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MEGA blog: Chris Ponting on Genomics "defining the molecular pathology of CFS/ME"

Simon

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The first blog from a MEGA omicist is up:
Petition update · Chris Ponting Blogs · Change.org
Professor Chris Ponting, Genomics

Professor Chris Ponting is Chair of Medical Bioinformatics and a Principal Investigator at the MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine (Univ Edinburgh)

"Multi-omics is the study of multiple genome-scale, often population-based, data sets and it lies at the heart of modern biomedical science. We are interested in carefully linking DNA variants to changes in molecules, processes, cells, organs and individuals. To do so we analyse high-throughput DNA, RNA abundance, DNA-binding, and phenotype (both human and model organism) data from primary tissues as well as from cell lines and single cells. One focus of our research is on genes that are not used to make protein – so called long noncoding RNAs – particularly those that modulate mitochondrial function in different cells and tissues. Other projects are investigating the biology of single cells, specifically neurons, glia and thymic epithelial cells.

CFS/ME researchers are in need of hypotheses about disease initiation and progression that are founded upon robust and reproducible data. Until then, it will be important first to apply the predictive power of population genetics, and then to generate experimentally testable hypotheses using functional genomics. Population genetics is key. This is because only it can provide definitive evidence on how susceptibility of CFS/ME is inherited which then should provide clues about what physiological processes have become dysfunctional and in what cells. Functional genomics – which includes multi-omics – is a toolkit used to investigate a wide-ranging set of hypotheses. I would be keen to apply my group’s long-standing computational and experimental experience in these areas to defining the molecular pathology of CFS/ME."
 
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Hi Simon, thanks for posting this. It does indeed look interesting. I'm glad you asked about funding, sample size and time scale in your comment. I have signed the petition opposing MEGA for reasons I'm sure you are aware of so I won't rehearse them here. I know we differ on this, but I still very much respect and appreciate your comments.

I'd love scientists such as Prof. Ponting to go directly to the already existing ME biobank for samples and apply for funding directly to do his study without the needing the involvement of the unwieldy MEGA project. I wonder how feasible that would be. Maybe I'll ask.
 

Simon

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Hi Simon, thanks for posting this. It does indeed look interesting. I'm glad you asked about funding, sample size and time scale in your comment. I have signed the petition opposing MEGA for reasons I'm sure you are aware of so I won't rehearse them here. I know we differ on this, but I still very much respect and appreciate your comments.
Thanks - though it wasn't my question, but someone else on PR who wanted to stay anonymous!

And I saw you asked :) The biobank question you put was answered in the reply from Chris Ponting to that first question (huge samples needed).
 

Simon

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Q&A from the blog. The final paragraph of Ponting's reply is particularly worth a read.

Q > Thank you, Professor Ponting. This is very interesting, especially, as you may know, that there's a lot of interest in the mitochondria in ME/CFS, following the recently published work of Professor Robert Naviaux in the US:

http://www.openmedicinefoundation.o...016/.../Naviaux...

To what extent could MEGA shed light on these kind of hypotheses which are a level up from metabolites/DNA etc. (i.e. at the cellular/organelle level, rather than the molecular level)? Which do you think is the most relevant level to look at in terms of determining the underlying mechanism(s) of a disease such as ME/CFS, and in finding effective treatments?

What sort of timeframe could MEGA expect to make those sorts of discoveries? Given that it's a 10,000-patient study, would we have to wait years until all those patients were recruited before we'd have useful results? What's the reason for having so many patients when Prof. Naviaux and Prof. Ron Davis at Stanford are looking at tens of patients and finding interesting things?

I'm sorry that that's rather a lot of questions but this kind of study is new to me (and I'm sure to a lot of us) and as patients, our focus is on speed!

Thank you for your interest in our disease - it's very much appreciated that someone of your calibre wants to be involved.


A > Reply from Chris Ponting:


Thanks for your great questions. The problem that I have with this ME/CFS study is that it doesn’t tell us whether these “metabolic features” are acquired because of illness, or whether they reflect its underlying cause. In Tweets I’ve read that some people with ME/CFS are relieved that these features might be diagnostic of your disease. Nevertheless, my own thoughts are that we need to find out the (likely several) root-causes of ME/CFS so that therapy not just for symptoms, but also for causes, can be developed.

