Steve Hawkins, who often comments here at the blog and quietly does a lot of useful activist stuff behind the scenes, left the following comment/proposal on the OMEGA petition site (and added it here in response to the previous post). I thought it was worthy of a wider audience so I’m reposting it here to kick off today’s blog:
‘It seems unfortunate that there has to be a petition of this kind against what, in the right hands, and with careful preparation of protocols in advance, would undoubtedly be a gathering of very useful data; and I feel uncomfortable that this will discourage some of the very able researchers and research teams who have been brought into the MEGA group but had no part in earlier ill advised research proposals; but it seems that something of this sort will have to be done, to ensure a complete new start, and clean break with the discredited ‘science’ of biopsychosocial egotists.
‘I apologise to the, well-meaning, I’m sure, Prof. Holgate, and those others who I fear have had to be reticent in criticising poor research, because of the binding conditions that were attached to membership of the Research Collaborative, under the direction of the partisan ‘Science Media Centre’, but the time really has come to return to both freedom of speech and information in this research field, after the gambit of crying ‘harassment’ after any honest questioning, has been so clearly shown up for what it was, in the courts.
‘I would advise that a new steering group be set up for a large and inclusive, data gathering and biomic sequencing and typing study with the major emphasis on the severely affected, who are the most likely to yield clear differences worthy of more intensive study. By all means collect data from a quota of less severely disabled/sick patients as well, but only to the number necessary to provide a control match for each of the seriously ill study subjects. A similar number of healthy controls will also be needed.
‘Thus the size and expense of the study should stem from the maximum number of seriously ill participants for statistical certainty… (plus controls). If that turns out to be a very big cost: then let all patient organisations and researchers get together and lobby for those necessarily big funds to be made available. With the skyrocketing costs of indefinite medical care, I would say that, no matter what the cost of such a project, it will be tiny compared with the costs of the failure to treat, into infinity.’
Like Steve, I feel that a focus on the severely affected would be a better idea than the sample which is currently proposed for MEGA. On top of the various concerns I’ve covered in earlier posts, the vast numbers proposed for MEGA seem impractical. Prof Malcolm Hooper and Margaret Williams have observed as follows:
‘The PACE trial had to assess 3,158 individuals to find 641 who met the broadest definition of “chronic fatigue” (the Oxford criteria) and who were willing to participate in the study. If the same ratio applies in MEGA, then about 60,000 people will have to be assessed to find the 12,000 said to be necessary to tease apart the presumed subgroups that fall within such a broadly defined cohort. Furthermore, such a large study group severely limits the range and quality of testing that can be applied to each individual due to budgetary constraints. Would a better understanding of the disease not emerge from more in-depth investigations of a smaller but better characterised cohort?’
If we want to study ME, would it not be best to use a sample based on the cardinal ME symptom of PEM? This would tend to focus on the severely and moderately affected patients but exclude those with other fatigue conditions who are more likely to be mildly affected. It would represent the ‘smaller but better characterised cohort’ that Hooper and Williams suggest.
We are told that a broad sample is required for an ‘omics’ study, but surely there is a need to balance this against the feasibility and expense of building such a sample? Is the 12,000 strong sample that has been suggested in the MEGA publicity really either necessary or feasible? From what we already know of the diversity of ME, would not a rather smaller sample of those with PEM still provide sufficient sub-groups to be discovered? Do we learn any more about ME from also including patients with other forms of fatigue – or do we just generate more expense?
Prof Chris Ponting of the MEGA team explained in the comments on his blog on the Change.org site: “adding a person who clearly does not have ME/CFS will reduce the study’s power”. So presumably the study’s power would be reduced by the patients with other fatigue conditions who would inevitably be included in the sample from the clinics which has been proposed. Prof Ponting adds further: “ 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.” I don’t think any of us will argue with that.
But how to obtain these patients with PEM that Prof Ponting is so clear that we need? Prof Jonathan Edwards has suggested we follow the lead of the existing UK Biobank. He says: ‘The Biobank recruited not from clinics but from primary care. That has the advantage that it picks up everyone in a defined population who is known to the GP to have ME. If someone is not known to the GP to have ME they are not going to be at a clinic either but there will be lots of patients that the GP is aware of but who do not attend clinics. As I understand it the patients were also vetted by a nurse specialist dedicated to the project to ensure that they conformed to various sets of criteria.’
So that’s it then. That’s what we do. I don’t know how big the sample size needs to be but it will be less than the original 12,000 because it won’t include the patients with other fatigue conditions who would be present in the sample from the clinics. The existing biobank has 500 patients to make a start with plus funding to expand. So testing could start right away (at least in a small way) which is more than could be said with the original proposal. So why not get this underway? It’s time to get together and sort this out and get this bird up and flying…
12 thoughts on “Getting Airborne”
The comments you report from Prof. Ponting are encouraging…
Yes, I agree. He gives the impression that he has some understanding of ME and is ‘on our side’. This study would be a much better prospect if only Prof Crawley were not involved. Then we might be able to talk them round to the sort of plan I mentioned in the post. It sounds like Prof Ponting might be open to it. But unfortunately Crawley is involved, apparently very much at the centre of things and she likes to do things her way.
