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

[barbc56]

The 'blog' posts are updates on the petition

Isn't this what we want? Transparency which can include updating information about the study.

 

[Jo Best]

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.

Just seen an update posted by JC - https://jcoynester.wordpress.com/20...etics-alliance-project-concerns-and-response/

 

[AndyPR]

Isn't this what we want? Transparency which can include updating information about the study.

Who gets notification of these updates? I assume those people who have signed the MEGA petition. Of the patient charities involved in MEGA, how many of them posted on their social media channels about the updates? I'm amazed at how quiet the charities have been in their support of MEGA, even AfME - surely they should be shouting about every update as it goes onto the petition. How many posts have been put on this forum to keep us, the most active ME forum, up-to-date?

I'm not saying that I don't want more information, what I'm saying is that they are going about it in a poor fashion, while at the same time asking us to support them. In order to gain my support they need to be far more professional, I hate to think how they are going to handle upwards of £5m when they can't even have a function in place to allow a researcher, who is part of MEGA, to reply directly to questions from patients on his own blog post.

 

[barbc56]

Thanks @Jo Best. I agree with Coynes points.

What I disagree with is the way these goals are being carried out by the patient community. What Dr Shepherd says most reflects my views.

I may not have made that clear.

I've made my points so will let others continue as I think I've covered what I believe and why.

Plus I'm exhausted from writing all these posts.

 

[Jan]

Who gets notification of these updates? I assume those people who have signed the MEGA petition. Of the patient charities involved in MEGA, how many of them posted on their social media channels about the updates? I'm amazed at how quiet the charities have been in their support of MEGA, even AfME - surely they should be shouting about every update as it goes onto the petition. How many posts have been put on this forum to keep us, the most active ME forum, up-to-date?

I'm not saying that I don't want more information, what I'm saying is that they are going about it in a poor fashion, while at the same time asking us to support them. In order to gain my support they need to be far more professional, I hate to think how they are going to handle upwards of £5m when they can't even have a function in place to allow a researcher, who is part of MEGA, to reply directly to questions from patients on his own blog post.

Precisely. Why put the petition on a site that requires a fb account, when at least some of them can't even access it to read patient concerns? There are hundreds of patient comments on there, is anyone reading them, or are we all wasting our time and precious energy?

 

[BurnA]

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

Hi barb56, I don't think anyone is criticizing the researcher here, it's the format used by MEGA. They appear disorganised, without a website etc.

I for one welcome all interaction from researchers and appreciate their efforts so criticism aimed at MEGA should not be interpreted as in any being critical of a researcher.

 

[Simon]

There are plenty more comments: I can't keep up (blog page)

But here's a question I asked on my own behalf, and the answer, which I think is well worth a read

Me>
The science is fascinating. Could you give an example of where this kind of approach has led to insight into disease mechanisms? Thanks very much

Reply from Chris P>

Thanks Simon. One study used 1,924 type 2 diabetes patients, and then a further 3,757 patients for replication, to find that if someone has two copies of a DNA change then they weigh – on average – 3 kg more (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646098/).

A detailed ‘omics study showed that this is likely due to altered regulation of heat generation in fat cells (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1502214). This is a large effect; for a smaller effect to be detected more individuals in the cohort would have been needed

Comment from me in reply>
Thanks very much, Chris.

I'd encourage people to look at that paper on heat generation, because it involves mitochondria, which may play a role in mecfs, plus it was in the top medical journal, the NEJM - and used some elegant science including gene editing with CRISPR. I realise that things might now work out so neatly with this illness but it looks to me like a pretty impressive example of using genetics and other technologies to likely get at causal mechanisms.

 

[trishrhymes]

There are plenty more comments: I can't keep up (blog page)

But here's a question I asked on my own behalf, and the answer, which I think is well worth a read

Me>
The science is fascinating. Could you give an example of where this kind of approach has led to insight into disease mechanisms? Thanks very much

Reply from Chris P>

Thanks Simon. One study used 1,924 type 2 diabetes patients, and then a further 3,757 patients for replication, to find that if someone has two copies of a DNA change then they weigh – on average – 3 kg more (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646098/).

A detailed ‘omics study showed that this is likely due to altered regulation of heat generation in fat cells (http://www.nejm.org/doi/pdf/10.1056/NEJMoa1502214). This is a large effect; for a smaller effect to be detected more individuals in the cohort would have been needed

Comment from me in reply>
Thanks very much, Chris.

I'd encourage people to look at that paper on heat generation, because it involves mitochondria, which may play a role in mecfs, plus it was in the top medical journal, the NEJM - and used some elegant science including gene editing with CRISPR. I realise that things might now work out so neatly with this illness but it looks to me like a pretty impressive example of using genetics and other technologies to likely get at causal mechanisms.

