An important report was published in the USA just before Christmas that was designed to a) identify research gaps in ME/CFS, b) identify methodological and scientific weaknesses, c) suggest research needs, and d) move the field forward through an unbiased, evidence-based assessment of a complex public health issue.
The report was published as part of the Pathways to Prevention programme of the National Institutes of Health (NIH), and was produced by a panel of independent academics – none of whom had ‘history' in ME/CFS. What they came up with could have worldwide repercussions for the way ME/CFS is researched in the future.
Here, DR CHARLES SHEPHERD, medical adviser to The ME Association, summarises the key findings of the draft executive summary and considers where we might go from here.
This is an important report from the National Institutes of Health (NIH) Pathways to Prevention Workshop that took place on 9-10 December 2014. It is likely to have a significant impact on future ME/CFS research strategy in America, and possibly elsewhere.
The report identifies a number of issues relating to the way research has been carried out in the past – as well as recommendations for how this should change in the future.
It should therefore be required reading for everyone involved in funding research, driving research policy, and carrying out research. I have therefore sent a copy to my colleagues on the ME/CFS Research Collaborative, including MRC representatives.
Overall, the report contains a number of valid, helpful and sensible conclusions and recommendations. This is what my summary below concentrates on.
However, the report also contains conclusions and recommendations that I would not agree with. For example, I do not agree that there is a significant overlap with major depressive disorder (line 33); I do not understand why homoeopathy should be regarded as a research priority at this point in time (line 274); and the economic burden in America must be well in excess of £1 billion (line 7).
The conclusions and recommendations relating to the use of CBT (cognitive behaviour therapy) and GET (graded exercise therapy) in lines 113-117, 135-138 and 348-349 has failed to take account of the very robust and consistent patient evidence – certainly from here in the UK – that CBT is ineffective for the majority of people with ME/CFS, and that around of 50% of people consistently report that GET makes their condition worse, whilst over 90% report that pacing is the most effective and safe form of activity management.
And while research funding is briefly referred to in lines 317-327, a great deal more thought needs to be given as to how these research objectives can be achieved without a recognition from government funded research bodies (on an international basis) that biomedical research into ME/CFS is not proportionate to the number of people affected along with the high level of disability and ill health that this disease causes. So there has to be a very significant shift in who funds biomedical research into ME/CFS. This can no longer be largely left to the charity sector – such as The MEA Ramsay Research Fund.
There are also some clear factual inaccuracies (e.g. a research focus on men in line 52) and questions to which the answers are already substantially there (e.g. Does mononucleosis lead to ME/CFS in adolescents? In line 173. Answer: Yes it can – look at the literature!)
POSITIVE CONCLUSIONS AND RECOMMENDATIONS
As already indicated, I want to concentrate on what I regard as the positive and constructive aspects of this NIH Workshop report – because a number of statements have been made that are going to be helpful in both recognition of the problem facing research and the solutions to these problems.
INTRODUCTION and BACKGROUND
• ME/CFS is a chronic, complex, multifaceted condition
• ME/CFS results in major disability for a large proportion of those affected
• ME/CFS is an unmet health need with a large economic burden
• ME/CFS is an area where the research and medical community has frustrated its constituents by failing to assess and treat the disease and allowed patients to be stigmatised
• ME/CFS has a physical, psychological, social and economic impact at the individual and family level
• Society and the medical profession often treats patients with disdain, suspicion and disrespect
• Although psychological complications (e.g. depression) often follow ME/CFS, this is not a psychological or psychiatric disease in aetiology (= cause)
• Patients do not want to be labeled as complainers – they want their stories to be heard.
EPIDEMIOLOGY AND RESEARCH METHODS
• Lack of a universally accepted case definition for ME/CFS has led to difficulty in determining the prevalence (= total number of cases) and incidence (= number of new cases per year) and has led to variability in the estimated numbers being reported
• The Oxford criteria are flawed and include people with other conditions, confounding the ability to interpret the science. Continuing use of Oxford criteria may impair progress and cause harm.
• The Oxford criteria should be retired and the ME/CFS community should agree on a single case definition – even though it is not perfect
• Patients, clinicians and researchers should agree on a definition of meaningful recovery
• The lack of a consistent, specific, sensitive diagnostic test and set of diagnostic criteria has hampered research on pathogenesis (= cause) and treatment. This has prevented ME/CFS from being considered to be a distinct pathogenic entity.
RESEARCH FINDINGS AND RESEARCH CHALLENGES
• Over the past twenty years minimal progress has been made to improve the state of science for patients with ME/CFS
• Studies of ME/CFS are fraught with methodological problems – no agreed parameters for defining ME/CFS; small sample sizes; inclusion of participants with differing symptoms across studies; lack of inclusion of severe/housebound cases etc
• Many instruments used to evaluate ME/CFS are not validated, are inappropriate, and may be misleading
• Studies are too small to have power for subgroup analysis; do not address early disease or ME/CFS in children; fail to address harms or who dropped out or why; and include only short follow up
• Patients want their concerns to be heard, a meaningful recovery, and a cure
• The research community has a responsibility to address issues that are meaningful to patients.
