how do they prove that xmrv is causal for CFIDs or Prostate Cancer

[Navid]

"The drugs cannot ethically be tested in prostate cancer and chronic
fatigue patients, however, until it is shown that the virus actually
causes disease"....from HIV drugs combat virus that might be linked to prostate cancer and chronic fatigue

April 5, 2010 | 10:36 am
http://latimesblogs.latimes.com/boos...c-fatigue.html



Science ppl how is causality actually proven in disease?

Thanks, Lisa

 

[leelaplay]

Hi lisag - very good question. Thank you. While we're waiting for the science people to answer, there is this info from the US federal working group

In the second phase, also launched, a panel of around 350 different blood samples developed by Dr. Busch's team will be sent to four different labs. Some of the samples are from chronic fatigue patients known to have XMRV. Others from healthy donors have been spiked with the virus or have tested negative. All the samples are blinded, and the study will see whether the different labs can agree on XMRV positive status for chronic fatigue patients.

But I don't think that 'XMRV positive status for chronic fatigue patients' proves causality. (did you notice the lack of 'syndrome'?) It sounds like the the first necessary step though.

 

[CBS]

"The drugs cannot ethically be tested in prostate cancer and chronic
fatigue patients, however, until it is shown that the virus actually
causes disease"....from HIV drugs combat virus that might be linked to prostate cancer and chronic fatigue

April 5, 2010 | 10:36 am
http://latimesblogs.latimes.com/boos...c-fatigue.html



Science ppl how is causality actually proven in disease?

Thanks, Lisa

Lisa,

The traditional (and clearest) method would be to infect a previously healthy/active XMRV negative primate (or other lab animal) with XMRV and then watch for lethargy, fatigue, illness behaviors (whining and malingering). Then you look to see if the subject animal was actually replicating the virus in blood and tissue.

BUT, think about what Dr. Goff said in his Virology Blog talk with Dr. Racaniello. He doubts that XMRV is oncogenetic for prostate cancer. There are markers (adjacent cells of a particular type) that would strongly suggest that XMRV is a direct cause of cancer but so far they can't find them. Rather, Dr. Goff hypothesized that it is more likely to him that it is the immune impact of XMRV that leads to the development of prostate cancer in those with the genetic vulnerability.

In the case of XMRV as a causative agent, perhaps the first step will be the identification of immunological abnormalities (NK cells?) that develop after XMRV exposure in previously healthy and XMRV negative subjects.

 

[gracenote]

I'm also not a "science people" but I would like to keep this thread going. Here is a quote from Peterson.

"And so you can generate a hypothesis, much like the HIV hypothesis, is that you get an acute infection, you develop an antibody response, ultimately you have a failure of the immune system, and we postulate here that ultimately may be an NK cell numbers and function, resulting in very significant and prolonged disease. That is a model that could be fairly easily tested, and I think that that is something we should do rapidly and judiciously. "

Dr. Peterson, CFSAC committee meetings, October 2009

And here is a quote from Mikovits.

XMRV research is in its infancy and essentially nothing is known about the life cycle of XMRV. These are not diagnostic tests nor does any test at this time determine active vs latent infection. We are attempting to isolate and sequence XMRV from as many people as possible.

Dr. Mikovits, personal email communication, April 2010

It is still very early in XMRV research (although very late for many of us).

I wonder about this statement: "The drugs cannot ethically be tested in prostate cancer and chronic fatigue patients," and wonder if it is actually true.

I would also like to know what the next steps should be.

----------
ETA: as I've been writing this post, islandfinn and CBS have posted.

 

[Otis]

I wonder about this statement: "The drugs cannot ethically be tested in prostate cancer and chronic fatigue patients," and wonder if it is actually true.

Despite the low quality of life many of us have and the shorter lifespan we will probably have, I do worry about the speed with which trials may actually occur. It could be some time (years?) before there are drugs available that most docs would be willing to prescribe. This may be a case where "Do no harm" works against us. Sounds like a job for an advocacy org (once we can get a standardized test out of the way and show a high corralation of 'CFS/ME' to XMRV) to help put meds in our hands.

Those of us not able to wait may be left with trying to get off-label scripts from a Dr.

I woud very much like to be proven wrong about this so fire away people! :Retro smile:

Otis

 

[CBS]

To follow up on Gracenote's quote of Dr. Peterson, it isn't a matter of simply proving causality. Perhaps a better way to think of it is establishing "proof" of a casual mechanism through a series of steps that each build upon the earlier steps.

As for the time, I suspect that a lot of research has already been launched down this road. Dr. Singh stated that they were testing efficacy of three anti-retroviral drugs in an animal model. I'd be very surprised if they were simply be looking for the replication then eradication of XMRV. I suspect that markers of immune dysfunction such as NK cell function, etc. are already being assessed by a number of groups.

