BlueCross and BlueShield of Montana Medical Policy/Codes
DNA-Based Testing for Adolescent Idiopathic Scoliosis
Chapter: Medicine: Tests
Current Effective Date: July 18, 2013
Original Effective Date: August 01, 2012
Publish Date: July 18, 2013
Revised Dates: October 22, 2012; April 8, 2013
Description

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, affecting 1% to 3% of adolescents. (1) This disease, of unknown etiology, occurs in otherwise healthy children with the onset of and highly correlated with, the adolescent growth spurt. The vertebrae become misaligned such that the spine deviates from the midline laterally and becomes rotated axially. Deviation can occur anteriorly (a lordotic deviation) or posteriorly (a kyphotic deviation). Although AIS affects females and males in a nearly 1:1 ratio, progression to severe deformity occurs more often in females. Because the disease can have rapid onset and produce considerable morbidity, school screenings have been recommended. However, screening remains somewhat controversial, with conflicting guidelines supporting this practice or alternatively suggesting insufficient evidence for this.

Diagnosis is established by radiologic observation in adolescents (age 10 years until the age of skeletal maturity) of a lateral spine curvature of 10 degrees or more as measured using the Cobb angle. (2) The Cobb angle is defined as the angulation measured between the maximally tilted proximal and distal vertebrae of the curve. Curvature is considered mild (less than 25º), moderate (25º to 40º), or severe (more than 40º) in an individual still growing. Once diagnosed, patients must be monitored over several years, usually with serial radiographs for curve progression. If the curve progresses, spinal bracing is the generally accepted first-line treatment. If the curve progresses in spite of bracing, spinal fusion may be recommended.

Curve progression has been linked to a number of factors, including sex, curve magnitude, patient age, and skeletal maturity. Risk tables have been published by Lonstein and Carlson (3) and Peterson and Nachemson (4) to help in triage and treatment decision making about patients with AIS. Tan et al. (5) have recently compared a broad array of factors and concluded that using 30 degrees as an endpoint, initial Cobb angle magnitude produces the best prediction of progression outcome.

The familial nature of this disease was noted as early as 1968. (6) About one quarter of patients report a positive family history of disease, and twin studies have consistently supported shared genetic factors. (1) Genome-wide linkage studies have reported multiple chromosomal regions of interest, often not replicated. Ogilvie has recently suggested AIS is a complex polygenic trait. (7) He and colleagues at Axial Diagnostics have published a study evaluating an algorithm using 53 SNP (single nucleotide polymorphisms) markers identified from unpublished genome-wide association studies (GWAS) to identify patients unlikely to exhibit severe progression in curvature versus those at considerable risk for severe progression. The clinical validity of this assay has recently been reported in a retrospective case control cohort study using this algorithm. (2)

The ScoliScore™ AIS prognostic DNA-based test (Axial Biotech, Salt Lake City, UT) is a saliva-based genetic test designed to predict the risk of progression of scoliosis in patients with AIS. The test uses an algorithm incorporating results of testing for 53 SNPs, along with the patient’s presenting spinal curve (Cobb angle) to generate a risk score (ranging from 1 to 200), which can be used qualitatively or quantitatively to predict the likelihood of spinal curve progression. The test is intended for white (Caucasian) patients with a primary diagnosis of AIS between the ages of 9 and 13 years-old with a mild scoliotic curve (defined as <25º).

Regulatory Status

The ScoliScore™ AIS prognostic DNA-based test has not been approved or cleared by the U.S Food and Drug Administration (FDA) but is being offered as a laboratory-developed test. The laboratory performing this test is accredited by the Centers for Medicare and Medicaid (CMS) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

The FDA has indicated an interest in changing its policy for use of enforcement discretion in the oversight of laboratory-developed tests, but the status of this proposed change in policy and the impact of any particular laboratory-developed test are currently unknown.