Unfortunately, studies that do this require very large numbers of patients. This is because they need to look across all parts of their DNA which vary in different people to test whether DNA differences cluster in people with ME/CFS. And lots of people’s DNA is needed so that this clustering is not found just because of random chance.

Yes, the timeframe is long-term, certainly many years and I cannot forecast more precisely when, because the study (and its funding) are not in place. Why should we embark on this long-term project when interesting studies, such as Prof Naviaux’s, can be done faster? My answer to this is that we – as scientists – need to be humble about what could be causing ME/CFS: we should expect the unexpected, and not only test every potential cause of the disease – one by one – as they come to mind, but test *all* possible DNA causes, including those whose biology is entirely unexpected. (Although we know more about fundamental biology than we did a decade or two back, there is so very much more that we still have to learn.)

So I think the value of the MEGA study is that it seeks underlying causes, by being objective (in scientific jargon: “hypothesis free”) and being as comprehensive as possible, whilst knowing that there are likely to be several underlying causes. It is likely that many of these causes will be environmental - not from DNA changes. Yet, when we find DNA-based causes these will – I strongly believe – lead us quickly to what these environmental causes are. This is probably the best way of finding environmental explanations of disease, because scientists are unable to easily compare environmental exposures between people with ME/CFS and those without.

I hope this helps. One last thing from me, if I may: Scientists are people, just like anyone else. The reason I started doing biology research was the hope that I could make a difference to people and, in large part, those people (friends and family) around me whose lives have been blighted by disease. There would be no better – and more thrilling – outcome of this study than its definition of the causes of this debilitating disease.
 

Simon

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New Question, and answer, replying to @trishrhymes

Thanks for your comments. Yes, this project would unfortunately take several years to come to fruition. I’m not sure that it would be prohibitively expensive, however, because funders such as the Wellcome Trust, Medical Research Council and the National Institutes of Health (in the USA) have previously funded similarly sized projects. It should also be said that any funds given to this project are very unlikely to redirect (the limited) funds currently available to other studies.

I’m not an expert in patient recruitment for such studies butI think you're right that the most severe sufferers would be excluded, but as I understand it there are many moderate patients in NHS clinics. This is not a show-stopper because what we learn from the more moderate sufferers is likely to be highly relevant to the more severe sufferers. Or at least this is what is seen in other studies.

Unfortunately the 300 ME biobank data is just not enough with which to explain the genetics of ME/CFS. If it were, then we would immediately do the study. I entirely agree: “Patients have waited too long already. We need answers soon.” I do hope that we can get this study funded and running ASAP.

Finally, I have always collaborated and shared data with scientists from across the world, and am a strong advocate of open consented data. In particular, it is clear that the MEGA study would have to work alongside the USA based studies.
 

Jo Best

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I still feel sure that a large population study of people who have the disease that's under investigation would yield better quality data. I think we're so close to biological markers now (not dependent on cause) that it would be worth waiting so that we know we have 10,000 ME/CFS patients. The studies that found high rates of misdiagnosis didn't depend on advanced differential diagnostic techniques as far as I'm aware. That pre-screening is vitally important so that the scientists know they're looking at sub-types of a disease (like cancer) rather than misdiagnoses.

The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same - http://1.usa.gov/1EOPwJW

Alternative diagnoses to chronic fatigue syndrome in referrals to a specialist service: service evaluation survey - http://1.usa.gov/1CihoUY
 
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I note that Ponting says that such a study would take 'many years'.

I just had a brainwave.

If I understand it correctly, what he needs for his study is each person's completely sequenced genome. What if this were to be done as a world wide cooperation, with every ME researcher, clinic and specialist around the world getting the DNA sequences of, say, 50 to 100 patients, properly diagnosed and in the correct proportions of severity etc and the required number of controls - we may not even need controls, if healthy people have already been sequenced for other studies and can be used.