 

[consuegra]

I think very soon there will be trials of existing drugs, drugs that already had been rigorously tested, so that this efficacy part can be bypassed. I think various people are looking at drugs that might work on XMRV, and some drugs are emerging. Then I think someone, most likely the WPI, will take a flyer and start trials on patients that have the XMRV markers. If the drugs works, they have proof. I think this process is quite primitive and is based on trial and error. All indications are that WPI is going to be starting trials by the end of the year, perhaps with multiple single drugs or cocktails of drugs. They don't seem to be slowing down on getting after this illness.

Chris
http://cfspatientadvocate.blogspot.com

 

[Eric Johnson from I&I]

This statement from LA Times is probably not too accurate. If XMRV is 100% correlated with CFS, it will be considered highly likely to the the cause. Even though it would be conceivable that CFS instead causes people to get the virus, this would be unprecedented and quite unlikely. I am pretty near certain that antiviral trials would go forward at that point.

 

[Gemini]

Lisa, very good question.

Can look at how was it done in HIV science (Dr. Mikovits' hypothesis is XMRV is to CFS/ME as HIV is to AIDS).

UK HIV charity AVERT's website summarizes the evidence proving the virus, HIV, causes AIDS:

www.avert.org/evidence.htm

An excerpt from AVERT's summary:

How can we prove that HIV causes AIDS?

Koch's Postulates

In the nineteenth century, the German scientist Robert Koch developed a set of four "postulates" to guide people trying to prove that a germ causes disease. Scientists agree that if HIV satisfies all of these conditions with regard to AIDS then it must be the cause of AIDS:15

Koch 1: The germ must be found in every person with the disease
Koch 2: The germ must be isolated from someone who has the disease and grown in pure culture
Koch 3: The germ must cause the disease when introduced into a healthy person
Koch 4: The germ must be re-isolated from the infected person

Other evidence

Even Koch recognized that in some cases not all of his conditions could be met, so other evidence should also be considered. This is particularly true when the germ is a virus rather than a bacterium.16 Modern scientists are willing to consider a wide range of evidence. In particular, we can ask five key questions:

Do surveillance statistics show a relationship between HIV and AIDS?
How well does HIV infection predict illness?
Do drugs designed to combat HIV benefit people with AIDS?
Are there any credible causes besides HIV?
What can we learn from Africa?

You can read more by going to the website.

Gemini

 

[Gerwyn]

"The drugs cannot ethically be tested in prostate cancer and chronic
fatigue patients, however, until it is shown that the virus actually
causes disease"....from HIV drugs combat virus that might be linked to prostate cancer and chronic fatigue

April 5, 2010 | 10:36 am
http://latimesblogs.latimes.com/boos...c-fatigue.html



Science ppl how is causality actually proven in disease?

Thanks, Lisa

In essence very simple, create an explanatory model re causation accounting for all the observations. Make predictions based on this model.If predicted scenarios observed then causation established.In practice time and resource consuming and needs the accumulation of a weight of evidence

 

[VillageLife]

I still think putting the animals on the 'Tilt table test' is the best idea to prove CFS/XMRV!

(poor things though!)

 

[Hope123]

Coming from a different point of view, I like Bradford Hill criteria. Koch is good for labwork whereas Bradford Hill looks more at populations. Here's a quick link:

http://www.southalabama.edu/coe/bset/johnson/bonus/Ch11/Causality criteria.pdf

Dr. Klimas mentioned at one point that since CFS is considered an "orphan" illness and that antiretrovirals are already in use, it will help expedite trials.

 

[Doogle]

I believe it will happen like it did with Ampligen. Some doctor will give an XMRV positive patient whose illness is life threatening an AID's drug or antiviral combination. If the patient improves and their XMRV viral load decreases then another cohort will be put in a phase II experimental trial. If that's successful you will see a paper saying symptom severity correlates with XMRV viral activity, and then it will be off to the races on phase III study trials. Phases I and II took approximately three years with Ampligen. The phase III trials will probably be contentious because the shrinks will be trying to enroll Oxford criteria patients in retroviral studies without being XMRV positive to prove you can't improve "CFS" patients with antivirals. IMO

 

[hvs]

In essence very simple, create an explanatory model re causation accounting for all the observations. Make predictions based on this model.If predicted scenarios observed then causation established.In practice time and resource consuming and needs the accumulation of a weight of evidence

"In essence," indeed. I know you and many others know this, Gerwyn, but our disease is a special case... Because of politics and prejudice we will have a long struggle long after the evidence is piled high.

