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New MEGA study website (30 November 2016)

Jo Best

Senior Member
Messages
1,032
Doesn't this approach just show the stark contrast with MEGA.. http://kavlifondet.no/2016/12/new-study-on-pathological-mechanisms-in-me-from-bergen-research-group/
More than 200 patients have been included in our studies after thorough medical assessment according to internationally accepted («Canadian») criteria. These patients are subject to systematical and standardized follow-up in the studies, and regularly donate blood samples to a research biobank. Based on the material collected in the biobank, the research group has conducted a comprehensive and detailed mapping of the metabolism in 200 patients and 100 healthy controls. The project was supervised by the authors (Karl Johan Tronstad, Øystein Fluge and Olav Mella), and conducted in collaboration with Bevital AS and Per M. Ueland.

As a result of these metabolic analyses, we detected specific biochemical changes in the blood of ME/CFS patients. These findings have now been published in the Journal of Clinical Investigation Insight.

The analyses of blood samples from the ME/CFS patients showed that the levels of certain amino acids were reduced compared to healthy control subjects. The pattern of amino acid changes gave us important information about the symptom mechanisms, and in particular about the patients’ energy metabolism.
PR thread on this study - http://forums.phoenixrising.me/inde...function-in-myalgic-encephalopathy-cfs.48446/
 

Cinders66

Senior Member
Messages
494
In b
For me Esther Crawley is not really the problem-- even people who still want to support the trial are willing to do so only with the caveat of her not being involved (a point I consider naive since there is no study here without her).

Stephen Holgate on the other hand, supposedly is not part of bPS psychiatric model and wants good bio research for people with ME (despite his unwillingness to engage with said people and his patronising attitude when answering non-questions).

The fundamental flaw in most research in the UK up to now has been what's been called the 'big tent' inclusive approach. Always said with a sense of superior knowledge we poor sufferers of disease cannot appreciate as if it's an issue that equates to bigotry not to include everyone.

I think what we need from MEGA (which we may or may not have--I'm not sure) is a very crystal clear statement of what they hope to achieve with the data from a biomedical standpoint. Maybe then we could ask around (as stakeholders for whom the research matters) in the larger scientific community ; how would they go about designing a study to achieve the biological information sought. What design would yield the best clearest conclusions (whatever they might be).

Since I'm not science literate perhaps this is a little simplistic. I've read Jonathan Edwards say that he didn't think a 'fishing expedition' type approach would be useful--that there should be some sort of hypothesis.

My point is; given what we know so far about ME maybe the question should be asked: what type of study (in detail) is likely to yield something of use. What would the study look like. How would it be designed.

I think that taking the time to answer this and defend it would be a good pro-active step toward (in my opinion) knocking down this 'big tent' which I find to be utter nonsense.


In big tents, if you mean open wide definitions, the more severe get lost, that's the result and the BPS people simply don't care about that. I think from their perspective those who got severe were accidents that shouldn't happen as much now more is known about management, therefore just let these generations die off without help.

Holgate interestingly called those in the Navieux study more severe forms of CFS/ME, which surprised me as I had had a discussion with a fellow severe sufferer whose concern was that Naviauxs participants were Such high function (Cort Johnson wrote of his involvement in Naviauxs follow up study as something he shot down to after attending a wedding the day before etc , these are hardly the more severe in the ME world yet in the big tent /wide net , they are. That just makes people in homes and beds "extreme and rare" and we all know want happens to that category.

There needs from the MRC a five year plan, ring-fencing put up and that should driving research covering all sorts, with about £10m on the table. MEGA can run as well but should as Jane Colby said be renamed as its not an ME study.

If you mean big tents as including multi views, BPS then I agree we need a move to a biomedical collaborative as the open medicine foundation has put together.
 

Jo Best

Senior Member
Messages
1,032
If you mean big tents as including multi views, BPS then I agree we need a move to a biomedical collaborative as the open medicine foundation has put together.
That was evolving before CMRC was formed - via the Invest in ME Research strategy. Your mention of the new Spanish study is a good example as Elisa Oltra spoke at the 11th Invest in ME Conference this year (as linked to in the MEA article) enabling networking with other researchers / research funders.

