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MEGA 'Why broad definition should be used as a starting point - by Prof Stephen Holgate'

Discussion in 'General ME/CFS News' started by aimossy, Oct 14, 2016.

  1. aimossy

    aimossy Senior Member

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    'Why broad definition should be used as a starting point - by Prof Stephen Holgate'

    M.E./CFS Epidemiology and Genomics Alliance (MEGA)

    United Kingdom
    Oct 14, 2016 — “Several of the patient/public concerns seem to relate to the worry that firstly severe disease will not be included or that we will be recruiting from a broader definition of the disease(s) beyond Fukuda and Canadian definitions. I want to reassure people on this and explain the reasons why we need to broaden the definition.

    “I believe the point George Davey-Smith was making in his CMRC presentation with his example of migraine is that to find causative pathways and uncover molecular mechanisms we need a broad range of disease severity and clinical manifestation. In the study looking for shared pathways between migraine and coronary artery disease (CAD) (http://ng.neurology.org/content/1/1/e10.full) the investigation was preceded by the statement ‘.....Migraine affects 19% of women and 11% of men worldwide and causes more years lost to disability than any other neurologic disorder. In about one-third of patients, headache attacks are preceded by transient neurologic symptoms termed migraine aura, and migraine with and without aura (MA and MO, respectively) are believed to have a partially distinct pathogenic basis.’

    “Then, after conducting the GWAS the following emerged ‘Our study provides novel insights into the relationship between migraine and CAD. Intriguingly, and unexpectedly, there was no genetic overlap between MA and CAD, for which epidemiologic studies suggest comorbidity, but there was compelling evidence for a genetic overlap between MO and CAD, where the impact of risk variants overall was in opposite direction for the 2 disorders. The results do not demonstrate that shared common genetic risk factors drive comorbidity between the two disorders. However, dissecting the mechanisms underlying the shared risk loci may improve our understanding of both disorders’. An analogy exists for CFS/M.E. in that we have imposed a descriptive definition based on symptoms Fukuda and Canadian) in the absence of knowing any causative mechanisms or genetic risk factors.

    “Clearly this will incorporate both severe disease and people who conform to the Fukuda and Canadian definitions but there will be others too with early onset disease and a spread of clinical manifestations. The US IOM recent definition (2015) seems to fulfil this and would enable us to merge data with our US colleagues later as Chris Ponting has pointed out (but not renaming the disorder!). The key as far as I see it is to ensure that each patient is deeply phenotyped and with the same operating procedures (SOPs) if you are successful in recruiting 10,000 such individuals.

    “The normal controls could be the spouses as well as the historical Wellcome Trust normal population collections (e.g. Sanger news) and https://wellcome.ac.uk/press-release/1000-genomes-project-publishes-most-comprehensive-map-date-human-genetic-variation/). It will then be possible using the many phenotypic variables collected to undertake a cluster-type analysis and interrogate the genome for each cluster. Equally it will be possible to segregate the patients in the 10,000 collection according to whether or not they conform to the Fukuda or Canadian criteria (or indeed any other of the current definitions used e.g. very severe disease) and see if molecular pathways map on to these.

    “I think we are in for some surprises in that there may well be several prominent clusters each with mild, moderate and severe manifestations but utilising different causative pathways. This is what is happening in airways disease (my own interest) in that patients we previously classified as having COPD are turning out to have a form of asthma despite lack of reversibility of airflow obstruction in these patients (the classical definition of asthma) (see linked papers on airway treatable traits). Thus identifying treatable traits linked to causal mechanisms is opening up therapeutic opportunities in those patients with airways disease in whom there was no known disease-modifying treatment offered to them previously.”

    https://www.change.org/p/support-th...w&utm_source=petition_update&utm_medium=email
     
  2. aimossy

    aimossy Senior Member

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    Last edited: Oct 14, 2016
  3. A.B.

    A.B. Senior Member

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    Way to miss the point Stephen: recruiting from NHS centers will likely result in very few, if any, severely affected patients in your 12000 person sample:

    a) these patients have physical difficulties visiting these centers
    b) the treatment offered is CBT/GET, and NICE guidelines state that severely ill should not do CBT/GET.

    A sample from the NHS referal centers will likely contain fewer patients that find CBT/GET inappropriate, and more mildly affected patients, and few long term patients. Many patients consider the CBT/GET completely inappropriate and this likely a result of characteristics of their illness. Patients and doctors are intelligent and will make a decision whether the treatment offered there is appropriate and whether to refer or visit.

    I don't think this is difficult to understand and continue to be skeptical when people such as Crawley and White are involved, which belong to a school of thought that has a long history of focusing on the mildly affected end of the spectrum in order to facilitate their dubious claims about psychosomatic causation.