• Strong evidence indicates immunological and inflammatory pathologies, neurotransmitter signaling disruption, microbiome pertubation, and metabolic or mitochondrial abnormalities
• There is reproducible evidence of neurocognitive dysfunction with abnormalities in functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies
• Current research has neglected many of the biological factors underlying ME/CFS onset and progression
• Small poor-quality studies and a lack of a gold standard for diagnosis and treatment has led to confusion
• Findings in the literature are inconsistent and there are many gaps
RESEARCH RECOMMENDATIONS
• It is critical to include patients with limited access to clinical services (e.g housebound) in research studies
• A clear case definition with validated diagnostic tools is required
• To advance the field, retrospective, prospective and longitudinal studies that are practical and reproducible are needed
• Longer follow up and lifespan perspectives are needed
• Endpoints need to be clarified – what is clinically and statistically significant
• Innovative biomedical research is urgently needed to identify risk and therapeutic targets
SPECIFIC RESEARCH RECOMMENDATIONS
• Assemble a team of stakeholders – patients, clinicians, researchers etc – to reach consensus on the definition of ME/CFS
• Develop valid prognostic tests that can guide treatment strategies using genomic, epigenomic, proteomic and metabolomic strategies to identify critical biomarkers
• Develop a registry/repository of all patients with ME/CFS and establish a central archive of de-identified data and tissue sharing. CS note: This is what we are already starting to do here in the UK with the ME Biobank at UCL and the post-mortem research we are collaborating on and funding.
• Immunologic mechanisms of ME/CFS and pathways associated with disease progression must be defined and characterised – e.g defining cytokine profiles involved in pathogenesis; studying inflammation; comprehending the basis for natural killer cell dysfunction.
• Studies of gene expression among identical twins to identify gene expression biomarkers
• Future studies (clinical trials) must be collaborative, multicentre efforts and must include large, diverse samples across the lifespan
TREATMENT
• Patients usually have to make extraordinary efforts, at extreme personal costs, to find a physician who will correctly diagnose and treat ME/CFS symptoms
• Patients are frequently treated with psychiatric and other drugs that may cause harm
• Limited patient and professional education has impaired progress in managing ME/CFS
• Clinicians have a poor understanding of ME/CFS
• ME/CFS is a distinct disease that requires a high quality multidisciplinary care team: physicians, nurses etc to optimise care
• Proper training of that workforce is crucial
• In general, little attention has been given to how self-management may empower and improve health and quality of life for people with ME/CFS
• Physicians are inadequately trained to instruct patients in self management skills such as pacing
• Patients must become active participants in their overall treatment and decision-making.
THE PRESENTATIONS FROM BOTH DAYS ARE AVAILABLE TO WATCH HERE:
9 December 2014 (Day One): http://videocast.nih.gov/summary.asp?Live=14723&bhcp=1
10 December 2014 (Day Two): http://videocast.nih.gov/summary.asp?Live=14727&bhcp=1
THE AGENDA FOR THE WORKSHOP IS AVAILABLE HERE
Once the evidence-based review of the research literature had been digested, and the workshop presentations delivered, the P2P panel retired to consider the findings and produce a draft report with recommendations.
The report attempts to answer the original questions laid before P2P and identifies future research priorities – all of which can be read in the report. It comprised 403 lines of text and can be read in full HERE
The report will not be finalised until after 16 January 2015. In the meantime it is open for public comment. If you do wish to leave a comment then please follow the advice here:
See ‘Comments on the Panel’s Draft Report’: https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs/workshop-resources#draftreport
Once the report is officially signed off by the panel it will then be delivered to the National Institutes of Health who will determine precisely how to answer the recommendations.
Thank you Dr Shepherd for identifying all the points which need to be addressed and the recommendations put forward.
I feel this report is crucial to our future here too and would urge as many people as possible to read, digest and comment in line with your advice.
We need to get this right in the hope that we can all help to influence the decision making in a positive way.
Please help
Thank you
Annx
great summary dr shepherd.
the small charities have had to privately fund a lot of the quality research that has come out.
this is a shocking reflection on the people who decide on which research proposals to fund, both in america and in the united kingdom.
it is a very sad indictment of the very low value that these agencies put on the lives of patients with ME.
proposals from serious high calibre researchers are repeatedly turned down by nih and other officials, on the grounds that they are poorly formulated and lack merit
one researcher was recently told that cfs was psychological and by implication, the researchers medically oriented application was therefore unneeded.
i really hope that the beaurocrats who are responisible for the perpetuation of the misery and devastation to millions of patients around the world, through stifling research and benefitst to patients and trying to frame the illness as psychological or even a form of laziness,will be held fully accountable for their misconduct and disciplined accordingly
jeremy bearman
as the psychogenic school are master wordplayers I would suggest a change:
• Although psychological complications (e.g. depression) often follow ME/CFS, this is not a psychological or psychiatric disease in aetiology (= cause)
to
“Psychological complications (e.g. depression) often follow as a s reaction to the experience of ME/CFS. This is reactive/situational depression as found in many states of distress.
In SOME cases neuroinflammation within the brain may contribute to depressive symptoms as may also peripheral problems, e.g. gut flora disturbance, affecting brain function.
The presence of depressive symptoms of any type in no way turns an illness with manifestly physical symptoms into a mental illness (i.e into one with mainly mental symptoms).
Nor do psychiatruic symptoms indicate psychological aetiology.
Neuropsychiatric aetiology of mental symptoms, where present, is to be considered only in the light of the above factors.
Of course all the above applies to organic ME/CFS. It is up to medics to filter out any neurotics/ “I fear exercise”hypochondriacs/ “I fear my symptoms” hysterics etc. by appropriate exclusion diagnoses, which involve proper bio testing.(when will NICE ever learn???)
(though one cannot assume that those with exercise aversion CF would not show any organic changes, of course).