Invest in ME Conference 12: First Class in Every Way
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New IBS D research. Test and Validation of biomarker?

Discussion in 'General ME/CFS News' started by aimossy, May 15, 2015.

  1. aimossy

    aimossy Senior Member

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    Last edited: May 15, 2015
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  2. aimossy

    aimossy Senior Member

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    It's from Cedars-Sinai medical group.

    • Mark Pimentel,
    • Walter Morales,
    • Ali Rezaie,
    • Emily Marsh,
    • Anthony Lembo,
    • James Mirocha,
    • Daniel A. Leffler,
    • Zachary Marsh, …
    • Stacy Weitsman,
    • Kathleen S. Chua
    • Published: May 13, 2015
    • DOI: 10.1371/journal.pone.0126438

    Abstract


    Diarrhea-predominant irritable bowel syndrome (IBS) is diagnosed through clinical criteria after excluding “organic” conditions, and can be precipitated by acute gastroenteritis. Cytolethal distending toxin B (CdtB) is produced by bacteria that cause acute gastroenteritis, and a post-infectious animal model demonstrates that host antibodies to CdtB cross-react with vinculin in the host gut, producing an IBS-like phenotype. Therefore, we assessed circulating anti-CdtB and anti-vinculin antibodies as biomarkers for D-IBS in human subjects. Subjects with D-IBS based on Rome criteria (n=2375) were recruited from a large-scale multicenter clinical trial for D-IBS (TARGET 3). Subjects with inflammatory bowel disease (IBD) (n=142), subjects with celiac disease (n=121), and healthy controls (n=43) were obtained for comparison. Subjects with IBD and celiac disease were recruited based on the presence of intestinal complaints and histologic confirmation of chronic inflammatory changes in the colon or small intestine. Subjects with celiac disease were also required to have an elevated tTG and biopsy. All subjects were aged between 18 and 65 years. Plasma levels of anti-CdtB and anti-vinculin antibodies were determined by ELISA, and compared between groups. Anti-CdtB titers were significantly higher in D-IBS subjects compared to IBD, healthy controls and celiac disease (P<0.001). Anti-vinculin titers were also significantly higher in IBS (P<0.001) compared to the other groups. The area-under-the-receiver operating curves (AUCs) were 0.81 and 0.62 for diagnosis of D-IBS against IBD for anti-CdtB and anti-vinculin, respectively. Both tests were less specific in differentiating IBS from celiac disease. Optimization demonstrated that for anti-CdtB (optical density≥2.80) the specificity, sensitivity and likelihood ratio were 91.6%, 43.7 and 5.2, respectively, and for anti-vinculin (OD≥1.68) were 83.8%, 32.6 and 2.0, respectively. These results confirm that anti-CdtB and anti-vinculin antibodies are elevated in D-IBS compared to non-IBS subjects. These biomarkers may be especially helpful in distinguishing D-IBS from IBD in the workup of chronic diarrhea.
     
  3. aimossy

    aimossy Senior Member

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  4. aimossy

    aimossy Senior Member

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  5. nandixon

    nandixon Senior Member

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    I wonder what the results of this testing would have looked like in ME/CFS patients, who often seem to have IBS (and I guess more often the "D" form?).

    In the conclusion, the authors also mention:

     
  6. aimossy

    aimossy Senior Member

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    I think they do get a lot of patients with ME/CFS and Fibro in Gastroenterology @nandixon
     
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  7. acer2000

    acer2000 Senior Member

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    Yeah this group has been studying post infectious IBS for a while. Their focus is that the infection causes SIBO due to damage to the migrating motor complex. In turn this causes the IBS symptoms. I guess they have now found an autoimmune reaction that might lead to this?
     
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  8. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    I am not overimpressed by the findings. The data are expressed in the usual unhelpful way, focusing on p values rather than actual data and using box plots instead of scatter plots. The immunological story really hinges on the anti-vinculin antibodies and these are not separable from the normal population in the way one would expect from an autoimmune disease. There is broad overlap. Vinculin is also an antigen I would take great care over interpreting antibodies to. It is a widely distributed adhesion related cytoskeletal molecule of a sort that could easily give non-specific binding (like laminin in matrix).