Policy

Investigational

Blue Cross Blue Shield of Montana (BCBSMT) considers DNA-based prognostic testing for adolescent idiopathic scoliosis experimental, investigational and unproven.

Federal Mandate

Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. BCBSMT recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Rationale

Introduction

Validation of genotyping to improve treatment outcomes is a multistep process. In general, important steps in the validation process address the following:

  • Analytic validity: measures technical performance, i.e., whether the test accurately and reproducibly detects the gene markers of interest.
  • Clinical validity: measures the strength of the associations between the selected genetic markers and clinical status.
  • Clinical utility: determines whether the use of genotyping for specific genetic markers to guide treatment decisions improves patient outcomes such as survival or adverse event rate compared to standard treatment without.

Literature Review

Analytical validity: There are no published reports on analytical performance of this test. It is offered by a CLIA-accredited laboratory and requirements for analytical performance and quality control are components of this process.

Clinical validity: Ward et al. (2) have recently described a company-sponsored clinical validation study of a DNA-based prognostic test to predict spinal curve progression in adolescent idiopathic scoliosis (AIS). This test involves use of a proprietary algorithm to integrate information from 53 single nucleotide polymorphisms (SNPs) identified as exhibiting an association with AIS in a case-controlled genome-wide association studies (GWAS) study of 2,750 patients. The GWAS was used to develop a 1 to 200 scoring system. A cut-point of 40 or less was selected during the GWAS to identify patients at low risk (less than 1%) of developing severe curvatures requiring surgical intervention. Following generation of data, an analysis of patients with scores of 190 or greater was performed to determine risk for developing severe curves.

Clinical validation of this test (2) was performed in a retrospective analysis of cases preselected by curvature severity (mild, moderate, or severe) and assigned into 3 cohorts identified as: 1) a screening cohort of white females; 2) a spinal surgery practice cohort of white females; and 3) a male cohort. Inclusion/exclusion criteria were cited as being used, but not explicitly provided, although a component of cohort development was matching of prevalence of disease by severity according to that expected from review of the literature or survey of clinical practices. There is minimal information provided about the demographics of patients assigned to each cohort.

Assignment of curvature severity was performed using expert opinion of a single orthopedic spine surgeon and was supplemented by external blinded review of the spinal surgery practice patients using an outside panel of 3 independent scoliosis experts.

The screening cohort was composed of patients (n=176) recruited to ensure 85% exhibited mild or improved curves, 12% moderate curve progression, and 3% severe curve progression. Using a risk score cut-off of 41 or less, the predictive value of a negative test (defined as identification of patients without severe curve progression) was 100% (95% confidence intervals [CI]: 98.6 to100%). No analysis was performed to demonstrate whether this was a statistically significant improvement in prediction of negatives, given the low initial prevalence of patients expected to exhibit severe progression.

The spine surgery practice cohort was composed of patients (n=133) recruited to ensure 68% exhibited mild or improved curves, 21% moderate curve progression, and 11% severe curve progression. Using the risk score cut-off of 41 or less, the predictive value of a negative test (defined as identification of patients without severe curve progression) was 99% (95% CI: 95.4 to 99.6%). No analysis was performed to demonstrate whether this was a statistically significant improvement in prediction of negatives.

In the male cohort (n=163), the prevalence of patients with progression to severe curvature is 11% before testing. The negative predictive value after testing was 97% (95% CI: 93.3 to 99%).

Although there is a description of positive predictive value in patients exhibiting high risk score values, recruitment of patients into this category appears to be derived from patients pooled from different and undescribed sources making interpretation difficult.

A subsequent GWAS evaluating 327,000 SNPs in 419 families with AIS (8) failed to duplicate the associations reported in the study by Ward et al (2).

Clinical utility: No studies have been performed examining the impact of testing on health care outcomes.

