Tuesday, 16 October 2012

CCSVI - time for Sir Bradford-Hill's criteria for causation

An edited reposting! 

Did you know that there is a whole science behind causation? It started way back in the later 1800's when Robert Koch formulated his postulates to persuade his contemporaries that the he had found the cause of tuberculosis. 

His postulates are:

1. The specific organism should be shown to be present in all cases of animals suffering from a specific disease but should not be found in healthy animals.

2. The specific microorganism should be isolated from the diseased animal and grown in pure culture on artificial laboratory media.

3. This freshly isolated microorganism, when inoculated into a healthy laboratory animal, should cause the same disease seen in the original animal.

4. The microorganism should be reisolated in pure culture from the experimental infection.



Kochs's postulates served us well, but broke down when we tried to apply them to viruses that only have one host. It then fell to the British Statistician, Sir Austin Bradford-Hill, to formulate more general and appropriate criteria of causation; the following are the Bradford-Hill criteria:

1. CONSISTENCY AND UNBIASEDNESS OF FINDINGS

2. STRENGTH OF ASSOCIATION

3. TEMPORAL SEQUENCE

4. BIOLOGICAL GRADIENT (DOSE-RESPONSE RELATIONSHIP)

5. SPECIFICITY

6. COHERENCE WITH BIOLOGICAL BACKGROUND AND PREVIOUS KNOWLEDGE

7. BIOLOGICAL PLAUSABILITY

8. REASONING BY ANALOGY

9. EXPERIMENTAL EVIDENCE



If you are interested in reading about these criteria I suggest the following references:

Bradford-Hill A. The environment and disease: association or causation? Proc Royal Soc Med 1965; 58:295-300.

Bradford-Hills Criteria

Bradford-Hill's criteria have also been modified to apply them to the problem of MS:

Giovannoni et al. Infectious causes of multiple sclerosis.Lancet Neurol. 2006 Oct;5(10):887-94.

"When you apply Bradford-Hill's criteria to CCSVI, the majority of the boxes, cannot be ticked. In addition, in light of new data the entity of CCSVI is questionable."


"Does CCSVI exist as a definite entity?"


"Is CCSVI the biggest fraud in the history of MS?" 

"Who is responsible for the deaths of the MSers who died having unproven  therapies that are not been done under an ethically approved clinical protocol?"

"Is is ethical to enroll MSers into invasive trials when the condition is unlikely to exist?"

"Is Zamboni a fraud?"

"Should Zamboni's University investigate the integrity of his research?"

"Why didn't Zamboni disclose his conflicts of interests?

"Should Zamboni disclose what he has gained financially from CCSVI?"

"Why are the NICE, ECTRIMS and FDA guidelines on CCSVI  being ignored?"

"Is it appropriate for charities and governments to be spending vast sums of money on CCSVI research when the unmet research need is so great in other areas of MS research?"

"These are all important questions that need an answer!"

35 comments:

  1. This comment has been removed by the author.

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  2. Prof G,

    Why are we wasting our time with this two bit theory (CCVSI)? I come on this blog to learn about B cells, EBV, Vit D... CCSVI ruined another MS website I used to visit and I can it happening here - the followers treat it as a religious cruscade. Let's take a decision not to give it any more time - there are plenty of other websites dedicated to CCSVI.

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  3. Irrespective of whether event A fulfills all criteria in order to be regarded the cause of B, it should be able to account for EVERY possible characteristic of B. Do you agree?

    Having that in mind, can you tell us which BH criteria does your dual virus hypothesis fulfill?

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  4. No answer to my second question. I'll examine it myself:

    1. Consistency: You suspect EBV virus and some other, yet unknown virus. Nothing to be inconsistent of. BLANK
    2. Strength of association: No association as EBV is omnipresent and the second one unknown. BLANK
    3. Temporal sequence: EBV seems to precede MS, but what about pediatric MS? And what about the unknown virus? BLANK
    4. Biological gradient: Is there really a scale for EBV action severity? No. Neither a relation to MS progression. BLANK
    5. Specificity: None. After all MS needs genetic factors too. Doesn't it? BLANK
    6. Coherence: The second virus is unknown, so how can we relate its action to known facts about MS? BLANK
    7. Biological plausibility: Something i do not know interacts with some unspecified susceptibility factors and causes something i can not explain. BLANK
    8. Reasoning by analogy: ADEM? BLANK
    9. Experimental evidence: Oh yes. The countless wheel-bound rodents with fatigue and slurred speech. BLANK

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  5. VV you should spend more time reading rather than using this blog to demonstrate your lack of understanding or ignorance of the topic. A good starting point is one of Prof. G's article on the topic. I not surprised that he has started ignoring your comments.

