Empowering Informed Scoliosis Treatment Decisions

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The ScoliScore Test is the first and only genetic test proven to give physicians and parents insight into the possible progression of Adolescent Idiopathic Scoliosis (AIS), thereby reducing the uncertainty of AIS progression, and allowing for a more personalized treatment plan.

The ScoliScore Test analyzes 53 genetic markers correlated with spinal curve progression in AIS patients and has a 99% negative predictive value (NPV) in determining the risk of progression in a manner that is superior to all current clinical predictors. The test was developed in collaboration with over 110 clinicians worldwide and was designed through the analysis of over 10,000 patient samples. After this extensive development, the ScoliScore test was validated in three multi-center independent clinical trials.

  • The ScoliScore Test assigns a numerical value (between 1 and 200) to the likelihood of curve progression based on a child’s DNA and current Cobb angle.
  • The ScoliScore Test is a highly accurate prognostic test for AIS curve progression.
    • 99% Negative Predictive Value (NPV) for the likelihood of AIS spinal curvature NOT progressing to >40º Cobb angle.
    • 95% probability in the High Risk category (ScoliScore of 181-200) for the likelihood that the AIS spinal curvature WILL progress >40º Cobb angle.
  • The ScoliScore Test is performed by collecting a saliva sample during a physician’s office visit. The sample is then sent to Transgenomic for analysis.
  • Within four weeks of the laboratory receiving the sample, the ScoliScore Test result report will be sent to the ordering physician’s office.
  • The ScoliScore Test assigns a numerical value (between 1 and 200) to the likelihood of curve progression based on the child’s DNA and current Cobb angle.
  • The physician can then use this information, combined with other clinical factors, to determine a personalized treatment plan.
  • Is performed by a state-of-the-art laboratory regulated under and by the Clinical Laboratory Improvement Amendments (CLIA) of 1988.

The ScoliScore Test is appropriate for:

Indications
  • Adolescent Idiopathic Scoliosis
  • Between the ages of 9 years – skeletal maturity
  • Self reported Caucasian males and females (North American, South American, European, Eastern European, Middle Eastern)
  • Mild Curve (10° – 25° Cobb angle)

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Genetics Influence Progression

The existing methods of assessing curve progression are based on reported observational criteria alone, and may result in inefficient patient care. Recent studies51 have shown a strong genetic link to Adolescent Idiopathic Scoliosis (AIS) progression and have paved the way for science based, personalized patient care decisions.

lc_study3

Current Prognostic Standards

The diagnosis of Adolescent Idiopathic Scoliosis (AIS) is straightforward given that most mild curves are visible or can be detected with a forward bending test, a scoliometer, or a radiograph. Due to a lack of useful prognostic tools, the standard treatment pathway following diagnosis with a mild curve is currently driven by the uncertainty of progression leading to months and perhaps years of office visits and radiographic series to assess further curve progression.

Following initial diagnosis of AIS, patients today are often forced to “watch and wait”, and are subjected to observational x-rays every 4 – 6 months to determine curve progression. If the curve progresses to at least 25°, bracing to try to arrest curve progression is eventually prescribed to 7 – 10% of initially diagnosed patients,2 despite the success rate of bracing being largely unknown.16

Out of approximately 4,000,000 children in the US in the indicated age group,17 each year 100,000 present to physicians with a mild AIS curve ≥10°. Approximately 1,000 – 4,000 will eventually experience curve progression necessitating an instrumented fusion procedure.1-3 This means that approximately 96,000-99,000 of these newly diagnosed patients will not progress to a curve requiring instrumented fusion (Figure 3). As a result of this inability to predict which patients will require surgical intervention and which patients will not, a large majority of patients undergo medical and radiographic monitoring that may not be required.

schoolscreeningObservational Inefficiency

Adolescent Idiopathic Scoliosis (AIS) diagnosis is estimated to result in more than 600,000 physician visits annually.1

In one study of 26,947 children screened for AIS, 1,222 patients were identified to have the disease of which only 584 had curves greater than 10º. Only 77 of these patients (13%) progressed to a curve of greater than 21º.2 Yet all patients identified to have the disease were monitored and radiographed identically.