Current practice includes careful follow-up of patients. Those with progressive disease are frequently treated with bracing, or in severe cases, with surgical intervention. Careful follow-up and treatment of patients with scoliosis would be expected to have an impact on the gold standard endpoint being used to evaluate this test in this study—severe curvature. Test-induced changes in outcome will provide insight into the clinical utility of the test. Because treatment outcome is used as the endpoint of interest in characterizing the test, changes in outcome may also produce changes in the test’s clinical validity.

Summary

Idiopathic adolescent scoliosis is a disease of unknown etiology that causes mild to severe spinal deformity in approximately 1 to 3% of adolescents. While there is controversy about the value of both screening and treatment, patients once diagnosed are frequently closely followed. In cases with significant progression of curvature, both medical (bracing) and surgical (spinal fusion) interventions are considered. Classification tables for likelihood of progressive disease have been constructed to assist in managing patients, but these have not proven to be highly reliable and the impact of their use on outcomes is unknown.

Investigators affiliated with Axial Biotec have recently reported on use of a test based on an algorithm incorporating results of 53 SNPs along with the Cobb angle to predict progression of scoliosis. Preliminary clinical validity results for the ScoliScore™ AIS prognostic DNA-based test are available, indicating a high negative predictive value and an uncertain positive predictive value. A single study has been published reporting a high negative predictive value in ruling out the possibility of progression to severe curvature, in a population with a low baseline likelihood of progression. It is not clear if the increase in certainty provided by testing is statistically or clinically meaningful. Furthermore, a similar recently published GWAS study has failed to identify overlapping SNPs for identification of disease progression (prognosis).

The clinical utility of the test remains unknown. There is no direct evidence demonstrating that use of this test results in changes in management that improve outcomes. The value of early identification and intervention(s) for individuals at risk for progression of disease is unclear. As a result, DNA-based testing for AIS is considered experimental, investigational and unproven until results of further research on both clinical validity and utility have been reported.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

Rationale for Benefit Administration
 
ICD-9 Codes

Experimental, investigational and unproven for all codes

ICD-10 Codes

Experimental, investigational and unproven for all codes.  M41.122-M41.129

Procedural Codes: 83891, 83898, 83903, 83912
References
  1. Weinstein SL, Dolan LA, Cheng JC et al. Adolescent idiopathic scoliosis. Lancet 2008; 371(9623):1527-37.
  2. Ward K, Ogilvie JW, Singleton MV et al. Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976) 2010; 35(25):E1455-64.
  3. Lonstein JE, Carlson JM. The prediction of curve progression in untreated idiopathic scoliosis during growth. J Bone Joint Surg Am 1984; 66(7):1061-71.
  4. Peterson LE, Nachemson AL. Prediction of progression of the curve in girls who have adolescent idiopathic scoliosis of moderate severity. Logistic regression analysis based on data from The Brace Study of the Scoliosis Research Society. J Bone Joint Surg Am 1995; 77(6):823-7.
  5. Tan KJ, Moe MM, Vaithinathan R et al. Curve progression in idiopathic scoliosis: follow-up study to skeletal maturity. Spine (Phila Pa 1976) 2009; 34(7):697-700.
  6. Wynne-Davies R. Familial (idiopathic) scoliosis. A family survey. J Bone Joint Surg Br 1968; 50(1):24-30.
  7. Ogilvie J. Adolescent idiopathic scoliosis and genetic testing. Curr Opin Pediatr 2010; 22(1):67-70.
  8. Sharma S, Gao X, Londono D et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet 2011; 20(7):1456-66.
  9. DNA-Based Testing for Adolescent Idiopathic Scoliosis. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (August 2011) Medicine 2.04.74.
History
March 2012  New policy for BCBSMT: Policy created with literature search through June 2011; considered investigational; Non-specific CPT codes.
October 2012 Policy updated with literature review and results of clinical vetting, reference 9 added. No change to policy statement.
April 2013 Policy language and formatting revised.  Policy statement unchanged.  Removed codes 83891, 83898, 83903, 83912.
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DNA-Based Testing for Adolescent Idiopathic Scoliosis