    Giovannoni G, Cutter GR, Lunemann J, Martin R, Münz C, Sriram S, Steiner I, Hammerschlag MR, Gaydos CA. Infectious causes of multiple sclerosis. Lancet Neurol. 2006 Oct;5(10):887-94.

    Prof G do you have anything to say?

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  6. Now you have your own question and answer session! Maybe you can just cut out the middleman and talk to yourself and leave the rest of us out of it, so we don't have to suffer this endless prattling.

    No wonder Prof G can't be bothered to answer you

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  7. 1. Consistency: 99.9% vs. 94% (Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.)

    2. Strength of association: chances of getting MS if your EBV-ve = 0.06 (almost zero) (Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: the role of infection. Ann Neurol. 2007 Apr;61(4):288-99.)

    3. Temporal sequence: EBV seroconversion occurs in all subjects prior to developing MS compared to 36% of controls (Levin et al. Primary infection with
    the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010 Jun;67(6):824-30.)

    4. Biological gradient: not relevant to infectious diseases; this criterion only applies to toxic exposures in individuals. However, a biological gradient may apply to age of infection; Ramagopalan et al. Geography of hospital admissions for multiple sclerosis in England and comparison with the geography of hospital admissions for infectious mononucleosis: a descriptive study. J Neurol Neurosurg Psychiatry. 2011 Jun;82(6):682-7.

    5. Specificity: non-specific, but may be specific for autoimmunity in general (rheumatoid arthritis, SLE, etc.). This not a problem conceptually as EBV is known to cause many other diseases.

    6. Coherence: we and others are currently working on this. We have an interesting publication in press. If you are interested you may find the interaction between EBV and human endogenous retroviruses of interest.

    7. Biological plausibility: how long is a piece of string? As anon suggests trying reading Giovannoni et al. Infectious causes of multiple sclerosis. Lancet Neurol. 2006 Oct;5(10):887-94.

    Unfortunately, this review is now 5 years old and a lot has happened in that time. A better update will be Ramagopalan SV, Dobson R, Meier UC, Giovannoni G. Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurol. 2010 Jul;9(7):727-39.

    8. Reasoning by analogy: http://multiple-sclerosis-research.blogspot.com/2011/06/hot-topic-new-animal-model-of-ms-rumps.html

    9. Experimental evidence: effect of Rituximab (anti-CD20) in MS. Rituximab is the only licensed anti-EBV drug on the market. (Hauser et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008 Feb 14;358(7):676-88.)

    Enough said? I have work to do.

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  8. This comment has been removed by the author.

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  9. Doctor, thank you for your time.

    You might agree that the first three criteria are interconnected as far as EBV is concerned: by proving the nonexistence of the temporal sequence the other two (and possibly criteria 4, 5, and 7) fall apart by themselves.

    The article you referenced states that the interval between primary EBV infection and MS onset was 2.3 to 9.4 years, where MS onset is defined as the date of development of neurological symptoms. Unfortunately, there is no reference about the nature of those symptoms.

    The problem is that the exact time of MS beginning does not coincide with the development of neurological symptoms that need medical consultation. As you know, early manifestations of MS, like fatigue, transient cognitive or emotional irregularities, date far back in time before MS diagnosis. Under this perspective, the EBV infection could practically come second in time and possibly contribute to the accelaration of MS.

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  10. 8. What makes the disease MS-like? Demyelination and neurological symptoms are common in many different diseases. Where there Dawson's fingers? Was there axonal hypertrophy in the spine? Also, it seems that the implication of the herpesvirus is not yet causal but just associative.

