Monday, September 6, 2010

The murky side of physician prescribed LDTs

Apparently the LDT community are not too happy with DTC genomics for having stirred up the regulatory hornets nest, well maybe that’s not such a bad thing. I have argued previously that physician prescribed tests can be more dangerous and more necessary of regulation than DTC and below is a good case for the argument.

First a huge huge thanks to @laikas for a) her excellent beautifully detailed and analytical posts on the CFS virus story (XMRV & MRV: here, here and here) and b) for specifically asking me and others to comment. I had been aware of the controversy but no more than that so Laika’s request made me read more – my first inclination was that it reminded me of the helicobacter story, scepticism followed by acceptance, cures and nobel prizes, but reading further it unfortunately looks more like the MMR / Autism debacle which was Laika’s comparison.

I’m not going to discuss the various findings here, no point as Laika has done that far better – what I do want to talk about is the commercial test that was put on the market as soon as the paper was published – it’s not a pretty story.

1. Lombardi et al of the Whittemore Peterson Institute (WPI) published in Science. They report the detection of a retrovirus, XMRV, in 68 of 101 CFS patients (67%) and 8 of 218 (3.7%) healthy controls - http://www.ncbi.nlm.nih.gov/pubmed/19815723

2. In the Science paper there is a “Note added in proof”: V.C.L. [Lombardi] is operations manager of Viral Immune Pathologies Laboratory, which is in negotiations with the Whittemore Peterson Institute to offer a dianostic test for XMRV.

3. In the same month www.vipdx.com began offering a $650 test for the XMRV – “essentially 100% accurate…”

4. Four independent follow-up studies failed to find the virus and a 5th found a virus, not the XMRV but related MLV sequences were detected (all detailed here by Laika)

5. WPI group now say that they also find similar variants

6. Vipdx update their test so it now detects “other human MLV-related viruses” (so now essentially even more 100% accurate…)

7. Some things were missed out on the Science “note added in proof”, but they are in Laika’s blog posts, such as:

“Furthermore there is an intimate link between WPI and VIP Dx, both housed in Reno. Vip DX is licensed by WPI to provide the XMRV-test. Vipdx.com links to the same site as redlabsusa.com, for Vip Dx is the new name of the former RedLabs.

Interestingly Lombardi (the first author of the paper) co-founded Redlabs USA Inc. and served as the Director of Operations at Redlabs, Harvey Whittemore owns 100% of VIP Dx, and was the company President until this year and Mikovits is the Vice President of VIP Dx. (ME-forum). They didn’t disclose this in the Science paper.”

So that’s it – basically an unregulated clinical test is being offered to a very vulnerable and exploitable group based on 1 paper on a small isolated sample, with no independent confirmation…on the contrary…and some unfortunate conflicts of interest that were not reported when and where they should have been. They say all profits go back into research but that is irrelevant and meaningless (what are profits? What is left after paying everyone? Also the sales will increase the value of the company they own). But even without the COI – what would happen if 23andMe et al offered a “100% accurate” genetic test for CFS risk (or autism, yes, WPI are getting XMRV into that as well…ouch, just got hit by another bandwagon).

What exactly is wrong:

  • No independent confirmation
  • No demonstration of human-human infection
  • It’s a hypothesis that the viral presence is causal (it could be there, if it is, due to reduced immunity in CFS)
  • Test positive what do you do? Answer: of course some doctors are prescribing anti-retrovirals already
  • Some patients will naturally feel better even if by placebo, leading to testimonials of success
  • There will be alarms about infecting family members to drive sales (and fear). In fact this already goes on, by the senior author (Mikovitz) who says in an email to an individual: “To be clear..I do think even if you tested negative now that you are likely still infected with XMRV or its closest cousin..”

In retrospect this last sentence in the Science paper has an interesting tone:

“Finally, it is worth noting that 3.7% of the healthy donors in our study tested positive for XMRV sequences. This suggests that several million Americans may be infected with a retrovirus of as yet unknown pathogenic potential”.

