologic tests for ASCA-IgA, ASCA-IgG, and atypical perinuclear anti-neutrophil cytoplasmic antibody (pANCA) are standard of care in the diagnostic work-up of IBD, (Conrad, 2014; Laass, 2014) although not all authors include these tests in recommended diagnostic strategies (Ordas, 2012; Kornbluth, 2010; Baumgart, 2012; Lichtenstein, 2009). These 3 markers are included in the 17-marker panel. Based on a meta-analysis of 60studies (total N=11,608), pooled sensitivity and specificity of the 3-test panel were 63% and 93%, respectively, for diagnosing IBD.36 Because the product monograph does not include a comparison of the17-marker panel with the 3-marker panel, incremental improvement in diagnosis with the 17-marker panelis unknown. Shirts et al calculated an ROC AUC for the 3-marker panel of 0.899.
 
Studies of the clinical utility of IBD sgi Diagnostic™ were not identified.
 
Summary of Clinical Validity
Published evidence supports associations of each marker in the 17-marker panel, alone and in combination, with IBD diagnosis. Based on manufacturer data, accuracy for IBD diagnosis of the 17-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 suggests that the panels may perform similarly. Performance characteristics for the 17-marker panel to distinguish UC from CD were not provided.
 
Summary of Clinical Utility
No studies examining the clinical utility of IBD sgi Diagnostic™ were identified. Although manufacturer data support clinical validity of the test for diagnosing IBD, this evidence is insufficient to support an indirect chain of evidence for clinical utility due to lack of details about study methodology and lack of replication of the findings. For distinguishing UC from CD, clinical validity has not been established; therefore, an indirect chain of evidence for clinical utility for this purpose cannot be established.
 
Practice Guidelines and Position Statements
AGA practice guidelines for UC30 (2010) and for CD33 (2010) do not include recommendations for multimarker panels that include genetic tests to facilitate diagnosis or prognosis.
 
Section Summary
No studies examining the clinical utility of IBD sgi Diagnostic™ were identified. Although manufacturer data supports clinical validity of the test for diagnosing IBD, this evidence is insufficient to support an indirect chain of evidence for clinical utility due to lack of details about study methodology and lack of replication of the findings. For distinguishing UC from CD, clinical validity has not been established; therefore, an indirect chain of evidence for clinical utility for this purpose cannot be established.
 
SEPT9 Methylated DNA (ColoVantage, Various Manufacturers; Epi proColon, Epigenomics, Berlin)
Early detection of colorectal cancer (CRC) reduces disease-related mortality, yet many individuals do not undergo recommended screening with fecal occult blood test or colonoscopy. It is thought that a simpler screening blood test may encourage screening and decrease mortality, although this has not been proven. Serum biomarkers that are shed from colorectal tumors have been identified and include Septin 9 hypermethylated DNA (SEPT9). Septin 9 protein is involved in cell division, migration, and apoptosis, and acts as a tumor suppressor; when hypermethylated, expression of SEPT9 is reduced.
 
Description
ColoVantage blood tests for serum SEPT9 methylated DNA are offered by several laboratories (ARUP® Laboratories, Quest Diagnostics®, Clinical Genomics). Epi proColon® currently is unavailable in the United States, but Epigenomics has licensed its Septin 9 biomarker technology to ARUP and Quest. ColoVantage and Epi proColon® are both PCR assays; however, test performance characteristics vary across tests, presumably due to differences in methodology (eg, DNA preparation, PCR primers, probes). Sensitivity as high as 90% with 88% specificity and 99.9% negative predictive value (NPV) (4% positive predictive value [PPV]) have been reported for ColoVantage.37,38 In comparison, reported sensitivity and specificity for Epi proColon® were 68% and 80%, respectively.39 (In March 2014, an FDA Advisory Committee voted 5 to 4 in favor of a positive risk-benefit profile of Epi proColon®.40) Serum SEPT9
methylated DNA testing is intended for individuals 50 years of age or older who have an average risk of
colorectal cancer (ARUP Laboratories, 2014).
 
Literature Review
In case-control studies involving more than 3000 patients, overall sensitivity of SEPT9 DNA methylation screening was 60% to 70% and specificity was 89%.37,38,41-43 Modifications to ColoVantage methodology increased sensitivity to 90% with little decrement to specificity (Warren, 2011; ARUP Laboratories).
 