Thanks for this Simon. It is indeed interesting. It makes me wonder why we need 12000 patients in the ME study. Could it be perhaps because of the determination of Crawley et al to make it a fatigue study, so the numbers have to be huge so that by chance a few might actually have ME.

Perhaps I could suggest a hypothetical study that might have been done instead of this diabetic study to ram my point home.

Hypothetical study of type 2 diabetes:

A study that purports to be a diabetes study but that is actually an umbrella study of obese patients, some of whom are likely to have type 2 diabetes. Such a study will need to include 12000 participants in order to be likely to include a couple of thousand diabetic patients and be justified on the grounds that we need biomedical evidence to distinguish between obese diabetics and obese non diabetics.

Use as your experts to advise on how to recruit patients for this study, the perpetrators of a slimming method that is medically shown to be unsound and ineffective and to actually make diabetic patients sicker. Recruit patients for the study only from slimming clinics run by these dodgy slimming 'experts', and which only take diabetic patients if they are mildly effected and recently diagnosed.

Before a detailed protocol has been designed for the study, set up a petition asking diabetic patients to sign in support of the study. Sell it on the grounds that great scientists are involved and don't mention that the recruitment method is such that few if any of the long term serious sufferers being asked to sign the petition have a snowball's chance in hell of being included in the study.

Then try to frighten them into signing by saying if you don't, or if you criticise, all the great researchers will run away and there won't be any study of diabetes ever again. Sorry, I'm getting a bit carried away here...

Can you see any parallels?

 

[AndyPR]

Spot on @trishrhymes

 

[AndyPR]

Follow up Q&A from an earlier Q&A.

Question

Many thanks for the info which is much appreciated. So it seems that even 12,000 would be a bit on the low side? Bearing in mind that this sample will be *very* heterogeneous, embracing numerous subgroups which are believed to constitute neurological ME plus patients with other fatigue conditions (including depression, burnout etc) which will be included in the extremely broad NICE criteria, I just wonder if this is really a viable study even at 12,000 patients? Sorry to be negative (and I really appreciate you and the other researchers wishing to be involved in this) but patients are concerned. Oh, yes, and the 12,000 will apparently include children as well, which again seems a lot to add to the mix. (Would it be usual to include adults and children together like this ?)

Answer

The selection of individuals for this study is critical and all that I have heard on this makes me believe that post-exertional malaise criteria should lie at the heart of this. The patient advisory groups that will be set up need to have a strong voice on this issue.

Is this study viable at 12k patients and given the heterogeneity? We do not know – which is why the results of this research are needed. We could go round-and-round on this issue, but until we have data/evidence no-one will know. CFE/ME may present clinically in a heterogeneous manner, but this might belie a less heterogeneous set of genetic contributions.

For example, are adult and adolescent CFS/ME the same or different? My guess is somewhere in between and, if so, understanding one will help to understand the other. Even if a 12k study does not produce clear results, when combined with other studies’ results (e.g. from the USA), it might yet. I think it worthwhile to attempt this study: scientifically it is the right thing to do next, although as with any study there is no guarantee of success

Now this answer is the sort of thing I've been looking for so that I can believe in MEGA having some value. Can they get 12,000 patients, all with PEM, could be another issue entirely though.

 

[Snowdrop]

Now this answer is the sort of thing I've been looking for so that I can believe in MEGA having some value. Can they get 12,000 patients, all with PEM, could be another issue entirely though.

The validity of the whole study hinges on the answer to that Q. There is absolutely no reason or need to prevaricate on the answer to that. It is of central importance to getting any useful information on ME and the community of PwME deserve to know/have that clearly and contractually nailed down before signing up their support

 

[AndyPR]

Thanks for the information, Dr. Ponting. This is all very interesting.

A couple of questions for you: One is, how likely is it that there is a genetic signal at all? And if there is, will it necessarily point us to the root cause? I don't intend those questions skeptically -- I just don't know the answer. Looking at other diseases, do they have genetic signals? MS, diabetes, heart disease, cancer, ALS (particularly the type that isn't strongly hereditary)?

Also, I would think that the need for a large sample would also mean that it would be especially important to have that sample be well defined. Wouldn't including someone who is very tired but doesn't have ME/CFS at all be worse than useless? Both a waste of money and a dilution of the signal? It seems like the argument is being made that it's actually good to have some of those folks, and I don't understand that at all.

Dear Julie,

Thank you for these questions. It is highly likely that genetics will contribute, but clearly environment (e.g. infection) contributes too. Here is an analogous situation: of all who are infected by the flu virus, you are far more likely to be hospitalised if you have a rare change in your DNA (IFITM3 rs12252 polymorphism; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648786/).

