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CDC Multi-site Study - An interview with Beth Unger

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The CDC multi-site clinical assessment of CFS/ME is now underway, and Bob took the opportunity to interview Dr Beth Unger, the lead scientist in charge. The outcomes of this significant study are likely to be widely influential and the means by which the CDC employ objective measures has become something of a hot potato, especially in relation to exercise testing...


Elizabeth, R. Unger, PhD, MD
Chief, Chronic Viral Disease Branch

The CDC department that oversees chronic fatigue syndrome, under the leadership of Dr Beth Unger, has begun a large study using data from 450 ME/CFS patients, collected at seven well known clinical sites across America (see below).

The CDC website describes the study as a "multi-site clinical assessment of chronic fatigue syndrome (CFS) to characterize patients with CFS or myalgic encephalomyelitis (ME) in clinical practices of clinicians with expertise in CFS/ME."

"The study started in 2012 and aims to enrol 450 patients. Any patient (aged 18 – 70 years) that is managed or diagnosed with CFS, post-infective fatigue (PIF) or myalgic encephalomyelitis (ME) at any of seven participating clinical sites is eligible for participating in the study."

No specific official clinical criteria (such as the Fukuda CFS criteria or the Canadian Consensus Criteria for ME) are required for patient recruitment. Instead, the participating clinicians are asked to use their own clinical judgement to include CFS/ME/PIF patients in the study.

The CDC website says: "The study will examine the differences and similarities between CFS/ME patients in the clinical practices of experienced CFS clinicians." "The data collected using a standardized approach from expert clinical practices will be used to address the CFS case definition. Ultimately, this study aims to improve how we measure illness domains of CFS. This may allow patients to be sub-grouped to improve therapy and allow the underlying biology to be discovered."

On paper, the CDC seems fairly ambitious in its aims:

"CDC is fully committed to working with the CFS Advisory Committee (CFSAC) and DHHS to develop consensus about the case definition and name of this devastating illness. The need is not only for a case definition but also for reproducible standardized approaches to applying it, as well as for biomarkers to refine subgroups within the overall CFS patient population."

The first stage of the study collected subjective measures from the patients, including clinical assessments and medical histories.​

Dr Unger has said that 'biologic' measures are crucial to further characterize and sub-group patients, and has indicated that the early stages needed to be self-report measures in order to test the logistics of such a large study. She has said that the logistics were found to be successful in the first stage, and that they are now moving on to the second stage.

The second stage will enroll paediatric/adolescent CFS patients, as well as recruiting the controls (healthy people and people ill with other fatiguing illnesses), as comparison groups.​

The devil is in the detail...

Dr Unger seems to be taking a robust evidence-based approach to defining the illness, illnesses, or subsets. If the study is done well, it could turn out to be a ground-breaking project, but if done badly, it could be worse than meaningless. If objective biological tests are not included in the long-term, then this might turn out to be a large but very shallow study, costing a lot of money and not providing any ground-breaking answers.

Depending on its ultimate design, and its implementation, this large study could potentially be ground-breaking. Extensive objective and biological measures are not yet included in the study, but the study is evolving, and Dr Unger explains that the current study may pave the way to, and enable, future biological testing in better defined cohorts.

However, strong feelings of discontent have been expressed - by patients and advocates - over Dr Unger's decision not to include extensive objective or biological testing from the start. One such objective test that has been called for, is a two-day cardio-pulmonary exercise test (CPET), which seeks to measure cardio-pulmonary efficiency (by measuring values such as: effort, energy expenditure, oxygen intake, and heart rate) when patients use an exercise bicycle in two separate tests on consecutive days.


Hooked up for a CPET

In small studies by Dr Christopher Snell and colleagues, CFS/ME patients were seen to have fairly similar CPET results to sedentary healthy controls on the first day's test. But, significantly, for one of the efficiency measures, the healthy controls improved in performance in the second day's test, whereas the performance among the CFS/ME patients was substantially worse on the same test.

This has been seen as a means of objectively demonstrating the symptom of post-exertional malaise - considered a key symptom of CFS/ME - and Dr Snell has said that this abnormal response to exercise is something he has seen only in these patients (see: Repeat Test Reveals Dramatic Drop in Exercise Capacity).

Dr Snell's latest research study was small, but these intriguing initial results, if replicated by larger studies, may well confirm that 2-day CPET testing is a useful biomarker for the disease.

Members of the Chronic Fatigue Sydrome Advisory Committee (CFSAC) have suggested that Dr Unger contact Dr Snell to discuss the merits of a two-day CPET, which she has now done. We do not know the extent to which they discussed his research, or what will occur as a result, but Dr Snell has hinted that Dr Unger appeared to be open minded to including such a test at some stage in the future - indeed she does not rule it out in the answers provided to my questions (below).