A more recent case control study that compared Epi proColon® with fecal immunochemical testing (FIT) for colorectal cancer screening enrolled 102 patients with CRC and 199 patients who presented for screening (Johnson, 2014). Colonoscopy was the reference standard. Sensitivity and specificity were 73% and 82% for Epi proColon®, respectively, and 68% and 97%, respectively, for FIT. In 290 paired samples, sensitivity of the 2 tests was similar (»70%), but specificity of Epi proColon® was lower (81% vs 97%). Similar results were observed in a subsequent retrospective case control study that used a second generation version of the test (Jin, 2014).
 
In 2014, Church et al reported an international prospective screening study of Epi proColon®, called PRESEPT (Church, 2014). Patients 50 years of age or older with average risk of CRC who were scheduled for colonoscopy were enrolled (N=7941). Of these, 1516 (19%) were selected for laboratory analysis in stratified random sampling; colonoscopy identified 53 patients (3%) with invasive adenocarcinoma, 315 (21%) with advanced adenoma, 210 (14%) with nonadvanced adenoma, and 938 (62%) with no evidence of disease. Overall sensitivity, specificity, PPV, and NPV for Epi proColon® detection of invasive adenocarcinoma were 48%, 92%, 5%, and 100%, respectively. Sensitivity for advanced adenoma was low (11%). As observed by the study authors, detection of only half of preclinical cancers and a small proportion of advanced adenomas limits clinical utility of the test.
 
Tham et al (2014) reported on a smaller prospective cohort study in Singapore (N=150) (Tham, 2014). Investigators measured methylation levels of 7 genes, including SEPT9, in patients with stage I-III CRC who underwent curative resection. Blood samples were collected 1 week before, and 6 months and 1 year after surgery. At median follow-up of 59 months (range, 5-79), 43 patients (29%) developed recurrence. Although a statistically significant association between methylated SEPT9 level at 1 year and recurrence was found, interpretation of this result is limited by lack of correction for multiple comparisons. Additionally, cutoff values for a positive test were determined by median levels rather than prespecified. ROC analysis using optimized cutoffs for SEPT9 at 1 year yielded an (AUC=0.70 (95% confidence interval [CI], 0.58 to 0.82]). AUC for carcinoembryonic antigen at 1 year was similar (AUC=0.69 [95% CI, 0.57 to 0.80]).
 
Summary of Clinical Validity
Evidence for clinical validity of screening for CRC comprises case control studies and 2 prospective screening studies. Test performance characteristics were better in case control studies, suggesting that tests intended for screening be prospectively tested in the screening setting (Church, 2014). Based on results from the prospective screening study, clinical validity of SEPT9 methylated DNA screening is limited by low sensitivity and low PPV of the test.
 
Summary of Clinical Utility
Studies comparing survival outcomes in patients who undergo CRC screening with SEPT9 methylated DNA testing versus standard screening were not identified. Such comparative studies with clinically meaningful outcomes (survival) are necessary to demonstrate incremental improvement in net health outcome compared with current standard screening approaches (FIT, colonoscopy) and to address leadtime bias for cancers identified through screening. Because evidence for clinical validity is currently lacking, an indirect chain of evidence establishing clinical utility of SEPT9 methylated DNA cannot be established.
 
Practice Guidelines and Position Statements
Current National Comprehensive Cancer Network (NCCN) guidelines for colon cancer (v.2.2015) do not include a recommendation for genetic testing (eg, SEPT9 methylated DNA) for early detection of colon cancer (NCCN, 2015).
 
Section Summary
Studies comparing survival outcomes in patients who undergo CRC screening with SEPT9 methylated DNA testing (ColoVantage, Epi proColon) versus standard screening were not identified. Such comparative studies with clinically meaningful outcomes (survival) are necessary to demonstrate incremental improvement in net health outcomes compared with current standard screening approaches (FIT, colonoscopy) and to address lead-time bias for cancers identified through screening. Evidence for clinical validity also is lacking; therefore, an indirect chain of evidence establishing clinical utility of SEPT9 methylated DNA testing cannot be established.
 
Risk Assessment
Celiac Plus (Prometheus®, San Diego, CA)
Previously reviewed.
 
Prognostic Tests
Crohn’s Prognostic (Prometheus®, San Diego, CA)
Recent studies have identified serologic (Targan, 2005) and genetic (Ippolliti, 2010; Abreu, 2002) correlates of aggressive CD that is characterized by fistula formation, fibrostenosis, and the need for surgical intervention. Prometheus® laboratory has developed a blood test that aims to identify patients with CD who are likely to experience an aggressive disease course.
 