X-Ray Exposure

Studies show that average radiation doses from spinal x-rays of the lumbar region are about 30 times higher than two conventional chest x-rays.3

The U.S. Food and Drug Administration (FDA) has issued public warnings to scoliosis patients about the cancer risk associated with frequent X-ray examinations and emphasized the importance of keeping radiation doses to the breast as low as possible. 52

The National Cancer Institute (NCI) further emphasized that the risk of breast cancer depends on dose of radiation and age at exposure, with the highest risk occurring during puberty. No dose of radiation should be considered completely safe, and attempts should be made to keep radiation doses as low as possible.53

Lonstein and Carlson

For the past 25 years, Lonstein and Carlson’s4 study of 727 patients has been the basis for physicians’ estimates of probability of curve progression. While the study was in many ways forward thinking;

  • Its outcome only predicted progression of 5º – 10º.
  • The accompanying progression factor formula and nomogram were only valid for curves between 20º -29°.
  • The predictive value for a patient with a curve of less than 20° was invalid.

Lonstein-Carlson 1984 Study

Today’s management of the Adolescent Idiopathic Scoliosis (AIS) patient is quite similar to what it has been for the past 25 years. Since Lonstein and Carlson published their criteria for predicting curve progression in 1984, no other research built on their original work has ever been published in a peer reviewed journal. Surgeons however, have taken what Lonstein and Carlson proposed and liberally applied these criteria, expanding the interpretation of the data beyond the 20 – 29° Cobb angle and beyond just 5 – 10° of progression, to encompass lesser curve magnitudes and subsequent progression much greater than 10°.

Though Lonstein-Carlson criteria for progression of an AIS curve represented interesting observations with respect to understanding the disease of AIS at the time, its use as a prognostic tool has the same reported limits today as it did in 1984. Because the criteria are based solely on observational parameters that have already occurred (age, Risser sign, Cobb angle), the criteria have less predictive value.

The progression factor equation and resulting graph were reported to be valid only for curves of 20 – 29° and could be used to estimate further risk of progression of 5 – 10°. This very narrow predictive capability does not approach the curve magnitude generally accepted as a reasonable point at which instrumented correction would be considered.

Given these extensive limitations, use of Lonstein-Carlson criteria to predict curve progression is just slightly better than the random chance of assessing progression by flipping a coin.

 

Familial Characteristics of AIS

For over forty years, physicians have suspected a genetic link to Adolescent Idiopathic Scoliosis (AIS). Recent breakthroughs in genetic research have confirmed that AIS is a complex, multifactorial genetic disorder having a strong pattern of inheritance. This further supports that current prognostic practices alone cannot accurately predict the likelihood of progression of AIS curves.

Below is an example of an actual pedigree chart going back five generations and demonstrating the relatedness of people with AIS.

 

 

Strong Genetic Linkage

Though the familial aspect of AIS was suggested in 1968 by Wynne-Davies,6 and later supported by Riseborough,8 and Cowell et. al.,7 the mode of heritability of AIS was not well understood until recently. Early genetic research could not accurately detect whether AIS was passed on to offspring via a dominant gene, or through a multi-factorial (multi-gene) pathway. It was Cowell et. al. who noted that the literature contained little information about male-to-male transmission of the disease suggesting an X chromosome dominant inheritance pattern.

Multi-Factorial Expression

In 200010 and 2005,18 Miller hypothesized that variability in phenotypes (observed characteristics) of patients with AIS, was more likely to be evidence of a multi-factorial genetically expressed disease, meaning multiple genes across multiple chromosomes played a role in the genetic expression of the disease. However, there was no strong evidence for that hypothesis.

In 2006, Ogilvie et. al.11 interviewed 145 people with AIS and found that 100 were from families known to have members affected by AIS. Individuals from the 100 families as well as the 45 “sporadic” cases were searched against a proprietary database, GenDB, containing 18 million names of ancestors and 3 million descendants from the original founders of the Salt Lake Valley in Utah. This was done to identify genealogical links between families.

  • Of the 145 individuals, 127 (97%) were related to at least one other scoliosis family.
  • In this study, the kinship coefficient compared 1,000 control sets of 100 individuals to the 131 known to have AIS, demonstrating a high degree of relatedness of the individuals with AIS compared to the controls.