Professors Simon Carding and Tom Wileman have been working steadily on the IiMER Centre of Excellence translational biomedical research strategy, @Jonathan Edwards and Jo Cambridge are making excellent contributions to the development of this work, and joined by Angela Vincent at Oxford. Their research is already including patients with severe ME, with samples taken at home.

The international collaboration is second to none, I would suggest, and is facilitated by the IiMER international conference events, including the biomedical researchers colloquium, and the European ME Research Group formed last year. This all just reinforces the fact that Stephen Holgate could have supported and helped develop what is being done by IiMER instead of veering off to set up the 'big tent' CMRC. For example, 2013, the same year the CMRC was formed, Jonathan Edwards wrote - http://www.ukrituximabtrial.org/Rituximab news-July13 01.htm
My interest in ME/CFS was sparked when I was invited, unexpectedly, by IiME to the IiMEC8 Conference in May.

The meeting was impressive: not just professional science, but at a high level. I was particularly impressed that negative findings were given adequate weight.

It became clear to me that there was a community committed to identifying and encouraging the very best research in a difficult and neglected field.
 

Chrisb

Senior Member
Messages
1,051
Someone with active working memory tell me if this has already been discussed here. Please.

Has the whole scale of the problem of sample collection been greatly underestimated? There seem to be rumblings about home visits to the severely affected. Have the problems of the "mildly" affected been considered?

There are mildly affected people in whom the illness takes a cyclical pattern. They would , of course, be quite capable of making their way to a doctor, or to a clinic, to have samples taken. The problem is that they would only be able to do this when they were reasonably well. At the times when it would probably be most useful to obtain the samples they are unable to leave their bed, let alone the house, and they may well be unable to communicate with the world that they are in such a state, even if the world were interested in the predicament.

ME is probably unusual amongst illnesses in that one can generally only get to see a doctor at a time when one is as well as one ever gets. At such times one might reasonably expect differences between the ME sufferer and a control to be at a minimum.

If this problem is to be ignored, it would be necessary first to show that, by the methods to be used, it is not possible to show a difference in a group of susceptible individuals between the times of minimum and maximum effect.

Or am I wrong. As usual.
 
Messages
2,158
Someone with active working memory tell me if this has already been discussed here. Please.

Has the whole scale of the problem of sample collection been greatly underestimated? There seem to be rumblings about home visits to the severely affected. Have the problems of the "mildly" affected been considered?

There are mildly affected people in whom the illness takes a cyclical pattern. They would , of course, be quite capable of making their way to a doctor, or to a clinic, to have samples taken. The problem is that they would only be able to do this when they were reasonably well. At the times when it would probably be most useful to obtain the samples they are unable to leave their bed, let alone the house, and they may well be unable to communicate with the world that they are in such a state, even if the world were interested in the predicament.

ME is probably unusual amongst illnesses in that one can generally only get to see a doctor at a time when one is as well as one ever gets. At such times one might reasonably expect differences between the ME sufferer and a control to be at a minimum.

If this problem is to be ignored, it would be necessary first to show that, by the methods to be used, it is not possible to show a difference in a group of susceptible individuals between the times of minimum and maximum effect.

Or am I wrong. As usual.

I think you make a very good point that is likely to be a problem when measuring things that vary. For genetic tests it doesn't matter what we are feeling like, because our genes don't change, but for epigenitics, metabolomics etc, I assume it would vary for example according to whether we are in the midst of PEM, have just exercised (eg getting to the clinic) or are well rested.

That's why some people are doing longitudinal studies looking at biochemistry in different phases for the same person.
 

CFS_for_19_years

Hoarder of biscuits
Messages
2,396
Location
USA
There are mildly affected people in whom the illness takes a cyclical pattern. They would , of course, be quite capable of making their way to a doctor, or to a clinic, to have samples taken. The problem is that they would only be able to do this when they were reasonably well. At the times when it would probably be most useful to obtain the samples they are unable to leave their bed, let alone the house, and they may well be unable to communicate with the world that they are in such a state, even if the world were interested in the predicament.