Genetic differences contribute to all of the diseases you mention (and many more, these are listed here: https://www.ebi.ac.uk/gwas/, e.g. for ALS: https://www.ebi.ac.uk/gwas/search...).

Yes, adding a person who clearly does not have ME/CFS will reduce the study’s power. This goes back to the dialogue that is needed on the inclusion criteria which should include input from people with CFS/ME (see previous comments). Looking in from the outside on this debate, however, I think that there is a risk here: specifically, because (even using criteria e.g. PEM/Canadian) there is no consensus / strong evidence-base about who should be included or excluded then this issue will delay any evidence being acquired. And I do understand the urgency of gathering evidence sooner rather than later to better understand CFS/ME. With the genetic data to hand, it is plausible that the genetics signals will help separate patients according to their different underlying causes.

 

[Jan]

Quote 'Looking in from the outside on this debate, however, I think that there is a risk here: specifically, because (even using criteria e.g. PEM/Canadian) there is no consensus / strong evidence-base about who should be included or excluded then this issue will delay any evidence being acquired.'

I didn't think there was a problem with consensus.

People with ME have the Canadian Criteria symptoms, and must have post exertional malaise/exacerbation of symptoms. If they don't, it's not ME.

ME was clearly defined by Melvin Ramsay 50 years ago, it's the psychiatrists who hi-jacked the illness who have muddied the waters by including anyone with varying degrees of fatigue and depression.

From http://www.name-us.org/defintionspages/deframsay.htm

Ramsay definition 1986

A syndrome initiated by a virus infection, commonly in the form of a respiratory or gastrointestinal illness with significant headache, malaise and dizziness sometimes accompanied by lymphadenopathy or rash. Insidious or more dramatic onsets following neurological, cardiac or endocrine disability are also recognised. Characteristic features include:

(1) A multisystem disease, primarily neurological with variable involvement of liver, cardiac and skeletal muscle, lymphoid and endocrine organs.

(2) Neurological disturbance – an unpredictable state of central nervous system exhaustion following mental or physical exertion which may be delayed and require several days for recovery; an unique neuro-endocrine profile which differs from depression in that the hypothalamic/pituitary/adrenal response to stress is deficient; dysfunction of the autonomic and sensory nervous systems; cognitive problems.

(3) Musculo-skeletal dysfunction in a proportion of patients (related to sensory disturbance or to the late metabolic and auto immune effects of infection)

(4) A characteristically chronic relapsing course."


Dr. Ramsay, together with Dr. Dowsett, listed this criteria for M.E. in 1990 in the same article (just prior to his death):

"We adopted the following criteria:

"A syndrome initiated by a viral infection commonly described as a respiratory/gastro intestinal illness but a gradual or more dramatic onset following neurological, cardiac or endocrine disability is recognised.

"The cardinal features, in a patient who has previously been physically and mentally fit, with a good work record are:

(1)Generalised or localised muscle fatigue after minimal exertion with prolonged recovery time.

(2)Neurological disturbance, especially of cognitive, autonomic and sensory functions, often accompanied by marked emotional lability and sleep reversal.

(3)Variable involvement of cardiac and other bodily systems.

(4)An extended relapsing course with a tendency to chronicity.

(5)Marked variability of symptoms both within and between episodes."


The failure to agree on firm diagnostic criteria has distorted the data base for epidemiological and other research, thus denying recognition of the unique epidemiological pattern of myalgic encephalomyelitis." Dr. A. Melvin Ramsay, quoted on NAME.US.org.

In Redefinitions of ME/CFS – A 20th Century Phenomenon, Dr. E.G. Dowsett summarizes historic ME and CFS definitions and emphatically states, "To Summarise: I would urge all our colleagues to look again at the literature prior to 1988 before redefining this illness''

But the psychitrists did not listen, they wanted it to be called chronic fatigue, and that is when the whole mess started.

I think there needs to be a specific ME study first, then study the fatigue patients after this. The reason I put ME patients ahead of people with other fatigue illnesses is that people are dying from ME right now, and many hundreds of thousands are rotting away in darkened bedroom denied any sort of life. People are dying and we don't yet know what the illness is due to so many years of neglect from the medical profession.

 

[Jan]

Melvin Ramsay "The illness, though similar to non-paralytic poliomyelitis in many clinical aspect, could clearly be distinguished and was diagnosed as Benign Myalgic Encephalomyelitis. This name gives a clearer clinical description than many of the eponyms used previously (Iceland Disease, Akureyri's Disease, Epidemic Neuromyasthenia) or invented subsequently (Post viral syndrome, Chronic Fatigue Immune Dysfunction Syndrome). These share the common disadvantage of obscuring the world-wide incidence or of trivializing the clinical severity of the illness."

