CAM 20474

Genetic Testing for Adolescent Idiopathic Scoliosis

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:June 2013    

Description
Adolescent idiopathic scoliosis (AIS) 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. The ScoliScore AIS prognostic DNA-based test (Transgenomic, Omaha, NE) uses an algorithm incorporating results of testing for 53 single-nucleotide polymorphisms (SNPs), along with the patient’s presenting spinal curve (Cobb angle), to generate a risk score (range, 1-200), which can be used qualitatively or quantitatively to predict the likelihood of spinal curve progression. 

For use of single-nucleotide polymorphism (SNP)‒based testing in the management of patients with existing AIS, the evidence consists of a number of cross-sectional studies reporting on the clinical validity of the ScoliScore test, along with cross-sectional studies reporting on the association with SNPs in various genes and scoliosis progression. Preliminary clinical validity results for the ScoliScoreAIS prognostic DNA-based test indicate a high negative predictive value and an uncertain positive predictive value. A single study has been published reporting a high negative predictive value for 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 predictive accuracy provided by testing is statistically or clinically meaningful. Other genetic studies have not demonstrated significant associations between the SNPs used in the ScoliScore and scoliosis progression. Studies have identified additional SNPs that may be associated with AIS severity, but these associations have not been reliably replicated. The clinical validity of DNA-based testing (either through testing of individual SNPs or through an algorithm incorporating SNP results) for predicting scoliosis progression disorder in patients with AIS condition has not been established because studies of the association of DNA-based testing and scoliosis progression have had mixed findings. 

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 people at risk for progression of disease is unclear. Therefore, the evidence is insufficient to permit conclusions about the clinical utility of DNA-based predictive testing for scoliosis.

Background
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 is 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), posteriorly (a kyphotic deviation) or laterally. 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 an insufficiency of 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 10º 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 (<25º), moderate (25º--40º) or severe (>40º) in a patient 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 Carlson3 and Peterson and Nachemson4 to help in triage and treatment decision making about patients with AIS. Tan et al.5 recently compared a broad array of factors and concluded that using 30º as an end point, 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 Ogilvie et al. at Axial Diagnostics published a study evaluating an algorithm using 53 single-nucleotide polymorphism (SNP) markers identified from unpublished genome-wide association studies 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 (Transgenomic, Omaha, NE), which 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 (range, 1-200), can be used qualitatively or quantitatively to predict the likelihood of spinal curve progression. The test is intended for white (Caucasian) patients, aged 9 to 13 years, with a primary diagnosis of AIS with a mild scoliotic curve (defined as <25º).

Regulatory Status:
The ScoliScore AIS (adolescent idiopathic scoliosis) prognostic DNA-based test (Axial Biotech, Salt Lake City, Utah) 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 & Medicaid Services (CMS) under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).

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.

Related Policies
20183 Interventions for Progressive Scoliosis

Policy:
DNA-based prognostic testing for adolescent idiopathic scoliosis is considered INVESTIGATIONAL.  

Policy Guidelines
The ScoliScore AIS (adolescent idiopathic scoliosis) prognostic DNA-based test (Axial Biotech, Salt Lake City, UT) has a specific CPT code:  

0004M Scoliosis, DNA analysis of 53 single nucleotide polymorphisms (SNPs), using saliva, prognostic algorithm reported as a risk score 

Benefit Application:
BlueCard®/National Account Issues
There are no specific CPT codes for ScoliScore analysis. However, these pathology tests are commercially available only at a single reference laboratory, Axial Biotech (Salt Lake City, Utah). The sputum specimen is mailed to Axial Biotech for analysis.

Rationale
CLINICAL CONTEXT AND TEST PURPOSE
The purpose of the ScoliScore AIS prognostic DNA-based test and other individual single-nucleotide variant (SNV)-based tests for scoliosis prognosis is primarily to determine whether patients with scoliosis are at higher likelihood for curve progression. Such patients could undergo more frequent surveillance than they would without testing. The current standard for management of patients with scoliosis that is not severe enough to undergo bracing or surgery is observation with routine radiographic or clinical follow-up. 

