Diagnosis of Childhood Growth Hormone Deficiency and Prediction of Therapeutic Response Using Gene Expression Data

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Growth Hormone Deficiency is a condition in which children grow very poorly without treatment with injections of growth hormone. It is very important to make this diagnosis as children with growth hormone deficiency will grow to a normal height if treated. Currently to make a diagnosis of growth hormone deficiency doctors need to undertake a combination of blood tests and brain scans. It is very difficult to measure growth hormone during the day as children produce this hormone only overnight. Since blood tests overnight are not easy doctors use special type of test called a stimulation test to diagnose growth hormone deficiency using blood taken during the day. The stimulation tests involve children having a drip placed in an arm, administration of medication via the drip (this medication causes the body to produce growth hormone) and many blood samples over the next 3 hours. The medication often have side effects such as nausea and vomiting. These tests require the child to be admitted to a hospital ward for the morning and a dedicated nurse to do the test thus they are relatively expensive for the NHS. We have started to develop a new method for testing if a child has low growth hormone levels using the level of gene activity in the blood. This test uses a single blood sample, does not require the use of mediation (thus avoiding any unpleasant side effects) and would not require the child to be admitted to hospital. The test works by measuring the activity levels of all the genes in the blood and the using a mathematical technique called Random Forest Analysis to tell whether children have low growth hormone levels or not. Our initial studies have indicated that this test works extremely well but before it is rolled out across the NHS we need to test it on larger number of children to be completely sure that it works. We will therefore recruit another 60 children with low growth hormone levels and 60 children with normal growth hormone levels from the Royal Manchester Children's Hospital. Each child will have a blood sample taken to measure their gene activity levels and we will then compare how accurate our test is compared to the results of the current growth hormone stimulation tests. Once children are diagnosed with growth hormone deficiency they are treated with injections of growth hormone once each day. Although generally this treatment works well sometimes children don't respond to the treatment. At the moment the only way of telling who will respond is to give them injections for 6-12 months and measure how well they grow. We have been able to show that the gene expression levels measured on the same test we use to diagnose Growth Hormone Deficiency can also tell us who will not respond to treatment. It would be great to identify those children who won't respond to treatment so we could either give them a larger dose of growth hormone or in some cases we may choose not to treat them (thus the child avoids up to 1 year of ineffective daily injections). Once again we need to confirm our initial findings in a second group of children. For those children with growth hormone deficiency recruited to the study we will look 1 year after treatment to see who has responded well and who has responded badly. We will then use the gene expression levels and the Random Forest Analysis technique to validate out technique for predicting who does not respond well to treatment. The result of this study is that with one blood sample we will be able to 1. Tell if a child has low growth hormone levels - saving the child side effects from medication, the need for multiple blood tests and saving the NHS significant bed and nursing time2. Tell whether a child will grow well when treated with growth hormone. This may save the child a year of unnecessary injections or allow us to use a higher dose to ensure they do benefit from the injections.