Sadly, how true this turned out to be, the illness was trivialised and patients were told for many years that it was psychosomatic. If there had been no involvement from psychs, where would this illness have been today?

 

[Jo Best]

I've no reason to doubt the good intentions or professional integrity of Chris Ponting. His comments show why it's unwise to do such a study in collaboration with the BPS school and why the data is unlikely to yield the answers that pwme and the biomedical scientists currently working on ME/CFS are seeking in a methodical manner.

He says,

For example, are adult and adolescent CFS/ME the same or different? My guess is somewhere in between and, if so, understanding one will help to understand the other.

I wonder if Chris Ponting knows that Esther Crawley relied upon the differences she claimed exist between children and adults with ME/CFS to justify why she should carry out a study of the Lightning Process in youngsters before it was tested on adults. I admit I don't know about differences in childhood cancer, for example, compared with cancer in adults. If there are important age-related differences, is this a sort of sliding scale until adulthood or are there identifiable stages between child - adolescent - adult - and would the MEGA study aim to answer such questions.

I think the following points are far too conjectural to justify my support of the MEGA study. The timing is wrong because of the diagnostic mess that the BPS school has created in UK. Wait for the biomarkers. Then study as many patients as needed and compare with other fatigue-inducing illnesses if necessary. With such pitiful funds spent on UK biomedical research thus far and with the lion's share already going to CMRC researchers, I think it's wasteful of research funds. If the funds are privately-sourced then so be it. I object to tax-payers funding a large, long-term project with so many ifs, buts and maybes at the outset.

Even if a 12k study does not produce clear results, when combined with other studies’ results (e.g. from the USA), it might yet. I think it worthwhile to attempt this study: scientifically it is the right thing to do next, although as with any study there is no guarantee of success

 

[Cinders66]

I think research into immune aspects is showing differences between long and short term patients and th e moderate and severely ill. Are these then not Important subgroups? Indeed WHY some get rapidly severely ill and others don't is a great mystery which perhaps this type rescan unravel. I'm disappointed that, again, as always the severe are the last thing on people's minds, Yet we are the ones in extremis. I quite understand these new biomedical researchers not being particularly aware of the real issues affecting patients, unlike the norwegian drs who have through their hands on research kept the severe well and truly a focus , but can we trust Crawley, AfME, White, even Newton to be arguing our case here, I don't think it seems like it.

I think that is the problem of , as the CMRC have, approaching this as a fatigue spectrum. That type of language just isnt used in severe cirules where discussions focus on being severely unwell, the weakness and massive payback caused by everyday activities, pain, intolerances of stimulation etc. My concern regarding research being supposedly necessary to subgroup fatigue spectrums or NICE CFS criteria is it validates the UK establishments long argument that ME cannot be separated and approached in its own right as we could not prove a difference from UK CFS. I have long felt that wrong and don't believe either that we need research to prove ME is different from undiagnosed chronic fatigue, that is what eminent ME drs spent hours around tables defining criteria for , including the IOM commitee who felt SEID could be a positive diagnosis with PEM, not fatigue, at the fore.

I'm glad C Ponting recognises the importance of PEM but there's quite mixed messages generally so far about the breadth and type of umbrella they are subgroup ing.

 

[trishrhymes]

Hi @Cinders66, I've just said much the same thing about the involvement of Crawley et al on the OMEGA thread. We do need the severe and long term sufferers included. Clearly this is the last thing the biopsychosocial lot want, as there would be a danger (from their perspective) that the scientists might actually prove we really are ill

 

[justy]

Surely, apart from the more severely ill, housebound and those who don't have an ME/CFS clinic in their area (or country in the case of Wales), it will also exclude the long term ill who may have been to a clinic many years ago, but no longer bother, or have been discharged.

The sort of patients they will be recruiting will be short term, mild patients who live in certain areas of the UK and feel disposed to bother going to a 'Fatigue/CFS clinic'.

Not helpful IMHO

 

[eafw]

Can someone ask Chris Ponting the following "Within MEGA who is responsible for briefing the scientists on ME/CFS itself, that is the nature of the illness, current treatments, past research ?" and "Does he feel that he (and others who are new to the condition) have been adequately informed on this apsect of things ?"

As an aside (ie not addressed to Ponting) can we somehow request the MEGA organisers to put together a better platform for communication - primarily one that doesn't require f*cebook. They should have their own site with Q and As, links and refs, and researcher's blogs on there.

 

[Wildcat]

.
Good points eafw - but scientists new to ME may not actually know whether or not they have been adequately informed on 'the nature of the illness', 'current treatments', and 'past research'. They may think they have been adequately informed, but patients/activists would know what (for a hypothetical example) may have been left out, or spun.
.