Selection bias & disease misclassification undermine the validity of ME/CFS studies

Posted on 03/13/2017 by wames

Research abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome has been a controversial diagnosis, resulting in tensions between patients and professionals providing them with care.

A major constraint limiting progress has been the lack of a ‘gold standard’ for diagnosis; with a number of imperfect clinical and research criteria used, each defining different, though overlapping, groups of people with myalgic encephalomyelitis or chronic fatigue syndrome.

We review basic epidemiological concepts to illustrate how the use of more specific and restrictive case definitions could improve research validity and drive progress in the field by reducing selection bias caused by diagnostic misclassification.

[After highlighting the danger  in generalising the results of studies using patients with unspecific ‘chronic fatigue’ (which could include people with a range of diagnoses, including mental health conditions) to people with ME/CFS, and proposing that strict selection criteria are used in research trials, the Biobank team go on to recommend specialist services do the opposite and accept a broader range of patients:]

Priorities for clinical practice

Nevertheless, it is important to distinguish research from clinical practice. While the former should focus on better definition of disease status, sub-groups and the trialling of preventative and treatment interventions, the main role of the clinician is to provide the best care and support to their patients, irrespective of a diagnosis or lack of it. Therefore, clinical services should be open to people with a broader range of conditions, presenting with, for example chronic fatigue.

Historically, patients accepted by ME/CFS Specialist Services in the United Kingdom have often been required to meet the centers for disease control and prevention (CDC)-1994 criteria (Fukuda et al., 1994) or even broader case criteria (NICE, 2007). We propose that criteria such as the Institute of Medicine (Institute of Medicine, 2015) or the CDC-1994 could still be used as a guide for primary care professionals to refer patients to Specialist Services, provided an adequate workout of cases conducted in primary care to enable the practitioner to suspect a diagnosis of ME/CFS. This could be the case until we have a better understanding of ME/CFS and are in a position to diagnose reliably and offer specific treatments. It is also important to acknowledge that many with chronic fatigue currently referred to ME/CFS specialist services would benefit from alternative care pathways, avoiding overloading already stretched services. This is particularly important for those with an alternative diagnosis explaining their symptoms, including some chronic medical and psychiatric diseases. It has been suggested that between 40 and 64 per cent of cases referred to CFS Specialist services do not meet diagnostic criteria for CFS, so robust referral procedures need to be established (Devasahayam et al., 2012; Newton et al., 2010).

How have selection bias and disease misclassification undermined the validity of myalgic encephalomyelitis/chronic fatigue syndrome studies? by Luis Nacul, Eliana M Lacerda, Caroline C Kingdon, Hayley Curran, Erinna W Bowman in Journal of Health Psychology [Published March 1, 2017]

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NVCBR researchers close in on a diagnostic test for ME/CFS patients

Posted on 03/10/2017 by wames

Nevada Center for Biolomedical Research news item, by Kellen Jones, 28 February 2017: NVCBR researchers close in on a diagnostic test for ME/CFS patients

Physicians lack effective tools to aid in the diagnosis and treatment of those who are impacted by ME/CFS, a complex and often disabling disease.  That could change now that scientists at Nevada Center for Biomedical Research (NVCBR) have taken the first step in developing a clinical assay for diagnosing ME/CFS patients through the creation of an antibody immune signature.

The work was conducted in collaboration with Drs. Stephen Johnston and Phillip Stafford, at Arizona State University’s Biodesign Institute, Innovations in Medicine, and Drs. Karen Schlauch and Richard Tillet, from the University of Nevada, Reno, as well as other researchers from around the world.

