The P2P Draft report is out

Ember

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The subgrouping results in the PACE Trial are a shabby sop.
The ME criteria used for the ‘secondary analysis’ in the PACE trials are considered so broad as to risk including “a large number of other important diseases/conditions...having similar symptoms and signs.” Dr. Shepherd, one of the authors, comments on using these criteria for research purposes:
Additional information on the London Criteria:

ASSESSMENT, INVESTIGATION AND DIAGNOSlS
When diagnosing M.E. for research purposes, particular attention must be paid to two factors:

- many of the symptoms and signs evident in people suffering from M.E./PVFS could be due to a large number of other important diseases/conditions.
- M.E. may run in parallel with other diseases having similar symptoms and signs.
Because it is vital that the M.E. study groups we use in research are as ‘pure’ as possible, the existence of a parallel disease would be grounds for disqualification. The most common alternative diagnoses/parallel. diseases to be borne in mind before referring a research subject volunteer to an M.E. study group can be considered under the following headings:

Chronic infections:
toxoplasmosis, Lyme disease, HIV infection, chronic active hepatitis, schistosomiasis, brucellosis, occult sepsis, tuberculosis, giardia.

Endocrine disorders:
hypothyroidism, thyrotoxicosis, Addison’s disease, Cushing’s syndrome, diabetes mellitus, hyperparathyroidism.

Neuromuscular disorders:
myasthenia gravis, multiple sclerosis, mitochondrial myopathy, Parkinson’s disease.

Cardiovascular disorders:
cardiac ischaemia.

Metabolic disorders:
sleep apnoea syndrome, chronic renal failure.

Malignant disease:
occult tumours such as undiagnosed lymphomas, retroperitoneal sarcomas; renal and liver tumours; frontal lobe tumours.

Auto-immune disease:
rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, Sjogrens syndrome. Haematological disorders: leukaemias and anaemias of varying origin.

Miscellaneous:
heavy metal poisoning, chronic intoxications due to prolonged exposure to chemicals such as petrol, benzene, organo-phosphorous compounds and methylene chloride; drug side effects such as those due to beta-blockers, and long-term benzodiazepine usage; chronic alcoholism; coeliac disease.

Psychiatric:
primary depressive illness, anxiety neurosis.

OTHER REASONS FOR EXCLUSION FROM RESEARCH INTO M.E.

Of particular importance is to eliminate chronic fatigue primarily associated with psychological factors. If there are signs of persistent anhedonia, apathy, low self-esteem, feelings of worthlessness and guilt, the possibility: of primary depressive illness should be actively considered and, if there is any doubt whatsoever, the subject eliminated from the research study.

If the subject has had any other diseases or conditions in the last three months they should be excluded from, research into M.E.

If the subject has taken any treatments – orthodox, complementary or nutritional – in the last three months they may have to be excluded from certain research projects.
Dr. Shepherd provides version 2 of the criteria, commenting, “I understand that this is version 2 as used in the PACE trial – please note that I did not prepare version 2.” Despite the stated need to exclude many parallel diseases/conditions, version 2 makes only one exclusion, “There is no primary depressive illness present and no anxiety/neurosis:”
Criteria 1 to 4 must be present for a diagnosis of ME to be made.

1. Exercise-induced fatigue precipitated by trivially small exertion (physical
or mental) relative to the patient’s/participant’s previous exercise tolerance.

2. Impairment of short-term memory *and* loss of powers of concentration, usually coupled with other [neurological and psychological} disturbances such as:

[NB These should be asked for as symptoms, not tests, and do not have to be total or persistent for the whole period. These symptoms (in a-e) should be recorded but are not necessary, in order to make the diagnosis.]

a) emotional lability [feeling easily upset by things that would not normally upset the participant, but the upset is brief and has usually gone within a few hours, and certainly by the next day]

b) nominal dysphasia [difficulty finding the right word]

c) disturbed sleep patterns [of any sort]

d) disequilibrium [a feeling of imbalance]

e) tinnitus [ringing in the ears]

3. Fluctuation of symptoms

[The usual precipitation by ‘”physical or mental exercise”, should be recorded,
but is not necessary to meet the criteria.]

usually precipitated by either physical or mental exercise.