The plans for the CDC's study currently include a one-day CPET test, along with 48-hour post-exertional cognitive tests and post-exertional self-reported illness and symptom scores. Dr Snell has indicated that he believes there may be merit in using the proposed post-exercise cognitive tests and post-exercise symptom scores. It is possible that these measures may demonstrate post-exertional symptom exacerbation unique to CFS/ME patients, or a subgroup of CFS/ME patients.

But it seems clear that Dr Snell and many patients are of the opinion that a two-day CPET should be included. The CDC study is of such significance that it seems a wasted opportunity not to do so.

Interviewing Dr Unger

There is limited official information available about the study, so I recently put some questions to the CDC. In reply, Dr Unger explained that she considers it important to first of all collect a comprehensive range of subjective data that will enable, stimulate, and pave the way for further studies using biological testing.

The questions and answers are quoted below, exactly as they were asked and responded to. The answers were received on December 19th, 2013.

1. What are you ultimately hoping to achieve from your study e.g. to create a new clinical or research diagnostic criteria, to determine biomarkers, to define subsets, to discover any research leads?

We hope that this study will help determine the best measures of the major illness domains of CFS. These include measures of function, pain, fatigue, sleep, and additional symptoms cited in various case definitions. These measures are needed in order to determine if patient subsets can be identified that will correlate with biologic measures that could guide therapy.

These measures are also important to assist researchers in selecting patients that are better defined, a feature of study design that will help the field achieve replication and validation of results. In addition, we hope that our study will contribute to developing outcome measures needed for clinical trials. The data collected in this study will be useful in evaluating current and proposed diagnostic criteria, but creating new CFS case definition criteria is not a goal.

Our study will also provide descriptive analyses of the clinical management of CFS by the participating experts. Information on medication and other therapeutic and management tools could begin the process of developing evidence-based guidance for best practices for CFS care.

2. What data are you collecting about the patients? What biological/objective testing are you carrying out, or are you likely to add to the study? Are you collecting any tissue samples, and if so, what tests will you perform on the samples? If you are collecting DNA, what are you looking for in the DNA e.g. genetic predisposition?

In the first stage of the study we are collecting standardized self-reported measures of CFS illness domains. These include measures of function, pain, fatigue, sleep, and additional symptoms cited in various CFS case definitions. We are also using data abstraction forms to collect information from study participants on the history of the present illness, detailed medical history, medications, lab test results, family history, infection and immunization history, and physical examination.

In this second stage of the study, which began November 2013, we are collecting saliva to measure the wakening cortisol response. We are also collecting blood to create a small biorepository of DNA and RNA that could be used to replicate promising findings from other groups.

3. Is the methodology of the study evolving as you proceed i.e. are you adding more elements to the study as you feel you need to? Is the study open ended? How will you know when your study is complete i.e. what data will you have collected? what type of conclusions will you have made?

The study methodology is evolving. Follow-up of patients involved in the first stage of the study will be continued in the second stage using a smaller set of questionnaires that will give data on disease course and on how well the instruments measure changes in their health.

The second stage will enroll pediatric/adolescent CFS patients. In addition, we are enrolling healthy people and those ill with other illnesses that include fatigue as comparison groups. Other components that are being added in the second stage include measures of cognition and exercise capacity as well as response to exercise.

The study is currently being conducted under a contract that allows one-year extensions for up to five years if funds are available. While data collection will end when the contracts are closed, analysis and publication of the findings will continue. The study is expected to provide data to support new initiatives throughout the CFS research community.

4. Are you seeking to have an over-arching definition of fatiguing illnesses or is your focus on well defined subsets? Are you seeking to attempt to define subsets of the current Fukuda CFS diagnosis? Do you consider that post-exertional malaise (aka post-exertional neuro-immune exhaustion) i.e. delayed and prolonged post exertional symptom exacerbation that is not relieved by rest, could potentially define a distinct subset of Fukuda CFS? Are you actively looking for such a subset?

A new definition of CFS is not the objective of this study. We do believe the study will help identify subsets of CFS patients, and equally important, will provide the tools for clinicians and researchers to use to identify similar subsets. An essential feature of this study is that we did not use a case definition to enroll patients. The study relies on the clinical expertise of those physicians who have extensive experience in caring for those with CFS.

Post-exertional malaise or post-exertional neuroimmune exhaustion is an important characteristic of CFS with no currently validated measures. We believe that the data collected in our study will help identify the best options for either measuring post-exertional malaise, or for identifying measures that correlate with this characteristic.

