NIH intramural research program update

[Denise]

I do not have further info. I was simply commenting that Walitt's presence is of huge concern to the community.

@Kati - (my bad) I wasn't trying to put you on the spot. My question about additional info was to anyone/everyone who may have info.

 

[searcher]

I was really happy to wake up to the news on FMD controls and hope we will hear more news soon about other changes in response to patient feedback. I know that Vicky was also concerned from the beginning about FMD as a control group (she saw the protocol at the same time as all of us as she was not involved in planning the intramural study).

I've said this before but I am with @leela about lyme being an odd control group. If you need to compare to a group that recovered from an infection, EBV/mono or HHV6 makes more sense. But since EBV and HHV6 are incredibly common, almost everyone in the population is asymptomatic carriers so people who have recovered from them are basically just healthy controls. I suspect they may have added the Lyme group because of the similarities described at http://directorsblog.nih.gov/2016/0...-signatures-may-catch-the-infection-sooner-2/, but have no idea.

 

[Simon]

I'd like to see the Lyme group gone too. More than one control group makes me nervous, for reasons of statistical power.

I think that's an important point. The study is small in any case - particularly when you consider how many diff measures they are making-hundreds, at least). So I don't get the logic of 20:20:20 controls groups: with samples that small it would be hard to get a statistically significant results that, say, mecfs patients were different from healthy controls but not from post-Lyme controls. (Even a big difference may well end up a not statistically significant).

Would be good to know see an analysis plan/power calculaiton for the study, or at least understand the rationale.

 

[Simon]

But since EBV and HHV6 are incredibly common, almost everyone in the population is asymptomatic carriers so people who have recovered from them are basically just healthy controls

I'm not sure that's quite right. Presumably there could well be a difference between people who had glandular fever/mono due to EBV, and recovered - and those that carry EBV but never developed the illness.

I suspect they may have added the Lyme group because of the similarities described at Lyme Disease: Gene Signatures May Catch the Infection Sooner | NIH Director's Blog

I wondered too if Lyme was just a hot topic (the blog by Francis Collins was interesting, and reported that the asymptomatic recovered Lyme patients had gene expression patterns that were much more similar to chronic cases than they were to healthy controls).

 

[viggster]

Oh @viggster, I meant *only* healthy controls, for clarity.
What is the purpose of having recovered Lyme patients as a control group?
I know several recovered (formerly severely ill) Lyme patients as well. I hope you didn't take my post (or this one) as antagonistic.
I'm all for this study, and for it being the best it can be. I know emotions have run high here, and you don't know me. Ask @searcher, I'm not the enemy here.

I don't think you are.

Just trying to clarify. NIH has already said why they are including a *recovered, asymptomatic* Lyme control group: "Control groups: Asymptomatic Lyme was chosen to contrast post-infectious ME/CFS patients to patients who recovered from an infection."

If you look up this thread many pages you'll see J Edwards explain that having a disease control group can be very powerful.

I don't understand why people keep talking about chronic Lyme patients. There are no chronic Lyme patients in the study. If someone has symptoms from Lyme, they will not be in the study.

 

[searcher]

I'm not sure that's quite right. Presumably there could well be a difference between people who had glandular fever/mono due to EBV, and recovered - and those that carry EBV but never developed the illness.


I wondered too if Lyme was just a hot topic (the blog by Francis Collins was interesting, and reported that the asymptomatic recovered Lyme patients had gene expression patterns that were much more similar to chronic case than they were to healthy controls).

Good point Simon. I somehow forgot that everyone doesn't develop glandular fever/mono after EBV exposure. So presumably someone who had glandular fever/mono and recovered could be relevant, but it seems like that money would be better spent on studying more patients. Lyme just seems like an odd choice because it's not a well-accepted trigger for ME/CFS by the research community, and it's so mired in uncertainty and controversy. I look forward to hearing NIH's rationale for including "asymptomatic Lyme" patients as controls.

 

[mfairma]

I don't understand why people keep talking about chronic Lyme patients. There are no chronic Lyme patients in the study. If someone has symptoms from Lyme, they will not be in the study.

I think the issue is that if you don't know enough about the difference between asymptomatic lyme and chronic lyme -- I am assuming they don't have the relevant comparisons for the measures being done here, someone please correct me if this assumption is wrong -- then will attempting to make comparison with another murky group help or mislead? Given where this disease is politically, it seems like a mistake to try to make comparisons that could very well mislead, particularly when doing so means looking at fewer patients with the disease to be studied. Can you shed more light on how this comparison will be useful, when it seems a bit like comparing apples and oranges?

 

[duncan]

The NIH needs to come right out and say the patients culled from the Lyme community are cured. We of all people should be well-acquainted with the risks associated with the word "recovered."

Moreover, depending on from where these Lyme patients come, there is up to a 50% chance they have a co-infection - one that may be quiet right now. It puzzles me to no end how anyone knowledgeble about TBD's would include "Lyme" as a control group.

 

[Bob]

I still don't understand the objections to the post-Lyme control group, despite trying hard to understand.

