MRC Funded Research: Dr Wan Ng: Identifying the biological fingerprints of fatigue

[Firestormm]

Right. I'm going to have a go at these new bits of information. Am not really feeling up to it but am 'unhappy' at the relentless tirade on Facebook right now. And anyway I get more space to do it here.

Not that I don't want to debate this research - it's just that the constant stream of 'do-do' from some quarters gets on my nerves after a while.

I did like the 'lay' summary followed by the 'technical' and much smaller one beneath each of these explanations. Made me giggle (yes I do giggle on occasion).

There are some perhaps key questions that do remain e.g. cohort definitions for the 'CFS' individuals who will be compared to the findings or used directly in the research; but hopefully these arrangements (and those criteria) will be published later.

Anyway...

Let's start with probably the most contentious bit of research; now commonly referred to as The Sjorgen's/Not ME Study I believe.

And yes my comments are probably naive but that's me: Mr Simple

MR/J002720/1

PI: Dr Wan Ng, Newcastle University

Title: Identifying the biological fingerprints of fatigue

Start Date: 01/01/2012
End Date: 31/12/2014
Award Amount: 451,572.73

Lay Summary

Context of the research:

Chronic fatigue syndrome (CFS) affects 1 in 300 people in the UK and is associated with a significant healthcare-related cost to the society. Severe, persistent fatigue is a key symptom of CFS and a major factor leading to loss of productivity in this illness.

The cause of CFS and the underlying biological mechanisms of fatigue are poorly understood. As a result, accurate diagnosis of CFS can be difficult and effective treatment is not available.

I thought the above was interesting. An acknowledgment (explained more below) that existing cohorts are perhaps not adequate and may adversely impact on research. Something I would tend to agree with - broadly speaking - especially perhaps when looking at the immune system.

A growing body of evidence suggests that CFS may be linked to a faulty immune system. However, in what ways the immune system is not working properly is not clear. Therefore, by uncovering the abnormalities of the immune system in CFS in detail, it will help make the diagnosis of CFS easier and more accurate as well as give us clues to develop effective treatment of this condition.

So an acknowledgment of more recent research findings and that the CFS criteria or means of diagnosis may be including people that do not share common cause. And they are hoping that by examining the immune system in detail it could impact on the way in which the condition itself is diagnosed in future (or perhaps a sub-category).

Since the diagnosis of CFS is unreliable at present, a group of "CFS" patients may in fact consist of individuals with different diseases.

This presents a major obstacle to the progress of CFS research and may also explain why data from different CFS research studies are often conflicting.

Therefore, in order to better understand the underlying biological mechanisms of CFS, a different approach is needed.

Whoa! So here comes the contentious bit. I'll take the plunge here: CFS patient cohorts are possibly so screwed that it is far easier, cheaper, and more likely to result in a greater scientific and medical understanding, if a separate and specific cohort of patients are used.

Recent data show that intense fatigue is also a common symptom for many chronic conditions. Interestingly, most of these conditions are due to a faulty immune system. Furthermore, research also suggests that severe fatigue in these various conditions is driven by similar biological mechanisms.

If so, we may be able to find out the underlying defects of the immune system causing disabling fatigue in CFS by using one of these chronic conditions as a disease model. This is precisely what we will do in this study.

Bone of contention in some quarters would appear to surround the notion that 'fatigue' is nothing other than a symptom and shouldn't be researched in the context of 'ME'. What is said here though is that 'fatigue' is not only a common symptom across other conditions but that this could correspond to a 'faulty immune system' or similar 'biological functions'.

I'll stick my head in the noose and say that however you define it, 'fatigue' is a constant and unrelenting key component of my debilitation. 'Even' the ICCME (correct me if I am wrong) employs the term 'neuroimmune' exhaustion (though exhaustion isn't a medical term is it? and 'fatigue' - like it or not - most definitely is).

So, finding a cohort of suitable patients with a diagnosis of 'CFS' (synonymous in the UK and with the NIH in the US with ME - like it or not) has been deemed unfeasible but they want to look at the immune system and see how it might cause 'fatigue' specifically.

So they've chosen another chronic condition that also has a key symptom of 'fatigue' but is far easier to definitively diagnose. This is obviously a shame. It would have been far more accepted amongst patients for them to have felt able to use a cohort with 'CFS' - it was after all meant for 'CFS' research.

But they couldn't and if 'fatigue' is indeed related to immune system dysfunction generally, then why not use a better defined and in some ways clinically similar condition? Makes sense to me. Simpleton that I am.

We will carry out a comprehensive analysis of the immune system of a large number of patients with a condition called primary Sjgren syndrome (PSS). We will analyze the data obtained from these experiments to find out what abnormalities of the immune system are linked to fatigue.

Since these experiments typically produce a vast amount of data, we will apply statistical methods and mathematical modelling specifically designed to analyse large volumes of biological data (known as bioinformatics and biostatistics) in order to identify the biological "fingerprints" of fatigue.

We will then test whether these biological fingerprints of fatigue are present in CFS patients and whether it will help us to diagnose CFS more accurately.