5. I have heard patients and advocates expressing concern that it is very important that your exercise testing is carried out over two days, but you have highlighted the practical difficulties of such a study. Could a small exploratory two-day testing program be carried out, with patients who are safely able to participate, to see how useful the results are?

Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms.

Maximal cardio-pulmonary exercise testing (CPET) with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition), and Drs. Dane Cook and Connie Sol (exercise). We chose the one-day test so that more patients could be tested at multiple sites with rigorous standardization.

The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic, and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients.

Results of the study will guide the next steps. It may be that a trial of a two-day protocol could be indicated for some patients or to explore other aspects of the illness.

6. Over the years, the CDC has not always been popular with the ME/CFS community. Is there anything you can say that will provide patients with confidence in the CDC's current program and with your department's general attitude towards the patient population and the illness? Is the CDC making a fresh start with regards to ME/CFS?

CDC’s CFS Program is committed to reducing the clinical morbidity associated with CFS while at the same time improving the quality of life for CFS patients and their families. We are focusing on projects addressing the most pressing needs associated with CFS. During our meetings with CFS advocacy groups, we heard repeatedly about the need for improved health care services for CFS patients.

We currently have two types of initiatives related to this identified need. First, our study to collect data on CFS patients in multiple clinical practices; and second, developing educational materials, particularly targeted to healthcare providers, to advance the recognition and treatment of CFS.

Additional Information:

The seven participating clinical sites:
  • Pain and Fatigue Study Center, NY .............. (Lead clinician: Dr. Benjamin Natelson)
  • Center for Neuro-Immune Disorders, FL ..... (Lead clinician: Dr. Nancy Klimas)
  • Open Medicine Clinic, CA ............................. (Lead clinician: Dr Andreas Kogelnik)
  • Sierra Internal Medicine Associates, NV .... (Lead clinician: Dr Daniel Peterson )
  • Fatigue Consultation Clinic, UT ................... (Lead clinician: Dr Lucinda Bateman)
  • Hunter-Hopkins Center, NC .......................... (Lead clinician: Dr Charles Lapp)
  • Richard Podell Clinic, NJ ............................... (Lead clinician: Dr Richard Podell)
Summary of Objective Tests:

Current or proposed objective testing and biological sample taking:
  • One-day maximal cardiopulmonary exercise testing (CPET); with 48 hour post-exercise online cognitive testing (and also pain and symptom questionnaires) to attempt to identify post-exertional changes.
  • Saliva to measure morning (wakening) cortisol response
  • Blood samples to create a small bio-repository of DNA and RNA that could be used to replicate promising findings from other groups.
  • Natural Killer (NK) cell function and counts; sample for serum archive.
  • Blood sampling for gene expression changes.
Possible future tests (i.e. tests that have not been proposed but not ruled out):
  • Two-day CPET.

Further Reading:
Multi-site Clinical Assessment of CFS
CDC website (click here)


Redefining ME/CFS? CDC Chief Reveals First Fruits Of Multi-Center Doctor Study At FDA Stakeholder Meeting
Simon McGrath, 11 May 2013 (click here)


Opportunity Lost
Jennie Spotila, 10 September 2013 (click here)


Discussion of Dr Snell's recent two day CPET study
Repeat Test Reveals Dramatic Drop in ME/CFS Exercise Capacity
Simon McGrath, 29 Jul 2013 (click here)


Advocates Rebuffed: CDC Whiffs On Opportunity to Prove Reduced Exercise Capacity Present in Major Chronic Fatigue Syndrome Study
Cort Johnson, 15 September 2013 (click here)


Phoenix Rising Forum Discussion - New Dr Snell paper on exercise and CFS (click here)

CFSAC committee meeting - Spring 2013
Beth Unger discusses the CDC's multi-centre study - YouTube Video: (Click here to view video on YouTube)


CFSAC committee meeting - Spring 2013 Stage 2 of Multi-site CFS Study - YouTube Video: (Click here to watch video on YouTube)

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For it to be meaningful, and ground-breaking, she's got to assess the data with an open mind, looking for unexpected patterns in the data and attempting to define subgroups based on the data and not on pre-existing (consensus) diagnostic criteria.

Subgroups presuppose groups, and identifying them may not be ground-breaking:

Optional Considerations
Classifying patients by subgroups to enable the comparison of patients within the diagnosis of ME may be helpful in some studies.

1 Onset: acute infectious or gradual.
2 Onset severity may be a good predictor of severity in the chronic phase.
3 Symptom severity: mild, moderate, severe, very severe.
4 Criterial subgroups: neurological, immune, energy metabolism/transport or eclectic.

By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?
 
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I feel like a stranger in a strange land with all of this talk about the CPET test. I took a cardiac stress test 9 years ago which cause very severe disease progression and heart damage. I am now in diastolic heart failure as a result of this stress test. I also lost my ability to talk.