Updates:

  • Via Twitter: @Vansteenwinckel: yet another commercial test for #xmrv ? pfff http://bit.ly/bFJBlV #mecfs
  • Via Carlitos, who comments below: 1st International Workshop on XMRV. Tuesday and Wednesday, September 7 & 8, 2010, Bethesda, Washington, DC – please go to Carlitos’ blog for more details, it will also be partially videocast

8 comments:

  1. Good points Keith. We should not discuss about medical/not medical: the problem is that the world is full of people that want to make profit without caring about science. I hope that the new regulation will wipe away all the tests like this, DTC or not. One day you should post a list of all the crappy genetic tests that are sold in the internet.

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  2. I do not think you are aware that there are already replication studies that confirm the Lombardi group findings on XMRV and CFS patients...

    One is already published in PNAS by NIH and FDA, but this week in the 1st international XMRV consortium in USA, there are at least 3 more studies that will confirm the assoctiation of XMRV with CFS.

    http://www.xmrv.blogspot.com

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  3. @carlitos - I was aware of the published paper, in fact I refer to it in the post (the 5th paper, see point 4 above). It's not a proper replication though, I don't go into the details but refer to the Laika's post which discusses this very paper.

    I wasn't of course aware of the "3 more studies that will confirm the association of XMRV with CFS" - I hope they do and I hope that the confusion is sorted out quickly. I doesn't change my opinion about it being far too early for this test to be sold at a profit to patients.

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  4. Good post and thanks for the contributions to the discussion at my blog. You make it very clear (also to patients) why such test are dangerous and should not be done out of the research setting.


    BTW, I have checked the URL redlabsusa.com again, and now it doesn't show the same page as vipdx.com but it is a page "under construction"/for sale -funny enough with "links"(read advertorials) to diagnostic tests and chronic fatigue syndrome....

    Prof. K. de Meirleir (form Belgium) who also claims to have found XMRV in most CFS blood samples also works with RedLabs (Europe).

    And (2) According to the new PNAS paper by Lo et al the presence of MLV in normal individuals is even 6.8%.

    (3) Probably the WPI/ VPdix doesn't even know what accuracy is. this is not only determined by the positive but also by the NEGATIVE PREDICTIVE value (emphasis on both words). Assuming that the XMRV/MLV virus presence in CFS will be reproducible, future experiments should also address which CFS populations are affected the most (quantitative studies required), if the XMRV/MLV really predicts CFS(or certain symptoms) and to which extent CFS is unique for CFS.
    (I'm not even talking about causality here).

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  5. Thanks Laika - odd about the redlabs site, some hasty rearrangement going on there??

    You're right about the test as well - we are SO FAR from having a proper assay, even if the virus is proven to be involved. What data do they have on reproducibility, sensitivity, specificity, negative predictive value, positive predictive values etc

    It looks like it is not a straightforward assay to detect the viral sequences so I am guessing that there could be a high false negative rate - do they explain this to the physician/patient?

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  6. Is this a new chapter in the whispering campaign against WPI?

    VIPdx is a Nevada and California State Licensed Clinical Laboratory and is CLIA Certified. Have you taken up your concerns with those regulatory bodies? This lab offers a dozen other clinical tests useful to the CFS patient community and others. They are now a part of the U of Nevada Center for Molecular Medicine. They have tested 949 samples for XMRV through July, 2010. Hardly a huge money maker for them!

    All the patients with ME/CFS that I know of are/were aware of everything presented in this blog. You infer that Lombardi or WPI pulled a fast one on people wanting to be tested. You position yourself as a savior to the "vulnerable and exploitable" CFS patient community. CFS patients agonized and analyzed long and hard before choosing to test or to wait, for all the reasons you mention, and then some.

    You and Laika, who merely quotes ERV (the CFS patient hater/ WPI hater/ Mikovits hater), and who is not particularly analytical or accurate, seem to have a joint effort to smear VIPdx, WPI and Dr Mikovits. CFS patients are fully aware of the Redlabs connection. Why wouldn't European researchers use Redlabs?...there isn't another lab there that CAN test for XMRV and probably not for any other MLVs.