Description
Crohn’s Prognostic is a panel of 6 serologic (n=3) and genetic (n=3) biomarkers. Limited information about the test is available on the manufacturer’s website.
 
Literature Review
No studies of the 6-marker panel were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
None identified that address a test like Crohn’s Prognostic.
 
Section Summary
Direct and indirect evidence for clinical utility of the Crohn’s Prognostic test to identify individuals likely to have an aggressive disease course is currently lacking.
 
DecisionDx-Melanoma (Castle Biosciences Inc.)
Description of disease
Cutaneous melanoma represents less than 5% of skin malignancies but results in the most skin cancer deaths. The incidence of cutaneous melanoma continues to increase, and it is currently the sixth most common cancer in the United States. Standard treatment options for stage I and II melanoma are excision ± sentinel lymph node examination. Current risk factors to predict localized tumor aggression include Breslow tumor thickness, tumor ulceration, and mitotic rate of the tumor cells. Regional lymph node involvement, the likelihood of which increases with increasing tumor thickness, significantly negatively impacts the rate of survival.
 
Description of Test
The DecisionDx-Melanoma is a gene expression profile test that is a signature of 31 genes, 28 discriminating genes, and 3 control genes. The test is used to measure risk of metastasis in patients with stage I and II cutaneous melanoma and classifies tumors into 2 groups of risk of metastasis¾high or low (class 1 and 2, respectively). The test purports to give an independent prediction of risk of tumor metastatic risk, independent of currently used metrics of risk assessment (eg, Breslow’s thickness, ulceration status, and mitotic rate; American Joint Committee on Cancer stage, sentinel lymph node biopsy status), so that patients with high-risk stage I or II disease can possibly undergo more aggressive
surveillance treatment than they would have otherwise received.
 
Literature Review
No full-length, peer-reviewed studies of DecisionDx-Melanoma were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
NCCN guidelines for melanoma (v1.2015) state that “while there is interest in newer prognostic molecular techniques such as gene expression profiling to differentiate melanomas at low-versus high-risk for metastasis, routine genetic testing of primary melanoma (before or following sentinel lymph node biopsy) is not recommended outside of a clinical trial”.
 
Section Summary
Evidence for clinical validity and utility of the DecisionDx-Melanoma test to identify individuals likely to have an aggressive disease course is currently lacking.
 
DecisionDx-Thymoma (Castle Biosciences Inc.)
Thymomas and thymic carcinomas are rare epithelial tumors of the thymus. Most are diagnosed in individuals between 40 and 60 years of age. Thymic epithelial tumors range from histologically benign tumors, to microscopically or macroscopically invasive low- or high-grade malignant tumors. However, even tumors that are histologically benign can behave aggressively.
 
Description
DecisionDx-Thymoma is a gene expression profile test that measures the activity of 23 genes within the thymic tumor. Its intended use is to distinguish between thymic carcinoma and thymoma, and to predict tumor aggressiveness by likelihood that the tumor will metastasize.
 
Literature Review
No full-length, peer-reviewed studies of DecisionDx-Thymoma were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
NCCN guidelines for thymomas and thymic carcinomas (v1.2014) do not address the use of gene expression profiling of tumors of the thymus.
 
Section Summary
Evidence for clinical validity and utility of the DecisionDx-Thymoma test to identify individuals likely to
have an aggressive disease course is currently lacking.
 
Tests for Genetic Variants That Alter Response to Treatment or to an Environmental Factor
Response DX Colon (Response Genetics, Los Angeles, CA)
 
Description
Response Genetics currently markets 2 colon cancer genetic panels to guide treatment selection, as well as separate tests for 11 genes associated with colon cancer prognosis and/or treatment response. The Driver Profile panel comprises PCR mutation testing in KRAS, BRAF, and mismatch repair genes (microsatellite instability), plus NRAS exon 2 and 3 sequencing. These gene tests are addressed in other Policies and therefore this panel is not reviewed here. The Comprehensive Colon Profile comprises the 4 tests in the Driver Profile plus: EGFR expression; PI3K exon 1, 9, and 20 sequencing; TS expression; ERCC1 expression; UGT1A1 SNP testing (rs8175347 and rs4148323); VEGFR2 expression; and MET amplification by fluorescence in situ hybridization). Evidence for clinical validity and clinical utility of the Comprehensive Colon Profile was sought.
 