"Findings which suggest mitochondrial metabolic dysfunction similar to mitochondrial encephalomyopathy in CFS patients led CFS expert Professor Paul Cheney to comment. ‘The most important thing about exercise is not to have patients do aerobic exercise. I believe that even progressive aerobic exercise is counter-productive. If you have a defect in mitochondrial function and you push the mitochondria by exercise, you kill the DNA.’ Numerous heart, lung, brain and other abnormalities also show strong evidence that exercise can have extremely harmful effects on CFS patients in many different bodily systems, permanent damage may be caused, as well as disease progression." (Williams 2004, [online]).

"Not only is it inappropriate for CFS patients to undergo a treadmill stress test or be pushed toward age-predicted target heart rates, but this is potentially dangerous." Philipa Corning, Ph D, Vice President Quest 61, 2003

Dr. Paul Cheney wrote (www.cheneyresearch.com), "We have a rising case load of diastolic dysfunction seen in 97% of our CFS cases (avg. age 49) and some appear to have what I would call compensated diastolic heart failure. I would define compensated DHF in CFS as an extremely low cardiac output with a cardiac index (CI) below 2.0 and very poor functional capacity combined with the inability to stand which is the corollary in DHF to the inability to lay down flat in systolic heart failure (SHF). Heart failure patients are typically below 2.0 in CI. I have several CFS patients below that number and they cannot stand still for more than 15-30 seconds without having to sit down or fall down. Walking or moving helps which makes sense as that would increase filling pressures and equivalent to laying down. They might be diagnosed as having orthostatic intolerance by others."

"Recently, Jason et al (2006) reported that the mean age of patients with myalgic encephalomyelitis/chronic fatigue syndrome dying from heart failure, i.e. 58.7 years, is significantly lower than the age of those dying from heart failure in the general US population, i.e. 83.1 years."

So I am totally shocked by these exercise tests going on. Unless, I have a different disease, which I don't believe I do, or that there is a difference between ME and CFS, then I don't understand why PWCs taking this cardio test aren't having the same horrific results that I've had. If these tests expand in this study, and PWCs aren't warned of the possible results of severe permanent disease progression, then I fear what might happen to some patients.

Furthermore, I don't understand why there are no research studies going on today reg. the effects that ME/CFS has on the heart, i.e. this is one of the main causes of death from ME/CFS.

When I look at the current research most of it seem irrelevent to me. None of it is going to save my life.

So I just wanted to put out this warning for PWCs taking these cardio stress tests, because there seems to be no serious warning out there. I don't think most ME/CFS doctors understand the possible consequences.

The CPET test is not the same test as the walking cardiac stress test.

The CPET is done on a bicycle, not a treadmill. The bicycle does not force a particular speed on the patient the way a treadmill does. The cardiac stress test only records EKG and BP. The CPET also includes pulmonary gases, so the tester knows when the patient has reached his/her anaerobic threshold and can adjust the test accordingly so as not to severely overwork the patient. The cardiac stress test has all patients exercising at the same speed and incline, healthy or ill. That can be a serious problem with PWME. The CPET (properly performed for PWME) allows for adjustment of work depending on the capability of the patient.

I suspect that the CPET test (properly done for PWME) is not as severe as many PWME fear. I've done it (the one day test) twice now and neither time was it as terrible as I expected. Both times it was done in the office of an ME/CFS specialist by people who understand the illness. The test ran about 8 minutes. The pedaling resistance was set so easy that it was like waving my legs around, not pushing with any power at all. I didn't feel great afterwards, but I didn't have a massive crash, either.

I do not have mild ME/CFS. I'm about 5/10 on most scales. I couldn't walk more than 100 ft without PEM the last time I did the test, so it's not like I'm not susceptible to PEM or have a high threshold for PEM.

I'm not saying the test is trivial for all PWME. I think many of us have some (relatively small) consequence such as several days to a week of moderate PEM, but not a long-term crash. It's important to note that it is NOT the same test as the cardiac stress test most people imagine, which would probably seriously crash most of us, especially when done by technicians unfamiliar with the limitations of PWME.
 
Subgroups presuppose groups, and identifying them may not be ground-breaking:

Optional Considerations
Classifying patients by subgroups to enable the comparison of patients within the diagnosis of ME may be helpful in some studies.

1 Onset: acute infectious or gradual.
2 Onset severity may be a good predictor of severity in the chronic phase.
3 Symptom severity: mild, moderate, severe, very severe.
4 Criterial subgroups: neurological, immune, energy metabolism/transport or eclectic.
I think there's a wide consensus that CFS and CFS/ME are heterogeneious, and that ME might be heterogenous.
I personally think it's absolutley essential to use data to attempt to identify subgroups, in order for research to advance.