The group’s findings recently appeared in the prestigious journal Molecular Neurobiology:

Humoral Immunity Profiling of Subjects with Myalgic Encephalomyelitis Using a Random Peptide Microarray Differentiates Cases from Controls with High Specificity and Sensitivity, by  Sahajpreet Singh, Phillip Stafford, Karen A. Schlauch, Richard R. Tillett, Martin Gollery, Stephen Albert Johnston, Svetlana F. Khaiboullina, Kenny L. De Meirleir, Shanti Rawat, Tatjana Mijatovic, Krishnamurthy Subramanian, András  Palotás,  Vincent  C. Lombardi [Published online: 15 Dec 2016]

The immune system produces proteins called antibodies that bind to the surface of pathogens, such as viruses and bacteria, to neutralize the pathogens. Occasionally, this system becomes dysregulated and produces antibodies to our own tissue, resulting in autoimmunity. Utilizing a microchip comprised of thousands of small random protein sequences (referred to as random peptides), researchers at NVCBR, in collaboration with the scientists at ASU’s Biodesign Institute, screened blood sera from ME/CFS cases and healthy controls, from two geographic distinct cohorts, and identified a diagnostic pattern of antibody/peptide binding that identifies ME/CFS patients with high specificity and sensitivity.

“The purpose of screening sera with a random peptide array is to identify things that our body sees as foreign such as the molecules that make up pathogens or the proteins of our own tissue, in the context of autoimmunity,” explained Dr. Vincent Lombardi, NVCBR Research Director. “Now that we have identified a group of random peptides that differentially bind with the antibodies of ME/CFS patients, our next challenge is to figure out what antigens these random peptides represent in the real world. Much can be learned about the causes of this disease once the antigens are accurately identified.”

Dr. Lombardi originally conceived of the project with the aim of identifying potential pathogens associated with ME/CFS as well as autoantigens. In addition to identifying prospective pathogen-associated antigens and autoantigens, the data also produced an immunosignature that can accurately identify ME/CFS patients from healthy controls. Future in-depth analysis of these data will help researchers determine which antigens are most relevant to the disease process and whether or not there are existing treatments available to target the implicated biochemical pathways.

Going forward, NVCBR researchers intend to confirm the work using a larger ME/CFS cohort as well as other disease cohorts with overlapping symptomology such as multiple sclerosis. The immunosignature technology, developed by ASU, has been used successfully with other neuroimmune diseases including Alzheimer’s disease.

“The goal of our research program is to ascertain the underlying mechanisms of neuroimmune disease as well as identify disease-related biomarkers and more effective treatments for the patients,” stated Dr. Lombardi. “A robust immunosignature of ME/CFS would help achieve these goals.”

Comments on paper: Pheonix rising forum

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Anxiety – autonomic nervous system in ME/CFS to blame?

Posted on 03/10/2017 by wames

Health rising blog post, by Cort Johnson, Dec 10, 2016: The Anxiety Question in Chronic Fatigue Syndrome and Fibromyalgia: Is the Autonomic Nervous System to Blame?

Anxiety type symptoms are common in chronic fatigue syndrome (ME/CFS), fibromyalgia, Gulf War Ilness (GWI), and postural orthostatic tachycardia syndrome (POTS). Dr. Baraniuk, an ME/CFS and GWI researcher, has long thought that researchers missed the boat by focusing on depression in ME/CFS; anxiety, he believes is far more prevalent.

That certainly fits my experience. Trouble concentrating, feeling tense or jumpy, anticipating the worst, irritability, restlessness, feeling like your mind’s gone blank, nausea, muscular tension, dizziness, restlessness, fatigue and problems in concentration, headache, abdominal pain, shortness of breath, sweating and frequent urination can all be found in anxiety, ME/CFS and fibromyalgia.

The “anxiety” in POTS, ME/CFS and FM: is it primarily emotional or physical?
The diseases are different. Flu-like symptoms are more common in ME/CFS and pain is much more intense in FM. Post-exertional malaise – a key symptom in ME/CFS – is never mentioned in connection with anxiety and is apparently not present. The crippling feelings of dread and fear often present in anxiety are rarely present in ME/CFS; many studies indicate that emotional issues contribute little to the functional problems in ME/CFS while physical issues dominate.

Still a common core of symptoms – feeling tense, trouble concentrating, muscle tension, dizziness, abdominal pain, shortness of breath, etc. – are found in ME/CFS, FM and anxiety. It’s as if the more extreme emotional symptoms have been stripped away leaving a body and mind on edge.  Emotional issues are often present, but at a “sub-clinical” level. They’re not enough to trigger a diagnosis of anxiety but are enough to be aggravating. Plus, similar problems of catastrophizing and hypervigilance are fairly common.