4. These symptoms should have been present for at least 6 months and should be ongoing.

5. There is no primary depressive illness present and no anxiety/neurosis.

[N.B. This means that if any depressive or anxiety disorder are present, the London criteria are not met.]

Version 2, 26.11.2004
 

Sidereal

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So they used an unauthorised modification of an unvalidated case definition for ME when they could have used the Canadian criteria.
 

alex3619

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So they used an unauthorised modification of an unvalidated case definition for ME when they could have used the Canadian criteria.
Why is this a surprise. Part of the modus operandi is to redefine things to suit them, then continue in common discussion (but often not in their papers if you read closely) as though no meaning were altered.
 

Sasha

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@Hope123 (and others), I've just looked at the 'recovery paper':

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/

CFS case definition: the International (Centers for Disease Control and Prevention, CDC) criteria
The research assessor used participant ratings to judge whether participants met the International (CDC) criteria for CFS at 52 weeks (Reeves et al. 2003), which included: (1) severe chronic fatigue for at least 6 months with other known medical conditions (whose manifestation includes fatigue) excluded by clinical diagnosis; and (2) concurrently have four or more of the following symptoms: post-exertional malaise, impaired memory or concentration, unrefreshing sleep, muscle pain, multi-joint pain without redness or swelling, tender cervical or axillary lymph nodes, sore throat, headache. For the purposes of this study, the four or more symptoms needed to be present within the previous week of the assessment date, rather than the previous 6 months (Reeves et al. 2003).​

These don't appear to be entry criteria, just a way of assessing whether, at 52 weeks after treatment started, patients would have fulfilled the Fukuda criteria.

On entry to the trial, were patients assessed by Fukuda as well as Oxford? Were any identified as fitting proper Fukuda (six months) criteria on entry?

Sorry if I'm misunderstanding this!
 

Nielk

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I don't believe that NIH funded research ever used the Oxford criteria. Therefor, the statement that the Oxford criteria will be "retired" by the NIH is meaningless.
 

biophile

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On entry to the trial, were patients assessed by Fukuda as well as Oxford?

Were any identified as fitting proper Fukuda (six months) criteria on entry?
I doubt it, check out page 156 of the complete protocol:

A6.4 CDC. Please score whether you have had any of the following symptoms in the last week: Score each symptom by putting a circle round the number that most closely resembles the frequency and intensity of that particular symptom.

http://www.meactionuk.org.uk/FULL-Protocol-SEARCHABLE-version.pdf

[edit]

A freedom of information request from the ME Association revealed the following: "A symptom was counted as present if scored as 'more often than not', or more frequently than that."

http://www.meassociation.org.uk/wp-content/uploads/2011/06/FOI+from+Queen+Mary.pdf
 
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Anne

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I think the apparent effectiveness of CBT is an artifact of poor research methods, much like the placebo effect. What we really need are some objective measures of improvement and long term follow ups.
Yes, exactly!

I hope lots of people send comments to the P2P draft saying just that: They have to make solid recommendations on 1) that NIH issue new RFAs for ME/CFS and 2) that NIH request of any treatment trial that the researchers include (and publish...) objective measures of improvement and long term follow-ups such as return to work or studies.
 

Sasha

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biophile

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Sasha

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Sasha

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I've edited the following para into my post about Oxford/PACE:

http://forums.phoenixrising.me/inde...l-points-in-the-p2p-report.34630/#post-540676

Please note that although data were collected in relation to Fukuda symptoms, it is not the case that a subset of Fukuda-criteria patients can be identified. Patients were asked about Fukuda criteria only in relation to the past week, not the required six months (p. 156 in this document: http://www.meactionuk.org.uk/FULL-Protocol-SEARCHABLE-version.pdf and in the ‘CFS case definition: the International (Centers for Disease Control and Prevention, CDC) criteria’ section of this document: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776285/.​
 

biophile

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Re London ME criteria comparison of Version 1 and Version 2 ...

