Once Is Not Enough.....by Simon McGrath

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Thank you for this explanation. It has been bothering me for a long time.

I couldn't agree more; replication studies are key. It drives me crazy that every time ME/CFS is mentioned, they say "there are no biomarkers," and yet over the years many potential biomarkers have been identified. What has been lacking is replication studies. It's difficult to get funding for replication studies from universities, because they are not seen as enhancing the reputation of the institution or of the researcher. That's one reason why government funded research is so important. Theoretically, it's supposed to be independent of that sort of competitive atmosphere so that it concentrate on the science.

ME/CFS research is caught in a Catch-22: without biomarkers it's difficult to ensure that research is done on a well-defined patient cohort, and because research is done on poorly-define patient cohorts, it's hard to find biomarkers. I think it will be difficult to make real progress with research until we break through this deadlock.

Every time I hear someone from one of our government health research agencies say that there are no biomarkers for ME/CFS, I want to scream "Then why don't you follow up on the dozens of studies that have identified potential biomarkers?!!" The CDC hasn't even followed up on THEIR OWN studies which they said found possible biomarkers.

I think if we took a rigorous look at how many positive studies have not been followed up on we'd be in for a bit of shock. One problem may be that with such poor funding some studies are so small that they're not convincing enough for other researchers to take them on...Look at the Non-Hodgkins Lymphoma studies - most have suggested something is going and its been 20 years and we still don't have a really good study on that...A study was presented at the 2009 Reno conference that seemed to nail it- but that study was never published....its's frustrating!

Good article, Simon. Thanks.

“because psychology is under threat and this could look bad”

I wonder who is to blame for that situation? Surely not shoddy sub-standard work in the first place by the psychs themselves?

Surely not?

Thanks, Simon and Cort, lucid writing and concise and to the point. Sure helps fill in the full picture.

Thanks to Simon for writing the piece and in such a graceful fashion.

Simon, I think we are within 5 years of a biomarker.

One you didn't mention was Komaroff differentiating depression from CFS patients with EEG. I remember his saying he was going to do a bigger one as a follow up.

And whatever happened to the Sakudo results that was able to diagnose 100% of healthy and 93% of ME/CFS patients: http://128.121.104.17/cfs-inform/CFS.case.def/sakudo.etal06.pdf He did another one in 2009: http://www.ncbi.nlm.nih.gov/pubmed/19248775 Last I heard he was trying to get a patent. But that was four years ago. What's the news on that now? I have half a mind to call him.

And then there is some urine tests we are hearing about.

Also, there's Stacy Stevens study showing oxygen absorption and heart rate differences after exercise.

Yeah, we'll have a biomarker soon.

Ha! Some good news! Glad you brought that up because I was going to check his earlier results. Sakudo just published again a couple of weeks ago.

Clin Chim Acta. 2012 May 11. [Epub ahead of print]
Visible and near-infrared spectra collected from the thumbs of patients with chronic fatigue syndrome for diagnosis.
Sakudo A, Kuratsune H, Kato YH, Ikuta K.
Source
Department of Virology, Center for Infectious Disease Control, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita, Osaka 565-0871, Japan; Fatigue Clinical Center, 21st Century COE Program, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.
Abstract
BACKGROUND:
Currently, diagnosis of chronic fatigue syndrome (CFS) is based on clinical symptoms and therefore relies on the experience and skill of the doctors. Here, we have examined the possible diagnosis of CFS based on spectral information and chemometrics analysis, such as principal component analysis (PCA) and soft modeling of class analogy (SIMCA).
METHODS:
Visible and near-infrared (Vis-NIR) spectroscopy was used to examine possible changes in the region of 600-1100nm in thumbs and assessed.
RESULTS:
The Vis-NIR spectra of thumbs from 57 CFS patients and 74 healthy volunteers were subjected to PCA and SIMCA to develop multivariate models to discriminate between CFS patients and healthy individuals. The model was further assessed by the prediction of 120 determinations (60 in the healthy group and 60 in the CFS patient group). The PCA model predicted a discrimination of the masked samples; specifically the SIMCA model correctly predicted 51 of 60 (83.3%) healthy volunteers and 42 of 60 (70%) CFS patients.
CONCLUSIONS:
Despite the relatively small number of subjects involved in this trial, who were exclusively Japanese, our results imply that Vis-NIR spectroscopy of the thumb combined with chemometrics analysis may provide a valuable tool for diagnosing CFS.
Copyright © 2012 Elsevier B.V. All rights reserved.

Surprised the author left out the 37 kda Rnase-L research. Replicated by four independent labs, though sample sizes were small, then simply dropped by the research community without real explanation. The test was available in the US up through 2009. This was a better biomarker for identifying Ampligen responders than NK cell function. Science has moved backward.