The evaluation of a prognostic genetic test 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 (prognostic performance of the test [sensitivity, specificity, positive and negative predictive values] in predicting course of clinical disease); and (3) clinical utility (i.e., a demonstration that the prognostic information can be used to improve patient health outcomes).

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with a diagnosis of adolescent idiopathic scoliosis (AIS) that is not yet severe enough to require bracing or surgery.

Intervention
The intervention of interest is testing for SNVs, including testing with the specific ScoliScore AIS prognostic test, which uses multiple SNVs along with the Cobb angle in an algorithm.

Comparator
The following practices are currently being used to make decisions about follow-up for patients with AIS that is not severe enough to require bracing or surgery: routine radiographic or clinical follow-up, at an interval that is generally determined by the individual patient and physician in shared decision making. The test is an adjunct to existing clinical information and test results.

Outcomes
The general outcomes of interest are change in disease severity (i.e., progression in scoliosis curve), morbid events (i.e., development of severe scoliosis, which is generally considered to be a Cobb angle >40°) or symptoms of back pain.

Beneficial outcomes resulting from a true test result, if a true test result is followed by earlier detection of scoliosis by either clinical or radiologic testing, would be earlier detection and treatment of scoliosis. Potential harms from the test include those from a false positive or a false negative: false-positive results could lead to increased clinical or radiologic surveillance, while false-negative tests could lead to premature stopping of surveillance.

Time
The relevant follow-up period depends on the timing of presentation relative to cessation of growth; however, it is generally over the course of 2 to 3 years.

Setting
Outpatient.

ANALYTICAL VALIDITY
Analytic validity is the ability of a test to accurately and reliably measure the marker of interest. Measures of analytic validity include sensitivity (detection rate), specificity, reliability (repeatability of test results) and assay robustness (resistance to small changes in preanalytic or analytic variables).

No published reports on analytic performance of the ScoliScore test were identified. It is offered by a Clinical Laboratory Improvement Amendments (CLIA)‒accredited laboratory and requirements for analytic performance and quality control are components of the CLIA accreditation process.

CLINICAL VALIDITY
Study Selection Criteria
For the evaluation of clinical validity of the ScoliScore and other SNV-related testing for scoliosis progression, studies that meet the following eligibility criteria were considered:

  • Reported on the accuracy of the marketed version of the ScoliScore test OR describes the specific SNVs measured;
  • Patient/sample clinical characteristics were described;
  • Patient/sample selection criteria were described.

Clinical Validity of ScoliScore SNV-Based Testing
The development of the ScoliScore algorithm is discussed briefly in the Background section (Ward et al., 2010).

In 2010, Ward et al. described the validation of the ScoliScore algorithm in a group of patients who had a diagnosis of AIS but who had not been previously involved in any AIS/genotype-related studies.2 These subjects were preselected by curvature severity (mild, moderate, 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 disease prevalence by severity according to that expected from review of the literature or survey of clinical practices. Ward provided minimal information 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 277 patients recruited to ensure 85% exhibited mild or improved curves, 12% moderate curve progression and 3% severe curve progression. Using a risk score cutoff of 41 or less, the predictive value of a negative test (defined as identification of patients without severe curve progression) was 100% (95% confidence interval [CI], 98.6% to 100%). 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 257 patients recruited to ensure 68% exhibited mild or improved curves, 21% moderate curve progression and 11% severe curve progression. Using the risk score cutoff 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 was 11% before testing. The negative predictive value (NPV) after testing was 97% (95% CI, 93.3% to 99%). 

Although there is a description of positive predictive value calculations using a risk score cutoff of 190 or more, recruitment of patients into this category appears to have been derived from patients pooled from different and undescribed sources, making interpretation difficult. 