People say that it's a murky control, but if someone doesn't have symptoms and says they've recovered then that seems straight-forward to me. (Assuming the participants are actually asymptomatic.) The study will be comparing a post-infection group with symptoms (ME patients) to a post-infection group at risk of symptoms but without symptoms (post-Lyme). The essential factor is the presence or lack of symptoms.

A reason given against the post-Lyme control is that the bacterial infection might still be present but simmering, but the same could be said for ME (that an infection is simmering) so that seems perfect to me. Even with a simmering infection, the post-Lyme patients are still asymptomatic so I don't understand that argument.

Every time I think it through I come to the same conclusion that its a helpful control. I realise that I'm in a minority of one or two people here!

 

[Bob]

I think that's an important point. The study is small in any case - particularly when you consider how many diff measures they are making hundreds, at least). So I don't get the logic of 20:20:20 controls groups: with samples that small it would be hard to get a statistically significant results that, say, mecfs patients were different from healthy controls but not from post-Lyme controls. (Even a big difference may well end up a not statistically significant).

Would be good to know see an analysis plan/power calculaiton for the study, or at least understand the rationale.

Perhaps it's a case of trial design by committee. Everyone wants to influence the study and wants their favourite interest included in the study.

 

[Kati]

I still don't understand the objections to the post-Lyme control group, despite trying hard to understand.

People say that it's a murky control, but if someone doesn't have symptoms and says they've recovered then that seems straight-forward to me. (Assuming the participants are actually asymptomatic.) The study will be comparing a post-infection group with symptoms (ME patients) to a post-infection group at risk of symptoms but without symptoms (post-Lyme). The essential factor is the presence or lack of symptoms.

A reason given against the post-Lyme control is that the bacterial infection might still be present but simmering, but the same could be said for ME (that an infection is simmering) so that seems perfect to me. Even with a simmering infection, the post-Lyme patients are still asymptomatic so I don't understand that argument.

Every time I think it through I come to the same conclusion that its a helpful control. I realise that I'm in a minority of one or two people here!

Lyme comes with its own set of controversies regarding diagnosis, treatment, case definition, etc. The IDSA vs ILADS fiasco is not over. Recommended laboratories, what is the definite test that ascertains that this was really a case of Lyme, or not, and clinically very difficult to discriminate between a ME pt vs Lyme pt are all factors which will muddy the waters further.

Considering that the likelihood that ME patients are heterogenous is high, let's not muddy the waters further.

 

[mfairma]

I still don't understand the objections to the post-Lyme control group, and I'm trying to understand.

As I see it, the issue is that, assuming patient selection is perfect (something I'm not sure is necessarily reasonable), you're comparing two separate disease processes -- ME to Lyme -- and little is known concretely about either. As others mentioned, why not compare other infections, if there is value in that approach. Or, alternatively, why not find twenty people that had post-infectious ME that recovered, because at least you would be comparing the same disease? If you can't find any such patients, wouldn't that then say something about the value of trying to make a comparison with another disease? These are just my loose thoughts. It seems like a poor choice that introduces extra variables with little obvious potential for gain.

 

[Bob]

Lyme comes with its own set of controversies regarding diagnosis, treatment, case definition, etc. The IDSA vs ILADS fiasco is not over. Recommended laboratories, what is the definite test that ascertains that this was really a case of Lyme, or not, and clinically very difficult to discriminate between a ME pt vs Lyme pt are all factors which will muddy the waters further.

Considering that the likelihood that me patients are heterogenous is high, let's not muddy the waters further.

Thanks for your thoughts.

It's the muddy waters argument again, but when I analyse all of the issues in turn, they all seem irrelevant to me.

The issue of whether a patient had Lyme or not won't be an issue if they're using officially recognised tests.
Treatment is irrelevant: only the outcome matters.
Case definition is irrelevant: either they were infected or they weren't.
The issue of recommended laboratories is irrelevant because they'll be using officially recognised test results.
And the argument re the inability to discriminate between Lyme patients and ME patients seems like an argument in favour of the post-Lyme cohort. (They may be comparing the same types of people but with/without symptoms which is an absolutely perfect control!)

 

[Denise]

"The issue of whether a patient had Lyme or not won't be an issue if they're using officially recognised tests."
Are there unequivocal Lyme tests that for current and or past infection? (I thought one of the big problems with Lyme was the difficulty in diagnosing.)

 

[Kati]

Thanks for your thoughts.

It's the muddy waters argument again, but when I analyse all of the issues in turn, they all seem irrelevant to me.

The issue of whether a patient had Lyme or not won't be an issue if they're using officially recognised tests.
Treatment is irrelevant: only the outcome matters.
Case definition is irrelevant: either they were infected or they weren't.
The issue of recommended laboratories is irrelevant because they'll be using officially recognised test results.
And the argument re the inability to discriminate between Lyme patients and ME patients seems like an argument in favour of the post-Lyme cohort. (They may be comparing the same types of people but with/without symptoms which is an absolutely perfect control!)