    9. Re "Rituximab is the only licensed anti-EBV drug on the market"

    Licensed does not mean effective. An effective drug for MS would halt progression. Relapses and lesions do not affect long term disability. After all, MRI has a difficulty in portraying cortical lesions.

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  11. Re "VV you should spend more time reading rather than using this blog to demonstrate your lack of understanding or ignorance of the topic."

    I'll take your advice. You should also try reading "The investigation" by Stanislaw Lem. It's fun, and more.

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  12. You had written you might be changing your mind about EBV. Could you say something about that?

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  13. "When you apply Bradford-Hill's criteria to CCSVI at present, the majority of the boxes, cannot be ticked. "

    CCSVI is not about toxins or viruses, but about the implications of impaired CNS blood outflow. However, let's give it a try, bottom-up. Remember that CCSVI has been around 3 years only, so the research is far from complete.

    9. EXPERIMENTAL EVIDENCE
    None. However there is a mouse model under development in Stanford. No publication yet, only an abstract:
    "A murine model of CCSVI is associated with mild but significant impairment of gait as assessed by neurobehavioral testing."

    8. REASONING BY ANALOGY
    Budd-Chiari Syndrome: Occlusion of hepatic veins, more common in females
    http://en.wikipedia.org/wiki/Budd%E2%80%93Chiari_syndrome
    If occluded hepatic veins cause trouble to the liver, why can't blocked CNS draining veins cause trouble to the CNS?

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  14. 9. There is a mouse model under development.

    http://ccsvism.xoom.it/ISNVD/Abstract-Thanaporn.pdf

    Methods: This is double ligation of the jugular veins and reported an effect on Schwingspeed of legs within 1 week of ligation and no other outcome affected.

    There was a published paper see
    we commented on

    http://multiple-sclerosis-research.blogspot.co.uk/2012/03/research-animal-studies-show-ccsvi-is.html

    Method used double ligation of jugular veins. Reported no effect over a six month observation, but did not look at schwingspeed of legs.

    VV COMMENTS ON THE ABOVE NEGATIVE STUDY

    "CCSVI is much more than 2 blocked jugulars. The model is simplistic as it doesn't recreate the necessary blood flow reversals"

    "Is six months enough"-in Standford study it was a week.

    "The mouse brain is healthy, the MSer's is not.No reflux in the mouse model. CCSVI is about abnormal valves, not blockages".

    Therefore you want it both ways, when it suits you the model is rubbish and when it suits you the same model is useful.....good for politicing..but Bad Science?

    8. Occuluded vessels in the CNS cause trouble in the CNS..it is can be called a STROKE

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  15. 9. Please read: I wrote "None", that is, i agree there is no experimental evidence in animals yet. Why is that, is a different topic.

    8. Are you deliberately confusing things? CCSVI is NOT about occluded vessels (arteries & veins) IN THE CNS, but about EXTRACRANIAL flow obstructions in VEINS ONLY. In Budd-Chiari there is occlusion of VEINS draining the liver, that is OUTSIDE the liver.

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  16. Re: "Budd-Chiari Syndrome: Occlusion of hepatic veins, more common in females
    http://en.wikipedia.org/wiki/Budd%E2%80%93Chiari_syndrome
    If occluded hepatic veins cause trouble to the liver, why can't blocked CNS draining veins cause trouble to the CNS?"

    Budd-Chiari causes venous stasis in the end-organ. This is a very distinct pathological entity. In MS there is no evidence of venous stasis; the closest you get to the latter is chronic venous sinus thrombosus or dural aterio-venous fistula. The latter arterialises the venous system and can mimic venous status to an extent.

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  17. Firstly, thank you for answering to the point. Secondly, allow me to disagree.

    from
    http://www.merckmanuals.com/home/liver_and_gallbladder_disorders/blood_vessel_disorders_of_the_liver/budd-chiari_syndrome.html

    "Budd-Chiari syndrome is caused by blood clots that completely or partially block the large veins that carry blood from the liver (hepatic veins) into the inferior vena cava."