In 2015, Roye et al. reported on an independent validation of the ScoliScore algorithm in a sample of 126 patients with AIS who were enrolled at 2 centers using a retrospective cohort design.9 Eligible patients had AIS with an initial Cobb angle of 10° to 25° and were white with skeletal immaturity. ScoliScore results were provided as continuous and categoric variables; categories were low (1-50 points), intermediate (51-179 points) or high (180-200 points) risk for progression. Outcomes were defined as progression (curve progression to >40° or requirement for spinal fusion) or nonprogression (reached skeletal maturity without curve progression >40°). The mean ScoliScore overall was 103 (SD=60). In unadjusted analysis, the continuous ScoliScore value was not significantly associated with curve progression (odds ratio [OR], 0.999; 95% CI, 0.991 to 1.006; p=0.664). The proportion of patients with curve progression did not differ significantly by ScoliScore risk group. The ScoliScore test PPV and NPV were 0.27 (95% CI, 0.09 to 0.55) and 0.87 (95% CI, 0.69 to 0.96), respectively.

In 2012, Roye et al. reported retrospective results for 91 patients evaluated using ScoliScore.10 Although they noted a positive correlation between Cobb angle and ScoliScore results (r=0.581, p<0.001), ScoliScore appeared to be providing information very different from that observed using a standard risk score, with a marked increase in low-risk patients and a decrease in high-risk patients. However, no clinical end points were examined in association with classification results, and so interpretation of results observed remains unclear.

In 2016, Bohl et al. reported results from a small retrospective cohort study comparing ScoliScore results among patients with AIS undergoing bracing whose scoliosis progressed to those undergoing bracing who did not have progression.11 Authors contacted 25 patients with AIS treated at a single institution who underwent night-time bracing; 16 subjects provided saliva samples to allow ScoliScore testing. Authors reported that the 8 patients whose curves progressed to greater than 45º had a higher mean ScoliScore than those whose curves did not progress (176 vs. 112, respectively; p=0.03). No patient with a ScoliScore below 135 progressed to greater than 45º. The interpretation of these results is unclear due to the study’s small size and potential for selective response bias.

Studies Using SNV Subsets From ScoliScore
Some studies have evaluated subsets of the SNVs used in the ScoliScore algorithm. Tang et al. (2015)12 evaluated the association between 25 of the 53 SNVs used in the Ward et al. study (previously described), along with 27 additional SNVs in high linkage disequilibrium with the other SNVs, and severe scoliosis in a case-control study involving 476 AIS patients of French-Canadian background. None of the SNVs was significantly associated with scoliosis severity.

The ScoliScore algorithm was developed and validated in a sample of white patients. Other studies have evaluated the association of specific SNVs from the algorithm in nonwhite populations.

In 2015, Xu et al. reported on the association between the 53 SNVs in the ScoliScore panel with scoliosis in a retrospective case-control study of 990 female Han Chinese patients with AIS and 1,188 age-matched healthy controls.13 At 4 loci, patients with AIS differed from controls: they had had higher frequency of alleles G at rs12618119 (46.5% vs. 40.2%, OR=1.29; 95% CI, 1.15 to 1.46; p<0.001) and A at rs9945359 (22.6% vs. 18.4%; OR=1.29; 95% CI, 1.12 to 1.50; p<0.001), and lower frequency of alleles T at rs4661748 (15.6% vs. 19.4%; OR=0.77, 95% CI, 0.66 to 0.90; p<0.001) and C at rs4782809 (42.4% vs. 47.4%; OR=0.82, 95% CI, 0.72 to 0.92; p<0.001).

In 2016, Xu et al. reported on the association between the 53 SNVs in the ScoliScore panel with scoliosis progression in a retrospective case-control study of 670 female Han Chinese patients with AIS.14 Patients were identified from a set of patients who visited trialists’ scoliosis center for a time period that overlapped with that for the patients in the 2015 Xu study, but it is not specified whether the data overlap. Of the 670 patients, 313 were assigned to the nonprogression group (defined as a Cobb angle <25° at final follow-up) and 357 were assigned to the progression group (defined as a Cobb angle of >40° at final follow-up). The overall follow-up duration was not specified. At 2 loci, allele frequencies differed between groups: the progression group had a significantly higher frequency of allele A at rs9945359 (25.7% vs. 19.5%; OR=1.42; 95% CI, 1.09 to 1.88; p=0.01) and a significantly lower frequency of allele A at rs17044552 (11.5% vs. 16.4%; OR=0.65; 95% CI, 0.47 to 0.91; p=0.01).

