Chrome Study Seeks Diagnostic Biomarkers For Me/cfs
DxTerity a Los Angeles company specializing in diagnostics is conducting the Chrome ME/CFS study
A study seeking to uncover a diagnostic biomarker for chronic fatigue syndrome that you can participate in from your home? That was unexpected.
I had never heard of Dxterity or the CHROME study until a couple of days ago. The company a biological diagnostic company based in Los Angeles has four other studies underway. Besides their catchy titles, the studies had two things in common: they were all focused on more cheaply and effectively monitoring autoimmune diseases.
- LIFT study for Lupus
- EMPOWER study for multiple sclerosis
Metabolomic Analysis In Patients With Me/cfs
In recent years, there has been an increase in studies involving metabolomic analysis for the purpose of developing objective diagnostic biomarkers that reflect the pathophysiological mechanisms of ME/CFS. Metabolomics provides direct small-molecule information and the results can provide immediately actionable treatment information using readily available small-molecular nutrients, cofactors, and lifestyle intervention, which may, in turn, be useful for both diagnosis and personalized treatment .
This section aimed to review human metabolomic analysis based on the type of samples used.
Functional Studies Imaging And Laboratory Values
Hand grip strength was assessed using an electric dynamometer assessing maximal and mean force of maximal pulls repeated ten times and a second assessment 60min later . Blood pressure and heart rate were assessed in sitting position as well as in standing position immediately after standing up and after 2, 5, and 10min. Postural orthostatic tachycardia syndrome is defined as pulse increase of more than 30bpm compared to sitting or over 120bpm both within 10min after standing up and signs of orthostatic intolerance,. Orthostatic hypotension is defined as a decrease of more than 20mmHg of systolic or 10 mmHg of diastolic blood pressure compared to sitting. Laboratory parameters including full and differential blood count, lymphocyte subsets, interleukin 8 in erythrocytes, mannose-binding lectin , C-reactive protein , immunoglobulin subsets, anti-nuclear antibodies , extractable nuclear antigen , complement C3/4, anti-thyreoperoxidase antibodies, thyroid-stimulating hormon , free triiodothyronine/thyroxine , ferritin, creatinine, liver enzymes, angiotensin-converting enzyme 1/2 , N-terminal prohormone of brain natriuretic peptide were determined at the Charité diagnostics laboratory . ACE2 was assessed by an enzyme-linked immunoassay .
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Dysfunction Of Tca And Urea Cycles
A 2016 study in Japan, by Yamano, et al, looked at the differences in intermediate metabolite concentrations in the tricarboxylic acid and urea cycles in CFS patients versus healthy controls: “CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 and 0.750 for training and validation datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma.”
Obstacle for use: The specialized laboratory equipment needed for this test is usually only available in facilities engaged in research. The findings in this published study need to be validated through replication by other studies.
Immortalised Lymphocytes From Me/cfs And Patient Blood Samples Can Be Distinguished By The Phosphorylation State Of 4e
The foregoing results showed that good biomarkers for ME/CFS are provided by both the death rates of stored lymphocytes after 48 h in culture medium and the respiratory function of cultured lymphoblasts derived from them. In both cases, the optimum thresholds were found to discriminate ME/CFS from control cells with a reliability better than 80% , with an overall error rate of less than 20%. However, in both cases, the errors at these optimal thresholds were not proportionately distributed between the patients and controls. Thus, although more than 90% of patient samples were correctly identified as such , the specificity was relatively low in that more than 40% of the control samples were also classed incorrectly as being ME/CFS. Using ROC analysis to find the best threshold to minimise the error rates resulted in only small improvements. We, therefore, conducted similar analysis to determine whether the elevated TORC1 activity in lymphoblasts might perform better as a biomarker of ME/CFS than the lymphocyte death rates or the lymphoblast respiratory dysfunction.