So a diagnosis of Sjorgen's is more reliable. They know who has Sjorgen's and who doesn't. I mean this also says so much about our criteria and the ability of those doctors doing our diagnosing that I would suggest it is something we could make more use of with e.g. NICE.

Get them to ensure the criteria are better used and/or changed/tightened - improve the education of GP's and get some damn specialists trained and employed.

Though hopefully this research might enable a 'test' and 'marker'. And that's another contentious issue I guess. What if you don't suffer from 'fatigue' even I suppose after exercise? Maybe if this 'test' actually comes to fruition it will only be used as a part of a criteria or would help identify another category of patients?

What if your 'CFS' is not related to the immune system? Not everyone arrives with this diagnosis for the same reasons of course. And what if the 'marker' is as 'fluctuating' as the extremes of the condition?

Anyway, it's research so we'll have to wait and see but if it means at the end of the day that those who do not have immune system abnormalities linked to 'fatigue' can be treated more effectively by another means then that has to be good news.

We chose PSS as a disease model for several reasons:

(i) PSS and CFS have many shared clinical and biological features including profound fatigue.

(ii) Clinical samples from over 550 PSS patients across the UK, as well as their clinical data, are available for this study. Access to such samples is a distinct advantage because this is one of the largest clinical sample collections in PSS in the world. It would be time-consuming, labour-intensive and expensive if we had needed to collect the same amount of clinical samples and accompanied clinical data from fresh.

(iii) There are well-established diagnostic criteria for PSS and so this avoids the problem of studying patients with potentially mixed diagnoses as in the case of studying CFS patients.

Kind of says (but better) what I was trying to above.

Aims of the study, potential applications and benefits:

The main objective of this study is to find the biological fingerprints of fatigue. By doing so, it will improve our understanding of the biological mechanisms of fatigue.

This study is looking solely at the immune system. So if they cannot find the 'biological fingerprints of fatigue' in the immune system I guess they would look with other research elsewhere.

At least it advances the knowledge about 'fatigue' and the role of the immune system. And I think it must have a role. A key role. But whether it will be an observable role in a condition that has continued beyond the acute phase I don't know.

I do hope so as it will not only help with our condition but also with other chronic conditions too including, potentially, other neurologically categorised ones.

The data will enable us to develop treatments for the fatigue that plagues so many patients with CFS and other chronic conditions. It will also help us to design a clinical test for the diagnosis of CFS.

Well there we have it. Bit scary I thought. A 'test'. Blimey. Not that I shall raise my hopes and see them dashed once again. But a 'test' would be so cool.

I don't see how this 'test' could be for the condition itself I think it might form part of any diagnosis of 'fatigue relating to immune system dysfunction' or something.

And if they can understand it better and 'test' for it they hopefully they can indeed learn how to better 'treat' it.

Technical Summary

This study aims to identify the biological fingerprints of fatigue using primary Sjogren's syndrome (PSS), an autoimmune condition with several clinical and biological features similar to chronic fatigue syndrome (CFS) including intense fatigue, as a disease model. We will then test whether these biological fingerprints are also present in patients with CFS.

I mean there is nothing in the world of 'CFS' currently that can identify 'fatigue' and link it to the immune system or link the immune system to 'fatigue'.

What there this might do I guess is add to the patchy stuff that is around and more importantly serve to define our condition as well as further legitimise it.

And let's go 'wild' for a moment - maybe this could explain why Rituximab has such a seemingly dramatic effect. Who knows? But it would be cool to find out.

We will perform whole blood gene expression profiling (using genome-wide microarray) and measure serum markers of immune dysregulation (using fluorescent bead-based multiplex technology) of an existing biobanked samples from a large cohort of clinically well-characterized PSS patients (the UK PSS registry).

Further information concerning the cohort can be found on the cohort website http://www.sjogrensregistry.org/index.php and Annex 1.

Whatever. Above my 'pay-grade'. Couldn't find 'Annex 1' either. But the link is there if anyone wants to take a look.

The data from these experiments will be analyzed using various bioinformatics techniques in order to identify a biological profile of fatigue, which will be validated using a second blinded test cohort of PSS patients.

The 'bioinformatics' is touched on above. Of note here is the validation employed with the two blindings I think.

We will also investigate whether the biological profile changes over time and responds to biological treatment of fatigue in PSS patients.

The data from these investigations will then be integrated to identify a set of biomarkers that will maximally discriminate fatigued subjects from non-fatigued individuals.

Finally, we will test whether these biomarkers of fatigue are present in CFS patients and if so, whether they can be used to correctly classify CFS from active or sedentary healthy individuals.

Ok. I don't understand the first sentence. I get that they will (once identified) follow the profile over time - makes sense especially with a chronic condition and chronic symptom. It's the 'biological treatment of fatigue' that threw me. Any thoughts?

I am unfamiliar with Sjorgen's and therefore with the treatment options but perhaps they mean some treatment for Sjorgen's that also helps with 'fatigue' but indirectly? Or maybe there is a treatment for 'fatigue'?! Blimey.

So the final part is a test all of it's own I guess. It will perhaps tell if CFS has the same biomarkers for 'fatigue' as Sjorgen's (assuming they get that far).

