Hypothesis testing

[Diwi9]

Dr. Ron Davis applied for an NIH grant and was rejected on the basis that his research was not hypothesis testing. His rebuttal was that ME/CFS is still in an an observational state. I agree with Dr. Davis. The research is so weak at this point, amounting to only keyholes of information into biological anomalies. I have two questions:

1) If Dr. Davis were to make an hypothesis, what could be proposed? What research would support this proposed hypothesis?

2) What was the hypothesis formed to fund the PACE trial (although the UK may have different criteria for funding) or other BPS studies, and how was that hypothesis supported?

 

[Barry53]

The stupid thing is that significant research effort can be needed to develop even a hypothesis, when the problem in question is very poorly understood. I can appreciate that in some cases funding pre-hypothesis research could be highly risky, but it would be very blinkered to ignore such research completely. For something such as ME, you have to start somewhere.

 

[Jonathan Edwards]

Dr. Ron Davis applied for an NIH grant and was rejected on the basis that his research was not hypothesis testing. His rebuttal was that ME/CFS is still in an an observational state. I agree with Dr. Davis. The research is so weak at this point, amounting to only keyholes of information into biological anomalies. I have two questions:

1) If Dr. Davis were to make an hypothesis, what could be proposed? What research would support this proposed hypothesis?

2) What was the hypothesis formed to fund the PACE trial (although the UK may have different criteria for funding) or other BPS studies, and how was that hypothesis supported?

All experiments can be said to test a hypothesis of some sort. The PACE trial tested the hypothesis that CBT and GET are useful treatments. Ron Davis's application probably tests the hypothesis that the symptoms of ME are somehow related to shifts in metabolism. So this 'not hypothesis testing' criticism is really lazy shorthand for saying 'we do not think the applicants have explained clearly enough why the clinical picture of the disease should make us think something important will be found by doing these tests' or something like that.

I think there are two sides to the case here. I do think that 'fishing' for any abnormality we can find is legitimate in ME/CFS because we are so short of leads. So I have no problem with the Davis approach.

On the other hand, if I were setting out to look at the metabolic side I would want some more solid indication that there is actually a metabolic problem relating to energy usage. I think I would do that by studying muscle and other tissues by MR spectroscopy at rest and after exercise. The MR spectroscopy gives you measures of a large number of metabolites in a single trace without needing to do any biochemical analyses. So if we are accepting an observational approach I would go for a more direct observation of disordered metabolism in vivo linked to symptoms first and then maybe work out detail in vitro.

 

[Aroa]

You can spend decades testing stupid Hypothesis if you don´t have enough understanding of the problem. But apparently that is not a concern for the NIH

Time will tell whether they were wrong or not dismissing Ron Davis RFA, after decades of no results.

 

[Diwi9]

On the other hand, if I were setting out to look at the metabolic side I would want some more solid indication that there is actually a metabolic problem relating to energy usage. I think I would do that by studying muscle and other tissues by MR spectroscopy at rest and after exercise. The MR spectroscopy gives you measures of a large number of metabolites in a single trace without needing to do any biochemical analyses. So if we are accepting an observational approach I would go for a more direct observation of disordered metabolism in vivo linked to symptoms first and then maybe work out detail in vitro.

I am curious if his grant rejection was, in part, also denied on political grounds because of the NIH's current study with Dr. Nath. That study is essentially fishing...or attempting to observe the disease that they then expect other researchers to build on. My understanding from some participants in the study who are on PR is that the NIH is performing muscle biopsies, but I don't think they are applying the technique you in your suggestion...which is more comprehensive. My feeling is that anomalies found in research can often be attributed to patients in PEM and patients not in PEM.

 

[msf]

I don´t think reasonable hypotheses are that hard to generate, but I think Davis wants the science to lead him to the true one, rather than just try one hypothesis after another or rely on his hunches - I think he should be applauded for that, but the NIH obviously doesn´t agree.

 

[msf]

Also, any hypothesis of the pathophysiology of ME that involves infection (which Davis doesn´t seem to favour, but has probably considered) relies on their being accurate tests to establish the presence of the particular infection you are looking for, which is where several attempts to establish an infective hypothesis have foundered before. There is also the fact that any hypothesis about ME relies on successful sub-setting, which Lipkin and others have tried to do by dividing patients into flu-like onset and non subsets, which touches upon the infective issue again.

 

[alex3619]

You can spend decades testing stupid Hypothesis if you don´t have enough understanding of the problem.

Can? How about this has already happened. CBT/GET studies being the most egregious example, though there have been many more. In particular studies into specific pathogens that have failed to show anything, especially EBV, were then used to justify the unproven claim that nothing could ever be found.

 

[RYO]

I am curious if his grant rejection was, in part, also denied on political grounds because of the NIH's current study with Dr. Nath. That study is essentially fishing...or attempting to observe the disease that they then expect other researchers to build on. My understanding from some participants in the study who are on PR is that the NIH is performing muscle biopsies, but I don't think they are applying the technique you in your suggestion...which is more comprehensive. My feeling is that anomalies found in research can often be attributed to patients in PEM and patients not in PEM.

No offense to Dr Jonathan Edwards, but I have asked the researchers at the NIH working on Dr Nath's intramural study to contact the experts in muscle metabolism to inquire about how they would approach the problem. I was told that the NIH may reach out to a world renowned expert in the field of muscle/mitochondrial disorders to determine the best way to evaluate metabolic function in ME/CFS patients.

It may include MR spectroscopy or Seahorse, but perhaps there are other unknown methods that may shed some light on this matter. In my opinion, it is difficult to even know if we are even asking the right question.

 

[Diwi9]

@RYO - Under what conditions did you have a muscle biopsy? After rest, after exercise, after exercise-induced PEM? Just curious how the NIH is approaching this.

 

[RYO]

@RYO - Under what conditions did you have a muscle biopsy? After rest, after exercise, after exercise-induced PEM? Just curious how the NIH is approaching this.

They are in the process of adjusting the design of the study to include muscle biopsy in part 2 of phase 1. The NIH has not performed muscle biopsies on any of their patients. Part 2 may begin as soon as late summer of 2017 according to @viggster. They are trying to reach out to other experts outside the field of neuroimmunology to figure out how to best set up experiments on muscle samples.

 

[RYO]

It would be helpful if there was more information from Dr Davis about the metabolic experiments he is conducting. I have suggested to the NIH that they contact Dr Davis. I was told someone from Stanford is planning a trip to NIH to represent Dr Davis. This information has not been confirmed. It makes sense to me that researchers from outside the NIH should collaborate if possible.