Wait, where is the discussion of a blind trial? Is this going to be based on what was predicted by the meta analysis, or have I filled in too many blanks?
From their latest newsletter:
Moving towards a diagnostic test:
We have come a long way since Dr Rob Powell started the first gene study Altered gene expression in CFS , firstly under Professor Jeff Almond at the University of Reading and then under Professor Stephen Holgate at Southampton University. Until then research worldwide had studies different aspects of the illness but as a result of this study, and the information received from other disease studied funded by the Foundation the Research Committee decide to study the basis of the disease. Scientists were studying the involvement of genes in many illnesses and the Research Committee decided that a study should take place to compare the genes of CFS/ME patients with those of normal healthy people.. Dr Jonathon Kerr, who has already carried out some research funded by the Foundation, was invited to submit a grant application. He planned an ambitious project using scientists from laboratories in three British Medical Schools and one in the USA. This project needed courage because in gene research, samples taken from lesions are studied but there are no lesions in CFS/ME so the scientists decided to use white blood cells. This had never been attempted before in any illness so there were several nail biting years while we waited to see if ythis could be successful. When Dr Kerr announced that he had found 88 genes in CFS/ME patients that were abnormal but remained normal in the healthy group, CFS/ME research was changed worldwide. Dr Kerr took his research further and published a paper in the Journal of Infectious Diseases; a journal which is known for its very high standards, suggesting that the 88 gene profiled could be divided into 7 subtypes.
The CFS Research Foundation has always insisted on the highest standards of research and the ability to reproduce the results of ant study is always paramount. Professor Paul Kellam, Dr Jonathon Kerr, Dr Tim Harrison and Dr Dan Frampton carried out a blinded study to determine whether the gene expression profile was able to discriminate between patient and controls.
Unfortunately this was not the case. When the study was completed, Dr Ker decided to return to clinical work but the gene research is to continue building on Dr Kerrs work.
After the pioneering work of Dr Kerr and colleagues was published other research groups throughout the worlds have carried out similar studies, but there have been some differences in the results. This was to be expected as there was some variation in the technical features of the scientific methods used, in the classification of patients and where the study was conducted. But in all studies results showed clear differences between patients and controls.
Clearly this needed further study so Professor Paul Kellam, Virus Genomics Team Leader at the Welcome Trust Sanger Institute, Cambridge together with Dr Tim Harrison designed a 2 part study, Meta analysis of gene expression data to discover diagnostic and mechanistic signature in the peripheral blood of CFS patients. They submitted this study as a grant application to the CFS Research Foundationm and the Foundation agreed to fund it for 2 years.
Because the different laboratories in different coutries have used a similar approach in their research it is possible to analyse their results in combination using powerful computing and a method called meta analysis. Using this advanced computing the results of these studies will be analysed together with those derived from Dr Kerrs work. The advantage of this approach is that analysing the studies in combination is much more powerful than any of the studies considered individually and the team expect that the original group of 88 genes will be modified to generate a more formidable set. In addition, if small effects that dont appear to be significant in one study can be reported across several studies, they will have a better idea of which genes are involved in CFS/ME. Without combining these studies it would be impossible to identify such subtle effects.
Currently this group is chasing gene expression data from 8 CFS/ME studies concluded across the world, from the Uk to the USA, from Japan to Sweden. The detective work of finding the raw data is only half the battle, the second is ensuring that the studies are comparable, the data is compatible and the CFS/ME classifications behind each study are reliable.
These scientists are aiming to combine these existing studies from around the world, analyse them and identify such genes that are changed in this way across each of the studies what are called CFS marker genes. They will then test their predicted marker genes in a separate study using more blood samples from both CFS/ME patients and healthy volunteers. If gene expression patterns can be reliably produced they will have successfully identified a robust set of CFS marker genes that can be used as a diagnosis.
One issue they need to consider is that there exists several subtypes of CFS/ME some with more severe symptoms than others and these might be expected to have different patterns of gene expression. By combining data from several studies it may be possible to identify the underlying subtypes and noting key differences in the gene expression patterns which might have been missed on an individual study or attributed to samples variation. The outcome of this will be a modified stet of genes which can be used potentially to discriminate between patients and controls.
They will then proceed to the second part of this study when they will test the findings of the first part for accuracy. They will recruit a new set of patients and controls when the expression of a new set of genes will be tested in a blinded study. The samples will be placed in tubes, each one coded then frozen. One of the scientists will keep the code and no-one else will know it until the time set for unblinding. It will then be possible to test the accuracy of teh first part of this study.
If this 2 part study produces gene expression patterns which can be reliably reproduced Professor Kellam and his team will have successfully identified a robust set of CFS marker genes which can be used as a diagnosis.
This is likely to have a profound effect on CFS/ME research. The problem we have been battling with at the Foundation has been lack of research applications of a sufficiently high standard. We have to acknowledge that the scientists are hesitant to undertake research into a disease for which there is no diagnosis, but interest in the possibilities of research into CFS/ME has been growing. Following the publication of the XMRV paper groups throughout the world tried to reproduce this study. One journalist said that scientists were leaping out of bed in the mornings to study the XMRV. Sadly no other groups were able to reproduce this study and subsequent studies have found the problem to be contamination. If scientists can feel confidence in a diagnosis then surely they will come to us with new ideas for research projects. So much hangs on this study which is being undertaken by Professor Kellam and his team. A diagnosis would change the way CFS/ME is regarded by doctors and scientists alike.
It would be wrong to easily assume that this ambitious study will yield the answers we wish for. There are two years of hard work ahead, but the study has been carefully planned and has enjoyed the criticism and help of eminent scientist s specialising in this field. It has the greatest chance of success and we shall all be awaiting the results with hope.
The research funded by the foundation has made enormous strides since 1998 and we must be grateful to the scientists who have taken us forward with such speed that we can hope that we may soon have a diagnostic test. All this would not have been possible without the outstanding generosity of our supporters who have not only funded our research but have given us such encouragement throughout the years. We must now brace ourselves for the demands of this new and exiting study. We have achieved so much that we must confidently expect that we shall successfully take forward our research. We are on the point of finding a diagnostic test and that would lead us to new therapies and then a cure. A few years ago that would have been only a dream but now it is within our sights.
Anne Faulkner. Hon Director