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Raman Spectroscopy Analysis Supports Composition Differences In Me/cfs Plasma Evs
Intrigued by the fact that four out of the six physical associated parameters of EVs , corresponding to the size and zeta potential of vesicles were discriminating features selected by our initial PLS-DA model , we decided to further explore the differential nature of ME/CFS EVs by Raman spectroscopy analysis, an approach that has proven to differentiate EVs from various cell sources and has been successfully used to detect ME/CFS specific changes in PBMCs .
Raman analysis of the 15 severe ME/CFS cases and 15 HC EVs isolated from aliquots of the plasma used in our earlier study , clearly show prominent Raman bands at 1,158 and 1,521 cm1 . These bands are characteristic of carotenoids with the CC stretching mode contributing to the 1,158-cm1 band and the C = C stretching mode of the conjugated chain in carotenoids contributing to the 1,510-cm1 band . Further quantification of results for these two bands are shown in Figure 3B, illustrating a significant higher content of carotenoids in ME/CFS patients than in HCs .
The Mrna Revolution Comes To Me/cfs
The CHROME ME/CFS study will be assessing mRNA , metabolites and DNA
ME/CFS is obviously different. It has no validated treatments. Finding a diagnostic biomarker, on the other hand, is near the top of just about everyones list and thats what Dxterity hopes to do with this study.
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Time will tell, of course, if that will work. A lot will depend on the genes, metabolites, etc. theyre looking at. Other ME/CFS studies have looked at more genes, or more metabolites, or more DNA, but none has attempted to put all three together in the manner that Dxterity has.
Dxterity appears to recognize what theyre getting into. Gilly described the ME/CFS term as a kind of broad descriptor which may contain many different subsets. Still, they feel that ME/CFS is ripe for this kind of analysis.
For one, it appears to be an inflammatory chronic disease, possibly with an autoimmune component and thats pretty much Dxteritys bailiwick. They believe their RNA testing gives them a particularly good window into immune disorders.
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Biomarkers In Chronic Fatigue Syndrome: Evaluation Of Natural Killer Cell Function And Dipeptidyl Peptidase Iv/cd26
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Affiliations Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America, Miami Veterans Health Care Center, Miami, Florida, United States of America, Department of Psychology, University of Miami, Coral Gables, Florida, United States of America
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Affiliations Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America, Miami Veterans Health Care Center, Miami, Florida, United States of America
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Affiliation Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America
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Affiliations Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America, Miami Veterans Health Care Center, Miami, Florida, United States of America
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Affiliation Department of Psychology, University of Miami, Coral Gables, Florida, United States of America
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Affiliation Department of Psychology, University of Miami, Coral Gables, Florida, United States of America
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Affiliation Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
Ohio State Researchers Isolate Biomarker To Test For Chronic Fatigue Syndrome
Myalgic encephalomyelitis/chronic fatigue syndrome and Gulf War illness are complex, chronic diseases with overlapping symptoms and no definitive way to diagnose or differentiate between them.
The one symptom they share in common is long-term, disabling fatigue. But widely varying symptoms affecting the immune, endocrine and neurological systems may occur, including muscle and joint pain, concentration and memory problems, headaches, sleep problems, fever, sore throat and tender lymph nodessymptoms that are common to a number of different illnesses, making diagnosis of ME/CFS even more challenging.
Around 50% of patients who develop ME/CFS report that their symptoms occurred after exhibiting flu-like symptoms, leading some researchers to look into the role that certain viruses play in triggering an ME/CFS infection and its impact on the bodys immune system. Viruses such as Epstein-Barr virus, human herpesvirus 6 and varicella-zoster virus, all of which establish latent infections in their host, can be periodically reactivated over a persons lifetime.
The impact value of our findings is enormous, when you think about the fact that there is currently no commercially available test to measure the concentration of antibodies against the herpesviruses dUTPase proteins present in patients sera, says Dr. Ariza.
