Coverage Policy Manual
Policy #: 2016019
Category: Laboratory
Initiated: July 2016
Last Review: August 2022
  Short Tandem Repeat Analysis for Specimen Provenance Testing (know error® system)

Description:
According to the American Cancer Society (ACS), an estimated 1.7 million Americans will be diagnosed with some form of cancer in 2015. In the majority of cases, cancer diagnosis involves the pathological review of  a tumor to establish the type and stage of cancer. Procurement and processing of biopsy specimens for pathological review is a complex, multistep process. Errors during surgical pathology review may involve specimen defects, specimen mislabeling, processing errors, and reporting defects. These errors may have serious consequences for disease management given that treatment decisions are often based partially or wholly on pathological findings. It has been estimated that nearly 3 million specimen misidentification events (also known as "specimen provenance errors") occur annually in the United States, leading to approximately160,000 adverse events. A small study reported such errors in 2.4% of 41 men who had prostate needle biopsies. Another larger study reported that up to 0.4% of prostate specimens were misidentified. Finally, a very large study involving 17,000 prostate biopsies found that the error rate ranged from 0.26% to 0.67% of all specimens (Marberger, 2011; Pfeifer, 2011; Pfeifer, 2013).
 
A number of methods have been proposed to reduce or eliminate specimen provenance errors, including preoperative timeouts to ensure that the correct individual and correct anatomical site are being sampled; bar coding of specimens; differential coloring of specimens processed at the same time; and radiofrequency identification of specimens. Molecular identity testing using polymorphic DNA markers (often called short tandem repeats or STRs) have been proposed to decipher suspected specimen provenance errors. Another approach involves taking constitutional DNA specimen from all individuals undergoing biopsy at the time of their procedure and then cross-matching all positive pathological results to ensure that no specimen provenance error has occurred (Pfeifer, 2011; Pfeifer, 2013).
 
The know error DSPA is a polymerase chain reaction (PCR)-based molecular diagnostic test used to confirm that a biopsy specimen belongs to the proper individual for the purposes of making an accurate diagnosis of cancer or other histopathological condition. The know error system involves a DNA verification test that is intended to eliminate diagnostic errors due to specimen provenance complications. The process encompasses four distinct stages: 1) DNA extraction; 2) amplification; 3) separation and analysis; and 4) interpretation and reporting. The DSPA test compares the profile from the biopsy specimen with that determined from DNA isolated from an individual's reference sample (obtained by a buccal swab at the same time as the biopsy). According to the manufacturer, the know error system has the ability to detect errors that are not generally captured by current laboratory protocols, which may have important implications for human safety in routine surgical pathology practice. The know error DSPA system may help prevent adverse events associated with misdiagnosis, including unnecessary treatment for a healthy individual or delayed treatment for an individual with disease.
 
STR analysis using the know error DSPA system is not subject to federal regulation by the Food and Drug Administration (FDA). Genetic tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA) Act of 1988. Premarket approval by the FDA is not required provided the assay is performed in a laboratory facility that observes CLIA regulations.  

Policy/
Coverage:
Effective July 2021
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing to confirm the identity of a biopsy specimen using short tandem repeat based methodology [know error® DNA Specimen Provenance Assay (DSPA)] does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing to confirm the identity of a biopsy specimen using short tandem repeat based methodology [know error® DNA Specimen Provenance Assay (DSPA)] is considered not medically necessary. Services that are considered to be not medically necessary are specific contract exclusions in most member benefit certificates of coverage.
 
Effective Prior to July 2021.
Genetic testing to confirm the identity of a biopsy specimen using short tandem repeat based methodology [know error®  DNA Specimen Provenance Assay (DSPA)] does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, genetic testing to confirm the identity of a biopsy specimen using short tandem repeat based methodology [know error®  DNA Specimen Provenance Assay (DSPA)] is not medically necessary. Services that are considered to be not medically necessary are specific contract exclusions in most member benefit certificates of coverage.

Rationale:
The know error® system is a commercially available genetic test that matches the DNA of a biopsy sample that is positive for malignancy with a reference DNA sample, in order to reduce the likelihood of an error in assignment of tissue origin (‘provenance error”).  As such, this test does not affect the underlying accuracy of a tissue biopsy, but may reduce incorrect conclusions that result from provenance errors, i.e., human errors in processing and labeling tissue specimens.
 
The body of evidence regarding the analytical validity, clinical validity, and clinical utility of STR analysis using the know error DSPA system is sparse and of low quality. There are a few retrospective and prospective case series that evaluated STR analysis for the purpose of identity confirmation. There are no studies identified in the peer-reviewed medical literature that specifically evaluate the analytical validity, clinical validity, or the clinical utility of the know error DSPA system.
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Know Error Specimen Provenance Assay
Clinical Validity
Evidence for 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 (Pfeifer, 2012), but these data are not specific to the Know Error test.
 
Clinical Utility
Direct evidence for clinical utility is lacking. It is not possible to construct an indirect chain of evidence for clinical utility due to the lack of clinical validity.
 
Section Summary: Know Error Specimen Provenance Assays
There is a lack of published evidence on the use of the Know Error test to confirm tissue of origin. Studies are needed that compare use of Know Error to standard laboratory quality measures, and that demonstrate a reduction in specimen provenance errors associated with use of Know Error.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 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 June 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 June 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
81265Comparative analysis using Short Tandem Repeat (STR) markers; patient and comparative specimen (eg, pre transplant recipient and donor germline testing, post transplant non hematopoietic recipient germline [eg, buccal swab or other germline tissue sample] and donor testing, twin zygosity testing, or maternal cell contamination of fetal cells)
81479Unlisted molecular pathology procedure
84999Unlisted chemistry procedure

References: American Cancer Society (ACS). Cancer facts and statistics. 2015. Available at: http://www.cancer.org/research/cancerfactsstatistics/index. Accessed on June 27, 2015.

know error system®. Be DNA certainTM [Website]. Strand DiagnosticsTM LLC; Indianapolis, IN. Available at: http://knowerror.com/. Accessed on July 22, 2016.

Layfield LJ, Anderson GM.(2010) Specimen labeling errors in surgical pathology: an 18-month experience. Am J Clin Pathol 2010; 134(3):466-70.

Lippi G, Blanckaert N, Bonini P et al.(2009) Causes, consequences, detection and prevention of identification errors in laboratory diagnostics. Clin Chem Lab Med 2009; 47(2):143-53.

Marberger M, McConnell JD, Fowler I, et al.(2011) Biopsy misidentification identified by DNA profiling in a large multicenter trial. J Clin Oncol. 2011; 29(13):1744-1749.

National Library of Medicine (NLM).(2016) Genetic Home Reference. July 22, 2016. . Available at: http://ghr.nlm.nih.gov/. Accessed on July 22, 2016.

Pfeifer JD, Liu J.(2013) Rate of occult specimen provenance complications in routine clinical practice. Am J Clin Pathol. 2013; 139:93-100.

Pfeifer JD, Liu J.(2013) Rate of occult specimen provenance complications in routine clinical practice. Am J Clin Pathol. 2013; 139:93-100.

Pfeifer JD, Singleton MN, Gregory MH, et al.(2012) Development of a decision-analytic model for the application of STR-based provenance testing of transrectal prostate biopsy specimens. Value Health. Sep-Oct 2012;15(6):860-867. PMID 22999136

Pfeifer JD, Zehnbauer B, Payton J.(2011) The changing spectrum of DNA-based specimen provenance testing in surgical pathology. Am J Clin Pathol. 2011; 135:132-138.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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