This could then be published to a central data bank along with their phenotypes (symptom pattern based on a standard questionnaire).

All Chris Ponting would have to do then would be to apply his big data analytical process. Bingo! Results in a couple of years.

Ok, I know it's won't happen, and doesn't get around the huge cost, but don't wake me up yet, it's a lovely dream.

------

Seriously, though, do we want all this ME research funding to be tied up for years ahead on an as yet unproven hypothesis that the secret of ME will be found in our genes? It may find nothing.
 
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New Question, and answer, replying to @trishrhymes

Thanks for your comments. Yes, this project would unfortunately take several years to come to fruition. I’m not sure that it would be prohibitively expensive, however, because funders such as the Wellcome Trust, Medical Research Council and the National Institutes of Health (in the USA) have previously funded similarly sized projects. It should also be said that any funds given to this project are very unlikely to redirect (the limited) funds currently available to other studies.

I’m not an expert in patient recruitment for such studies butI think you're right that the most severe sufferers would be excluded, but as I understand it there are many moderate patients in NHS clinics. This is not a show-stopper because what we learn from the more moderate sufferers is likely to be highly relevant to the more severe sufferers. Or at least this is what is seen in other studies.

Unfortunately the 300 ME biobank data is just not enough with which to explain the genetics of ME/CFS. If it were, then we would immediately do the study. I entirely agree: “Patients have waited too long already. We need answers soon.” I do hope that we can get this study funded and running ASAP.

Finally, I have always collaborated and shared data with scientists from across the world, and am a strong advocate of open consented data. In particular, it is clear that the MEGA study would have to work alongside the USA based studies.

I'm grateful for this reply and will thank him on the blog. The paragraph that worries me in this reply is the bit about patient recruitment - I don't agree that leaving out a representative proportion of severe sufferers is un-problematic. I think it very likely that if there are genetic influences on the development of ME, severe sufferers may have a different genotype to mild sufferers, and this can only be established by including them.
 

Simon

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The studies that found high rates of misdiagnosis didn't depend on advanced differential diagnostic techniques as far as I'm aware.
They didn't, but those studies found a high rate of misdiagnosis by GPs referrring patients to CFS clinics, not misdiagnosis by the clinics themselves, eg the Julie Newton study. Here's more I posted elsewhere:

Re 50% misdiagnosis
That was 50% misdiagnosis by GPs referring patients to clinics, not misdiagnosis at the clinics themselves. Also, I think almost all the errors were down to known medical/psychiatric exclusionary causes of fatigue. 13% of diagnostic errors were cases of unexplained fatigue that didn't have enough symptoms to qualify for (FUkuda) CFS.


The Newcastle NHS Chronic Fatigue Syndrome Service: not all fatigue is the same. - PubMed - NCBI

Abstract said:
.. This service evaluation examined the proportion of those referred to a specialist CFS service fulfilling the Fukuda diagnostic criteria for CFS and the alternative fatigue-associated diagnoses. The CFS database was interrogated to include every patient referred to the Newcastle service from November 2008 to December 2009. All medical notes were reviewed and the diagnosis, sex and age recorded. Data were compared to a previous service evaluation (2005-07).

In 2008-09, 260 subjects were referred: 19 referrals per month (260/14), compared with 17 referrals per month in 2005-07 (375/24). The proportion of patients diagnosed with CFS increased significantly compared with 2007 (36% [20/56] vs 60% [157/260]; p < 0.0001).

Of the 40% of patients subsequently found not to have CFS the most common diagnosis was fatigue associated with a chronic disease (47% of all alternative diagnoses); 20% had primary sleep disorders, 15% psychological/psychiatric illnesses and 4% a cardiovascular disorder. Thirteen per cent remained unexplained (5.2% of the total referrals).

This study found a significant increase in the proportion of patients referred to National Health Service (NHS) CFS services diagnosed with CFS. A large proportion of patients presenting with fatigue are not eligible for referral to the Department of Health specialist fatigue services, which represents an unmet need in terms of symptom management in current NHS services.