Literature Review
No full-length, peer-reviewed studies of the Comprehensive Colon Profile were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
Although current NCCN guidelines for colon cancer (v.2.2015) consider the clinical utility of genetic testing for specific genes to guide treatment selection (eg, “EGFR testing has no demonstrated predictive value; therefore routine EFGR testing is not recommended”), gene panels for colon cancer are not addressed (NCCN, 2015).
 
Section Summary
Evidence for clinical validity and utility of the Comprehensive Colon Profile to guide treatment selection in patients with colon cancer is currently lacking.
 
TransPredict Fc Gamma 3A (Transgenomic® Inc., Omaha, NE)
Rituximab is a humanized IgG monoclonal antibody against the CD20 antigen, which is commonly expressed on B-lymphocytes. It is FDA-approved for treatment of non-Hodgkin lymphoma, chronic lymphocytic leukemia, and nononcologic uses (eg, rheumatoid arthritis) (Genentech, 2014). Although rituximab has demonstrated improved response and survival rates in combination chemotherapy regimens in patients with follicular lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma compared with chemotherapy alone, not all patients respond. Altered binding to lymphocyte-bound rituximab by cytotoxic effector cells (eg, natural killer cells, macrophages) has been identified as a mechanism of reduced rituximab efficacy. Effector cells with a Val158Phe substitution mutation in their surface receptors for IgG molecules (eg, rituximab) have impaired binding affinity, and cellular cytotoxicity is reduced. A genetic test for the Val158Phe mutation of the gene that encodes the IgG receptor on effector cells, FCGR3A, has been developed and investigated as a means of predicting response to rituximab.
 
Description
TransPredict Fc gamma 3A (formerly PGxPredict:Rituximab) is a PCR assay that uses a blood sample to detect the Val158Phe variant of the FCGR3A gene. For patients who are homozygous for valine, the test reports a high likelihood of response to rituximab; for all other patients (homozygous for phenylalanine or heterozygous), the test reports an average probability of response. The test is intended for patients with follicular, CD20positive, Bcell nonHodgkin lymphoma who are being considered for treatment with rituximab.
 
Literature Review
In a multicenter study from France, Cartron et al (2002) compared objective response rates (including unconfirmed complete remission) among 49 previously untreated patients with follicular lymphoma who received rituximab (Cartrpm. 2002). Ten patients (20%) had the homozygous valine genotype of FCGR3A, 17 patients (35%) were homozygous for phenylalanine, and 22 patients (45%) were heterozygotes. At 2 months, objective response rate was 100% in valine homozygotes, 70% in phenylalanine homozygotes, and 64% in heterozygotes (Fisher exact test, p=0.09). At 12 months, objective response rate was 90%, 59%, and 45%, respectively (Fisher exact test, p=0.06). At both time points, the difference in response rate between valine homozygotes and phenylalanine carriers (homo- and heterozygotes) was statistically significant. With median follow-up of 35 months, there was no statistical difference in 3-year progression-free survival between valine homozygotes and phenylalanine carriers (56% vs 35%, respectively).
 
In a multicenter study from Korea, Kim et al (2006) compared objective response rates in 198 patients with diffuse large B-cell lymphoma who received first-line CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone; n=85) or rituximab plus CHOP (R-CHOP; n=113) (Kim, 2006). Fifty-three patients (47%) were valine homozygotes, 6 patients (5%) were phenylalanine homozygotes, and 54 patients (48%) were heterozygotes. In the R-CHOP group, complete response rate was statistically greater in valine carriers compared with phenylalanine carriers (88% in valine homozygotes, 50% in phenylalanine homozygotes, 79% in heterozygotes, respectively; Fisher exact test, p=0.002). In the CHOP group, response rates were similar across genotypes. With median follow-up of 420 days, no difference in event-free or overall survival across genotypes was found in either treatment group.
 
Subsequent, larger studies have not shown an association between FCGR3A genotype and outcomes in patients with follicular lymphoma (Ghesquieres, 2012; Prochazka, 2011; Weng, 2009; Carlotti, 2007) or chronic lymphocytic leukemia (Dornan, 2010) who received rituximab plus chemotherapy. Smaller studies in rituximab-treated patients with diffuse large B-cell lymphoma,(Varoczy, 2012; Fabisiewicz, 2011; Mitrovic, 2007) mantle cell lymphoma (Galimberti, 2007), and posttransplant lymphoproliferative disorder64 also have reported no association.
 