    The blockages in veins can only be partial. In this case there is no venous stasis, but impaired outflow.
    So the pathological entity is the reduced blood flow. Venous stasis is just the worst case, where there is no flow. That's why Budd-Chiari can be acute (no flow) or chronic (slow flow):

    "When the vein remains completely blocked, most people, if untreated, die of liver failure within 3 years. When the blockage is incomplete, life expectancy is longer but varies."

    "Eventually, severe scarring of the liver (cirrhosis) occurs."
    (lesions in the liver, with fibrosis and regeneration, another resemblance to MS)

    Of course in MS there is no evidence of venous stasis. If there was, MS would be an acute, not chronic disease. But there is hypoperfusion, and reduced cerebral circulation time (time needed for blood to travel from the carotid artery to the jugular veins). Evidence for the latter:
    http://radiology.rsna.org/content/262/3/947.abstract

    In the end, there should be no doubt that venous flow obstructions, whether full or partial, are capable of inflicting damage to the relevant organ.

    So, the Bradford-Hill criterion of REASONING BY ANALOGY should be ticked for CCSVI in relation to MS.

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  18. G said

    "others seem to spend most of their time in conflict with our worldview.
    ...............This conflict takes an inordinate amount of our time and I am not sure if it is a productive exercise".

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  19. I entirely agree. I don't give a damn whether Vasilis Vasilopoulos agrees with us or not. In fact he/she may be of the opinion that the moon is composed entirely of a fermented dairy product for all I care. We should not waste any more time giving reasoned arguments to a professional naysayer. It merely wastes time that could be better spent answering other peoples queries. Also there appears to be no evidence that VV is a real person rather than some CCSVI collective so I would treat any further missives as spam.

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  20. I think VV is who he says he is: a patient who had good results with CCSVI, is convinced of its benefits, & believes there is enough science to support it

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  21. Re VV Maybe...but sometimes his posts
    come via account of apparent different sex. Innocent mistake maybe. His blog site still a mystery?

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  22. Prof. G have you heard that the medical team involved with the case that died in California from CCSVI treatment are being sued? As the medical community can't sort this out the lawyers will.

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  23. @Anonymous 9:20:00 AM:

    Which medical team is being sued? There were two CCSVI-related deaths in California. Is this the case of the unfortunate lady from Canada who died hours after getting the procedure? I could see that being a solid case.

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    Replies
    1. I think it is Dr Dake from Stanford

      Delete
  24. Roshni
    "I think VV is who he says he is: a patient who had good results with CCSVI, is convinced of its benefits, & believes there is enough science to support it".

    I'm not so sure. I'm also not sure that VV (or the Borg collective calling themselves VV) has had the procedure. I'm not sure of his/her motives (might be a Zamboni?Hubbard plant for all we know) but maybe it's just one of those people who is convinced they are right in the face of evidence they are wrong, similar to climate change deniers or people still convinced that the MMR vaccine causes autism.
    VV claims to have a blog but always neglects to post a link to it so we can examine the bona fides.
    Until such a link is posted I view VV's posts with dubiety.

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  25. Anonymous (of course) 11.34 illustrates the downside of enabling comments on this subject.
    My response?
    Personally if we (or anybody) came up with a therapy for MS that cured it once and for all and that put me out of a job, I could live with that, in fact I'd be delighted!
    Best wishes
    MD2

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  26. I am a lay person but it seems to me that the venous pathology of MS lesions would be a more logical starting point for discussion of any treatment for MS. The evidence is well summarised in a book by Dr Franz Schelling.
    Multiple Sclerosis: The Image and its Message
    The Meaning of the Classic Form Lesions
    http://www.ms-info.net/ms_040504.pdf

    I am coming across some neurologists in the NHS who are finding this book 'very educational', particularly those better informed doctors who now realise that there is no evidence for 'autoimmunity' in MS. I am not that familiar with Bradford Hill myself, but I will have a read of the information you so kindly provide. My hunch is that 180 years of concrete post mortem evidence regarding the venous pathology of MS lesions would actually enable CCSVI to tick a fair few of the boxes, particularly when more recent MRI evidence regarding the formation of MS lesions is considered. Tan et al, Tallantyre et al spring to mind. And the more recent paper by Chen et al is of interest too.
    Alison Fisher

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  27. In my opinion drugs are wrong way in MS, dangerous and not slowing disease pregression in long run. Once again..

    http://www.medpagetoday.com/MeetingCoverage/ECTRIMS/35315

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    Replies
    1. Prof G will nodoubt post on this as his words are being twisted

      Delete
  28. "However, before deducing 'causation' and taking action we shall not invariably have to sit around awaiting the results of that research. The whole chain may have to be unravelled or a few links may suffice. It will depend upon circumstances."

