CINCINNATI - A new study by researchers at Cincinnati Children's Hospital Medical Center shows that genetic testing offers a less invasive and more cost efficient alternative in diagnosing inner ear hearing loss in children. In fact, the study shows that some of the standard tests conducted today are not necessary and should only be done on a case by case basis.
"Our paradigm emphasizes the use of genetic tests, particularly a screen for the GJB2 gene, as the initial diagnostic test of choice. Other tests, such as imaging or CT tests, should be done sequentially and not simultaneously to maximize the benefit of the test," according to John H. Greinwald, Jr., MD, assistant director of the Center for Hearing and Deafness Researchat Cincinnati Children's, and corresponding author of the article that appears in the December issue of Otolaryngology - Head and Neck Surgery.
In order to diagnose an infant or child suspected of having hearing loss, physicians conduct a number of diagnostic tests, including urine and blood tests, thyroid function tests, electrocardiograms and imaging studies. These tests are not foolproof and the turnaround time for the results can be slow. Plus, the tests can be costly and in the case of CT scans of the inner ear, the test poses some risk because younger children must be sedated for testing.
Dr. Greinwald and colleagues have been working on developing a gene-based diagnostic test that uses a gene chip and microarray technology to provide a rapid and accurate means for analyzing nucleic acid samples. The gene chip can test for the genetic causes of existing hearing loss and for the potential of future hearing loss in infants. It is expected that the test will become widely available in 2005.
Dr. Greinwald's suggests that genetic testing should be added to the standard testing paradigm. Doing so would be beneficial to both parents and the healthcare system alike, he said.
"If we can improve our ability to ascertain the etiology of hearing loss, then we are going to subject patients to far less scrutiny because we will know right away the cause of the child's hearing loss. Genetic testing will not rule out the need for the standard tests in every case, but we believe that 80 percent of children are candidates for microarray screening," Dr. Greinwald said.
BENEFITS OF EARLY DETECTION
While greater than 50 percent of inner ear hearing loss cases can be attributed to genetics, the remaining causes are due to environmental causes, such as infections, medications, metabolic disorders, illicit drug use, premature birth and other causes.
There are two types of hearing loss: inner ear hearing loss and the more commonly known "conductive hearing loss," which affects the outer and middle ear and is commonly associated with ear infections.
Inner ear hearing loss is one of the most common birth defects in the United States. Approximately 1.2 children per 1,000, or 40,000 children, will be diagnosed with moderate to profound inner ear hearing loss each year in the United States.
Inner ear hearing loss affects the delicate neural structures of the inner ear and is sometimes referred to as sensorineural hearing loss. Inner ear hearing loss can occur as a result of defects in the detection of sound in the inner ear and/or the transmission of the neural signal to the brain, or a combination of both. Half of all inner ear hearing loss cases have a genetic origin.
Hearing loss in infants can go undetected for months after birth and on average, children are diagnosed at age two-and-a-half, Dr. Greinwald said. Early detection and intervention can alleviate most of the developmental and behavioral difficulties found in hearing impaired children. The earlier intervention occurs with hearing-impaired children, the greater the enhancement of speech and language skills.
Early, accurate and specific genetic testing will aid in accurate and rapid diagnoses for children. Diagnosing hearing loss early can lead to early intervention and a personalized treatment plan for individual patients.
"Genetic testing can not only determine the cause of the hearing loss, but can help determine how a child's hearing will progress as the child ages. What will the child's hearing be like later in life? That's why this research is so important," Dr. Greinwald said. "This is predictive information. It is not absolute, but it is very good."
While there are as many as 150 genes suspected of being linked to inner ear hearing loss, at this point, the gene chip targets 13 key genes.
In the state of Ohio, all hospitals are required to test newborns for hearing problems. Similar laws have been passed or are under consideration in other states.
RESULTS FROM THE STUDY
The new study focuses on mutations in the GJB2 gene, which have been linked to inner ear hearing loss. The study focused on 810 patients, 650 of whom were diagnosed with inner ear hearing loss, although the root cause was not known. The patients, who ranged in age from one week to 18 years old, were seen by an otolaryngologist at Cincinnati Children's between 1993 and 2002. Hearing loss in the patients ranged from profound to moderately severe to mild hearing loss. In total, 2,676 tests were performed on 474 patients and of those, 195 tests were returned as abnormal indicating, but not confirming, inner ear hearing loss. The tests conducted included CT scans of the temporal bone in the inner ear and magnetic resonance imaging (MRI) scans.
Of the 810 patients, 161 underwent screening for mutations in the GJB2 gene and 29 (18 percent) tested positive for mutations in this gene (genetic testing became available in 2001). Twenty-one of the 29 patients also underwent other diagnostic tests. Of these, abnormalities were identified in only one patient. The study suggests that the paradigm of first starting with genetic testing in the evaluation of inner ear hearing loss might be more effective for severe to profound hearing loss.
The benefits of initial genetic testing in mild cases of inner ear hearing loss are more modest. New research findings will be announced in early 2005 that address genetic testing for those with mild inner ear hearing loss.
The study showed that 80 percent of the patients with hearing loss remained undiagnosed after their initial assessment based on standard diagnostic tests.
"These findings corroborate the results of a number of other studies recommending that routine, extensive laboratory evaluations be reconsidered," now that genetic testing is readily available, the authors write.
GENETIC TESTING IS COST EFFECTIVE
It is widely believed that genetic testing is more cost effective than traditional diagnostic tests and in fact, projections show it can save the healthcare system hundreds of thousands of dollars each year, Dr. Greinwald said. For example, at Cincinnati Children's a full round of diagnostic tests for inner ear hearing loss costs $1,932 ($360, full laboratory workup; $1,039, temporal bone scan; and, $533, GJB2 gene screen). Genetic testing for hearing loss would result in a savings of $38,000 at Cincinnati Children's alone.
The authors suggest that for children who test positive for mutations in the GJB2 gene, further diagnostic testing is not necessary.
"It has been accepted practice for more than 20 years to conduct a single comprehensive round of tests. We've established a baseline for normal results, but we really haven't done a true quantitative analysis of our scans. With the new measuring paradigm developed at Cincinnati Children's, we are increasing the accuracy of determining these forms of hearing loss by taking more of a quantitative approach instead of the accepted practice of qualitative measurements," Dr. Greinwald said.
In the newly published study, gene chip testing would have resulted in a savings of $20,180 in imaging costs and nearly $34,000 in laboratory costs per 100 children.
Dr. Greinwald's gene testing chip is one of four flagship research projects of the Computational Medicine Center, a biomedical informatics research center focused on making fundamental discoveries into the origins and causes of pediatric and adult diseases and designing treatment that will make disease more preventable, illness more predictive and treatment more personalized.
The center is a collaborative effort between Cincinnati Children's and the University of Cincinnati College of Medicine. It is funded with a $28 million grant from Ohio's Third Frontier Project.
"One of the goals of the CMC is to build upon this framework and try to determine the causes of inner ear hearing loss. If we can better diagnose the etiology of the genetic causes, then, we've hit upon a gold mine," Dr. Greinwald said.
The study in Otlarygology - Head and Neck Surgery was funded by The Cincinnati Children's Research Foundation.
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