A 2014 meta-analysis from Korea assessed the association between FCGR3A and IL-6 genotype and response to biologic therapies in patients with rheumatoid arthritis (Lee, 2014). Literature was searched through January 2014, and 3 studies of FCGR3A and rituximab were included (total N=500). Study quality was not assessed. A statistically significant association between FCGR3A genotype and response to rituximab was not observed (OR for nonresponse, valine homozygotes vs all other patients, 0.59 [95% CI, 0.10 to 3.4], p=0.55); statistical heterogeneity was considerable (I2=82%).
 
Summary of Clinical Validity
Small studies in patients with non-Hodgkin lymphoma suggested that the Val158Phe polymorphism of the FCGR3A gene may predict response to rituximab therapy, although survival outcomes did not differ by genotype. However, in subsequent, larger studies in rituximab-treated patients with follicular lymphoma and chronic lymphocytic leukemia, this finding was not replicated. Studies in other types of non-Hodgkin lymphoma also have reported no association between FCGR3A genotype and outcomes. Meta-analysis of studies in rheumatoid arthritis did not find an association between FCGR3 genotype and response to rituximab.
 
Summary of Clinical Utility
No studies examining the clinical utility of TransPredict Fc gamma 3A were identified. Factors that support an indirect chain of evidence for predicting response to rituximab are lacking, primarily because evidence for clinical validity of the test is lacking.
 
Practice Guidelines and Position Statements
Current NCCN guidelines for non-Hodgkin lymphomas (v.5.2014) do not include a recommendation for genetic testing (eg, TransPredict Fc gamma 3A) to predict response to rituximab therapy (NCCN, 2014).
 
Current (2012) American College of Rheumatology recommendations for the use of disease-modifying
antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis do not address FCGR3
testing (Singh, 2012).
 
Section Summary
No studies examining the clinical utility of TransPredict Fc gamma 3A were identified. Factors that support an indirect chain of evidence for predicting response to rituximab are lacking, primarily because evidence for clinical validity of the test is lacking.
 
December 2015 Update
 
ColonSentry (GeneNews, Ontario, Canada; Innovative Diagnostic Laboratory, Richmond, VA)
A cofounder of the biotechnology firm GeneNews developed a patented platform technology based on theSentinel Principle® (Liew, 2006). The Sentinel Principle® posits that because blood interacts with all bodily tissues, “subtle changes occurring in association with injury or disease, within the cells and tissues of the body, may trigger specific changes in gene expression in blood cells reflective of the initiating stimulus” (Liew, 2006). In this way, blood cells (specifically, leukocytes) may act as sentinels of disease. In studies that led to the formulation of this principle, investigators compared gene expression (total RNA levels) in blood samples with catalogued genes from 9 different organs (brain, colon, heart, kidney, liver, lung, prostate, spleen, and stomach) and estimated that 66% to 82% of genes encoded in the human genome are expressed in human leukocytes (Liew, 2006).
 
Description of Test
ColonSentry® is a PCR assay that uses a blood sample to detect expression of 7 genes found to be differentially expressed in CRC patients compared with controls (Yip, 2010): ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, and IL2RB. Per the company website, these genes are early warning signs of colon cancer, and test results can indicate the odds of having CRC compared with an average-risk person (Innovative Diagnostic Laboratory, 2015). An average-risk person is defined as one who is “at least 50 years old, is asymptomatic for CRC, has no personal history of benign colorectal polyps, colorectal adenomas, CRC, or inflammatory bowel disease, and does not have a first degree relative with CRC ” (Innovative Diagnostic Laboratory, 2015).  The test is intended for use in adults who are averse to colonoscopy and/or fecal occult blood testing. “Because of its narrow focus, the test is not expected to alter clinical practice for patients who comply with recommended screening schedules” (Chao, 2013).
 