    Sounds familiar? (Bradford Hill)

    1."Does CCSVI exist as a definite entity?". Before asking this question you should get updated with the latest CCSVI research and talk to some vascular experts. Your view of CCSVI is totally distorted.

    2."Is Zamboni a fraud?"
    "Should Zamboni's University investigate the integrity of his research?"
    "Why didn't Zamboni disclose his conflicts of interests?
    "Should Zamboni disclose what he has gained financially from CCSVI?"

    By linking CCSVI so closely with Zamboni you prove your limited knowledge of it. 20 years prior to Zamboni, Dr Schelling hypothesized the venous anomalies found in CCSVI. 30+ years prior to Zamboni, J. Aboulker (http://www.ncbi.nlm.nih.gov/pubmed?term=Aboulker%20J[Author]&cauthor=true&cauthor_uid=207127) found the same venous anomalies with phlebography. Now, plenty of original work exists that proves the existence of these anomalies with IVUS venography. To say that CCSVI does not exist is equal to blindness.

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    Replies
    1. The Schelling bible is as dull as dishwater as a read, you know that and I know that!. It is way too long and lacks any modern concepts.

      Do you think that Zamboni data is not correct or do you embrace the vision? Skirting round the question is what we expect and is meaningless, why not answer the question for a change!

      Delete
    2. Oh I don't know about 'dull as dishwater' regarding Dr Schelling's book. I found 180 years of the pathology behind the formation of venodynamic MS lesions very useful in researching the validity of CCSVI. Living and struggling with this disease I thought it was important to acquaint myself with some concrete evidence about MS. The bit about the way spinal MS lesions form via tugging on the denticulate ligaments (Oppenheimer 1978) was a revelation to me - explaining the formation of the spinal lesions seen in Sir Robert Carswell's first illustration of MS published in 1838. That is when I realised that some random inflammation didnt tug on my denticulate ligaments, nor a virus...the spinal lesions have a distinct pattern compared to brain lesions. How could that be?

      I found some real humour in the book too... a chapter headed up
      "CDMS: Chronically Delusive Misidentification Syndrome"

      But if we are doing book reviews then I really recommend
      William Harvey's "Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus" published in 1628 all about the circulation of the blood - 'modern concepts' haven't added a great deal to Harvey's findings - our blood still circulates just as he found. His woodcut showing how the valves in veins work is completely accurate in modern times.
      Alison Fisher

      Delete
    3. Good for you that you found it enlightening and funny. I gave it to a number of pathologists and neuros to read and comment, none of them bothered to do this, but it was apparently the best cure for insomnia......indeed it took me six attempts to get past the first few chapters. Maybe I will give it another go. Whilst it is enlighting that there was 180 years of enlightenment most of it stopped before the twenty first century began and uses archaic terminology perhaps because most of the source references are before 1900.

      Delete
  29. no one has ever said CCSVI is the cure, its gives patients a better quality of life .Patients who have had angioplasty on hearts for many years some have died , they are still allowed this daily. All the drugs for MS will never cure and thats why they are being dished out so much and why a cure will never be found while too many are earning profits out of all the MS patients.Many people will be accountable with the drugs thats for certain

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  30. Who is responsible deaths and horrible side effects with MS drugs? What about nearly 300 PML cases with tysbri? Why most common MS drugs are quite useless, not able to slow disease progression? What is biggest fraud in MS history? Is it useless interferones or cobaxone maybe?

    Peter O Behan seems to be wise man. His article says it all:

    "Futility of the autoimmune orthodoxy in multiple sclerosis research"

    No wonder MS patients are seeking better treatment options, no wonder..

    http://www.expert-reviews.com/doi/pdf/10.1586/ern.10.69

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