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Metabolomic Analysis Using Human Urine Samples
The metabolome analyses of urine samples using nuclear magnetic resonance spectroscopy reported a glycolytic anomaly in ME/CFS . According to studies that performed metabolomic analysis by NMR using serum samples in addition to other urine samples, reduced glycolysis inferred a reduced utilization of pyruvate and acetyl CoA in the citric acid cycle. The use of amino acids may be through glutamate forming 2-oxoglutarate via aspartate transaminase , which transfers the amino group to oxaloacetate to form and accumulate aspartate. This inefficient energy production together with a lowering of amino acid levels may be important in producing a fatigue phenotype in patients with ME/CFS. The observed increase in creatinine production may provide a means of anaerobic ATP energy for muscles, as well as a mode of nitrogen removal from deaminated amino acids . A previous study reported that an inhibited glycolysis pathway exists in patients with ME/CFS, along with an oxidative stress pathway and a reduced level of amino acids .
Chronic Fatigue Syndrome: What Are The Causes
The root causes of the disease remain unclear, although several theories exist. People with the condition often find it initially manifests as a run-of-the-mill flulike illness, leading many researchers to suspect that CFS/ME may be triggered by infectious disease. Long Covid could fall into this category.
Others believe that the condition could be caused by a change in the persons immune system and how it reacts to infection or stress, through chronic production of cytokines, low functioning natural killer cells or differences in markers of T-cell activation.
CFS/ME may also arise from a faulty hypothalamic-pituitary-adrenal axis , a network that controls the bodys reaction to stress and regulates processes related to immune response, digestion, energy usage and mood.
People with CFS/ME may also have differences in the way the cells in their bodies get energy, while studies done in twins and families suggest that genes and environment might have a role to play too.
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Demographic And Baseline Clinical Characteristics
We report on a total of 42 patients who presented to the Charité Fatigue Center with PCS all suffering from persistent moderate to severe fatigue and exertion intolerance six months after diagnosis of COVID-19. Details of patient selection is reported in the methods section. Table summarizes demographic and clinical characteristics of the study population. Most patients had mild COVID-19 and ten had moderate COVID-19 due to pneumonia, according to WHO criteria. Three of the ten patients with pneumonia were treated in hospital but none of them required oxygen or mechanical ventilation thus making critical illness myopathy unlikely to explain any symptoms. Supplementary Table shows the ten most frequent initial symptoms of COVID-19 reported by the patients.
Table 1 Demographic and baseline clinical characteristics
Ratio Of Active: Inactive Pkr
In 2018, Eiren Sweetman discovered, during work for her doctorate thesis, that a changed ratio of active:inactive Protein Kinase R in people with ME/CFS vs age-gender matched controls could potentially be used as a diagnostic biomarker. Protein Kinase R is an innate antiviral immune response protein. Upon measuring an antibody against a non-phosphorylated PKR fragment and an antibody against a Thr-446 phosphorylated PKR peptide, an increased ratio of phosphorylated PKR to non-phosphorylated inactive PKR was detected ME/CFS patients.
Obstacles in use: Further testing needed for confirmation test would need to be adapted from a research setting to a clinical setting for wide availability.
Main article: Short QT interval
“Automated measurement of QTc in clinical practise has potential utility as a diagnostic biomarker in CFS.”
The electrocardiographic QT interval is shorter in patients with ME/CFS than those of the general population. The only exception is in those who have a rare genetic illness, Short QT syndrome. Differentiation is easy to determine because those with Short QT syndrome also have tall and peaked T waves, whereas the T waves are normal in people with ME. Modern computer-based ECG machines are programmed to correct the QT interval in relation to heart rate, because a number of medical conditions elicit a prolonged QT interval.
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Pathway And Gene Enrichment Analysis
Analysis of predicted and validated miRNA-mRNA interactions was performed with the freely available software MiRTargetLink 2.0 . Gene ontology enrichment analysis was performed using the miEAA tool incorporated into MiRTargetLink 2.0, targets were retrieved, sorted by adjusted p-value, and presented in table format. Selected networks of mRNAs targeted by at least two miRNAs were drawn using Adobe Illustrator software.
Patient And Public Involvement
A German Facebook group maintained by patients suffering from long COVID contacted us first in June 2020 sharing their stories and symptom observations . Our study design was developed based on frequency, type, and severity of symptoms reported and discussed with the patient group. The possibility for local patients to participate in our study was communicated on their website.
