New Dr Kerr Gene Expression study published

[Esther12]

I'm totally out of my league here scientifically, but looking at Kerr's gene expression papers, the distinctions between the different groups' symptoms don't seem terribly clear cut.

From having just read the media reports, I really expected this to have an impact on further CFS research - eg: seeing if graded exercise etc is helpful for certain groups and not others. Instead it seems to have been rather passed by. Looking back at the orginial paper, I feel I understand better why it hasn't had the influence I expected.

Is this just me having misguided notions as to how science like this works? Is it sensible to talk of CFS patients as falling into clearly identifiable distinct groups? How normal is it for patients with other chonic illnesses to have similar diferences in symptoms and gene expression?

 

[Jenny]

Hi Ester12

I agree with you about the problems with these 'subgroups'. I tried to fit myself into some of them and none really fitted. But some seemed to fit better at some stages of my illness and others at other stages and he does say something in the paper about one or two categories being composed more of late stage patients.

We know how much this condition varies and changes over time and I do wonder how far most of the subgroups are more reflective of stage of illness than anything else.

In my experience these stages aren't particularly linear or progressive, just different, with different symptoms coming to the fore.

Jenny

 

[CBS]

Gene Expresion and Subgrouping

Jenny and Esther 12;

Dr. Kerr mentions in this study that the sub-grouping changed slightly from the first study and thus warranted the change from labels 1-7 (seven subgroups) to a-h (eight subgroups).

"As there was only moderate preservation of the previous CFS/ME patient groupings in the present study, we have designated the subtypes, A – H, to distinguish them from those of the previous study, which were designated 1 – 7.

Cluster analysis does not respect previous outcomes nor is it very stable when some subgroups only have a few subjects. This study is an interesting validation of the first study and is what I would consider the second of many iterations to come. The different genetic subtypes may be accounted for by various stages in the disease process (Jenny's idea), by different co-infections, or by too few subjects in less common subgroups.

The small numbers available at this time are a good example of statistical significance versus statistical stability. It is my impression that the 88 unique genes seem to be stable but because the diagnostic criteria is so broad and subjective (is my worst headache -from 1-10 I'd rate it an 8 - the same as yours?), we need much larger numbers on the subjective scales to reach some stability in identifying and describing the sub groups. I've analyzed groups derived from cluster analysis, it's half science and three quarters art.

I know the desire to make more of every new bit of information but my focus is on the article takeaways:

Take Home Messages
Expression of 88 human genes was confirmed as being significantly different between CFS/ME patients and normal controls.

Gene expression in endogenous depression patients was similar to that in the normal controls.

CFS/ME patients can be grouped into Genomic subtypes which have different clinical phenotypes.

There was evidence of subtype-specific relationships for Epstein-Barr virus (EBV) and enterovirus, the two most common triggers for CFS/ME.

It is going to be interesting to see if the distribution of subtypes by location holds up.

 

[Alice Band]

Esther,

Oddly enough, I don't think that the subgroups were the important part of that paper.

It was the difference between the PWCFS and those with depression, then it was the difference immune system viral data as compared to the controls.

 

[Smulan]

Esther,

Oddly enough, I don't think that the subgroups were the important part of that paper.

It was the difference between the PWCFS and those with depression, then it was the difference immune system viral data as compared to the controls.

Exactly. The study (now n=117) shows with great significance that CFS is not a depression disorder and it probably could be diganosed by lookning on gene expression that differs significant from healthy controls.

 

[Esther12]

Esther, what an "unusual" response to Kerr's latest research paper from you. I don't think that you are as ill-informed on science as you like to portray. You are quite clever at placing little pieces of negativity and sowing seeds of doubt about any research that casts doubt on the bio-psychosocial theroy for ME/CFS. Interesting. One could almost start to think that you are a clever plant by certain "interested parties" wanting to create doubt, confusion, conflict blah blah blah, on these type of lists. A fight back against the XMRV research news maybe?

Of course I might be wrong, and I'm sure you'll say I am, but then again I may be right. I don't recognise you from any other lists and I've been on them for years. You get to recognise peoples' styles of writing etc. You just seem to be playing the "dum" card a bit too cutely and playing the aplogetic pardon me for asking questions role a bit too much. If you're not one of these people there is definitely a concerted attempt to spread doubt and confusion, a smear campaign, going on lately. I urge people to question some peoples' motives.

By the way, this study hasn't received any media coverage as far as I'm aware. Also this study never had the intention of dealing in any way with GET and whether it's an effective treatment etc etc. I know it's something you're very keen on. Funny that. Anyway, nice try but science WILL win out in the end, and further study from Kerr et al will be part of it.

The first paper got a fair bit of media coverage. Their was a big bit in the Economist.