My point is that Lyme is not a well accepted disease. Ask any IDSA infectious disease dr. Ask any hospital dr to see if they consider Lyme as a differential diagnosis for any patient for whom they are not sure of their diagnosis. At least here in Canada, it is not mainstream. Igenex testing is not recommended (too many false positive, apparently).

It seems to me that NIH study is trying to compare fruit salad with fruit salad (sorry! ) and think that all the fruit salads will benefit from whatever testing that will be done. One of the fruit salad (FMD) has just been dropped, likely to the dismay of some NiH researchers who wanted to push their pet theories.

My view here is that well defined viral onset ME needs to be studied here, and that should they introduce another patient population as control, then a non-controversial, well defined disease population needs to be used, or none at all. (Multiple sclerosis, lupus, Sjogrens comes to mind)

 

[Forbin]

You know what would make more sense than a control group of "recovered" Lyme patients?

A control group of "recovered" ME/CFS patients.

I'm talking about people who were once diagnosed with CCC/ICC consistent ME/CFS but then became asymptomatic, or at least very, very close to asymptomatic. In his interview following the Grand Rounds at the NIH, Dr. Komaroff said that 5%-10% of people with ME/CFS "return to what they feel is a fully normal state", although he also said that a "substantial fraction" will have a relapse. This kind of "recovery" is also most likely in the first five years, which is consistent with the kind of ME patients that they are recruiting.

It seems to me that finding the differences between ME patients who had become asymptomatic and those with ongoing ME would be more valuable to than comparing ongoing ME patients to asymptomatic Lyme patients.

This comparison might be especially useful if the asymptomatic ME patients were also found to be different from both ongoing patients and controls. It might distinguish the pathways that are causing the symptoms from other abnormalities associated with the disease.

[If only there were there enough to test, it would also make sense to compare patients who had significantly improved on rituximab with ongoing ME patients.]

 

[Bob]

As I see it, the issue is that, assuming patient selection is perfect (something I'm not sure is necessarily reasonable), you're comparing two separate disease processes -- ME to Lyme -- and little is known concretely about either. As others mentioned, why not compare other infections, if there is value in that approach. Or, alternatively, why not find twenty people that had post-infectious ME that recovered, because at least you would be comparing the same disease? If you can't find any such patients, wouldn't that then say something about the value of trying to make a comparison with another disease? These are just my loose thoughts. It seems like a poor choice that introduces extra variables with little obvious potential for gain.

Thanks for your thoughts.

The post-Lyme patients are healthy controls but a more homogeneous cohort than the standard healthy control because they've all had the same infection whereas the healthy controls will have had many infections through their lives and so will be a very heterogeneous group.

As others have said, other post-infectious groups wouldn't be straight-forward either because some infections are asymptomatic or symptomatic. And nearly all the population is post-mono or post-herpes. I can't think of any post-infection groups that would be more helpful.

As for the suggestion of post-ME patients, that wouldn't work because everyone would say there's no such thing.

 

[Kati]

You know what would make more sense than a control group of "recovered" Lyme patients?

A control group of "recovered" ME/CFS patients.

I'm talking about people who were once diagnosed with CCC/ICC consistent ME/CFS but then became asymptomatic, or at least very, very close to asymptomatic. In his interview following the Grand Rounds at the NIH, Dr. Komaroff said that 5%-10% of people with ME/CFS "return to what they feel is a fully normal state", although he also said that a "substantial fraction" will have a relapse. This kind of "recovery" is also most likely in the first five years, which is consistent with the kind of ME patients they are recruiting.

It seems to me that finding the differences between ME patients who had become asymptomatic and those with ongoing ME would be more valuable to than comparing ongoing ME patients to asymptomatic Lyme patients.

This comparison might be especially useful if the asymptomatic ME patients were also found to be different from both ongoing patients and controls. It might narrow down the pathways that are causing the symptoms.

Dr Bell returned to his original cohort of young patient who contracted ME from an epidemic. Many of them considered themselved recovered. But interestingly, Dr Bell found that they had adapted their lifestyle to their disease and they were nowhere near recovered. Many did not have fulltime employment. Others could not sustain a normal social life. And so on.

Definition of recovery is difficult without biomarkers, just like leukemia remission establishment is difficult to determine without blood test and a bone marrow biopsy.

 

[Bob]

It seems to me that finding the differences between ME patients who had become asymptomatic and those with ongoing ME would be more valuable to than comparing ongoing ME patients to asymptomatic Lyme patients.

It's an interesting idea, but it would be too controversial to be accepted by the community: People would say that ME patients don't recover; And, if they do recover, then they didn't have ME.

 

[Bob]

"The issue of whether a patient had Lyme or not won't be an issue if they're using officially recognised tests."
Are there unequivocal Lyme tests that for current and or past infection? (I thought one of the big problems with Lyme was the difficulty in diagnosing.)

I think a positive rest result with an officially sanctioned/recognised company is widely accepted to be true? And that's the only result that seems relevant to this study. That's the test result that will allow participation in the study.