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Probably some heated debates going on backstage at MEGA between Dr. Crawley and the actual scientists. But, as you say, she seems to be in a strong position, especially with AYME involved. Really like the comments from Steve Hawkins and Prof Edwards too, btw. I’m in Wales so not a potential participant I think, but Prof. Edwards’ idea about using GPs would mean people like me in England could volunteer.
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Unfortunately I’m not sure there are any such heated debates. The word is that the scientists bow to Prof Crawley as an ME ‘expert’. Much as I try to be optimistic, I don’t think we’re going to get a helpful study as long as Crawley is involved. We need to somehow get the word out to the scientists about what an awful researcher she is. It’s not just her support for PACE that’s the problem. Her ‘Age 16’ study was just such a dreadful piece of work, especially in terms of patient selection. https://spoonseeker.com/2016/02/03/none-the-wiser-2/
I think people with ME would very much like to include the whole of UK if possible. The exclusion of Wales, Sctoland, NI was because the patients were going to come from the clinics. But if we can get that changed, the same restriction doesn’t necessarily need to apply.
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It doesn’t inspire a lot of confidence, when a group of, supposedly careful researchers either do not check the work of people they allow to lead them, or cannot, themselves, tell good from bad work.
It’s the same problem we’ve had with exposing PACE all along. People mistake standing and reputation for proof of competence.
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Thanks for taking up my suggestion.
A useful guide might be found in Griffith Uni’s recent study on protein kinases in moderate and severe patients. With their careful selection and access to severe patients, they were able to get significant results from as few as 11 moderate, and 12 severe patients. The severe patients were clearly distinguished by RNA differences:
“Method: Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years).
Results: The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls.
Conclusions: In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness. ”
Whilst it is still possible that these differences may prove to be a fluke with such a small patient cohort, it does seem to offer some indication of what might be achievable once we start seriously making an effort to involve those who are most obviously ill.
Good to hear from Hooper and Ponting. Not so good to hear that Crawley is the driving force rather than just one advisor. If that really is the case, then I can’t see the ‘Crawlaborative’ ever being trusted by the patient community, and would suggest going with a better thought out proposal using the Biobank resources and as many extra participants as necessary for best statistical practice.
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I can see how a small sample can sometimes produce a useful result but they seem to have set their heart on this being a big data study. I think I grasp the logic of this: in a field such as ME where so much is unknown, a big data study allows previously unsuspected patterns to emerge. However, my comprehension is – how shall I put it? – a few beans short of a full english breakfast…
Without a decent sized quota of the seriously affected, where differences from background are likely to be genuine, there will be no standard to hold up against all the noisy data from the ‘clinic’ quota who will be representing a full spectrum of fatiguing conditions. You could group them all, but you might not have any with actual M.E in the whole 13000, if they were all the ‘walking wounded’.
Big databases are being collected everywhere, now that servers are getting to be colossal. Some entrepreneurs are trying to pool all the medical records and gene sequences they can get hold of, with the objective of finding matches for any patient, in both test results and genes, and in symptoms and life/environmental parameters too. This is real astronomical number crunching that is the new cosmology to top mathematicians, but, for the purposes of M.E research, maxing on the severe quota will be the key that unlocks the rest. I don’t think it will help very much to spend masses of time and money sampling any more less serious cases, than necessary to show the differences from the severe cases. There ought to be clear boundaries of numbers set right from the start, or money could be wasted that could have been used for the actual test and trial proposals that will come after the data is assessed.
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There is a precedent here with Ron Davis study at Stanford ie., ” small can be beautiful” !!see the Invest in ME Conference info and DVD…
And on top of the waste of money MEGA might constitute, it occurs to me that a large collection of poorly documented samples from the clinics could potentially ‘pollute’ a future international pooled resource of ME data. Sonya Chowdhury has been at the IACFSME conference banging the gong for MEGA. Are US patients and researchers sufficiently aware of our concerns about the study? I’ve been hoping to do what little I could to make MEGA somehow work, but is the least damaging option for it to fail entirely? – unless we can somehow extricate Crawley (which seems unlikely).
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The more one looks into it, the more one begins to feel that we could end up with a vast store of authentic looking data defined by being associated with diagnoses that are baseless opinions of psychologists.
Whilst the general medical research community will still find a collection of measured parameters of any group of people useful as it adds to the sum of big data to look for patterns, its immediate use to the M.E researcher may be limited by the same ‘garbage in: garbage out’ that has been the norm for decades. 😦
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