Validation of DNA-Based Prognostic Testing to Predict Spinal Curve Progression in Adolescent Idiopathic Scoliosis

Study Design. Validation of a prognostic DNA marker panel. Objective. The goals of this study were to develop and test the negative predictive value of a prognostic DNA test for adolescent idiopathic scoliosis (AIS) and to establish clinically meaningful endpoints for the test. Summary of Background Data. Clinical features do not adequately predict which children diagnosed with minimal or mild AIS will have the progressive form of the disease; genetic markers associated with curve progression might offer clinically useful prognostic insights. Methods. Logistic regression was used to develop an algorithm to predict spinal curve progression incorporating genotypes for 53 single nucleotide polymorphisms and the patient's presenting spinal curve (Cobb angle). Three cohorts with known AIS outcomes were selected to reflect intended-use populations with various rates of AIS progression: 277 low-risk females representing a screening cohort, 257 females representing higher risk patients followed at referral centers, and 163 high risk males. DNA was extracted from saliva, and genotypes were determined using TaqMan assays. AIS Prognostic Test scores ranging from 1 to 200 were calculated. Results. Low-risk scores (<41) had negative predictive values of 100%, 99%, and 97%, respectively, in the tested populations. In the risk model, we used cutoff scores of 50 and 180 to identify 75% of patients as low-risk (<1% risk of progressing to a surgical curve), 24% as intermediate-risk, and 1% as high-risk. Conclusion. Prognostic testing for AIS has the potential to reduce psychological trauma, serial exposure to diagnostic radiation, unnecessary treatments, and direct and indirect costs-of-care related to scoliosis monitoringin low-risk patients. Further improvements in test performance are expected as the optimal markers for each locus are identified and the underlying biologic pathways are better understood. The validity of the test applies only to white AIS patients; versions of the test optimized for AIS patients of other races have yet to be developed.