There was no association between the 53 SNVs in the ScoliScore panel and curve progression in an earlier study of 2,117 Japanese patients with AIS.15

Clinical Validity of Other SNV Associations With Scoliosis Prognosis
In addition to studies evaluating the clinical validity of the ScoliScore algorithm specifically, other studies have reported results for associations between SNVs and scoliosis progression. 

In 2015, Noshchenko et al. reported on a systematic review and meta-analysis of predictors of progression in AIS, which included studies evaluating the association between ScoliScore and SNVs and curve progression.16 In total, reviewers included 25 studies, across a range of physiologic measures. Reviewers selected 2 studies that evaluated ScoliScore: Ward et al. (2010)2 and Bohl et al. (2016).11 Pooled results were presented; however, given the differences in intervention in the studies (Bohl et al. evaluated response to bracing), the results are more appropriately considered as individual studies, which are described above in the Clinical Validity of ScoliScore SNV-Based Testing section. Studies evaluating 6 additional SNVs in multiple genes, including CALM1, ER1, TPH1, IGF1, NTF3, IL17RC and MTNR1B, (N=7 studies) were included. The level of evidence based on GRADE for the studies was considered very low or low. Estimates for the pooled odds ratios for the association of the variant with the outcome ranged from 1.5 to 3.3. Reviewers concluded that "the levels of association were relatively low with small predictive capacity. All these findings have very low level of evidence due to the limitations of the studies’ design and the fact that only one study reported each finding."

Sharma et al. (2011) reported genome-wide association study results evaluating 327,000 SNVs in 419 families with AIS that found 3 loci significantly associated with scoliosis progression, which did not include any of the 53 SNVs included in the Ward et al. study previously described.17

In 2013, Fendri et al. reported results from a case-control study 6 AIS patients and 6 non-AIS controls evaluating differential gene expression profiling in AIS.18 Gene expression profiles from primary osteoblasts derived from spinal vertebrae of AIS patients (n=6) were compared with profiles from the same cells collected from age- and sex-matched previously healthy patients who underwent spinal surgery for trauma (n=6). One hundred forty-five genes displayed significant expression changes in AIS osteoblasts compared with non-AIS osteoblasts. After hierarchical clustering gene ontology analysis, the authors identified 5 groups based on molecular function and biologic process that fell into 4 pathways: developmental/growth differentiation of skeletal elements (i.e., HOXB8, HOXB2, MEOX2, PITX1), cellular signaling (i.e., HOXA11, BARX1), connecting structural integrity of the extracellular matrix to the structural integrity of a bone or a muscle fiber (i.e., COMP, HOXA2, HOXA11) and cellular signaling and cartilage damage (GDF15).

Studies have also associated variants in the promoter regions of tissue inhibitor of metalloproteinase-2 and neurotrophin 3 with AIS severity in Chinese populations.19,20 Replication of these genetic associations is needed.

Section Summary: Clinical Validity
Four retrospective case-control studies have reported on the clinical validity of the marketed ScoliScore test; 2 of them permitted a determination of the association of the test with curve progression, and they have conflicting results and are limited by their retrospective designs. A number of additional studies have reported on the association between scoliosis progression or presence and various other SNVs, with inconsistent results. The evidence is insufficient to draw conclusions on clinical validity.

CLINICAL UTILITY
No studies examining the impact of DNA-based predictive testing for scoliosis on health outcomes were identified. The value of early identification and intervention(s) for people at risk for progression of disease and whether laboratory testing improves disease identification beyond clinical evaluation are unknown. It is not possible to construct a chain of evidence for clinical utility due to the lack of clinical validity.