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Biomarkers Of Chronic Fatigue Syndrome/myalgic Encephalomyelitis
We agree with the suggestion of Silverman et al. that CFS/ME is an excellent model for addressing the biology of CF. All cases of CFS/ME have CF, which is required by the case definitions . Some relevant literature on a related syndrome, gulf war illness , also associated with CF, is included in this review. Population-based studies estimate the prevalence of CFS/ME at 0.230.41% . Hypothetical
Refinement Of The Initial Pls
The results of Raman spectrometry analysis show that to be developed as a more comprehensive diagnostic tool the use of further information is required. Therefore, we proceeded to reanalyze our first multi-block PLS-DA model to check if the relevant Raman wavelengths selected by the PLS-DA model on the spectroscopy data could be useful predictors when combined with the previously identified biomarkers.
To study this possibility, we fitted a PLS-DA model using the selected variables from the former PLS-DA model, adding the key differential wavelengths from our PLS-DA analysis of Raman spectroscopy data. It is important to highlight that the adequacy of this approach resides in the fact that the samples used to generate the two models came from the same blood samples. The reason for maintaining the use of PLS-DA, was that according to the previous results, it was a technique yielding one of the best classification performances and the only one enabling the interpretation of the discriminant power of the predictors, establishing a set of statistically significant biomarkers.
The observed vs. predicted values for the observations in the calibration set and in the external validation set, show that classes can be perfectly separated . This is also illustrated by the ROC curves in Figures 6D,F, showing that a threshold on the predicted outcome of 0.481 yields a perfect classification with an AUC of 1.
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Metabolomic Analysis Using Human Blood Samples
A broad-spectrum metabolomics study has shown ME/CFS to be a hypometabolic response of high concern to environmental stress that traces to mitochondria . Mitochondrial function is important for energy metabolism . Mitochondria are multifunctional organelles that play a critical role in energy harvesting, transformation, and storage, as well as other intracellular signaling processes .
Previous studies used metabolomic analyses to report a decline in the energy metabolism of patients with ME/CFS .
The TCA cycle, which in part generates energy from lipids and sugars to make ATP is a pathway that consistently surfaces in ME/CFS metabolomics analysis across platforms and populations. Since fatigue is a major debilitating symptom of this disease, the energy metabolism of such patients has been speculated to be dysfunctional .
In addition, taurine and hypotaurine metabolism as the central compound of this pathway, is reported to be dysregulated in ME/CFS . A decrease in the concentration of these metabolites might be reflective of the general effect on the pathway and consequences associated with the general metabolism of the body. Taurine has a number of functions in skeletal muscle, retina, and the central nervous system, and its concentrations may be relevant to the altered amounts of lipid metabolism besides being a part of the primary bile acid biosynthesis pathway, which physically supports the digestion of dietary fat .
Samples And Associated Clinical Data
Ethical approval of the study was granted by the Public Health Research Ethics Committee DGSP-CSISP, Valencia , study number UCV_201701 and by the UCL Biobank Ethical Review Committee-Royal Free London NHS Foundation Trust , study number EC2017.01 before the samples were released by the UKMEB.
Data for the initial PLS-DA analysis corresponded to Nanostring datasets generated during a previous study of our group , available from the NCBI Gene Expression Omnibus database and the of the cited article. The samples for the Raman analysis consisted of EV aliquots from the cited study isolated from 0.5 ml of platelet poor plasma from 15 severely ill ME/CFS females and 15 age-population matched healthy females, obtained from dipotassium EDTA blood-collection tubes by UKMEB professionals.
As previously described, patient recruitment and clinical assessment for the UKMEB was mainly performed through the UK National Health Service primary and secondary health care services . Compliance with the Canadian Consensus , CDC-1994 and Institute of Medicine criteria were ensured for patient recruitment . Clinical diagnosis was complemented with score differences in the SF-36 questionnaire and the GHQ , the last also assessed by a Likert scale .
All methods were performed in accordance with relevant guidelines and regulations. All subjects signed an informed consent before samples could be included in the corresponding sample collection.
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