    That patients could find out whether they have XMRV or its antibodies in their blood is "dangerous"?!?

    Your bullet points under "What's Wrong?" all have one or more errors.

    June press release:

    "The clinical laboratory will continue to operate under the name VIP Dx, until it moves to the University of Nevada's Center for Molecular Medicine in August 2010. At that time, the lab will operate within the Institute under the name Unevx, providing services and revenue to the Institute in a manner similar to other institutional clinical reference laboratories."

    This transfer apparently hasn't yet been finished, but there is no attempt to fool anyone, by Redlabs, VIPdx or WPI. There is nothing "odd", nothing "hasty" about abandoning the original website and it's current owner taking advantage of continued hits. This is rumormongering at its worst.

    Your last two bullet points are especially egregious.

    1 - Scientific studies have found that the placebo effect in CFS patients is lower than for non-CFS patients. So you smear those patients who do better upon treatment and trivialize their experiences by calling them "testimonials". There are people, including at least one physician, who have CFS and are able to continue to work because they are able to pay the $2200/month to get Ampligen. I think being able to work instead of being disabled is more than just a "testimonial".

    2) Infering that the Whittemore Peterson Institute is setting up "alarms" to "drive sales and fear" totally ignores the original reason the Whittemores began the search for real answers to CFS: their daughter who has been disabled by it for 20 years.

    Patients already know that it is infectious, at some times, under some circumstances. Outbreaks have been recorded since the 1930s. Patients just want to know when and under what circumstances they might be infectious.

    1934: Outbreak in LA County Hospital, mostly hospital personnel
    1955: UK, Royal Free Hospital staff

    See link for 61 more outbreaks:
    http://www.name-us.org/ResearchPages/ResEpidemic.htm

    You have no idea that we are "SO FAR" from having an accurate assay, so why say that? Researchers are working on that right now, as announced some time ago, and for all we know, have already developed one or more assays that just haven't been published yet.

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  7. @oerganix

    First, you do a gross injustice to Laika - have you really read well (and understood) her posts? I can assure you that there is a great deal of effort displayed and they are not mere quotes of someone else's blog.

    There is chapter and no campaign. The fact is that the connections to the lab and the commercial test are very strong yet they were not mentioned in the Science paper. All journals specifically ask for disclosures of possible conflicts of interest and for some reason the authors specifically did not mention them - that is murky. Why didn't they? If it was an oversight (which is hard to do) why hasn't it since been added to the on-line version? The most lenient reason I can think of is that they may have been worried that it would have reduced the chances of the paper being accepted. Other reasons are less charitable, but anyway whatever they are the fact remains that the assay is not ready to be sold for clinical use - the lack of transparency just makes the situation more worrisome.

    "dangerous" are some of the consequences - like taking anti-retro virals when there is no proof that they work. "dangerous" is having hopes raised and then dashed again. "dangerous" is buying tests (plural, possibility of infection of famiily, right?) that you may not be able to afford. And so on.

    You want to see a site covered in testimonials you can go to some odd hair test here: http://bit.ly/akYxSE (ironic, I found this from the advertorial link on the now "under construction" redlabs site...).

    Telling a person that he/she is likely to be infected is alarming, as is "...that several million Americans may be infected with a retrovirus of as yet unknown pathogenic potential”

    By "so far" I mean that there are many many validation steps that need to be carried out before an assay can be considered to be usable, I mentioned them in my answer above to Laika - reproducibility, specificity, etc. Of course there is also the small matter of actually getting convincing evidence a)that the virus is really present, b) that it is associated with the disease and c) demonstrating clinical utility of post test interventions.

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  8. Here is where to register for future clinical trials with the NIAID's HIV and Emerging Infectious Diseases Program. For information and to ask questions about participating in a study, please contact: Patient Recruitment and Public Liaison Office Toll Free: 1-800-411-1222 . Please pass this along, in hopes of swamping the NIAID with requests. Karen Hart

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