Medical Policy

This document addresses the clinical validity and utility of deoxyribonucleic acid (DNA) verification tests intended to validate the identity of laboratory specimens following collection. In particular, the know error^® DNA Specimen Provenance Assay (DSPA; Strand Diagnostics, LLC; Indianapolis, IN), is designed to confirm the identity of a biopsy specimen, the ToxProtect^™  DNA-verified Urine Drug Test (UDT) (Genotox Laboratories, Austin, TX) is used to verify the identity of urine specimens for drug screening, and other tests that analyze genetic material to identify specimens. (Note: confirmation of specimen identification is a laboratory quality control issue.)

Not Medically Necessary:

Genetic testing to confirm the identity of a laboratory specimen (for example, know error DNA Specimen Provenance Assay [DSPA] or ToxProtect) is considered not medically necessary.

The body of evidence regarding the analytical validity, clinical validity, and clinical utility of short tandem repeat (STR) analysis using tests such as the know error DSPA system and the ToxProtect^™  DNA-verified UDT is sparse and of low quality. There are a few retrospective and prospective case series that evaluated STR analysis for the purpose of biopsy 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 or the ToxProtect. Therefore, the medical necessity of these tests during the collection and analysis of laboratory specimens, and their role to confirm an individual’s identity, and reduce or eliminate diagnostic errors has not been established. Confirmation of specimen identification is generally considered a laboratory quality control issue.

According to the American Cancer Society (ACS), an estimated 1.8 million Americans will be diagnosed with some form of cancer in 2020. 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.

Genetic marker: A DNA sequence with a known physical location on a chromosome.

Histopathology: Microscopic examination of tissue in order to study the signs and characteristics of disease.

Polymerase chain reaction (PCR): A method to analyze a short DNA or RNA sequence to reproduce or amplify selections of this sequence.

Polymorphic genetic marker: Inherited characteristic that occurs within a given population as two or more traits.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as not medically necessary.

Peer Reviewed Publications:

1. Marberger M, McConnell JD, Fowler I, et al. Biopsy misidentification identified by DNA profiling in a large multicenter trial. J Clin Oncol. 2011; 29(13):1744-1749.
2. Pfeifer JD, Liu J. Rate of occult specimen provenance complications in routine clinical practice. Am J Clin Pathol. 2013; 139(1):93-100.
3. Pfeifer JD. Clinical next generation sequencing in cancer. Cancer Genet. 2013; 206(12):409-412.
4. Pfeifer JD, Zehnbauer B, Payton J. The changing spectrum of DNA-based specimen provenance testing in surgical pathology. Am J Clin Pathol. 2011; 135(1):132-138.

Government Agency, Medical Society, and Other Authoritative Publications:

1. National Library of Medicine (NLM). Genetic Home Reference. March 31, 2020. Available at: http://ghr.nlm.nih.gov/. Accessed on April 1, 2020.

1. American Cancer Society (ACS). Cancer facts & figures. 2020. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html. Accessed on March 26, 2020.
2. Know error system®. Be DNA certain™ [Website]. Strand Diagnostics™ LLC; Indianapolis, IN. Updated 2019. Available at: https://stranddiagnostics.com. Accessed on March 26, 2020.

know error DNA Specimen Provenance Assay (DSPA)
ToxProtect  DNA-verified Urine Drug Test (UDT)

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Federal and State law, as well as contract language, including definitions and specific contract provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The member’s contract benefits in effect on the date that services are rendered must be used. Medical Policy, which addresses medical efficacy, should be considered before utilizing medical opinion in adjudication. Medical technology is constantly evolving, and we reserve the right to review and update Medical Policy periodically.

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