    After an evasive answer about W & C, it's disappointing to read such a response.
     
    Last edited: Oct 14, 2016
  4. AndyPR

    AndyPR Senior Member

    Is it just me or does he try to explain why a broad criteria is required but doesn't explain how, or even if, severe ME patients will be included (as we know that they will need to go and find severe patients, the patients will not be able to get to MEGA).

    Also, on the point of the acronym, MEGA, shouldn't it really be CEGA, CFS/M.E. Epidemiology and Genomics Alliance, as they insist on pointlessly reversing it everywhere else. (Yes, I know it's a petty point to make but the name reversal seems petty to me, unless someone can point me towards a good reason for it.)

    He only believes? Possibly an unfortunate turn of phrase but I'd like him to know what his colleague meant, not to guess.

    I'll probably have other comments later :)
     
  5. slysaint

    slysaint Senior Member

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    Have watched them. If anyone was in any doubt about Esther Crawley watch her presentation(if you can:vomit:).
    She say's CFS in children is very common and they have a 60% recovery rate with her 'treatment'.

    'Children never mention/want biological definitions of recovery' (my paraphrasing).
    If any child is sick with any illness of course they just want to get better and be able to do the things they used to do and that is how they 'view' recovery.
    And in light of PACE it's a bit rich to talk about 'what is the definition of recovery'.
    Couldn't bear to watch all of it.
     
  6. slysaint

    slysaint Senior Member

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    One of the speakers highlighted this problem in her talk and the lengths they (the researchers) had to go to to recruit severely affected participants and the subsequent problems once they had found people who wanted to participate, but proved to be too ill to do what they wanted. Prof Stephen Holgate must have missed that presentation(?)
     
  7. Cinders66

    Cinders66 Senior Member

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    I often use the migraine analogy for why we can ALREADY , albeit not perfectly, cam subgroup the oxford /NICE guidelines and get away from the uk CFS umbrella which is grossly impeding our ability, in the severe complex form meeting ME criteria, to be understood and donated to as we deserve. Classic ME , even in early& /mild stages IMO doesn't present like chronic fatigue therefore we can distinguish it form CF as headaches are different to migraines.

    If he's suggesting taking IOM criteria over NICE and then sub grouping that (with what would have to be substantial numbers who also meet ICC and have severe forms of the ME illness (which are therefore extremely severe compared to life affecting fatigue) I will be ok with that. IOM have more legitimacy, scientific basis, world applicability and more specifics required, inc. PEM, as long as they were taught what PEM meant when it came to diagnosis. Is that what he's saying? Are uk fatigue clinics going to be able to apply tighter criteria , when many are non physician led.

    I'd personally rather Rename the "disorder" in the uk to SEID and get us a clean, respected slate, than persist with a CFS/ME umbrella outside this study and all it's baggage, IOM committee felt the CFS name was a hinderance to respect, understanding and progresd and I agree.

    One inexpensive easy way to tell who doesn't have ME in my opinion is those who call their illness a "disorder"!!
     
    Last edited: Oct 14, 2016
  8. Cinders66

    Cinders66 Senior Member

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    I agree with you on the video. Her grasp of "CFS" and approach to research is lumping and simplistic. Kids don't know what's best for them in terms of research and treatment which is why they don't ask for biological studies, but do ask for sweets and cola. They will be pro GET if it meant playing football more days which is probably how its presented, are they actually enjoying it , maybe a few are but is MAGENTA sub grouping so we can see if CF vs ME impacts on outcome? Interesting she used CFS throughout but in the media uses ME, I wish she wouldn't. I thought her response to the questions was interesting and was surprised she had not read the Rowe study, is she also unaware of the SNell GET research and the Lights & the PACE scandal? Also interesting that she said their clinic had to do GET/CBT & AM because they were in the NICE guidelines.


    Recovery is fully able bodied, as active as peers across physical, mental and social activity, feeling good and symptom free in my book. (It's not feeling much better in yourself Peter White)
     
    Last edited: Oct 14, 2016
  9. Keith Geraghty

    Keith Geraghty Senior Member

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    I will just make one short point on entry criteria - if you want to do an epigenetics study looking at biological mechanisms of illness - I'd head straight for the sickest patients with the least chance of mis-diagnosis - ie long standing clear ME/CFS with no other explanation. Two studies on referrals to CFS clinics have shown a rough 50% error rate in referrals - 50% wrongly diagnosed with CFS and sent back; these studies didnt follow up to see if the 50% kept on for CBT-GET actually had ME/CFS (this was accepted on face value).

    Saying we need to keep the net wide to look at all possibilities is fine, but you have to decide what fish you want to catch too, otherwise you'll have a mixed bag of fish and crabs.
     