Yes, there are various subgroups that are already defined, but Unger is carrying out a massive data analysis, and perhaps she may find unexpected groups, based on the data. I hope she is cross-referencing with already-defined subgroups, such as the ones you've identified here.

By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?
I think it would be narrow minded if the only hypothesis being tested was whether patients fit into currently defined diagnostic criteria. I hope that Unger is testing the collected data against Fukuda and the CCC/ICC. But I think many of us agree that CCC and ICC, although vastly preferable to Fukuda, are not set in stone.
 
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The CPET test is not the same test as the walking cardiac stress test.

The CPET is done on a bicycle, not a treadmill. The bicycle does not force a particular speed on the patient the way a treadmill does. The cardiac stress test only records EKG and BP. The CPET also includes pulmonary gases, so the tester knows when the patient has reached his/her anaerobic threshold and can adjust the test accordingly so as not to severely overwork the patient. The cardiac stress test has all patients exercising at the same speed and incline, healthy or ill. That can be a serious problem with PWME. The CPET (properly performed for PWME) allows for adjustment of work depending on the capability of the patient.

I suspect that the CPET test (properly done for PWME) is not as severe as many PWME fear. I've done it (the one day test) twice now and neither time was it as terrible as I expected. Both times it was done in the office of an ME/CFS specialist by people who understand the illness. The test ran about 8 minutes. The pedaling resistance was set so easy that it was like waving my legs around, not pushing with any power at all. I didn't feel great afterwards, but I didn't have a massive crash, either.

I do not have mild ME/CFS. I'm about 5/10 on most scales. I couldn't walk more than 100 ft without PEM the last time I did the test, so it's not like I'm not susceptible to PEM or have a high threshold for PEM.

I'm not saying the test is trivial for all PWME. I think many of us have some (relatively small) consequence such as several days to a week of moderate PEM, but not a long-term crash. It's important to note that it is NOT the same test as the cardiac stress test most people imagine, which would probably seriously crash most of us, especially when done by technicians unfamiliar with the limitations of PWME.
There have been times during my illness when 8 minutes of the mildest exercise would have caused me a severe relapse, lasting for months. I was especially reactive during my first 3 years of illness. I'm more stable now, after discover pacing and implementing it strictly, but my last relapse was severe for about 6 months, and then continued moderately for months after that.
I'm not sure how I'd currently react to an 8 minute maximal CPET test, but I'd be too cautious to attempt it, unless going through a prolonged stable spell.

If anyone is brave enough to attempt such a test in the name of science, then I'd be very grateful to them, but I think we've all got to be honest with ourselves that such a test could potentially be damaging to patients. I know we are desperate for answers, but we've also got to protect each other.

Patients have got to go into such a test with eyes-wide-open, and being fully informed and fully aware of the potential for adverse effects.
Personally, I'd recommend that new patients are not put through such a test, as they wouldn't have a full insight into the nature of their post-exertional reactions, and so can't make an informed decision about it.
 
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By insisting that Dr. Unger "assess data with an open mind, looking for unexpected patterns," are you denigrating the time-honoured practice of hypothesis testing?

Keeping an open mind while looking as what's going on and searching for patterns is the first step in science. It is called observation. It comes before the formation of a hypothesis. It's what hypotheses are based upon. First you have to develop the hypothesis, then you test it.
 
There have been times during my illness when 8 minutes of the mildest exercise would have caused me a severe relapse, lasting for months. I was especially reactive during my first 3 years of illness. I'm more stable now, after discover pacing and implementing it strictly, but my last relapse was severe for about 6 months, and then continued moderately for months after that.
I'm not sure how I'd currently react to an 8 minute maximal CPET test, but I'd be too cautious to attempt it, unless going through a prolonged stable spell.
If anyone is brave enough to attempt such a test in the name of science, then I'd be very grateful to them, but I think we've all got to be honest with ourselves that such a test could potentially be damaging to patients. I know we are desperate for answers, but we've also got to protect each other.

Patients have got to go into such a test with eyes-wide-open, and being fully informed and fully aware of the potential for adverse effects.
Personally, I'd recommend that new patients are not put through such a test, as they wouldn't have a full insight into the nature of their post-exertional reactions, and so can't make an informed decision about it.

I understand that many patients are afraid of the test. Exercise can be very risky for us. I'm simply suggesting that absolute rejection when you've never even seen the test done might be counterproductive.

An 8 minute maximal CPET test is not 8 minutes of maximal exercise, btw. It's only maximal (your own maximum) at the end.