Literature Review
Marshall et al (2010) conducted a genome-wide association study in 189 whole blood samples (98 controls, 91 patients with CRC) and identified 45 differentially expressed gene biomarker candidates using microarray hybridization (Marshall, 2010). Through logistic regression and bootstrapping (subsampling with replacement) in a training set of 232 samples (120 controls, 112 patients with CRC), 7 genes were selected for further development. Sensitivity, specificity, PPV, and NPV for detecting CRC were 82%, 64%, 68%, and 79%, respectively. AUC was 0.80 (95% CI, 0.74 to 0.85). In a test set of 410 samples (208 controls, 202 patients with CRC), sensitivity, specificity, PPV, and NPV were 72%, 70%, 70%, and 72%, respectively. AUC was 0.80 (95% CI, 0.76 to 0.84). The authors applied subsequent Bayesian modeling to incorporate the prevalence of CRC in the average-risk population (0.7%) and proposed relative risk categories to further stratify average-risk patients for CRC screening. Because of its crosssectional design, follow-up of controls to determine which strata developed CRC was not reported, limiting conclusions that can be drawn about the accuracy of the test for risk prediction. In a subsequent publication, the investigators reported test performance stratified by left- versus right-sided cancers and tumor stage (Chao, 2013).
 
Yip et al (2010) conducted a similar cross-sectional study in 210 blood samples (111 controls, 99 CRC) from patients in Malaysia (Yip, 2010). The Malaysian population has different ethnic groups with different CRC incidences (eg, 0.02% in Chinese Malaysians, 0.01% in ethnic Malays), and CRC in Asian populations is more likely to be nonpolypoid (ie, flat or depressed) compared with western populations in whom the test was developed. Sensitivity and specificity for detecting CRC were 61% and 77%, respectively. AUC was 0.76 (95% CI, 0.70 to 0.82). With optimized cut points, sensitivity and specificity were 72% and 71%, respectively. As previously, the cross-sectional design of the study limits conclusions that can be drawn.
 
Summary of Clinical Validity
Two cross-sectional studies do not permit full characterization of the ability of ColonSentry® to predict CRC risk.
 
Summary of Clinical Utility
No studies examining the clinical utility of ColonSentry® were identified. Factors that support an indirect chain of evidence for predicting CRC risk are lacking, primarily because evidence for clinical validity of the test is lacking.
 
Practice Guidelines and Position Statements
 
National Comprehensive Cancer Network
NCCN guidelines for CRC screening (v.1.2015) include category 2A recommendations for CRC screening in average-risk individuals (defined as above) using high-sensitivity or immunohistochemical-based stool testing, flexible sigmoidoscopy with or without interval stool testing, or colonoscopy (NCCN, 2015). Colonoscopy is recommended for screening individuals with increased risk. No recommendation for genetic or molecular testing of average-risk individuals was included.
 
American College of Physicians
Based on its review of U.S. guidelines, the American College of Physicians (ACP) issued a guidance statement in 2012 on screening for CRC (Qaseem, 2012). For average-risk adults age 50 to 75 years, ACP recommends using a stool-based test, flexible sigmoidoscopy, or optical colonoscopy for screening. For high-risk patients, ACP recommends using optical colonoscopy. No recommendation for genetic or molecular testing of average-risk individuals was included.
 
U.S. Preventive Services Task Force
USPSTF is currently updating its recommendation for CRC screening in adults.56 Existing recommendations include a grade A recommendation (high certainty that the net benefit is substantial) for CRC screening using fecal occult blood testing, sigmoidoscopy, or colonoscopy beginning at age 50 years and continuing until age 75 years (USPSTF, 2008).
 
No USPSTF recommendations for genetic/molecular tests for colon cancer have been identified.
 
Section Summary: ColonSentry
ColonSentry® is intended to stratify patients with average CRC risk who are averse to screening to identify those who may be at increased risk and therefore choose screening. However, 2 cross-sectional studies are insufficient to demonstrate the risk predictive ability of the test; that is, clinical validity has not been established. Direct and indirect evidence of clinical utility is currently lacking.
 
ImmunoGenomic® Profile (Genova Diagnostics®, Asheville, NC)
 
Description
The ImmunoGenomic® Profile is a buccal swab test that evaluates SNPs in 6 genes associated with immune function and inflammation: interleukin (IL)-10, IL-13, IL-1 beta, IL-4, IL-6, and tumor necrosis factor α (Genova Diagnostics, 2015). According to the company website, variations in these genes “can affect balance between cell (TH-1) and humoral (TH-2) immunity, trigger potential defects in immune system defense, and stimulate mechanisms underlying chronic, overactive inflammatory responses….The test uncovers 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 (cause of ulcers)….”
 