And it is obviously important to determine if said biomarker can indeed separate healthy individuals from those with 'CFS' BUT there are some patients who do claim 'fatigue' is not one of their symptoms. And some who claim 'fatigue' 'only' in terms of PEM or 'Neuro-immune exhaustion'. Same thing in my book but anyway.

There are known/assumed other causes of 'fatigue' of course and maybe this 'test' will help determine those in the CFS 'pot' who don't have immune-dysfunction-fatigue. But I don't think this research will determine if said individuals are suffering from an autoimmune condition - though I'm happy to be proven wrong of course.

Right. I'm done. Let battle commence.... I'll be in bed asleep.... with 'fatigue' :In bed:

 

[Esther12]

Just the summary knackered me out. Thanks for your work. To be honest, I've not read the technical summary bit, but the controversial bit:

Whoa! So here comes the contentious bit. I'll take the plunge here: CFS patient cohorts are possibly so screwed that it is far easier, cheaper, and more likely to result in a greater scientific and medical understanding, if a separate and specific cohort of patients are used.

I've got a lot of sympathy for this view. There's so much quackery around CFS, and it's difficult to move beyond that with this diagnosis. From the medical papers I've been reading over the last few years, it has seemed that understanding of the causes of the fatigue of CFS patients is more likely to come from the study of other illnesses than the study of 'CFS'. (edit: Just to make clear that the above point is based on an emotional response, rather than a careful examination of all the evidence... I've really got no idea).

Having said that, it's pretty shitty for those of us with CFS, which has had so little research devoted to trying to find the causes of the illness, to have what little funding there is directed to other illnesses in the hope that a breakthrough in other areas will be able to be translated to CFS.

Also... taking this approach does seem like something of an acknowledgement that the last two decades of research have been pretty wasted. Shouldn't there be some sense of outrage at this? Some desire to hold those responsible accountable for the fact that we're still on square one? Or at least, a sense that those responsible should be expected to explain themselves?

Even if this approach may be sensible, I understand people feeling angry about it too.

 

[oceanblue]

Thanks, Firestormm. I've just posted on the Pariente Interferon-alpha study on its existing thread.

 

[Ember]

CFS patient cohorts are possibly so screwed that it is far easier, cheaper, and more likely to result in a greater scientific and medical understanding, if a separate and specific cohort of patients are used.

This joke is being played on us...and on the authors of the CCC and ICC...

The Story:

A man was walking home late one night when he saw the Mulla Nasrudin searching under a street light on hands and knees for something on the ground. "Mulla, what have you lost?" he asked.

"The key to my house," Nasrudin said.

"I'll help you look," the man said.
Soon, both men were down on their knees, looking for the key.

After a number of minutes, the man asked, "Where exactly did you drop it?"

Nasrudin waved his arm back toward the darkness. "Over there, in my house."

The first man jumped up. "Then why are you looking for it here?"

"Because there is more light here than inside my house."

 

[Wildcat]

.

According to Charles Shepherd on the ME Association Facebook, this is likely to be the last and only 'Ring Fenced' MRC Funding for 'ME' (undefined 'CFS') research.
.

So, make the most of it, folks!
.

The only other 'Ring Fenced' 'CFS' funding was for the 'PACE Trial'.
.
Please wake up folks! We have been stitched up. MRC Funding for ME Biomedcial Research in the UK is finished now.

 

[Esther12]

.

According to Charles Shepherd on the ME Association Facebook, this is likely to be the last and only 'Ring Fenced' MRC Funding for 'ME' (undefined 'CFS') research.
.

So, make the most of it, folks!
.

Do you have a link for that? I'm only a facebook amateur, but couldn't find it. Ta.

 

[Wildcat]

.
Charles Shepherd ME Association Facebook. 13 April 2012:

https://www.facebook.com/pages/ME-Association/171411469583186?ref=ts


Charles Shepherd: Steve - we have discussed this on several occasions before. The money was ring-fenced by the MRC for biomedical research relating to ME/CFS. Ring fenced funding (as well as commissioning specific research) is not something that the MRC normally does and I suspect the ring fenced element is not going to turn into a regular event.
.

 

[Esther12]

Thanks Wildcat.

Discussions really are harder to follow over there.

 

[Wildcat]

You're welcome, Esther.

To be honest I can rarely follow Facebooks these days. I just happened to encounter this particular thread on ME Association FB, amongst many others that are totally in space and not in any chronological order.
The new FB Timeline nonsense has really messed us up in terms of any form of sequential discussion/debate.

xxxx Wildcat.

 

[Firestormm]

Facebook sucked anyway, it merely sucks even more now. 'Progress' my arse

Edit:

Links for the latest information relating to all the MRC funded Research:

Webpage: http://www.mrc.ac.uk/Ourresearch/ResearchInitiatives/CFSME/index.htm : See MRC-funded Research Projects: or hit this link for a download of the pdf. file: 12 April 2012: http://www.mrc.ac.uk/consumption/id...dID=35295&dDocName=MRC008582&allowInterrupt=1

General Thread: http://forums.phoenixrising.me/show...es-ME-CFS-Research-Projects-Worth-£1-6m/page5