I wonder if it might be informative to have a poll or some way of gathering info that would allow all members who have had the test to report the consequences they suffered. That might give us a better sense of whether it is truly dangerous for PWME and whether we should therefore discourage it's use... or conversely, whether patients are not reporting serious consequences and the test can safely be used a valuable objective measure for research studies.
 
Keeping an open mind while looking as what's going on and searching for patterns is the first step in science. It is called observation. It comes before the formation of a hypothesis. It's what hypotheses are based upon. First you have to develop the hypothesis, then you test it.
Can you articulate Dr. Unger's study design? Is she proceeding without research questions or hypotheses? Notice that she rejects Dr. Klimas' suggestion in the first 75 seconds here:


This quotation from “Research questions, hypotheses and objectives” may provide a useful commentary on Dr. Unger's "data-driven" approach:
The primary research question should be driven by the hypothesis rather than the data.1,2 That is, the research question and hypothesis should be developed before the start of the study. This sounds intuitive; however, if we take, for example, a database of information, it is potentially possible to perform multiple statistical comparisons of groups within the database to find a statistically significant association. This could then lead one to work backward from the data and develop the “question.” This is counterintuitive to the process because the question is asked specifically to then find the answer, thus collecting data along the way (i.e., in a prospective manner). Multiple statistical testing of associations from data previously collected could potentially lead to spuriously positive findings of association through chance alone.2 Therefore, a good hypothesis must be based on a good research question at the start of a trial and, indeed, drive data collection for the study.
A good hypothesis should precede and drive a study's data collection.
 
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I wonder if it might be informative to have a poll or some way of gathering info that would allow all members who have had the test to report the consequences they suffered. That might give us a better sense of whether it is truly dangerous for PWME and whether we should therefore discourage it's use... or conversely, whether patients are not reporting serious consequences and the test can safely be used a valuable objective measure for research studies.
I'm not sure that would be helpful. Just because either a minority or a majority of patients have found the consequences of a CPET test to be acceptable for themselves, does not mean that it would be safe for everyone.

I'd rather have open honest discussions about it and allow individuals to decide for themselves whether or not it would be safe for them.

Some of us will decide it would be relatively safe for us to participate while others will decide it would be dangerous or potentially dangerous for us.
 
i think we should all do what Jim Wilson did with lyme here in Canada......raise a few dollars .....open up our own labs....hire our own docs.....get er done! There is now a treatment center in his province of British Columbia to treat lyme and other associated illnesses......even cfs/fibro.
 
If they just tested dam people who fit the ccc for nk function, rnaseL, 2 day exercise test. Im sure klimas and co have some kind of research on cytokine patterns. Check for viral reactivations and common bacterial infections.

Come on how dam hard is it? Theres 30yrs of research and we have biomarkers just have to use the dam things.

It seems like they just want to invent the dam wheel. Aarrgghh! !!!
 
If they just tested dam people who fit the ccc for nk function, rnaseL, 2 day exercise test. Im sure klimas and co have some kind of research on cytokine patterns. Check for viral reactivations and common bacterial infections.

Come on how dam hard is it? Theres 30yrs of research and we have biomarkers just have to use the dam things.

It seems like they just want to invent the dam wheel. Aarrgghh! !!!

To me avoidance of doing 2 day exercise tests is to try to play the illness down as much as the CDC can do. It shows lack of change (I believe they are only doing what they currently are doing due to public pressure, they will keep doing as little as they can do)
 
Can you articulate Dr. Unger's study design? Is she proceeding without research questions or hypotheses? Notice that she rejects Dr. Klimas' suggestion in the first 75 seconds here:


This quotation from “Research questions, hypotheses and objectives” may provide a useful commentary on Dr. Unger's "data-driven" approach:

A good hypothesis should precede and drive a study's data collection.

Chicken and egg. What data do you collect, by what methods? In order to figure that out you need some idea of what to look for: one or more hypotheses. There are millions of possible tests, nobody is going to do them all.

There is a difference between an exploratory study, in which hypothesis testing is not the goal, and a rigorous study of mechanisms, treatment etc, in which hypothesis testing should be the goal. Exploratory studies are about getting data, yet as I said you can't do that unless you have some notion of what data you want: you have to have some kind of hypothesis.
 
Exploratory studies are about getting data, yet as I said you can't do that unless you have some notion of what data you want: you have to have some kind of hypothesis.
This seems to have been Dr. Unger's research question: “The question being asked over and over is, how do the patients differ in people's practices.... Is that why the findings in the laboratory are not always translatable?” To investigate the presumed heterogeneity among practices, Dr. Unger undertook “to collect standardized data on all the domains of illness included in the Canadian Consensus Criteria of CFS/ME (sic), the 1994 CFS definition and the newly proposed International ME definition.”

