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Adolescent Idiopathic Scoliosis

Update on Prognostic Genetic Testing in Adolescent Idiopathic Scoliosis (AIS)

Ogilvie, James W. MD

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doi: 10.1097/BPO.0b013e3181fd87eb
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Abstract

“If it were not for the great variability among individuals, medicine might as well be a science and not an art.” Sir William Osler 1892.

It has been suspected for several decades that adolescent idiopathic scoliosis (AIS) is a strongly familial disorder.1,2 When using a large 36 million name data base and constructing multigenerational family pedigrees, it has been demonstrated that 97% of AIS patients are related to other families with AIS.3 The complexity of AIS is further supported by the low penetrance and variable expressivity.

Although 80% to 85% of immature AIS patients with mild curves 10 to 25 degrees will not experience significant curve progression if left untreated, there is currently no method of accurately identifying those patients. Lonstein and Carlson4 noted that they could not develop a predictive algorithm for the risk of progression for Risser 0, 1, or 2 patients with curves <20 degrees based on clinical factors. Currently, all skeletally immature patients with mild curves are followed as though they had the potential for curve progression. This results in unnecessary physician visits, exposure to diagnostic radiation, anxiety, and inefficient medical care.

Recent case-control genome-wide association studies have identified more than 300 single nucleotide polymorphisms (SNPs) that are statistically related to AIS curve progression. AIS is a complex autosomal, polygenic disorder with dominant, recessive, and codominant patterns of inheritance. No relationship to the known estrogen receptors was noted.5

Step-wise backward logistic regression analysis of these SNP markers has further identified 53 markers that have the most utility for predicting curve progression from a mild curve <25 degrees to the severe range, defined as 40 degrees in immature children and 50 degrees at maturity.

Using a mathematical algorithm, these 53 markers were used to calculate a risk of progression score ranging from 1 to 200 (Fig. 1).6,7An initial set of 2684 AIS patients from a wide geographic distribution in the US was used to identify markers for curve progression and develop the complex mathematical algorithm that allowed the risk of progression scores to be developed. Subsequently an algorithm validation was performed on 1500 AIS subjects and 2 clinical trials of 277 and 257 subjects, respectively, were used in an intended use population to confirm the high negative predictive value (NPV). An additional clinical trial in 163 males was used to confirm the NPV in males.6,7 All research was conducted with the proper institutional review board authorization and was Health Insurance Portability and Accountability Act compliant.

F1-6
FIGURE 1:
The risk of progression increases exponentially with a higher risk of progression score. The bar graph on the right indicates the overall percentage of untreated AIS patients that will have an end result of mild, moderate, and severe curves.

In-vitro diagnostics (IVDs) such as the AIS prognostic test (AIS-PT) (The AIS-PT is marketed by DePuy Spine, Raynham, MA, under the trade name ScoliScore) are certified through the Clinical Laboratory Improvement Amendments (CLIA) of 1988 administered by the Centers for Medicare and Medcaid Services. This Centers for Medicare and Medcaid Services function covers approximately 200,000 of the service laboratories in the United States. The Food and Drug Administration does not routinely evaluate IVDs and has not claimed jurisdiction. The CLIA process involves a standard, but rigorous evaluation of the laboratory from federal inspectors. The laboratory must also receive an inspection and number from the College of American Pathologists. Both of these processes have been completed by the laboratory performing the analysis of DNA involved in the AIS-PT. Approximately 95% of currently used IVDs have undergone the CLIA-College of American Pathologists certification process. Research activities and the service function of providing AIS-PT scores to patients were performed in separate laboratories to avoid contamination or misidentification of DNA samples.

Genetic testing in skeletally immature AIS patients age 9 years and older is a surrogate outcome that provides physicians the ability to view the clinical course of a patient's scoliosis. The traditional age category for AIS has been 10 years at onset until skeletal maturity. With the younger onset of puberty and genetic analysis, it would appear that age 9 years is a more accurate threshold for AIS onset.

In unpublished internal data from our laboratory using the AIS-PT markers we testing more than 250 patients with juvenile onset idiopathic scoliosis that had progressed to surgery and all had a low risk of progression score. This would confirm that the AIS markers for progression do not apply to early onset idiopathic scoliosis below 9 years of age. Through internal validation, the AIS-PT markers have also proven valid when tested against all 6 Lenke types of AIS and at this time is not predictive of a particular Lenke type.

This saliva-based AIS-PT has been validated in White females and males. The test has been reliable in Hispanics, but additional samples must be tested to confirm the validity in this ethnic group. African-Americans have a varying degree of White genetic admixture thus the current SNP marker panel may have a good predictive value. Additional research into African-America AIS genetics is in progress. The current SNP markers are not predictive in Asians and Africans.