ME is probably unusual amongst illnesses in that one can generally only get to see a doctor at a time when one is as well as one ever gets. At such times one might reasonably expect differences between the ME sufferer and a control to be at a minimum.

In this 2004 paper co-authored by Peter White, there were dramatic changes in TGF-β just from getting up in the morning and traveling to the hospital (see Table 3).
https://niceguidelines.files.wordpress.com/2015/01/white-jcfs-2004.pdf

I hope the MEGA study will take into account whether samples were collected at home vs. any activity the patient had to go through just to have samples collected.
 
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Messages
2,391
Location
UK
Someone with active working memory tell me if this has already been discussed here. Please.

Has the whole scale of the problem of sample collection been greatly underestimated? There seem to be rumblings about home visits to the severely affected. Have the problems of the "mildly" affected been considered?

There are mildly affected people in whom the illness takes a cyclical pattern. They would , of course, be quite capable of making their way to a doctor, or to a clinic, to have samples taken. The problem is that they would only be able to do this when they were reasonably well. At the times when it would probably be most useful to obtain the samples they are unable to leave their bed, let alone the house, and they may well be unable to communicate with the world that they are in such a state, even if the world were interested in the predicament.

ME is probably unusual amongst illnesses in that one can generally only get to see a doctor at a time when one is as well as one ever gets. At such times one might reasonably expect differences between the ME sufferer and a control to be at a minimum.

If this problem is to be ignored, it would be necessary first to show that, by the methods to be used, it is not possible to show a difference in a group of susceptible individuals between the times of minimum and maximum effect.

Or am I wrong. As usual.
I think your observation is extremely pertinent. You highlight an easily (and maybe often) overlooked example of selective sampling, whereby the signals being sampled are cyclical in nature, and only the easier-to-acquire samples are being collected, effectively clipping the sampled signals (imagine a signal drawn on paper, and then you clip the top of it off with scissors). If the ignored signal values nonetheless represent an important part of the normal operating region, then you have serious problem - either analysis of the process (as here), and/or real time control of it.

Although clearly a major issue for ME/CFS, there must be plenty of other medical conditions where a similar problem applies; have strategies already been developed to help cope?
 

user9876

Senior Member
Messages
4,556
I think your observation is extremely pertinent. You highlight an easily (and maybe often) overlooked example of selective sampling, whereby the signals being sampled are cyclical in nature, and only the easier-to-acquire samples are being collected, effectively clipping the sampled signals (imagine a signal drawn on paper, and then you clip the top of it off with scissors). If the ignored signal values nonetheless represent an important part of the normal operating region, then you have serious problem - either analysis of the process (as here), and/or real time control of it.

Although clearly a major issue for ME/CFS, there must be plenty of other medical conditions where a similar problem applies; have strategies already been developed to help cope?

I think its less cyclic and more shock (exertion) driven but they need to understand samples as being part of a dynamic system. I've wondered if this is part of the issue with unreproducable samples.

If I was them the proposal I would be putting in would be a detailed study of a small number of patients and taking blood samples as often as possible along with monitoring activity and other health measures. Without knowing the stability of the measures anything else could be meaningless.
 

medfeb

Senior Member
Messages
491
This has been posted on another thread but what she (Nancy Klimas) says confirms again that MEGA is a waste of time,money and resources. IE the entry criteria should be MORE restrictive/targeted:
Thank you for posting. Couldn't agree more.

Its unclear what patients the big tent approach of MEGA will include. NICE is said to require PEM and yet it defines the exacerbation of symptoms following physical or mental exertion that is characteristic of PEM as optional. So how will MEGA define and operationalize PEM? And do they agree that properly defined ME cohorts will leave out some patients who have been swept into a "CFS" diagnosis but do not have ME.

Another potential red flag for me is the plan to include 10,000 patients. Given the lack of recognition and diagnosis, I would think even the U.S. would struggle to do a study with 10,000 bonafide ME patients and it's population is 5 times that of the U.K. Of course our fragmented health care system exacerbates that problem. The existence of the national health service could help but only if the services properly recognize the disease.
 

charles shepherd

Senior Member
Messages
2,239
Thank you for posting. Couldn't agree more.