I recently experienced an ebbing of many of these symptoms – the muscular tension, the trouble concentrating, the restlessness, the chronic pain, the difficulty taking deep breaths- while using a device that stimulates the vagus nerve. That made me wonder if  autonomic nervous system problems could be behind many of these symptoms.

Given the continuing emphasis on behavioral approaches to ME/CFS and FM in some countries it’s an important question. A recent study from Belgium reported that 45% of ME/CFS patients had a mood disorder. A 2013 UK study stated that symptom focusing and beliefs about damage were particularly prevalent in ME/CFS patients with anxiety.

The article goes on to look at a study where the authors hypothesized that the anxiety type symptoms experienced by POTS patients were due to an over-awareness of their physical symptoms. The article then looks at other ways to produce anxiety-like states in ME/CFS. Read more

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The Clinical & Scientific Basis of ME/CFS is now free to download

Posted on 03/09/2017 by wames

A research classic from 1992 is now available to download for free (725 pages – a heavy tome)

The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic Fatigue Syndrome

Edited by Byron Hyde, M.D. – Nightingale Research Foundation, Ottawa, Canada with editorial and conceptual advice from Paul Levine, M.D., NIH, Bethesda, Maryland, USA and Jay Goldstein, M.D., Chronic Fatigue Syndrome Institute, USA, 1992

Published by Nightingale Research Foundation simultaneously in Canada and the USA, 1992

 

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Collection of writings about the PACE trial

Posted on 03/09/2017 by wames

Investigator bias and the PACE trial, by Steven Lubet in Journal of Health Psychology[Published online: 7 March 2017]

Abstract: The PACE investigators reject Geraghty’s suggestion that the cognitive behavior therapy/graded exercise therapy trial could have been better left to researchers with no stake in the theories under study. The potential sources and standards for determining researcher bias are considered, concluding that the PACE investigators “impartiality might reasonably be questioned.”

Extract: Viewed in this light, Geraghty’s proposal is persuasive. By virtue of their own experience, the PACE investigators were confident in the effectiveness of CBT and GET as ME/CFS treatments. Their earlier public statements— attributing ME/CFS symptoms to “false cognitions”— certainly appeared to dispose them toward a result. Coupled with their mid-trial revision of certain outcome measures—in a direction favorable to their own theories of improvement and recovery—it is reasonable to conclude that non-blinded trials of CBT/GET should be designed and overseen by investigators with no preexisting stake in the outcome.

 

Overview by Family physician Dr Mark Vink from the Netherlands:

Assessment of Individual PACE Trial Data: in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, Cognitive Behavioral and Graded Exercise Therapy are Ineffective, Do Not Lead to Actual Recovery and Negative Outcomes may be Higher than Reported in Neurol Neurobiol 3(1) 2017 (full article)

 

news.com.au article by Jason Murphy, 17 jan 2017: How Alem Matthees’ letter helped solve Chronic Fatigue Syndrome mystery

 

The PACE trial missteps on pacing and patient selection, by  Prof Leonard A Jason in Journal of Neurology and Neurobiology, 10 January 2017

Abstract: As others have pointed out a variety of complicating factors with the PACE trial (e.g. changing outcome criteria), I will limit my remarks to issues that involve the composition of adaptive pacing therapy and issues involving patient selection. My key points are that the PACE trial investigators were not successful in designing and implementing a valid pacing intervention and patient selection ambiguity further compromised the study’s outcomes. [full article available on payment, excerpts available here]

 

Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? by M. Sharpe, T. Chalder, A. L. Johnson, K. A. Goldsmith & P. D. White in Fatigue: Biomedicine, Health & Behavior [Published online: 15 Feb 2017]

Abstract: Wilshire et al. suggest that we have overestimated the number of patients that recover from chronic fatigue syndrome (CFS) after receiving a course of either cognitive behaviour therapy (CBT) or graded exercise therapy (GET), as reported in a secondary analysis of outcome data from the Pacing, graded Activity and Cognitive behavior therapy; a randomized Evaluation (PACE) trial. We provide counter-arguments to this view.