Literature Review
No full-length, peer-reviewed studies of the ImmunoGenomic® Profile were identified.
 
Summary of Clinical Validity
Evidence for clinical validity is lacking.
 
Summary of Clinical Utility
Direct and indirect evidence for clinical utility is lacking.
 
Practice Guidelines and Position Statements
No guidelines were identified that address use of SNP testing for assessment of immune function and inflammation.
 
U.S. Preventive Services Task Force
No USPSTF recommendations for genetic/molecular tests for arthritis, asthma, allergies, or other chronic inflammatory disorders have been identified.
 
Section Summary: ImmunoGenomic® Profile
Evidence for clinical validity and utility of the ImmunoGenomic® Profile to predict risk of developing arthritis, asthma, allergies, or other chronic inflammatory disorders is currently lacking.
 
2018 Update
A literature search was conducted using the MEDLINE database through February 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
SEPT9 Methylated DNA: ColoVantage and Epi proColon
Yan et al (2016) reported a meta-analysis of 14 studies (total N=9870 patients) with similar results (sensitivity, 66%; 95% CI, 64% to 69%; specificity, 91%; 95% CI, 90% to 91%) Yan, 2016).
 
Nian et al (2017) published another systematic review including 25 studies (total N=9927 patients) and reported a higher overall sensitivity (71%; 95% CI, 67% to 75%) and similar specificity (92%; 95% CI, 89% to 94%) (Nian, 2017). Study designs (case-control vs cross-sectional), assays or kits used (Epi proColon vs other), country (Asia or other), sample sizes (>300 or <300), and risk of bias of included studies all contributed to heterogeneity. Only 2 studies were rated as having a low risk of bias in all QUADAS-2 domains.
 
One test has received U.S. Food and Drug Administration approval-the Epi proColon test. It was approved in 2016 for use in average-risk patients who decline other screening methods. Fewer studies have specifically evaluated the performance of the commercially available Epi proColon test. The 2017 review included 18 studies of Epi proColon test 1.0, 2.0, or a combination of the two. The sensitivity and specificity of Epi proColon 2.0 were 75% (95% CI, 67% to 77%) and 91% (95% CI, 80% to 96%), respectively (Nian, 2017).
 
The U.S. Multi-Society Task Force of Colorectal Cancer represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy (Rex, 2017). The 2017 clinical guidelines state that the advantage of SEPT9 assays for CRC screening is convenience. The disadvantage is “markedly inferior performance characteristics compared with FIT [fecal immunochemical test].” The guidelines state that the best frequency for performing the test is unknown and that the task force recommended not using SEPT9 assays for CRC screening.
 
DecisionDx-Melanoma
 
In a subsequent study of patients with melanoma who had undergone SLNB, Gerami et al (2015) compared prognostic classification by DecisionDx-Melanoma with biopsy results (Gerami, 2015). A total of 217 patients comprised a convenience sample from a database of 406 patients previously tested with DecisionDx-Melanoma. Patients who had undergone SLNB were eligible for the current study and might have overlapped with patients in the Gerami study discussed above. Most (73%) patients had a negative SLNB, and 27% had a positive SLNB; the SLNB-positive patients were AJCC stage III. Five-year OS for SLNB-negative patients was 70% and 62% for SLNB-positive patients. DecisionDx-Melanoma classified 76 (35%) tumors as low risk (class I) and 141 (65%) tumors as high-risk (class II). Five-year OS for class I patients was 89% and 55% for class II patients. Within the group of SLNB-negative patients, 5-year OS was 91% in class I patients and 55% in class II patients. Within the group of SLNB-positive patients, 5-year OS was 77% in class I patients and 57% in class II patients.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Practice Guidelines and Position Statements
 
