Seguimos (por ahora) jugando con las estadísticas, pero al parecer, el grupo europeo EUROMENE ha decidido que ha llegado el momento de empezar a investigar en serio. Entre los nombres, alguien que muchos aquí ya conocemos: Julià Blanco, de IRSIcaixa. Este primer estudio, lo único que ha hecho es analizar los estudios llevados a cabo en Europa en los últimos 5 años (2012-2016) --39 estudios en total-- y clasificarlos en 4 posibles grupos: inmunologicos, relacionados con infecciones, metabolicos or neurologicos. Aparte de repetir por millonésima vez que no se invierte suficiente dinero en investigar (concretamente, dice que "to promote research it is crucial to increase funding for ME/CFS which is currently still far below the budget funds for most other serious diseases in both the EU and the US" o sea, "para promover la investigación es crucial aumentar los fondos para el SFC/EM que está todavía muy por debajo de los presupuestos de fondos otorgados para otras enfermedades graves tanto en EU como en USA"), acaban listando una serie de obviedades en su tabla final:
Table 3
Estrategias para el desarrollo de biomarcadores diagnósticos en SFC/EM
1. Estandarización de la recolección de muestras y procedimientos de ensayo
2. Uso de una definición de caso clínico uniforme
3. Uso de cuestionarios para valoración de síntomas y su severidad para definir subgrupos
4. Estratificación de pacientes según sexo, inicio de la enfermedad y duración de la misma
5. Inclusión de grupos de control de la misma edad y sexo
6. Tamaño de la muestra suficiente e hipótesis predefinidas (para el análisis estadístico)
7. Confirmación de los resultados en estudios de valoración y multi-centro
8. Estudios combinados de biomarcadores, análisis de vías metabólicas o estudios funcionales.
En serio? No se nos hubiera ocurrido nunca!!! 
Bueno, aquí os dejo el estudio y el enlace para que podáis ver el resto de tablas e imágenes.
The European ME/CFS Biomarker Landscape project: an initiative of the European network EUROMENE
Carmen ScheibenbogenEmail authorView ORCID ID profile, Helma Freitag, Julià Blanco, Enrica Capelli, Eliana Lacerda, Jerome Authier, Mira Meeus, Jesus Castro Marrero, Zaiga Nora-Krukle, Elisa Oltra, Elin Bolle Strand, Evelina Shikova, Slobodan Sekulic and Modra MurovskaJournal of Translational Medicine 201715:162
Abstract
Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is a common and severe disease with a considerable social and economic impact. So far, the etiology is not known, and neither a diagnostic marker nor licensed treatments are available yet. The EUROMENE network of European researchers and clinicians aims to promote cooperation and advance research on ME/CFS. To improve diagnosis and facilitate the analysis of clinical trials surrogate markers are urgently needed. As a first step for developing such biomarkers for clinical use a database of active biomarker research in Europe was established called the ME/CFS EUROMENE Biomarker Landscape project and the results are presented in this review. Further we suggest strategies to improve biomarker development and encourage researchers to take these into consideration for designing and reporting biomarker studies.
Biomarker in ME/CFS
Although the exact pathogenesis of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) is still unknown, the most plausible hypothesis is that it is a complex multifactorial syndrome in which immunological and environmental factors play a crucial role. In addition, the severe fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction that delineate the disease point to the involvement of both the nervous system as well as metabolic disturbances [1]. Infection by various pathogens, including herpes viruses and enteroviruses, but also intracellular bacteria, are known as triggers of disease. The complex clinical picture and the disagreement on potential pathomechanisms make ME/CFS a controversial entity and compel the research for disease biomarkers that could aid in the diagnostic and clinical management. Biomarker per definition may include both markers with a certain sensitivity and specificity for diagnosing ME/CFS as well as those which may allow to classify subtypes of the disease, be of value as indicators of prognosis, and to be predictive for response to treatment [2].
The EUROMENE ME/CFS Biomarker Landscape project
EUROMENE is a network of researchers and clinicians from 17 European countries and one COST (Cooperation in Science and Technology) near neighbor country on ME/CFS supported by the European COST program within Horizon 2020 (http://www.cost.eu/COST_Actions/ca/CA15111).
The aims of EUROMENE are to foster strategies for collaboration and harmonization of diagnosis and research, and to compile an inventory of clinical and scientific data in ME/CFS. The Biomarker working group will also try to develop guidelines for the usage of biomarkers and synchronization of biomarker research.