Thanks to all for those kind words.

@ixchelkali:

You're right it's shocking the CDC hasn't followed up its own biomarker studies, given it comfortably has the cash to do so. However, I am surprised that more researchers don't follow their own findings, even where funding isn't easy to get.

Consider this situation: you've just published a paper showing you've identified a potential biomarker/bioabnormality for CFS, and have waxed lyrical in the discussion section about the importance of this discovery. There are now 2 options:

1. Take your promising results and apply for a new grant, pointing out that a replicated finding in CFS would be close to revolutionary and so well worth funding. It doesn't have to be a huge study, but replication of a finding even in a small study would help make a robust case for a definitive study, or may well interest other researchers. Or,
2. Move on to a new potential biomarker and repeat the process, leaving the potential finding just published to join hundreds of others in the CFS destined for obscurity.

As I said in the article, Jonathan Kerr took route 1 and was unable to validate his earlier gene expression findings, but that result in itself is immensley valuable and helps to move the field on. Other researchers may continue to pursue this line of inquiry - but their work will need to take account of Kerr's findings, pushing research standards higher and improving the chance of real progress in understanding CFS.

This kind of thing happens in other fields all the time - and XMRV is a good example of it unfolding now in CFS research. It's certainly a lot easier for such replication to take place in well-funded fields such as virology (XMRV researchers must have spent $millions, as well as huge numbers of research hours in barely 18 months). The battle for more CFS research funding must continue, but focusing meagre resources on nailing or disproving potential findings is probably going to give more bangs for the bucks that do exist.

Completely agree. Personally, I think the way forward is to take a large cohort defined according to several different criteria, measure a hatful of biological and clinical markers and see if robust clusers emerge. Potentially both the Lipkin/Chronic Fatigue Foundation work and the new CDC clinical study underway could end up doing just this.

I hope you're right! I'm not as optimistic, mainly because biomarkers are incredibly hard to find generally in medicine. Even with a disease like Rheumatoid Arthritis, where it's known to be an autoimmune disease and cytokine TNF-alpha is known to play an important role in at least a significant number of patients, they haven't yet managed to pin down a biomarker.

As for the Sakudo study, the new paper Cort quoted showed the figures are much less impressive:

According to Lenny Jason, you need at least 85% in both of those measures, and preferably over 90%, to be clinically useful .

yes, I think immune system variability makes finding a biomarker in immune system diseases harder. I still think the PEM as a result is showing great promise in more than just immune system problems.

Remember the spinal fluid protein study with ME/CFS and Lyme folks? It holds promise also.

I think, actually, we already have many. The question is which is more accessible. Right now, likely the Staci Stevens test is easiest and more accessible.

Tina

PEM should be good; in fact Lenny Jason has got better specificity and sensitivity with questions about the nature of fatigue than I've seen for any biomarker.

Would like to see a replication of the interesting Stevens work: there was talk this was in the pipeline over a year ago, but no replication seems to have been published yet, AFAIK.

Yes, small studies and I kept expecting to see a big replication giving it would be revolutionary if proven. IIRC, Judy Mikovits said the RNAase-L work was what led her to look for retroviruses in the first place, but the RNAase-L link didn't hold up in their own work.

I think the CFI with $10 million will bring the larger cohort. Also, Peterson working with Australians might increase cohort numbers. The CDC CASA project has seven clinics. Ian Lipkin is doing something with multiple clinics.

Finally, our researchers are working together in joint studies, using patients from multiple places.
Also, the organizations are finally starting to work together.

We are more powerful together.

I doubt that a single biomarker will become a replacement to the current process of diagnosing ME/CFS. Perhaps multiple mediocre biomarkers of limited sensitivity or specificity could be combined to strengthen the reason for the diagnosis?

Maybe! One of the dangers is that such mediocre 'markers' are merely markers of ill-health, rather than specific to CFS, a point Komaroff raises in his paper. Actually, I agree that multiple markers may help, but the more markers you use, the easier it is to find differences by chance between healthy people and CFS patients, so robust replication would be essential.

Usually, potential biomarkers are compared between CFS patients and healthy controls, which isn't that much use in diagnosis - a child can usually manage to spot the difference between such groups. In other areas, biomarkers are useful to detect differences that aren't obvious. E.g in diagnosis in identifying a cancer in someone with mild but generic symptoms, or in prognosis eg discriminating between the likely progression of disease (and best treatment options) of two patients with the same cancer and level of symptoms. For CFS, the equivalent would be in identifying 'true' ME/CFS cases from other cases of chronic fatigue, including those caused by other as-yet-undiagnosed physical illnesses.

What is so interesting to me is that I can talk to someone else for ten minutes, sometimes even five, and can tell if they have the disease.

Some things just ring true and are distinctive.

Tina