But Dr. Unger's interim analysis showed more heterogeneity within the patient population than among the clinics, and her questionnaires failed to identify robust subgroups:
This is just an interim analysis, and I would like to emphasize that I think that this interim analysis so far has shown us that there is a heterogeneity in the CFS population as a whole. There is a little bit between clinics but more in the patients than between clinics. This is also giving us a hint that phenotypic measures themselves may be limited in their ability to distinguish robust phenotypes or robust subgroups and that's why we're proposing to expand this study to some other measures, and it could very well be that other biologic correlates will be needed in order to better define subgroups.
Nevertheless, Dr. Unger is refusing to use credible biogenic correlates to better define subgroups.

In addressing the IOM Committee, Dr. Unger presented her study's objective this way: “To describe what the patients in these clinical practices actually look like. And so to provide data both to address how case definitions might work as well as to identify subgroups that we could find from these patients.” Dr. Unger freely expresses her opinions about how case definitions might work:
I sit here and I believe that there is no one case definition that is going to get us to homogeneity in this illness. It is way too diverse. We have to understand how to handle that diversity. I think we handle it by giving clinicians the tools to understand the full spectrum of the illness. Therapies can then be targeted to the various aspects of the disease. It’s a broad umbrella with various degrees of severity.
But beyond describing "a broad umbrella with various degrees of severity," and despite having the relevant data, Dr. Unger isn't prepared to use either Fukuda, the ICC or the CCC to better characterize her study's cohort.
 
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But beyond describing "a broad umbrella with various degrees of severity," and despite having the relevant data, Dr. Unger isn't prepared to use either Fukuda, the ICC or the CCC to better characterize her study's cohort.
Unger is pro-actively looking for subgroups based on the data. I'd be surprised, and disappointed, if she wasn't using existing CFS & ME definitions to see if her data matches those subgroups. However it works out (i.e. if the data either matches or doesn't match the existing criteria) then that will give us helpful new information. (As long as the study is carried out competently, honestly and comprehensively, which isn't guaranteed of course.)

Beth Unger said:
I sit here and I believe that there is no one case definition that is going to get us to homogeneity in this illness. It is way too diverse. We have to understand how to handle that diversity. I think we handle it by giving clinicians the tools to understand the full spectrum of the illness. Therapies can then be targeted to the various aspects of the disease. It’s a broad umbrella with various degrees of severity.
That's exactly what we want her to do, isn't it?
 
I had forgotten the content of this video. I think perhaps it's the best review of the study that Unger has presented so far:
http://www.tvworldwide.com/events/f..._archive.cfm?gsid=2251&type=flv&test=0&live=0

@Simon reviewed it in his health-rising article:
http://www.cortjohnson.org/blog/201...c-chronic-fatigue-syndromemulti-clinic-study/

Unger starts the presentation @86.00

Some snippets:

Collected clinical data includes:
Basic Demographics.
History of illness (e.g. age of onset.)
Medical history.
Lab and other diagnostic tests.
Family history.
Infection/immunization history.

Mental health and role emotional scores are 'preserved' in CFS in all of the clinics. (i.e. CFS patients have normal outcomes for mental health scores.) (This is a novel conclusion for the CDC.)

Unger is testing the DePaul Symptom Questionnaire, along with the various diagnostic criteria.

Unger mentions that the study demonstrates that the MFI general fatigue scale is not useful for research into CFS because 40% of patients had the maximum possible score.
 
I'd be surprised, and disappointed, if she wasn't using existing CFS & ME definitions to see if her data matches those subgroups.

In the first 75 seconds of the IOM Committee's Q & A, Dr. Unger indicates that she isn't prepared to use existing CFS & ME definitions. She claims that she doesn't know “how to set the criteria for each of the various points of the disease criteria. In other words, there's not a cut point for any of these.”

Her description of “a broad umbrella with various degrees of severity” isn't supported by the ICC. It identifies a subgroup that needs to be removed based on much more than severity. Dr. Unger would risk identifying such an ME subgroup were she to use the 2-day CPET.
 
Yes, she [Dr. Unger] must move on to including comprehensive biomedical testing, and I hope she will, quickly. If she doesn't then the trust of the patient community will not be gained...Anyway, these are just my own opinions.

Agree. Would like Dr. Unger to build on the existing science & incorporate biomarker candidates in her study.

NIH State-of-the-Knowledge Workshop (2011) identified 5 biomarker candidates [with qualifications]:
1. NK cell function [methodological issues?]
2. Perforin [by flow cytometry, a surrogate for NK cell function]
3. Dipeptidyl peptidase-4 (CD26) [an excellent cell membrane biomarker candidate]
4. Neuropeptide Y [correlates with severity of illness]
5. Cytokine panels

Byron Hyde's SPECT Scan test & the Duffy/Komaroff EEG Spectral Coherence test are additional candidates.