(a rough analysis of information from Goudsmit/Shepherd for Version 1 and from PACE/AfME for Version 2):

The five criteria categories between the two versions are essentially identical except for one crucial difference. Both say for the 3rd criteria that "Fluctuation of symptoms, usually precipitated by either physical or mental exercise." However, Version 2 adds that "The usual precipitation by 'physical or mental exercise', should be recorded, but is not necessary to meet the criteria." Whereas Version 1 states later on in the notes that "it is absolutely characteristic that they tend to be exacerbated by physical or mental exertion and the association should always be sought whilst taking the history".

This is a major red flag to me, it means that the London ME criteria Version 2 can be met with "fatiguability" but without PEM, PENE or other forms of post-exertional symptoms other than fatigue.

Important notes for clinical context are missing from Version 2 that are included in Version 1, such as: additional but optional symptoms and characteristics of ME which "in the right symptomatic context they contribute to the validity of the diagnosis"; physical signs which may have increased the probability of being excluded from the PACE Trial due to its exclusion policies e.g. lymph node enlargement; and exclusionary conditions or parallel diseases excluded for research purposes.
 
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Ember

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This is a major red flag to me, it means that the London ME criteria Version 2 can be met with "fatiguability" but without PEM, PENE or other forms of post-exertional symptoms other than fatigue.
The Evidence Report confirms that the London criteria don't require PEM, PENE or other forms of post-exertional symptoms other than fatigue:
Appendix 1: Published Case Definition Criteria Case Definition Statements: London Dowsett et al., 199447

General Diagnostic Criteria: Must meet all three criteria: 1. Exercise induced fatigue, see fatigue criteria. 2. Impairment of short-term memory and loss of powers of short-term concentration, usually coupled with other neurological and psychological disturbances, see neurological/cognitive criteria. 3. Fluctuation of symptoms, usually precipitated by either physical or mental exercise.

Fatigue: Exercise-induced fatigue precipitated by trivial small exertion (physical or mental) relative to the patient's previous exercise tolerance.

Post-Exertional Malaise: Nothing noted

Sleep: Nothing noted

Pain: Nothing noted

Neurological/Cognitive: Impairment of short-term memory and loss of powers of short-term concentration, usually coupled with other neurological and psychological disturbances such as emotional lability (being upset by things that would not normally cause distress), nominal dyspepsia (not being able to find the right word), disturbed sleep patterns, disequilibrium (imbalance or unsteadiness rather than vertigo/spinning round) or tinnitus (noises in the ear).

Other Criteria: Fluctuation of symptoms, usually precipitated by either physical or mental exercise.

Additional Considerations: None (emphasis added)
47. Dowsett E, Goudsmit E, Macintyre A, et al. Report from The National Task Force on Chronic Fatigue Syndrome (CFS), Post Viral Fatigue Syndrome (PVFS), Myalgic Encephalomyelitis (ME). Westcare. 1994

Version 2 notes with respect to fluctuation of symptoms that "the usual precipitation by ‘physical or mental exercise', should be recorded, but is not necessary to meet the criteria."
 
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Hope123

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Sasha,

I would not get too hung up on when they assessed for Fukuda. They're using whatever method they use to argue that the CBT/GET works for people fitting Fukuda so I would concentrate on that point rather than if they assessed at entry or at outcome time.

The PACE trials documents on the official site include a form to assess for Fukuda which makes me think they assessed beforehand and not after. Also, their Table 1's in both papers detail how many fit Fukuda and how many didn't. Usually, the Table 1 (or Fig. 1) in a paper describes basic demographics of the study, not subgroup analyses done later.

(If anyone wants to verify and I don't have the time today, look at the original protocol for PACE.)

