Why broad definition should be used as a starting point - by Prof Stephen Holgate
Oct 14, 2016 — “Several of the patient/public concerns seem to relate to the worry that firstly severe disease will not be included or that we will be recruiting from a broader definition of the disease(s) beyond Fukuda and Canadian definitions. I want to reassure people on this and explain the reasons why we need to broaden the definition.
“I believe the point George Davey-Smith was making in his CMRC presentation with his example of migraine is that to find causative pathways and uncover molecular mechanisms we need a broad range of disease severity and clinical manifestation. In the study looking for shared pathways between migraine and coronary artery disease (CAD) (http://ng.neurology.org/content/1/1/e10.full) the investigation was preceded by the statement ‘.....Migraine affects 19% of women and 11% of men worldwide and causes more years lost to disability than any other neurologic disorder. In about one-third of patients, headache attacks are preceded by transient neurologic symptoms termed migraine aura, and migraine with and without aura (MA and MO, respectively) are believed to have a partially distinct pathogenic basis.’
“Then, after conducting the GWAS the following emerged ‘Our study provides novel insights into the relationship between migraine and CAD. Intriguingly, and unexpectedly, there was no genetic overlap between MA and CAD, for which epidemiologic studies suggest comorbidity, but there was compelling evidence for a genetic overlap between MO and CAD, where the impact of risk variants overall was in opposite direction for the 2 disorders. The results do not demonstrate that shared common genetic risk factors drive comorbidity between the two disorders. However, dissecting the mechanisms underlying the shared risk loci may improve our understanding of both disorders’. An analogy exists for CFS/M.E. in that we have imposed a descriptive definition based on symptoms Fukuda and Canadian) in the absence of knowing any causative mechanisms or genetic risk factors.
“Clearly this will incorporate both severe disease and people who conform to the Fukuda and Canadian definitions but there will be others too with early onset disease and a spread of clinical manifestations. The US IOM recent definition (2015) seems to fulfil this and would enable us to merge data with our US colleagues later as Chris Ponting has pointed out (but not renaming the disorder!). The key as far as I see it is to ensure that each patient is deeply phenotyped and with the same operating procedures (SOPs) if you are successful in recruiting 10,000 such individuals.
“The normal controls could be the spouses as well as the historical Wellcome Trust normal population collections (e.g. Sanger news) and https://wellcome.ac.uk/press-release/1000-genomes-project-publishes-most-comprehensive-map-date-human-genetic-variation/). It will then be possible using the many phenotypic variables collected to undertake a cluster-type analysis and interrogate the genome for each cluster. Equally it will be possible to segregate the patients in the 10,000 collection according to whether or not they conform to the Fukuda or Canadian criteria (or indeed any other of the current definitions used e.g. very severe disease) and see if molecular pathways map on to these.
“I think we are in for some surprises in that there may well be several prominent clusters each with mild, moderate and severe manifestations but utilising different causative pathways. This is what is happening in airways disease (my own interest) in that patients we previously classified as having COPD are turning out to have a form of asthma despite lack of reversibility of airflow obstruction in these patients (the classical definition of asthma) (see linked papers on airway treatable traits). Thus identifying treatable traits linked to causal mechanisms is opening up therapeutic opportunities in those patients with airways disease in whom there was no known disease-modifying treatment offered to them previously.”
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