Its unclear what patients the big tent approach of MEGA will include. NICE is said to require PEM and yet it defines the exacerbation of symptoms following physical or mental exertion that is characteristic of PEM as optional. So how will MEGA define and operationalize PEM? And do they agree that properly defined ME cohorts will leave out some patients who have been swept into a "CFS" diagnosis but do not have ME.

Another potential red flag for me is the plan to include 10,000 patients. Given the lack of recognition and diagnosis, I would think even the U.S. would struggle to do a study with 10,000 bonafide ME patients and it's population is 5 times that of the U.K. Of course our fragmented health care system exacerbates that problem. The existence of the national health service could help but only if the services properly recognize the disease.

The MEA has consistently taken the position that the NICE guideline on ME/CFS is not fit for purpose

We also believe that the NICE guideline list of symptoms that should lead to the CONSIDERATION of a diagnosis of ME/CFS being made should NOT be used as a diagnostic criteria for ME/CFS - which it clearly is by some doctors

However, for the sake of factual accuracy it should also be noted that this list of ME/CFS symptoms from NICE is supposed to be there as a prompt for doctors to CONSIDER the possibility that the patient has a diagnosis of ME/CFS

And that the wording relating to post extertional malaise is quite specific:

Fatigue with ALL of the following features:
- new or specific onset
- persistent and/or recurrent
- unexplained by other conditions
- has resulted in a substantial reduction in activity level characterised by post exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days)

So PEM is not an optional extra in the NICE guideline list of symptoms!
 

duncan

Senior Member
Messages
2,240
has resulted in a substantial reduction in activity level characterised by post exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days)

"and/or fatigue"?

Doesn't the "and/or" alter the meaning of PEM, at least potentially?

One could interpret this as PEM is literally either malaise and/or fatigue after exertion - not a significant exacerbation of the ME/CFS symptom cluster.

Regardless, another way to interpret is that either PEM or fatigue after exertion is required, depending on the reader, so that PEM is rendered optional. I have not reviewed the website recently - perhaps it is clarified there.
 
Messages
2,125
the meaning of PEM
this needs much more clarification to the medical profession; maybe the use of gene expression (see Lucinda Batemans talks) of pw ME would explain better:
upload_2017-1-2_18-8-22.png


at the top are healthy people post exercise, at the bottom are people with MS and in the middle pwME.
 
Messages
2,391
Location
UK
Agreed. However Crawley habitually omits it from her studies, while still claiming that she recruits using NICE.

NICE criteria aren't that bad. But Crawley's interpretation of them is either extremely dishonest or completely incompetent.
It is classic of all such folk. They conveniently cannot see (in fact I sometimes think that the way they model the world means they really cannot see) that a partial truth can amount to a strongly inferred lie; lying by omission. They justify to themselves (and are typically baffled why others cannot abide their justifications) that by telling some of the truth, they are not therefore lying.

A (fictional) example I sometimes use goes like this, where everything Mr A says is true. Mr A tells people that he was walking his dog along the pavement, when Mrs B was driving past and without any warning suddenly swerved her car deliberately onto the pavement and injured his dog; Mrs B had never liked his dog he said. Word spreads and Mrs B is vilified. Then one day Miss X is telling Mr Y about it, and Mr Y replies "Yes, I know it was terrible - I saw it. But thank goodness Mrs B managed to miss that little girl who ran out in front of her".
 
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medfeb

Senior Member
Messages
491
Fatigue with ALL of the following features:
- new or specific onset
- persistent and/or recurrent
- unexplained by other conditions
- has resulted in a substantial reduction in activity level characterised by post exertional malaise and/or fatigue (typically delayed, for example by at least 24 hours, with slow recovery over several days)

So PEM is not an optional extra in the NICE guideline list of symptoms!

True. But then, NICE includes "physical or mental exertion makes symptoms worse" in the list of 10 symptoms of which the patient only needs to have any one. That makes this symptom optional.

Given that the exacerbation of symptoms following physical or mental exertion is the core of PEM, I am left unclear how NICE is really defining PEM. And I'd imagine it leaves a lot of latitude for interpretation.
 