Risk of progression scores of 50 or less indicate that there is a <1% probability of the patients curve progression to the severe range if left untreated. This accounts for approximately 80% of all AIS patients. Because of the large number of subjects in the low risk research data base, more than 3000, there is a high NPV. These patients can be monitored less frequently with less cost, both direct and indirect, and decreased x-ray exposure.

AIS-PT scores of greater than 180 have been designated as high risk. Although this is an arbitrary threshold it represents the exponentially increased risk in those with a high risk of progression score. Of the more than 300 subjects in our data base with AIS-PT scores of 195 or above, only one patient has avoided surgery even when treated with conventional bracing. Given the poor prognosis for this group, they may be ideal candidates for innovative treatment protocols.

Patients with intermediate scores of 51 to 179 are at risk for progression, yet they do not have an a priori bad prognosis. An intermediate score also excludes those who are at low risk that can be followed with a less intensive schedule. These patients will benefit most from close monitoring and current treatments.

DNA-based testing of AIS patients will also allow future clinical prospective trials of treatments to be more precise. It is not as valid screening test for patients without scoliosis and is designed only for AIS <25 degrees in the skeletally immature patient.

Risk of progression stratification will ensure that patients with a low risk of progression are not subjected to treatments that have no benefit and that those with a high risk are not placed in observation arms of treatment protocols. Genotype homogeneity in a study cohort will remove one of the variables that currently exist in some clinical trials that have conflated the subjects.

Although traditional point mutations are important in the genetics of AIS and the prediction of AIS progression, further work remains. Current research in our laboratory indicates that copy number variants, a recently discovered factor in genetic disorders wherein large segments of DNA in the 1 million or more base pair range are replicated or deleted, are also important in AIS. Genomic rearrangements may be of importance in AIS. This consists of aberrant meiotic recombination that can result in disease-causing chromosome microdeletions or microduplications related to conditions such as cancer and some inherited disorders.

Exome sequencing, sequencing of 1% of the genome responsible for inherited disorders, has become possible with advances in genetic science. In the future exome sequencing may supersede SNP analysis as it becomes less costly to directly sequence the coding regions of the genome. Further research is in progress to clarify these and other questions on the genetics of AIS and AIS progression.

Identifying important AIS progression markers for various ethnicities is a daunting task, but one that is achievable with current technologies. The collaboration of scoliosis clinicians with genetic scientists is essential to this work. Traditional designations of ethnic groups may require new perspectives as the genome is subjected to better analysis.

Although the AIS-PT is currently available for clinical use in Whites, additional research may provide even greater utility in predicting the course of mild AIS. The prognostic test involves laboratory analysis of 53 regions of the genome for the significant markers associated with progressive AIS. The stacked current procedural terminology codes for this analysis allow a charge of $5500 per test which is in line with other genetic tests such as the test for breast cancer genes BRCA1 and BRCA2. However, the AIS-PT has been marketed with a charge of $2950 and a generous patient assistance program assures that most patients will have minimal or no financial liability.

Genetic analysis of patients with progressive AIS may also provide insights into the molecular pathways that lead from DNA mutations to a curved spine. This holds the possibility that novel pharmacological treatments may play a role in the future therapy of AIS. Our discoveries are only the beginning of understanding the pathogenesis, prognosis, and treatment responses in AIS.

REFERENCES

1. Wynne-Davies R. Familial (idiopathic) scoliosis. A family survey J Bone Joint Surg Br. 1968;50:24–30
2. Cowell HR. Genetic aspects of orthopaedic diseases Am J Nurs.. 1970;70:763–767
3. Ogilvie J, Braun J, Nelson L, et al. The search for idiopathic scoliosis genes Spine. 2006;31:679–681
4. Lonstein J, Carlson M. The prediction of curve progression in untreated idiopathic scoliosis during growth J Bone Joint Surg Am.. 1984;66:1061–1071
5. Ward K, Ogilvie J, Nelson L, et al. Genetic markers associated with idiopathic scoliosis progression. Presented Scoliosis Research Society Annual Meeting, Salt Lake City, UT, 2008.
6. Ward K, Chettier R, Ogilvie J, et al. Genome-wide association study identifies novel progression markers for adolescent idiopathic scoliosis (AIS) Submitted BMC Genomics. 2010 In press.
7. Ogilvie J, Nelson L, Berry T, et al. Predicting curve progression in adolescent idiopathic scoliosis. Abstract presented at the Scoliosis Research Society, Salt Lake City, UT, 2008.
Keywords:

genome wide association studies; single nucleotide polymorphisms; adolescent idiopathic scoliosis risk of progression

© 2011 Lippincott Williams & Wilkins, Inc.