When comparing these data to the control data, kinship coefficients were calculated. A kinship coefficient is defined as the probability that one allele, selected randomly from each of two individuals is inherited from a common ancestor. For example, siblings are expected to share approximately half of their genetic material yielding a kinship coefficient of 0.25. Secondary relatives such as first cousins have a kinship coefficient of 0.125 or half of siblings.

The mean kinship coefficients for the randomly selected controls and the 131 individuals with AIS are shown demonstrating that individuals with scoliosis are far more connected to each other than individuals without scoliosis.

Further research of the pedigrees showed 50% of the patients were connected to individuals with AIS whose ancestors all resided in England in the mid-1500’s. The connections between previously unrelated pedigrees and the significantly higher kinship coefficient in the AIS cohort suggest it is highly likely that there is a major AIS gene for susceptibility to the disease. Additional research by Ogilvie et. al. suggested there are at least two different regions of linkage for AIS in these families.

 

 

Clinical Test Development

The ScoliScore Test was developed in collaboration with over 110 clinicians worldwide, and designed through the analysis of over 9,500 ethnic and racially diverse patient samples.

  • Test design and algorithm was validated in a large patient data set.
  • Identifying 28 progression and 25 protection associated markers (p-value of 2.34 x 10-165).
  • Clinical Trials confirmed highly predictive performance on multiple intended use patient populations.8

Clinical Validation

Further studies were performed to validate the Negative Predictive Value (NPV) of the ScoliScore Test using a different set of samples and three different clinical trials,19 on intended use populations.

Clinical Trial #1 – School Screening Population – Large Majority with Mild Curves
Sample Size = 277 Caucasian female patients as presenting for school screening for AIS and having at least a 10° curve.
85% Mild curve
12% Intermediate curve
3% Severe curve
Results: Negative Predictive Value of 100% (Confidence Interval, 99-100%)

 

Clinical Trial #2 – Intent to Treat Population – Spinal Deformity Practice
Sample Size = 257 Caucasian female patients with at least a 10° curve as presenting at a spinal deformity surgeon’s office following referral from a pediatrician.
68% Mild curve
21% Intermediate curve
11% Severe curve
Results: Negative Predictive Value of 99% (Confidence Interval, 99-100%)

 

Clinical Trial #3 – Intent to Treat Population – Spinal Deformity Practice
Sample Size = 163 Caucasian male patients with at least a 10° curve as presenting at a spinal deformity surgeon’s office following referral from a pediatrician.
78% Mild curve
11% Intermediate curve
1% Severe curve

 

 

Accurately Predicting the Likelihood of Progression

Using a scale of 1 – 200, the risk of progression increases with increasing test score. Given the tightness of the confidence intervals at the extremes, intervals of group risk were identified as follows:13

  • In indicated patient with a score in the Low Risk range of 1 – 50 has a >99% probability that she or he will not experience progression to a severe curve.
  • In clinical trial, 75% of the patients tested fell into the Low Risk category, while 24% were in the Intermediate Risk group.
  • In an indicated patient with a score in the High Risk range of 181-200, the patient has a >95% probability of progressing to a severe curve (>40º Cobb angle).
    • 1% fell into the High Risk group.

 Click to View larger: Risk of Progression Chart

Empowering Informed Decisions

The ScoliScore Test is the first, clinically validated and highly accurate prognostic test, developed to predict the likelihood of curve progression, thereby empowering informed patient care decisions when combined with existing radiographic and clinical information.

The ScoliScore Test :

  • Is performed on DNA extracted from saliva, making sample collection simple and pain-free.
  • Provides test results in weeks versus years of conventional observation.
  • Is performed by a state-of-the-art laboratory regulated under and certified by the Clinical Laboratory Improvement Amendments (CLIA) of 1988.
  • Calculates a progression score of 1 – 200 using marker weighting factors and a logistic regression algorithm.

The ScoliScore Test is appropriate for:

Indications
  • Adolescent Idiopathic Scoliosis (AIS)
  • Between the ages of 9 years – skeletal maturity
  • Self reported Caucasian males and females (North American, South American, European, Eastern European, Middle Eastern)
  • Mild Curve (10° – 25° Cobb angle)