 

Quick thoughts blog post, 20 Dec 2016, by James Coyne: Simon Wessely: Why PACE investigators aren’t keen on handing over the PLOS One data to Coyne

 

Undark podcast no.8, 31 Oct 2016: Worse Than the Disease

Prof David Tuller discusses a therapy commonly prescribed for chronic fatigue syndrome — one for which supporting research is now unravelling.

Undark case studies,  27 Oct 2017, by Prof David Tuller: Worse Than the Disease   [9000+ words]

 

Studies on Cognitive Behavioral Therapy and Graded Exercise Therapy for ME/CFS are misleading, by Sten Helmfrid (Assoc. Prof. of Physics, Member of the Swedish ME Association)

This is a translation of an article published in Socialmedicinsk tidskrift, Stockholm,
Sweden, on September 28 2016. Link to the original article in Swedish:
Citation: Helmfrid  S. Studier  av kognitiv beteendeterapi  och gradvis ökad  träning vid ME/CFS är missvisande. Soc Med Tidskr. 2016;93(4):433–44.

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Is health anxiety aka hypochondria common in people with CFS?

Posted on 03/09/2017 by wames

Hypochondria (health anxiety) is excessive worrying about your health, to the point where it causes great distress and affects your everyday life.

Some people with health anxiety have a medical condition, which they worry about excessively. Others have medically unexplained symptoms, such as chest pain or headaches, which they are concerned may be a sign of a serious illness, despite the doctor’s reassurance.   [from: NHS Direct Wales]

Research from the Bristol Chronic Fatigue Syndrome/ME Service and Department of Psychology, University of Bath, UK:

Abstract:

Objectives:
There is a lack of research examining the incidence of health anxiety in chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME), despite this being an important research area with potentially significant clinical implications. This preliminary study aimed to determine the incidence of anxiety and depression, more specifically health anxiety, in a sample of CFS/ME patients over a 3-month period.

Design:
The research was a cross-sectional questionnaire-based study, using a consecutive sample of patients who were assessed in a CFS/ME service.

Method:
Data were taken from the Short Health Anxiety Inventory and the Hospital Anxiety and Depression Scale to identify incidence of anxiety, depression, and health anxiety.

Results:
Data were collected from 45 CFS/ME patients over the sampling period. Thirty-one patients (68.9%) scored above the normal range but within the subclinical range of health anxiety, and 19 patients (42.2%) scored within the clinically significant health anxiety range. Anxiety and depression were common, with prevalence rates of 42.2% and 33.3% respectively, which is comparable to data found in a recent large-scale trial.

Conclusions:
Health anxiety in CFS/ME patients is likely to be common and warrants further investigation to provide a better insight into how this may influence treatment and symptom management.

Practitioner points

  • Anxiety and depression were common in a sample of chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) patients, with a high proportion meeting criteria for severe health anxiety.
  • While CFS/ME and health anxiety are distinct and separate conditions, it is unsurprising that patients with CFS/ME, who commonly report feeling ‘delegitimized’, may experience high levels of anxiety relating to their physical symptoms.
  • Clinicians should consider screening for health anxiety due to the possible clinical implications for treatment; mutual maintenance may negatively influence treatment success in a complex condition such as CFS/ME.
  • Health anxiety has been found to be common across other chronic medical conditions but has been shown to be effectively treated with appropriately tailored interventions.

Anxiety and depression in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): Examining the incidence of health anxiety in CFS/ME, by Jo Daniels, Amberly Brigden, Adela Kacorova in Psychology and Psychotherapy [Preprint February 28, 2017]

Comment:

As the researchers indicate, health anxiety has been researched and found to exist in other chronic conditions e.g. in Multiple sclerosis (Kehler, & Korostil).  The treatment often recommended for this is CBT.