SUMMARY OF EVIDENCE
For individuals with adolescent idiopathic scoliosis (AIS) who receive clinical management with prognostic testing with an algorithm incorporating single-nucleotide variant (SNV)based testing, the evidence includes cross-sectional studies reporting on the clinical validity of the ScoliScore test, along with cross-sectional studies reporting on the association between SNVs in various genes and scoliosis progression. Relevant outcomes are symptoms, morbid events and change in disease status. A single study on the clinical validity for the ScoliScore AIS prognostic DNA-based test has reported a high negative predictive value for 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 predictive accuracy provided by testing is statistically or clinically meaningful. Other genetic studies have not demonstrated significant associations between the SNVs used in the ScoliScore and scoliosis progression. Studies have identified additional SNVs that may be associated with AIS severity, but these associations have not been reliably replicated. The clinical validity of DNA-based testing (either through testing of individual SNVs or through an algorithm incorporating SNV results) for predicting scoliosis progression in patients with AIS has not been established. 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 people at risk for progression of disease and whether laboratory testing improves disease identification beyond clinical evaluation is unknown. The evidence is insufficient to determine the effects of the technology on health outcomes. 

CLINICAL INPUT FROM PHYSICIAN SPECIALTY SOCIETIES AND ACADEMIC MEDICAL CENTERS
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 specialty societies and 4 academic medical centers while this policy was under review in 2012. All agreed with this policy and indicated that DNA-based prognostic testing for adolescent idiopathic scoliosis (ScoliScore) should be considered investigational.

PRACTICE GUIDELINES AND POSITION STATEMENTS
In 2011, the Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment issued guidelines on the conservative treatment of idiopathic scoliosis.21 These guidelines did not address the role of DNA-based prognostic testing.  

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
In 2004, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine screening of asymptomatic adolescents for idiopathic scoliosis (grade D recommendation).22 No USPSTF recommendations for DNA-based testing for adolescent idiopathic scoliosis were identified.  

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT No. Trial Name Planned Enrollment Completion Date

Ongoing

NCT01776125

Genetic Evaluation for the Scoliosis Gene(s) in Patients With Neurofibromatosis 1 and Scoliosis

100 Aug 2015 (completed)

NCT: national clinical trial. 