It's always been clear to me that, at least amongst the people with CFS I know, depression and CFS are very different. This might be helpful against the most dogmatic of psychologists who still believe otherwise, but it wasn't important to me. I know GET wasn't a part of Kerr's paper, but at the time of the first paper I'd expected his research to go on to influence other work, including that from the psychological lobby.

I do tend to cast doubt. I think doubt's a good thing, and society would be a better place if more people were a bit more questioning about their beliefs.

As for being a plant...

 

[Smulan]

I guess the first paper was considered as a breakthrough in the respect that CFS was shown to be a somatic condition. The only critic I know about it was on the small number of PWCFS investigated. That would leave the sceptics something to hang on to. Now when the number of tested are fairly large, from different geografic location and the study is repeated three times this argument falls. But right now all the focus are on the XMRV research which I think also explains for less media attention.

 

[Alice Band]

Esther,

No published research that argues against them, influences the Psych lobby.

They just ignore it and keep producing their own "work"

 

[George]

My take

Funny how we all got something different from reading the same paper. For me I felt it was a strong argument for epigenetics and thus a paper that would raise the question of what is turning these genes from the normal to the abnormal, ergo (grins, I've always wanted to use that word!) a good jump off point for dovetailing the XMRV virus with the genetic abnormalities present in CFS/ME patients.

I thought the first paper was really about establishing the difference between depression and CFS/ME. The paper was two parts validating a theory (whoohoo) and one part politics. Most researchers disdain Psychology as pseudo science and superstition.

As for the subtypes, this indicates (to me anyway)

1. That there is a causative agent turning these genes from normal to abnormal.
2. The causative agent attacks specific gene sets.
3. Depending on what the person was born with and how it was regulated from birth to when the causative agent attacked is going to establish a pattern that can help to look for the causative agent

For now we will just call it mysterious agent X .(grins)

Anyway that's the way I'm reading it.

PS Does anyone have a handy dandy little list of what each of the genes does/is?? I've been trying to track them down on the great internet but I'm running into a lot of gobbly goo.

 

[Katie]

PS Does anyone have a handy dandy little list of what each of the genes does/is?? I've been trying to track them down on the great internet but I'm running into a lot of gobbly goo.

See picture below for my answer


On a more relevant and less joking note, I'm more on the same page as you George. I'm extremely interested to see how this research may or may not dovetail with XMRV. Even if XMRV is not causative we still have this gene expression research that could lead to a solid diagnostic test via genetic screening. Subsets have always fascinated me as a real possibility because of the variety of symptoms one ME'er has to another but still with the core problems. I've never really have stomach problems apart from a few intolerances so I expect to be in a different subset to an ME'er with stomach issues and IBS. This is all theory that is up in my unscientific head but I really appreciate the work Dr Kerr is doing and would love to see him play a significant role in ME/CFS research and politics in the UK.

I really would love a simple guide to our genes and their names. I'm sure their names are logical but Petri the pancreas gene and Frank the eye colour gene would have been cool. Enough silliness from me.

 

[Dolphin]

I am trying to read the study, too, but I'm having some problems. Can anyone explain this:

Results
Subjects and clinical characterisation
A total of 117 CFS/ME patients fulfilling CDC diagnostic criteria were used in this
study.

Wat, exactly, does this mean? I hope it doesn't mean the Reeves' criteria.

"CDC diagnostic criteria" has often been used as a short-hand for when researchers are using the Fukuda criteria. Someone corrected me on this after I should have known better! The Fukuda criteria were slightly updated in 2003 and this is what is referred to:

For all enrolled subjects (patients and controls), according to the recommendations of the International CFS Study Group [9], severity of physical and mental fatigue was assessed using the Chalder Fatigue Scale [10]; level of disability was assessed using the Medical Outcomes Survey Short Form-36 (SF-36); accompanying symptoms were characterised using the Somatic and Psychological Health Report (SPHERE); sleep abnormalities were assessed using the Pittsburgh Sleep Questionnaire; and assessment of type and severity of pain was performed using the McGill Pain Questionnaire.

9. Reeves, W.C., Lloyd, A., Vernon, S.D., Klimas, N., Jason, L.A., Bleijenberg, G., Evengard, B., White, P.D., Nisenbaum, R., Unger, E.R. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 2003;3:25.

There is no reference to the 2005 paper by Reeves which is the Reeves/empiric criteria (sometimes Reeves doesn't refer to that paper himself so one does have to be alert). I have seen no evidence that Kerr or anybody else (except Leonard Jason to criticise the definition) used the 2003 recommendations in the weird way that is done in the Reeves/empiric criteria e.g. if you say you don't do much because of your mood (but have no other disabilities on the SF-36) you can come up as having CFS (with Reeves/empiric criteria) (Role Emotional subscale). Also, with the Reeves/empiric criteria you don't have to have fatigue (not getting much done qualifies for this criteria (MFI-20 questionnaire - reduced activity subscale).