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  10. Yogi

    Yogi Senior Member

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    Absolutely. Typical evasive and obfuscating response that I completely expected from Holgate.

    Of course it should be CEGA. In the UK they always use CFS/ME. But hey they need to sell it to the ME charities and for them to sell it to gullible patients. This is what you learn in a marketing degree.

    The irony is MEGA WILL NOT INCLUDE ME patients.

    These people are not true scientists but marketers.

    E.g.

    MEGA
    PACE
    FINE
    SMILE:)
    FITNET
    MAGENTA:aghhh:

    This is where all the focus has been, not on science.

    They need to focus on severe ME patients and he doesn't address this given severe patients cannot attend and then avoid the NHS due to useless and harmful therapies.

    He criticises fukuda/CCC but doesn't similarly criticise NICE and Oxford criteria (which includes mental illnesses including depression). Remember Crawley re-diagnoses those with CFS/ME who don't get better especially the severe with GET as persistent refusal syndrome PRS. Do we go so broad that we include ALL PRS and somatoform disorders and hysteria? White and Wessely claim that somatoform, hysteria and CFS ME and fibromyalgia are all the same.

    I note he also doesn't talk about the important Crawley and White issue which means that study is fatally flawed and therefore we should not support it in its current form.

    It is not difficult to understand - why can't they. Because Holgate is friends with Wessely.

    I think MEGA should be be called GIGO!

    Garbage In Garbage Out
     
    Last edited: Oct 14, 2016
  11. Valentijn

    Valentijn Senior Member

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    I see the problem. Instead of a CMRC (CFS/ME Research Collaborative) we need a MCRC (ME/CFS Research Collaborative). That should keep out the quacks who can't abide calling it anything other than "CFS" or "CFS/ME". :nerd:
     
  12. trishrhymes

    trishrhymes Senior Member

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    Edit: I've just seen Keith Geraghty's post and he has made the points I wanted to make much more succinctly. Here's mine anyway, for what it's worth.

    Edit 2: spelling corrected Fukuda

    I've just looked up the Fukuda criteria. (see below).

    I can see how Crawley et al could easily squeeze into this group lots of kids who are, for example, tired because they've been on Facebook on their i-phones or watching TV during the night and not admitting it to their parents. (No teenager is going to admit to being addicted to watching porn!)

    Loads of kids have poor sleep patterns, loads are anxious or depressed because of social circumstances, loads tell their parents they are 'too tired' to co-operate with what parents want to do, loads are badly nourished, loads can't concentrate in school for all sorts of reasons, loads get a series of throat infections.

    And this is true for adults too. Then there's burn-out, which is different again.

    Here's the symptom list for these multitudes:

    Tired all the time,
    concentration problems at school or work
    muscle or joint pain from poor posture,
    headaches - (from tension, posture, poor sleep, poor diet)
    unrefreshing sleep.

    BIngo, CFS diagnosed by Fukuda criteria.

    And busy GP's may be tempted to refer them to a fatigue clinic rather than having the time or knowledge to do differential diagnosis. I doubt most GP's have even heard of post-exertional malaise, or understand it as it applies to ME.

    I think of a student I had in my teaching days who couldn't concentrate and kept falling asleep in class - he was working night shifts to keep himself in College and wasn't eating properly! He would have fitted the Fukuda criteria.

    I reckon I would have fitted the Fukuda criteria in my first year as a young teacher - tired all the time, lots of sore throats, poor sleep, trouble concentrating, headaches. All the consequences of a new stressful job. Nothing to do with ME.

    If it's people like Crawley doing the 'clinical evaluation' of patients as described in the Fikuda criteria, I have no trust that she would do it properly to exclude all the above factors, since she has past form on this, publishing, for example, a study of CFS prevalence based on parents filling in a questionnaire about their children.

    She seems to equate CFS with tatt (tired all the time). Since she believes all chronic fatigue is caused by wrong beliefs and lack of exercise, she will see no reason to understand any differences between fatigue conditions. And I doubt she really understands what post-exertional malaise is, if she's pushing kids to go on exercising through it. Will she tick the PEM box for patients if they say they feel achey after exercise and feel tired the next day after playing sport?


    That's why we need clinicians who really understand ME to do the diagnosis.


    There seem to me to be 3 groups who might be turning up at fatigue clinics:

    1. Mild to moderate ME sufferers with PEM;
    2. fatigue sufferers with some other undiagnosed internal problem but without PEM,
    3. people who, as I describe above are tired all the time because of external factors in their lives, not because of some internal physiological factor.

    I do see the point of having a comparison group who suffer unexplained fatigue as well as healthy controls, but these must surely be people from groups 1 and 2, not group 3.