In fact if they assessed AFTER entry, it's a post-hoc analysis, which we know PACE already is in other areas, and that makes the situation even less scientifically good than a planned study. It makes you think they only picked people based on Oxford and then realized later, "Oh @!*^%, most people in the US and internationally use Fukuda, not Oxford!."
 

Sasha

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I would not get too hung up on when they assessed for Fukuda. They're using whatever method they use to argue that the CBT/GET works for people fitting Fukuda so I would concentrate on that point rather than if they assessed at entry or at outcome time.
I think it makes a big difference - at 52 weeks, they're assessing patients to see if they're still sick enough to qualify as patients (that is, to see if they've recovered). The point we want to be making (if it's true, and it seems to be) is that on entry to the trial, no patient was assessed in terms of whether they had had symptoms for 6 months that would have made them Fukuda patients at entry.

It seems to me that all we can say about PACE patients is that all were Oxford, and the study authors don't know whether any were genuine Fukuda when they entered the trial. In other words, this is purely a trial on Oxford patients.
 

Ember

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Losing the plot here slightly but just in case no-one has posted this link yet, here's Jennie Spotila talking today about P2P:

http://www.occupycfs.com/2015/01/07/p2p-obstacles/
Unfortunately, Jenny thinks that the deadline for written public comment to CFSAC was yesterday.

Meeting of the Chronic Fatigue Syndrome Advisory Committee: “Only testimony submitted for public comment and received by January 7, 2015, will be part of the official meeting record and posted to the CFSAC Web site.”
 

Bob

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On entry to the trial, were patients assessed by Fukuda as well as Oxford? Were any identified as fitting proper Fukuda (six months) criteria on entry?
My own opinion is that we shouldn't focus on this. (But please ignore me if you don't agree.) The P2P evidence document doesn't include any Fukuda data for the PACE trial, as far as I can see, so I don't think it's an issue that we should spend much time on. In fact, by mentioning it, we might make the draft authors aware that PACE included a Fukuda-type subset analysis.

To answer your question, as far as I'm aware, the main PACE trial paper does not indicate that patients were assessed for their symptoms only in the previous week. This was only included in the recovery paper.

The recruitment criteria for the PACE trial was Oxford, and a subsequent sub-group analysis was carried out using Fukuda. So patients were not recruited via Fukuda.

Hope that's as clear as mud?
 

Wally

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Meeting of the Chronic Fatigue Syndrome Advisory Committee: “Only testimony submitted for public comment and received by January 7, 2015, will be part of the official meeting record and posted to the CFSAC Web site.”
Here is the link for the quote set forth above, which also includes additional information about submitting a public comment.
https://www.federalregister.gov/art...e-chronic-fatigue-syndrome-advisory-committee

Here in the U.S. it is January 7th and I believe there is still time to send in comments for the CFSAC Meeting.

When I asked the ODP about a cut-off time on the last day to submit Public Comments for the P2P Draft Report, I was told the following:
We do not set an exact closing time for the public comment period in order to give as many people as possible an opportunity to comment by Friday, January 16th in all time zones. There are four weeks to comment via email and we accept all public comments received by postal mail that is postmarked by the closing date.
Unless a Federal Advisory Committee falls under different rules, I would think that the CFSAC would follow similar guidelines to allow for comments to be accepted from all States (including Hawaii). The time difference between the East Coast and Hawaii is 7 hours. See, http://www.timetemperature.com/tzus/time_zone.shtml

If I am incorrect about the date and time for submitting Public Comments for the 1/13/2015 CFSAC meeting, please let me know.

[Edit - On a previous occasion I have submitted a Public Comment for a CFSAC meeting before the end of the day (11:59 pm) Hawaiian Standard Time and the comment was accepted. I made the argument that no cut-off time was stated for accepting comments on the last day for the submission, therefore it was my understanding that as long as the comment was received within a time zone for the last day, then I had met this deadline. In a follow-up phone conversation with the HHS/Office of Women's Health, I was told that I had met the requirement for submitting a comment within the time period allowed for comments.]
 
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