 

[Smulan]

CDC Gene study

Guess this must be old news but i did not know that CDC had done a gene study back in 2002!?

http://www.cdc.gov/cfs/publications/molecular_1.htm

 

[George]

Guess this must be old news but i did not know that CDC had done a gene study back in 2002!?

http://www.cdc.gov/cfs/publications/molecular_1.htm

Ouch! only 5 CFS patients and the 17 healthy controls. I missed this too! Thank you for pointing it out.

 

[Dolphin]

Guess this must be old news but i did not know that CDC had done a gene study back in 2002!?

http://www.cdc.gov/cfs/publications/molecular_1.htm

Yes [not sure if you are aware but Dr. Kerr and others from the CFSRF have done research before the current study - see: http://www.cfsrf.com/Publications.htm (which includes some links to full papers including on gene expression)].

The frustrating thing about a lot of the CDC research (but not that study) is that it used the empiric/Reeves criteria; basically most of the people who were said to have CFS didn't have CFS. This of course messes up the value of the studies.

It is disappointing that people have not really been making a fuss about this except for maybe the last nine months or so. Hopefully with pressure, something can be done about this ridiculous situation.

 

[George]

Hi ya

Yeah, knew about the Kerr studies 1 and 2 but missed the CDC's lick and a promise (oops missed the promise part) study. Man I can't believe I missed it. I've combed that site. I wonder if it was in response to Dr. Kerrs original proposal and theory???

 

[Dolphin]

Yeah, knew about the Kerr studies 1 and 2 but missed the CDC's lick and a promise (oops missed the promise part) study. Man I can't believe I missed it. I've combed that site. I wonder if it was in response to Dr. Kerrs original proposal and theory???

Much as I might not particularly like the CDC, etc., I doubt it was for that reason.

Gene expression research and other approaches (e.g. proteomics) which are somewhat scatter-gun (you look at lots of things at once and see what comes up) seem/seemed tailor-made for ME/CFS where, if one was looking for models that did not involve persistent infections (lots of people had discounted persistent infections), it wasn't clear what was causing it.

 

[Smulan]

From the CDC study:

"These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers."

Did CDC had their own CFS-criteria at this time? Why on earth did they not follow up on this study? Looking into child abuse does not look like the next logical step...

 

[Dolphin]

From the CDC study:

"These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers."

Did CDC had their own CFS-criteria at this time?

I just checked the paper. It used:

[14] G.P. Holmes, J.E. Kaplan, N.M. Gantz, A.L. Komaroff, L.B.
Schonberger, S.E. Straus et al., Chronic fatigue syndrome: A
working case definition, Ann Intern Med 108 (1988), 387389.

This is a strict definition that would generally only be satisfied by people with ME/CFS, I think. It's probably too strict in that many might not satisfy it but useful enough if you want a pure enough sample.

Why on earth did they not follow up on this study? Looking into child abuse does not look like the next logical step...

In some ways, they did follow it up. In 2003, everyone who had been diagnosed with CFS at least once between 1997 and 2000 in Wichita was brought in for two days of testing. In total, this study cost $2m so they spent in the region of $10,000 per person. One of the things they tested for was gene expression.

However the problem was that they used the empiric/Reeves criteria. This was then used to analyse the data and so the results aren't half as good as they could have been. I can't remember whether they are doing gene expression research on the Georgia patients - they may well be but because the sample is so bad, the results are virtually meaningless for ME/CFS.

In the UK, the government hasn't been paying for gene expression research. It is frustrating that the CDC has been doing a lot of "physical" research but because the sample is so bad, the results are pretty useless.

Also they also don't check their results with an extra test (e.g. Taqman) as one can get some "noise" with gene expression on its own (false positives/false negatives for individual genes) or so I've heard. I know Kerr does do that.

 

[Smulan]

Thats an interesting story Tomk, thanks. You could say that when the broad Reeves criteria was interduced (including all kinds of tired people) all scientific efforts to study ME/CFS was domed to fail.


Anyway now we have the of studies of J.Kerr et al. clearly showing how ME/CFS effect our genes.

 

[Dolphin]

You could say that when the broad Reeves criteria was interduced (including all kinds of tired people) all scientific efforts to study ME/CFS was domed to fail.

Yes, that's a good way to summarise it.

And of course it has knock-on effects as it can put findings by other researchers in doubt.

And people can say there are inconsistent findings.

And it can put researchers off looking at an issue as they can think it has already been investigated (and nothing found).

The CDC studies can look in some ways superior because they are random population studies so they can say they are not biased in terms of the patients involved.