As a first step, a database for active biomarker research in Europe was established called the EUROMENE ME/CFS Biomarker Landscape project. To achieve this, EUROMENE members performed a search for publications on biomarkers within their countries. The search strategy used the medical subject headings (MeSH) term “chronic fatigue syndrome”, which includes myalgic encephalomyelitis, and the respective country, and selected all publications from the last 5 years (2012–2016). The searches were reviewed by members of the biomarker working group. Studies not involving patients with ME/CFS, non-biomarker, and sole treatment studies were excluded, only one review article was included.
A total number of 39 studies were identified. Studies were categorized as being immunological, infection-related, metabolic or neurological. We summarize the findings in Fig. 1, which shows the number and type of studies identified in each country, represented by pie charts—their sizes being proportional to the number of identified studies, and their pieces representing the distinct categories of the studies. The number of research groups working on ME/CFS biomarkers in the EU countries is also illustrated in Fig. 1. Countries from which no publications on ME/CFS biomarker could be retrieved are shown in light green/grey, and European countries not participating in the EUROMENE are shown in white. The references listed per countries are shown in Table 1.
Studies on immune markers (n = 15) in ME/CFS explored immunoglobulins, autoantibodies, cytokines, and immune cell phenotype and function (summarized in Table 2) [3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. Four of 5 of the studies on ME/CFS-associated infection markers were focused on XMRV and confirmed the absence of this virus in European ME/CFS cohorts [18, 19, 20, 21, 22]. Neurological biomarker studies (n = 4) focused on neurotransmitter regulation, but excluded imaging and functional studies [23, 24, 25, 26]. The papers which could be retrieved for potential metabolic markers (n = 15) studied mitochondrial dysfunction, oxidative stress, cortisol regulation, and more comprehensive metabolic pathways [27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41].
Discussion
So far there is no single biomarker available for diagnostic use in ME/CFS. Most studies identified here were exploratory in design and lack sex and age-matched control groups or validation cohorts thus having a low evidence level as summarized for the immune marker studies in Table 2 [42]. Some studies report inconsistent data, too. For example an expansion of transitional and naïve B cells and reduced plasmablast levels was reported in one study [14], but could not be confirmed in two other studies [4, 12]. Immune cell phenotype and function analyses are, of course, hampered by variations in sampling and methodological differences between laboratories as most flow cytometric assays are not standardized. Further, immunological biomarkers reported mostly show alterations in subgroups only or with wide overlap to healthy control groups. Such heterogeneous results may be related to the fact that subgroups of ME/CFS patients exist with different immunological pathomechanisms. This concept is supported by the existence of clinical subgroups with heterogeneity in disease onset (infection- versus non-infection triggered), the variability of immune-associated symptoms, and the divergent response to B cell depletion therapy [43]. Research activity in infection markers on ME/CFS across Europe is sparse; however, there is currently no evidence from the available literature that there is a specific serological signature aiding in diagnosis of ME/CFS.
Similar to immunological markers, there is no single neurological or metabolic marker with sufficient specificity and sensitivity as a tool in ME/CFS diagnosis yet. However, recent studies analyzing multiple metabolites could show specific alterations in the majority of ME/CFS patients [37, 44, 45, 46] pointing to a probably common and specific metabolic profile. Further, metabolic studies consistently revealed different gender-related patterns [37, 44, 46]. Thus, instead of searching single markers fitting for diagnosing all patients, multiplexed determinations of biomarkers analyzing pathways together with patient stratification, may be necessary to develop diagnostic assays with sufficient sensitivity and specificity [47].
Conclusions
Heterogeneity of biomarker studies with different case definitions, low number of patients, lack of matched control groups, missing validation studies and potentially subgroup heterogeneity are possible reasons why no diagnostic biomarkers are available yet. Further, as result of the low amount of funding in CFS/ME research few and often small studies were performed so far. Therefore, strategies to improve the quality and to facilitate the comparability of biomarker studies are needed (summarized in Table 3). This starts with well-defined patient cohorts using strict case definitions [47], standardized and quantitative symptom assessment for subgroup analyses, well-defined age- and sex-matched controls, and large enough cohort size and a predefined hypothesis to power the statistical analysis. Detailed description of cohorts, assays performed and results achieved are important to facilitate confirmation studies. Reproducing results in cohorts from different countries, developing Standard Operating Procedures (SOPs) for assays, and multi-center studies are important steps for evaluating the suitability of biomarkers of interest as diagnostic markers. The building of translational networks of clinical and basic research groups like promoted in EUROMENE is an important first step to achieve such goals. Finally, to promote research it is crucial to increase funding for ME/CFS which is currently still far below the budget funds for most other serious diseases in both the EU and the US funding agencies, such as the National Institutes of Health (NIH) [48].
enlace: https://translational-medicine.biomedce ... 017-1263-z