    My fear is that the sample, however large, will be so 'contaminated' by group 3 that any evidence will be diluted into insignificance and a great deal of money and time will be wasted, and the biopsychosocial model will be apparently strengthened.

    Much as I want to see a large biomedical study of ME, I'm not convinced that this is it. Please, someone, prove me wrong!

    Fukuda criteria:


    Guidelines for the Evaluation and Study of CFS:A thorough medical history, physical examination, mental status examination, and laboratory tests must be conducted to identify underlying or contributing conditions that require treatment. Diagnosis or classification cannot be made without such an evaluation. Clinically evaluated, unexplained chronic fatigue cases can be classified as chronic fatigue syndrome if the patient meets both the following criteria:
    1. Clinically evaluated, unexplained persistent or relapsing chronic fatigue that is of new or definite onset (i.e., not lifelong), is not the result of ongoing exertion, is not substantially alleviated by rest, and results in substantial reducation in previous levels of occupational, educational, social, or personal activities.

    2. The concurrent occurrence of four or more of the following symptoms:

    • substantial impairment in short-term memory or concentration;
    • sore throat;
    • tender lymph nodes;
    • muscle pain;
    • multi-joint pain without swelling or redness;
    • headaches of a new type, pattern, or severity;
    • unrefreshing sleep; and
    • post-exertional malaise lasting more than 24 hours.
    These symptoms must have persisted or recurred during 6 or more consecutive months of illness and must not have predated the fatigue.
     
    Last edited: Oct 14, 2016
  13. A.B.

    A.B. Senior Member

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    Or we don't need a CMRC at all. Let Invest in ME handle research strategy during their conferences. Problem solved. Oh right, IIME doesn't care about psychiatric explanations, so whoever is attached to those needs a "broad church" like the CMRC.
     
  14. Cinders66

    Cinders66 Senior Member

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    I've just been reading MAGENTA and Crawleys definition in there is broad. That's people's concern here. But if they use IOM then it's a big improvement on the unexplained fatigue ideas which have been going around as the umbrella here, maybe they've modified their plan in response to the expression of partient concern?. I do think perhaps, after watching SHs CMRC presentation where he talks of the metabolomics study going on worldwide, that it is much better if there's going to be a large study with more common ground with what's happening elsewhere, which I didn't see when NICE criteria was being suggested (which it was in the original Q & As) although @Keith Geraghty as a researcher probably understands best how this research can work and he highlights concerns still.
     
    Last edited: Oct 14, 2016
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  15. worldbackwards

    worldbackwards A unique snowflake

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    You say Fikuda, I say Fukuda...
     
  16. John Mac

    John Mac Senior Member

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    Let's call the whole thing off
     
  17. aimossy

    aimossy Senior Member

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    This form of communication from cmrc and mega is ridiculous. I don't know how they can possibly think they are helping by communication being carried out this way. It's coming across all Wombles of Wimbledon and completely disorganised.

    It is unfathomable that mega and cmrc don't have a website to use. They need one! This is out of control, inneffective and probably causing stress to many least of all patients.

    They need to detail all their information and their plans on a website. They need to detail how they will communicate with patients and how patients will be able to submit things to mega otherwise I can't believe they will be taking patients seriously in this process.

    Have they even acknowledged to themselves what they need to do next and what priorities of tasks need to be done. Even NIH is doing education for their intramural people from specialist clinicians.

    Right now I can't even take this seriously because this quite frankly is Mickey Mouse and unprofessional.

    MEGA, go away and sort yourselves and the process out properly before you put anymore blogs out on a petition! If you don't you will receive more flak and basically you've earned that flak. This is disrespectful to a community full of many useful and intelligent people who could help you actually do something useful and help you acheive it, but you need to take patients seriously and seek their constructive input.

    Right now the only option your giving people is for them to get mad at you for doing a poor job of communicating and it is clear to us you are missing many important points in what you are sending out. Wake up for crying out loud this is just so darn insightless!
     
    Last edited: Oct 14, 2016
  18. trishrhymes

    trishrhymes Senior Member

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    Oops!

    I clearly have an inbuilt resistance to typing Fuk - u

    :rofl::rofl::rofl:
     
  19. worldbackwards

    worldbackwards A unique snowflake

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    That would assume that they will be making good use of the things that they find.
     
  20. aimossy

    aimossy Senior Member

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    Unfortunately @worldbackwards I feel strongly that this work could be amazing but only if done properly and I'm loosing all faith now that it will be and that patients will have sincere input in development. That's aside from Crawely White concerns I mean. How can you have any confidence in them listening if they go about things this way. I'm done with hope right now. The insightlessness from them just seems either ignorant or arrogant I don't know which at this point.
     

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