References  

  1. Weinstein SL, Dolan LA, Cheng JC, et al. Adolescent idiopathic scoliosis. Lancet. May 3 2008;371(9623):1527-1537. PMID 18456103
  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). Dec 1 2010;35(25):E1455-1464. PMID 21102273
  3. Lonstein JE, Carlson JM. The prediction of curve progression in untreated idiopathic scoliosis during growth. J Bone Joint Surg Am. Sep 1984;66(7):1061-1071. PMID 6480635
  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. Jun 1995;77(6):823-827. PMID 7782354
  5. Tan KJ, Moe MM, Vaithinathan R, et al. Curve progression in idiopathic scoliosis: follow-up study to skeletal maturity. Spine (Phila Pa 1976). Apr 1 2009;34(7):697-700. PMID 19333102
  6. Wynne-Davies R. Familial (idiopathic) scoliosis. A family survey. J Bone Joint Surg Br. Feb 1968;50(1):24-30. PMID 5641594
  7. Ogilvie J. Adolescent idiopathic scoliosis and genetic testing. Curr Opin Pediatr. Feb 2010;22(1):67-70. PMID 19949338
  8. Transgenomic. transgenomic.com. Accessed December, 2016. 
  9. Roye BD, Wright ML, Matsumoto H, et al. An independent evaluation of the validity of a DNA-based prognostic test for adolescent idiopathic scoliosis. J Bone Joint Surg Am. Dec 16 2015;97(24):1994-1998. PMID 26677232
  10. Roye BD, Wright ML, Williams BA, et al. Does ScoliScore provide more information than traditional clinical estimates of curve progression? Spine (Phila Pa 1976). Dec 1 2012;37(25):2099-2103. PMID 22614798
  11. Bohl DD, Telles CJ, Ruiz FK, et al. A genetic test predicts providence brace success for adolescent idiopathic scoliosis when failure is defined as progression to >45 degrees. Clin Spine Surg. Apr 2016;29(3):E146-150. PMID 27007790
  12. Tang QL, Julien C, Eveleigh R, et al. A replication study for association of 53 single nucleotide polymorphisms in ScoliScore test with adolescent idiopathic scoliosis in French-Canadian population. Spine (Phila Pa 1976). Apr 15 2015;40(8):537-543. PMID 25646748
  13. Xu L, Huang S, Qin X, et al. Investigation of the 53 markers in a DNA-based prognostic test revealing new predisposition genes for adolescent idiopathic scoliosis. Spine (Phila Pa 1976). Jul 15 2015;40(14):1086-1091. PMID 25811265
  14. Xu L, Qin X, Sun W, et al. Replication of association between 53 single-nucleotide polymorphisms in a DNA-based diagnostic test and AIS progression in Chinese Han population. Spine (Phila Pa 1976). Feb 2016;41(4):306-310. PMID 26579958
  15. Ogura Y, Takahashi Y, Kou I, et al. A replication study for association of 53 single nucleotide polymorphisms in a scoliosis prognostic test with progression of adolescent idiopathic scoliosis in Japanese. Spine (Phila Pa 1976). Apr 15 2013. PMID 23591653
  16. Noshchenko A, Hoffecker L, Lindley EM, et al. Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with meta-analysis. World J Orthop. Aug 18 2015;6(7):537-558. PMID 26301183
  17. Sharma S, Gao X, Londono D, et al. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes. Hum Mol Genet. Apr 1 2011;20(7):1456-1466. PMID 21216876
  18. Fendri K, Patten SA, Kaufman GN, et al. Microarray expression profiling identifies genes with altered expression in Adolescent Idiopathic Scoliosis. Eur Spine J. Jun 2013;22(6):1300-1311. PMID 23467837
  19. Jiang J, Qian B, Mao S, et al. A promoter polymorphism of tissue inhibitor of metalloproteinase-2 gene is associated with severity of thoracic adolescent idiopathic scoliosis. Spine (Phila Pa 1976). Jan 1 2012;37(1):41-47. PMID 21228746
  20. Qiu Y, Mao SH, Qian BP, et al. A promoter polymorphism of neurotrophin 3 gene is associated with curve severity and bracing effectiveness in adolescent idiopathic scoliosis. Spine (Phila Pa 1976). Jan 15 2012;37(2):127-133. PMID 22158057
  21. Negrini S, Aulisa AG, Aulisa L, et al. 2011 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis. 2012;7(1):3. PMID 22264320
  22. U.S. Preventive Services Task Force (USPSTF). Screening for Idiopathic Scoliosis in Adolescents. 2004; http://www.uspreventiveservicestaskforce.org/uspstf/uspsaisc.htm. Accessed December 29, 2016. 

Coding Section 

Codes Number Description
CPT 0004M Scoliosis, DNA analysis of 53 single nucleotide polymorphisms (SNPs), using saliva, prognostic algorithm reported as a risk score
ICD-9-CM Diagnosis   Investigational for all diagnoses
ICD-10-CM (effective 10/01/15)   Investigational for all diagnoses
  M41.122-M41.129 Adolescent scoliosis code range
ICD-10-PCS (effective 10/01/15)   Not applicable. There are no ICD-10-PCS procedure codes for laboratory tests.
Type of Service     
Place of Service     

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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/12/2019 

Annual review, no change to policy intent. 

07/18/2018 

Annual review, updating title to better reflect testing in policy. New title removes "DNA-Based testing" and is replaced with Genetic Testing". No other changes made. 

07/28/2017 

Annual review, no change to policy intent. Update rationale and references. 

04/25/2017 

Updated category to Laboratory. No other changes 

06/01/2016 

Annual review, no change to policy intent. Updating background, description, guidelines, rationale, references and coding section. 

06/17/2015 

Annual review, no change to policy intent. Updated rationale and references. Added coding. 

06/05/2014

Annual review. Added related policies, updated rationale and references. No change to policy intent. 


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