GP diagnostic accuracy improved substantially (the 50% was a combined figure for the two periods, I think)
The study said:
The proportion of patients diagnosed with CFS by the Newcastle service has increased significantly compared with the results of our previous audit in 2007 (36% [20/56] vs 60% [157/260]; F p<0.0001).

Added: looking at a strongly BPS clinic, this (less thorough) study by Peter White also comes up with a 50% figure, but again these cases were excluded so wouldn't be part of a MEGA-like cohort.
Alternative diagnoses to chronic fatigue syndrome in referrals to a specialist service: service evaluation survey
 
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Crawley, on the other hand, seems to include everyone with fatigue in her definition and studies. I cannot trust her not to do the same for this study, and I seem to remember about half the pace participants didn't fit any internationally recognised definition of ME.
 

Simon

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Another question and answer

Q

Simon Ounsley
·

Thanks for your blog and answers to comments, Prof Ponting, and thank you for your interest in helping us. I'm just wondering how many patients would be needed to make the study worthwhile. You say 300 is not enough, but do we really need as many as 12000? (Thanks in advance to Simon if you are able to pass this question on.)


A from Chris P

Unfortunately the patients' sample size really does need to be much larger than 300. The first reliable studies used data from 14,000 individuals (http://europepmc.org/articles/PMC2719288). It is possible that a strong signal would be found with, say, 3000. But funders (and ourselves) need larger numbers to be convinced that there will be value for money: that something will be found in this study.
 
It is great that he is responding but how the dialogue is happening highlights the poor organisation of MEGA so far, in my opinion.

The 'blog' posts are updates on the petition. Given the number of free and low-cost blogging/website options there are out there, this just strikes me as the amateur/lazy option taken here. Also, comments, and answers, can only be made on the updates/blogs if you have a Facebook account. So Professor Ponting is having to email Simon his answers, which Simon then posts on the update. Again, amateur level.

Look at the interaction we are having with Chris Armstrong, someone who isn't looking to engage with the patient community in order to prove there is support for his research. And then look at the 'interaction' we have had previously with MEGA personnel who want to do precisely that - I'm still waiting for a further response from Holgate about patient interact following my email to him, it would seem that I should count myself lucky that the petition is being updated.
 

Jo Best

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@Simon thanks for your reply and I take your point but I don't believe all the clinics are giving a reliable diagnosis and I'd wager that GPs were better at diagnosing ME before Oxford Criteria, NICE guideline and fatigue clinics, and I certainly would not rely on diagnosis by Esther Crawley and that is crucial to the paediatric cohort. Then there are points made by others, such as the number of pwme discharged by the clinics once there is no more offer. I don't know how many clinics there are in UK currently and how many patients on their books. As the PACE researchers had to expand their criteria for inclusion due to recruitment problems (which there may be for MEGA given the level of mistrust in the patients/carer community about handling of their personal data and what it may be used for) I think it unlikely to recruit 12,000 pwme. A wide scope isn't necessarily bad, just that it shouldn't be described as ME/CFS. Researchers should use the term ME/CFS in the context of the Canadian Consensus Criteria. It's pointless and wasteful at this stage to aim to compare samples with various criteria to see what they match. ME/CFS research has moved on from there.
 

barbc56

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3,657
Geeze, sometimes these researchers are put in a no win situation by us. I find that worrisomr. Very worrisome.

The researchers are under no obligation to respond. James Coyne said something to that effect that he wants to focus on the science. While I think some of his tweets were disturbing, inappropriate and are not justifiable, on this point I absolutely agree with him.

Imput and concerns by patients is one thing but to demand that we dictate how experiments should be run may carry the risk of being dismissed as arrogance. This doesn't mean we shouldn't do this and getting our views on record is important , but I wouldn't expect any miracles.

Scientist need to go into the research with no preconceived biases and that includes Crawly.

From what I've read about some of the participants such as Poling, I think the odds are that they will call anyone who is doing this. If they don't then that's where the focus of criticism should be but at the appropriate time.

We also need to look closely at the possibility that we may also be going into this with the preconceived notions. Not surprising given are history, but something to be cognizant about..
 
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