Perhaps a group here on PR could compile a biomarker list to suggest to Dr. Unger?

Sources:
1. "NIH ME/CFS State-of-the-Knowledge Workshop Report,""Diagnosis & Biomarkers" section, p13-4, April 7-8, 2011
http://orwh.od.nih.gov/research/me-cfs/pdfs/ORWH_SKW_Report.pdf

2. "Missed Diagnoses: Myalgic Encephalomyelitis & Chronic Fatigue Syndrome," Bryon Hyde, MD, Second Edition, 2010
http://www.lulu.com/us/en/shop/byron-hyde-md/missed-diagnoses-myalgic-encephalomyelitis-chronic-fatigue-syndrome-second-edition/paperback/product-18463888.html

3. http://www.ncbi.nlm.nih.gov/pubmed/21722376

Edited to add links to sources
 
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This has just come through on the CFSAC email list...

MARK YOUR CALENDARS:

CDC CFS Patient-centered outreach and communication activity (PCOCA) Conference Call

Tuesday, February 25, 2014

3:00 pm * 4:00 pm EST

Call number: 1-800-369-3365
Participant Code: 1471493


Meeting Agenda

3:00pm Welcome and Telephone Overview

3:05pm Updates from CDC - Elizabeth Unger, PhD, MD
Branch Chief, Chronic Viral Diseases Branch
Centers for Disease Control and Prevention​

3:15pm "CFS and Cognitive Function"
Gudrun Lange, Ph.D.
Consultant Clinical Neuropsychologist
Pain and Fatigue Study Center
Beth Israel Medical Center, NY, NY
Professor, Department of Physical Medicine and Rehabilitation Rutgers University​

3:45pm Questions from CFSPCOCACall Mailbox for Guest Speaker and CDC


Disclaimer: Although the content of calls is directed to patients, caregivers, health care professionals, and other interested parties, CDC has no control over who participates on the conference call. Therefore please exercise discretion on sensitive content and material, as confidentiality during these calls cannot be guaranteed.

Please note that questions for the Guest Speakers and CDC can be submitted only via email at:
CFSPCOCACall@cdc.gov
This mailbox cannot respond to inquires received and is in use only for the scheduled CFS PCOCA calls.

If you would like to be added to the call list, please send an email to: CFSPCOCACall@cdc.gov

Contact for CFS PCOCA Conference Call: CFSPCOCACall@cdc.gov
The CFSAC Support Team cannot answer questions about this upcoming call.
 
In the first 75 seconds of the IOM Committee's Q & A, Dr. Unger indicates that she isn't prepared to use existing CFS & ME definitions. She claims that she doesn't know “how to set the criteria for each of the various points of the disease criteria. In other words, there's not a cut point for any of these.”
I wonder if Dr Unger has seen Lenny Jason's recently published research that distinguishes CFS, CFS/ME and ME patients from healthy controls by using frequency and severity of certain symptoms:
http://forums.phoenixrising.me/inde...e-learning-and-featu.27975/page-2#post-427215

Her description of “a broad umbrella with various degrees of severity” isn't supported by the ICC. It identifies a subgroup that needs to be removed based on much more than severity. Dr. Unger would risk identifying such an ME subgroup were she to use the 2-day CPET.
Agreed. But she is correct to say that the CFS cohort is a broad umbrella, etc. (And her remit is to study the entire CFS population.)

But even if looking purely at the CCC or ICC population, then there will probably be heterogeneity. We don't know if all ICC patients have the same disease. All we know is that the characteristics of their illness/es are similar. Data and research is needed to investigate it further.

I absolutely agree that the CDC needs to include proper and comprehensive biomedical research in its study, including all the tests & research that have been mentioned in this thread.
I'll be deeply frustrated if they haven't started doing this before the end of 2014. But I think it seems quite sensible for them to gather clinical and demographic data for such a large study before they move towards collecting more specific biomedical research data.

I also agree that Unger's use of language, apparent failure to engage with the community, and an apparent lack of insight into the differences between CF and ME, is deeply disappointing and frustrating.

We need the ME research community to attempt to use data to distinguish subgroups.
The CCC/ICC are a helpful guide while more research is being undertaken.
They're helpful, but they are not going to lead to answers for us in themselves.
We need more research and more data.
I'm hoping that Unger is focusing on PEM and other symptoms used in the CCC/ICC, to measure her data against in attempt to distinguish subgroups.
And I hope that she understands the difference between fatigue and ME. Otherwise it's going to be another dead-end at the CDC.
 
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