    The most worrying thing is that the box plot for anti-toxin antibodies has a huge collection of 'outliers' at the bottom end that have presumably been excluded from the analysis. If they were included the results would probably be much less convincing. I do not accept exclusion of outliers in this sort of situation.

    I don't think I will be holding my breath for confirmation.
     
  9. aimossy

    aimossy Senior Member

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  10. aimossy

    aimossy Senior Member

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    It does seem there are some research groups around that are ace at marketing.
    I was really interested in the possibilty of antibodies but also the gut motility aspect.
     
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  11. Simon

    Simon

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    Monmouth, UK
    A few comments, though not on the underlying immunology

    The good things about this study are the huge D-IBS sample (n=2,375) and the focus on the comparison with a disease group - Inflammatory Bowel Disease, rather than healthy controls. That might make it more clincially useful.

    On the other hand, the results v healthy controls were very unimpressive, and I'm always suspicious of a study that's been hyped in the media - not to mention the immediate marketiing of IBScheck (TM) as a diagnostic test. That's premature, in my view. The biggest flaw (common in these 'biomarker' studies) is the failure to replicate in an independent sample, so the accuracy of the test is cherry-picked, using thresholds set to maximise accuracy in this particular set of data. The D-IBS sample was big enough to split into test and validation samples, which is how you are supposed to do these kind of studies. Peer reviews asleep on the statistical treatment, it seems.

    Even with these cherry-picked thersholds, the results aren't that good, with most cases of D-IBS missed (the best they achieved was a 60% successs rate - barely better than chance - but using that particular threshold meant a lot of IBD (disease) cases were misdiagnosed as D-IBS).

    I still think the study is interesting and worth following up, but they hype and rush to market are very disappointing. The ScienceDaily piece was merely churnalism, reworking the IBScheck press release.
     
  12. aimossy

    aimossy Senior Member

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    @Simon thanks very much. I was suspicious with them marketing a test this fast without it all being done on huge cohorts and checked out through other scientists - as in good old replication etc. It did have some elements in the design I thought seemed reasonable. It did have a high cohort and making some big claims so I posted it to see if any good. I just learnt a bit more from your post about cherry picking as well.

    It is pretty great to be able to post something and get really good critiques and analysis from members here. I do appreciate it takes effort to look at and give a critique on something!
     
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  13. nandixon

    nandixon Senior Member

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    If I understand correctly, it might be worth considering that this doesn't seem to be a case where the authors are simply pulling antibodies/autoantibodies out of thin air with no real prior groundwork.

    Rather, this (human) study might be thought of as validating, at least to a fair extent, their prior animal study:

    Autoimmunity Links Vinculin to the Pathophysiology of Chronic Functional Bowel Changes Following Campylobacter jejuni Infection in a Rat Model

     
  14. Jonathan Edwards

    Jonathan Edwards "Gibberish"

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    It depends on what you mean by validating, I think. There is a type of research that this could very easily fall into where essentially researchers go out wanting to get a particular result and make sure they get it. I had a colleague years ago who told his PhD students to repeat any experiments that did not produce the result he wanted. Since they would not get a PhD if they did not get these results they learnt to get them in the end. A research group that does work like this and then immediately markets a test would to my mind be a likely candidate to fall under this sort of practice. That may be harsh but increasingly most of what goes on in biomedical science labs is like that.

    What would worry me immediately is that vinculin is everywhere - not confined to gut or to nerve cells. So why did anti-vinculin antibodies give staining just of gut nerve cells? There may be a reason but as it stands that makes no sense. Anti-vinculin autoimmunity should produce a disease all over the body, not diarrhoea. Simple things like this tend to get glossed over. I have to admit that in this particular case I have not read all the relevant papers in great detail, but to be honest I am not very motivated to spend that much time on this one - I doubt it has anything to do with ME!
     
  15. nandixon

    nandixon Senior Member

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    Yes, I was actually thinking/worrying about that as I wrote the above post. And thanks for the additional information as well!
     
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  16. globalpilot

    globalpilot Senior Member

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    Ontario
    I did have the test and I wish I had read the paper beforehand. My thoughts were the same as Johnathons - there is a lot of overlap between the controls and IBS. My result of 1.96 for vinculin antibodies is high but according to the whisker boxes some of the controls are in this range as well. Note - only 43 controls vs 2300 IBS. Did anyone else bother with the test ?
     

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