 

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Cytokine inhibition in CFS

Posted on 03/08/2017 by wames

Research abstract:

Background:

Interleukin-1 (IL-1), an important proinflammatory cytokine, is suspected to play a role in chronic fatigue syndrome (CFS).

Objective:

To evaluate the effect of subcutaneous anakinra versus placebo on fatigue severity in female patients with CFS.

Design:

Randomized, placebo-controlled trial from July 2014 to May 2016. Patients, providers, and researchers were blinded to treatment assignment. (ClinicalTrials.gov: NCT02108210)

Setting:

University hospital in the Netherlands.

Patients:

50 women aged 18 to 59 years with CFS and severe fatigue leading to functional impairment.

Intervention:

Participants were randomly assigned to daily subcutaneous anakinra, 100 mg (n = 25), or placebo (n = 25) for 4 weeks and were followed for an additional 20 weeks after treatment (n = 50).

Measurements:

The primary outcome was fatigue severity, measured by the Checklist Individual Strength subscale (CIS-fatigue) at 4 weeks.

Secondary outcomes were level of impairment, physical and social functioning, psychological distress, and pain severity at 4 and 24 weeks.

Results:

At 4 weeks, 8% (2 of 25) of anakinra recipients and 20% (5 of 25) of placebo recipients reached a fatigue level within the range reported by healthy persons. There were no clinically important or statistically significant differences between groups in CIS-fatigue score at 4 weeks (mean difference, 1.5 points [95% CI, −4.1 to 7.2 points]) or the end of follow-up. No statistically significant between-group differences were seen for any secondary outcome at 4 weeks or the end of follow-up. One patient in the anakinra group discontinued treatment because of an adverse event. Patients in the anakinra group had more injection site reactions (68% [17 of 25] vs. 4% [1 of 25]).

Limitation:

Small sample size and wide variability in symptom duration; inclusion was not limited to patients with postinfectious symptoms.

Conclusion:

Peripheral IL-1 inhibition using anakinra for 4 weeks does not result in a clinically significant reduction in fatigue severity in women with CFS and severe fatigue.

Primary Funding Source:

Interleukin Foundation and an independent donor who wishes to remain anonymous.

Cytokine Inhibition in Patients With Chronic Fatigue Syndrome: A Randomized Trial by Megan E. Roerink MD; Sebastian J.H. Bredie, MD, PhD; Michael Heijnen; Charles A. Dinarello, MD; Hans Knoop, PhD; Jos W.M. Van der Meer, MD, PhD in Annals of Internal Medicine [Published online: 7 March 2017]

Comments:

ME association blog post, 8 March 2017, Dr Charles Shepherd: Why we shouldn’t dismiss the role of pro-inflammatory cytokines in ME/CFS: comment on Annals of Internal Medicine paper

Phoenix rising ME/CFS Forum posts, 7 March+: Comments by Prof Jonathan Edwards and others

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Standard research criteria would aid ME/CFS research

Posted on 03/07/2017 by wames

Research abstract:

Background:

The Institute of Medicine (IOM) recently developed clinical criteria for what had been known as chronic fatigue syndrome.

Given the broad nature of the clinical IOM criteria, there is a need for a research definition that would select a more homogenous and impaired group of patients than the IOM clinical criteria. At the present time, it is unclear what will serve as the research definition.

Purpose:

The current study focused on a research definition which selected homebound individuals who met the four IOM criteria, excluding medical and psychiatric co-morbidities.

Methods:

Our research criteria were compared to those participants meeting the IOM criteria. Those not meeting either of these criteria sets were placed in a separate group defined by six or more months of fatigue. Data analyzed were from the DePaul Symptom Questionnaire and the 36-item Short-Form Health Survey (SF-36). Due to unequal sample sizes and variances, Welch’s F tests and Games-Howell post-hoc tests were conducted.

Results:

Using a large database of over 1000 patients from several countries, we found that those meeting a more restrictive research definition were even more impaired and more symptomatic than those meeting criteria for the other two groups.

Conclusion:

Deciding on a particular research case definition would allow researchers to select more comparable patient samples across settings, and this would represent one of the most significant methodologic advances for this field of study.