American Cancer Society
The American Cancer Society (2018) has recommended that “adults aged 45 y and older with an average risk of CRC undergo regular screening with either a highsensitivity stoolbased test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy (Wolf, 2018).”  The stool-based tests listed as options are a fecal immunochemical test, fecal occult blood test, and multi-target stool DNA test. The College noted that “…at this time, mSept9 is not included in this guideline as an option for routine CRC screening for averagerisk adults.”
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
0019UOncology, RNA, gene expression by whole transcriptome sequencing, formalin fixed paraffin embedded tissue or fresh frozen tissue, predictive algorithm reported as potential targets for therapeutic agents
0152UInfectious disease (bacteria, fungi, parasites, and DNA viruses), microbial cell-free DNA, next generation sequencing, for significant positive pathogens
0163UOncology (colorectal) screening, biochemical enzyme linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor 1 [TDGF 1, Cripto 1], carcinoembryonic antigen [CEA], extracellular matrix protein [ECM]), with demographic data (age, gender, CRC screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas
0164UGastroenterology (irritable bowel syndrome [IBS]), immunoassay for anti CdtB and anti vinculin antibodies, utilizing plasma, algorithm for elevated or not elevated qualitative results
0203UAutoimmune (inflammatory bowel disease), mRNA, gene expression profiling by quantitative RT-PCR, 17 genes (15 target and 2 reference genes), whole blood, reported as a continuous risk score and classification of inflammatory bowel disease aggressiveness
0216UNeurology (inherited ataxias), genomic DNA sequence analysis of 12 common genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non uniquely mappable regions, blood or saliva, identification and categorization of genetic variants
0217UNeurology (inherited ataxias), genomic DNA sequence analysis of 51 genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non uniquely mappable regions, blood or saliva, identification and categorization of genetic variants
0228UOncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer
0249UOncology (breast), semi-quantitative analysis of 32 phosphoproteins and protein analytes, includes laser capture microdissection, with algorithmic analysis and interpretative report
81168CCND1/IGH (t(11;14)) (eg, mantle cell lymphoma) translocation analysis, major breakpoint, qualitative and quantitative, if performed
81229Cytogenomic constitutional (genome wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants, comparative genomic hybridization (CGH) microarray analysis.
81277Cytogenomic neoplasia (genome wide) microarray analysis, interrogation of genomic regions for copy number and loss of heterozygosity variants for chromosomal abnormalities
81327SEPT9 (Septin9) (eg, colorectal cancer) promoter methylation analysis
81382HLA Class II typing, high resolution (ie, alleles or allele groups); one locus (eg, HLA DRB1, DRB3/4/5, DQB1, DQA1, DPB1, or DPA1), each
81401Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G&gt;A [c.3992-9G&gt;A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, *2, *3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G&gt;A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G&gt;A, 1138G&gt;C, 1620C&gt;A, 1620C&gt;G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G&gt;A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A&gt;G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T&gt;G, m.8993T&gt;C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G&gt;A, m.3460G&gt;A, m.14484T&gt;C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A&gt;G, m.3271T&gt;C, m.3252A&gt;G, m.13513G&gt;A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A&gt;G, m.1494C&gt;T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A&gt;G, m.8356T&gt;C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A&gt;G, m.14709 T&gt;C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A&gt;G, m.1555A&gt;G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81479Unlisted molecular pathology procedure
81529Oncology (cutaneous melanoma), mRNA, gene expression profiling by real time RT PCR of 31 genes (28 content and 3 housekeeping), utilizing formalin fixed paraffin embedded tissue, algorithm reported as recurrence risk, including likelihood of sentinel lymph node metastasis
82397Chemiluminescent assay
82784Gammaglobulin (immunoglobulin); IgA, IgD, IgG, IgM, each
83520Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
84999Unlisted chemistry procedure
86021Antibody identification; leukocyte antibodies
86140C reactive protein;
86141C reactive protein; high sensitivity (hsCRP)
86255Fluorescent noninfectious agent antibody; screen, each antibody
87045Culture, bacterial; stool, aerobic, with isolation and preliminary examination (eg, KIA, LIA), Salmonella and Shigella species
87046Culture, bacterial; stool, aerobic, additional pathogens, isolation and presumptive identification of isolates, each plate
87075Culture, bacterial; any source, except blood, anaerobic with isolation and presumptive identification of isolates
87102Culture, fungi (mold or yeast) isolation, with presumptive identification of isolates; other source (except blood)
87177Ova and parasites, direct smears, concentration and identification
87209Smear, primary source with interpretation; complex special stain (eg, trichrome, iron hemotoxylin) for ova and parasites
87328Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme linked immunosorbent assay [ELISA], fluorescence immunoassay [FIA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative; cryptosporidium
87329Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme linked immunosorbent assay [ELISA], fluorescence immunoassay [FIA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative; giardia
87336Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme linked immunosorbent assay [ELISA], fluorescence immunoassay [FIA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative; Entamoeba histolytica dispar group
87798Infectious agent detection by nucleic acid (DNA or RNA), not otherwise specified; amplified probe technique, each organism

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