Dolphin

Senior Member
Messages
17,567
Prof Paul Little, University of Southampton

Prof Paul Little is Prof of Primary Care Research at the University of Southampton, a Fellow of the Academy of Medical Sciences, Emeritus NIHR Senior Investigator, and currently Director of the NIHR Programme Grants for Applied Research Board. Prof Little has led the largest trials and cohort studies to date for the management of infections and their complications in primary care. He is currently PI of a prospective study in acute fatigue to better understand how fatigue presents in primary care, what factors predict chronicity, and to develop an intervention to help manage fatigue before it becomes chronic. Prof Little wants to improve the understanding of ME/CFS because of a close family member.
I'm guessing this is him. Not a good sign that he is working with Rona Moss-Morris (who used to be based in Southampton).

Apologies if this is not new information, I haven't been following things that closely.


http://www.ehps.net/ehp/index.php/contents/article/view/1977

Predictors of on-going fatigue after acute infection: a systematic review
K. Hulme, J. Hudson, P. Rojczyk, P. Little, R. Moss-Morris

Abstract

Background
Fatigue is a prevalent and debilitating symptom, preceded by an acute infectious episode in some patients. This systematic review aimed to identify factors which predict lasting fatigue after an acute infection, to inform the development of a working model of post-viral fatigue.

Methods
Electronic databases (Medline, PsycINFO and EMBASE) were searched from inception to July 2015, for studies which investigated biopsychosocial predictors of on-going fatigue after an acute infection. Inclusion criteria were: prospective design; biological, psychological or social predictors; valid and reliably measured post-infectious fatigue. Studies were excluded if participants had a pre-existing medical condition (including chronic fatigue at baseline), infection was conceptualised as ‘vaccination’ or they were intervention trials.

Findings
Seventy-eight full texts were screened, of which seventeen met inclusion criteria. Over half included glandular fever populations. Other infections included dengue, ‘general’/’viral’ and Q-fever. A wide range of predictive factors were investigated, grouped under sub-themes: Biological; Social; Behavioural; Cognitive; Emotional Well-being. Conceptualisation of fatigue varied– some studies used criteria definitions, others used questionnaires. Despite this heterogeneity, certain variables were associated with the development of chronic fatigue in multiple studies and/or across time-points, including bed rest, total symptoms reported, distress and attribution style. Subsequently, a working model was developed.

Discussion
Core aspects of the model are related to patients’ illness response (e.g. behaviours engaged in, attributions and perceptions held, and emotional well-being) which are likely to be relevant in understanding the progression from acute to chronic fatigue. Thus, the model lends itself to informing a chronic fatigue prevention intervention.
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Copyright (c) 2016 K. Hulme, J. Hudson, P. Rojczyk, P. Little, R. Moss-Morris
 
Messages
2,158
@Dolphin do you have access to the full paper?

This abstract is remarkably uninformative. They have developed a working model, but don't say what it is.

'Variables associated with development of chronic fatigue included bed rest, total symptoms reported, distress and attribution style'.

Presumably this can be interpreted as either blame the patient, or sicker patients stay sicker.... Looks worryingly like another case of using correlations to deduce causations in the direction that fits their preconceptions.

No way of knowing with only the abstract available.
 

Dolphin

Senior Member
Messages
17,567
@Dolphin do you have access to the full paper?

This abstract is remarkably uninformative. They have developed a working model, but don't say what it is.

'Variables associated with development of chronic fatigue included bed rest, total symptoms reported, distress and attribution style'.

Presumably this can be interpreted as either blame the patient, or sicker patients stay sicker.... Looks worryingly like another case of using correlations to deduce causations in the direction that fits their preconceptions.

No way of knowing with only the abstract available.
My impression is that is no full text at the moment. Quite a few abstracts came out at the same time; I think they may be from a conference.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Prof Paul Little is Prof of Primary Care Research at the University of Southampton, a Fellow of the Academy of Medical Sciences, Emeritus NIHR Senior Investigator, and currently Director of the NIHR Programme Grants for Applied Research Board.

I'm guessing this is him. Not a good sign that he is working with Rona Moss-Morris (who used to be based in Southampton).

The abstract is miserably poor scientifically. The more I look at this coterie of mediocre politicos the more I am glad I am out of science.