Clinical criteria versus a possible research case definition in chronic fatigue syndrome/ myalgic encephalomyelitis by Leonard A. Jason, Stephanie McManimen, Madison Sunnquist, Julia L. Newton & Elin Bolle Strand in Fatigue: Biomedicine, Health & Behavior [Published online: 06 Mar 2017]

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Two year follow-up of sleep diaries & polysomnography in CFS

Posted on 03/07/2017 by wames

Research abstract:

Background:
Chronic fatigue syndrome (CFS) is a prevalent and debilitating symptom complex of unknown aetiology. Up to 96.8% of people with CFS report unrefreshing sleep and many describe, in qualitative interviews, changes in sleep over the course of their illness.

Purpose:
To establish whether subjective and objective sleep parameters change over a two-year follow-up period in patients with CFS.

Methods
Twenty-two participants with CFS were recruited during routine consultations at a clinic in the North-East of England. All had their sleep characterised in a previously published cross-sectional study. Two were excluded from this analysis because they fulfilled criteria for a primary sleep disorder. The remaining 20 were contacted and 15 repeated fatigue- and sleep-quality questionnaires and sleep diaries, two years after their sleep was first characterised. Seven participants also repeated two consecutive nights of polysomnography. Paired statistical tests were used to compare follow-up with baseline measures.

Results:
Subjective questionnaires and sleep dairies did not show differences over two years follow-up. However, polysomnography demonstrated a higher proportion of stage one sleep (P < .01) and more awakenings per hour (P = .04) at follow-up.

Conclusions:
This study is the first to longitudinally assess sleep parameters in people with CFS. The results suggest that subjective perceptions of sleep remain stable, although objective measures indicated a tendency towards increased periods of lighter sleep. However, the small number of participants increases the likelihood that observed differences are Type
I errors.

Two year follow-up of sleep diaries and polysomnography in chronic fatigue syndrome: A cohort study, by Sean L. Davidson, Zoe M. Gotts, Jason G. Ellis & Julia L. Newton in Fatigue: Biomedicine, Health & Behavior  [Preprint March 2, 2017]

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Inquiry into loneliness & isolation closing date 10 March 2017

Posted on 03/06/2017 by wames

The Welsh Government Health, Social Care and Sport Committee has launched an inquiry into loneliness and isolation. The closing date for responses is 10 March 2017

The Committee would welcome your views on any or all of the following points:

  • the evidence for the scale and causes of the problems of isolation and loneliness, including factors such as housing, transport, community facilities, health and wellbeing services;
  • the impact of loneliness and isolation on older people in terms of physical and mental health and wellbeing, including whether they disproportionately affect certain groups such as those with dementia;
  • the impact of loneliness and isolation on the use of public services, particularly health and social care;
  • ways of addressing problems of loneliness and isolation in older people, including interventions to specifically address the problems and other projects with wider aims.  Evidence for what works and the outcomes for older people in terms of health and wellbeing;
  • the extent to which initiatives to combat loneliness and isolation experienced by other groups may also help to address these issues for older people;
  • current policy solutions in Wales and their cost effectiveness, including the Ageing Well in Wales programme.  The approach taken by the Welsh Government in terms of maintaining community infrastructure and support, and using the legislative framework created in the Fourth Assembly, e.g. the Social Services and Wellbeing (Wales) Act 2014 and the Wellbeing of Future Generations (Wales) Act 2015.

Guidance

Submissions should be no longer than five sides of A4, with numbered paragraphs, and should focus on matters set out above. Please see guidance for those providing evidence for committees.

The deadline for responses is 10 March 2017.

Please send your views to: SeneddHealth@assembly.wales

Bilingual Policy

The Committee welcomes contributions in English or Welsh.

Disclosure of Information

You can find further details about how we will use your information at www.assembly.wales/InquiryPrivacy. Please ensure that you have considered these details carefully before submitting information to the Committee.

Committee address

Clerk: Sian Thomas

National Assembly for Wales
Cardiff Bay
Cardiff
CF99 1NA

Phone: 0300 200 6291

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