 

[cfs since 1998]

"The drugs cannot ethically be tested in prostate cancer and chronic fatigue patients, however, until it is shown that the virus actually causes disease"

That is just ridiculous in my opinion. There is a wide array of drugs that are FDA approved for conditions of unknown cause in which the drug mechanism of action is also unknown! There's been many trials of drugs on CFS based on speculation. As long as safety and the risk/reward ratio are considered carefully it is not unethical. What is unethical to me is not letting sick people buy medications that might help them because the government says so.

 

[HowToEscape?]

It sounds like we may be thinking a few steps ahead without knowing if it the correct road.

We don't know that XMRV causes M.E/CFID
. . . . . . . . . . Some possibilities I can think of offhand:
It may be the cause
It may be one of several factors, any of which can independently cause the disease
It may be a triggering agent: It sets off a process which sustains itself without further need for the causative agent i.e match|fire
It may be a part of a combination lock initiation: several factors must be present to set off the disease, and after that
--- --- removing any of the cause agents allows the body to reverse the disease process. Causes not limited to pathogens.
--- --- only removing all of the cause agents allows the body undo the disease process
--- --- only removing one or more of the cause agents plus fixing some damaged element - such as genes altered by a virus - allows the body undo the disease process
--- There is a family of diseases with overlapping symptoms which are now called CFID/ME, and XMRV is a or the cause of one branch. Note that I'm not included the useless category of "Chronic Fatigue", defined as "patient is inexplicably tired for six months". That is a hand-wave, not a definition of a disease.
--- It does not cause this disease, but is more common in people with it. Similar to: most people found on a military base wear dog tags, but a dog tag does not cause one to live/work on a base.
...................... and so on.
__________________________________________________________________________

It would be very convenient if this monster has one source and that source has been found. But just because that would be relatively good news does not mean it's true. We can't stop looking for the external triggers AND working to map the pathology of this thing only bc one likely villain has been found.
While labs are looking for XMRV there may be 7 other pathogens in shadow; look at how hard it is to find XMRV when specifically searching for it. It must be much harder to to find other demon molecules whose mug shot has never been seen.

 

[MaryAnn]

I am concerned about the speed in developing drug therapies too. I thought that Dr. Judy had stated that by the time the new WPI construction was complete (scheduled for Sep 2010) that she thought trails would begin. I recall something about 2 to 2 years for completion? This would be for anti-retrovirals that have already been through Phases I and II but need Phase III with CFS dx’d patients.

Also, the Whittemore’s have a vested interest in speed (besides the institute); their daughter is ill.

I admit I am not real knowledgeable about this but, isn’t it true that in the US it is not ethical to perform Phase III trails for life-threatening diseases with placebos, e.g. if pts have breast cancer and a drug has shown promise in Phases I and II, then in Phase III, the pts cannot be given placebos. In a double blinded trial, they may be given another type of medication/differing dosage to determine which is more effective.

Then again CFS may not be thought of as needing immediate attention or life threatening.

 

[usedtobeperkytina]

I think I read somewhere that part of the cause tests are in treatment tests.

If I remember, it goes something like this.

You find a bug. You look at what bug does. You find out how many of your sick people, illness A, have the bug. You see how many healthy people have the bug. If numbers are high in illness A and low in healthy, you can hypothesize cause and effect.

But, that is not enough to establish cause and effect.

But then you develop something that does away with bug. If the illness goes away when the bug goes away, then cause is established.

So at the same time you find treatment, you are establishing cause.

Tina

 

[Adam]

I think I read somewhere that part of the cause tests are in treatment tests.

If I remember, it goes something like this.

You find a bug. You look at what bug does. You find out how many of your sick people, illness A, have the bug. You see how many healthy people have the bug. If numbers are high in illness A and low in healthy, you can hypothesize cause and effect.

But, that is not enough to establish cause and effect.

But then you develop something that does away with bug. If the illness goes away when the bug goes away, then cause is established.

So at the same time you find treatment, you are establishing cause.

Tina

This is the best explanation of where things will/may go from here, so far, for the lay-idiot like me.

thanks Tina (and all the others on this thread too)

 

[Navid]

wow...thanks to everyone for their informative posts...i'm kinda w/adam and tina:

here's how i would prove causality:
xmrv+
diagnosed w/cfid's: meet canadian criteria and dx'd by a doc who has been studying and treating the disease from day1 (of the disease)
take some of the drugs that have shown efficacy vs xmrv (and don't have too bad of side effects...i .e. won't kill me after one dose)
start to feel better
recover:victory:
yahoo...xmrv caused my cfid's

i know that's pie in the sky dreamin' but that's how i'd like to see it go down...and i'm ready to volunteer...never mind infecting anymore of those poor monkeys and making them suffer with this SH_T

see this is why i'm not a scientist...just an impatient, sick mother of young kid