Prediction of complex human diseases from pathway-focused candidate markers by joint estimation of marker effects: case of chronic fatigue syndrome

Abstract:

BACKGROUND: The current practice of using only a few strongly associated genetic markers in regression models results in generally low power in prediction or accounting for heritability of complex human traits.

PURPOSE: We illustrate here a Bayesian joint estimation of single nucleotide polymorphism (SNP) effects principle to improve prediction of phenotype status from pathway-focused sets of SNPs. Chronic fatigue syndrome (CFS), a complex disease of unknown etiology with no laboratory methods for diagnosis, was chosen to demonstrate the power of this Bayesian method. For CFS, such a genetic predictive model in combination with clinical evidence might lead to an earlier diagnosis than one based solely on clinical findings.

METHODS: One of our goals is to model disease status using Bayesian statistics which perform variable selection and parameter estimation simultaneously and which can induce the sparseness and smoothness of the SNP effects. Smoothness of the SNP effects is obtained by explicit modeling of the covariance structure of the SNP effects.

RESULTS: The Bayesian model achieved perfect goodness of fit when tested within the sampled data. Tenfold cross-validation resulted in 80% accuracy, one of the best so far for CFS in comparison to previous prediction models. Model reduction aspects were investigated in a computationally feasible manner. Additionally, genetic variation estimates provided by the model identified specific genetic markers for their biological role in the disease pathophysiology.

CONCLUSIONS: This proof-of-principle study provides a powerful approach combining Bayesian methods, SNPs representing multiple pathways and rigorous case ascertainment for accurate genetic risk prediction modeling of complex diseases like CFS and other chronic diseases.

 

Source: Bhattacharjee M, Rajeevan MS, Sillanpää MJ. Prediction of complex human diseases from pathway-focused candidate markers by joint estimation of marker effects: case of chronic fatigue syndrome. Hum Genomics. 2015 Jun 11;9:8. doi: 10.1186/s40246-015-0030-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479222/ (Full article)

 

The theoretical basis for chronic fatigue syndrome from bladder meridian of foot-taiyang

Abstract:

The bladder meridian of foot-taiyang is considered as key of six meridians and the yang of the yang, which is the pivot of transportation for qi and blood in the meridians and zang-fu. The running route and treatment characteristic of bladder meridian is closely related with chronic fatigue syndrome (CFS). The bladder meridian belongs to brain and connects with governor vessel, which has a close relationship with zang-fu function, quality of sleep and fatigue. Besides, the running route of bladder meridian is highly consistent with the surface projections of important anatomical structures such as muscle, nerve and sympathetic trunk, etc. Therefore, regulating the meridian-qi of bladder meridian can harmonize five-zang and calm the mind, but also effectively relieve physical and mental fatigue in CFS.

 

Source: Yao F, Zhao Y, Jiang S, Fang M. The theorotical basis for chronic fatigue syndrome from bladder meridian of foot-taiyang. Zhongguo Zhen Jiu. 2015 Mar;35(3):295-8. [Article in Chinese] https://www.ncbi.nlm.nih.gov/pubmed/26062210

 

Computerized training improves verbal working memory in patients with myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study

Abstract:

OBJECTIVE: Patients with myalgic encephalomyelitis/chronic fatigue syndrome experience cognitive difficulties. The aim of this study was to evaluate the effect of computerized training on working memory in this syndrome.

DESIGN: Non-randomized (quasi-experimental) study with no-treatment control group and non-equivalent dependent variable design in a myalgic encephalomyelitis/chronic fatigue syndrome-cohort.

SUBJECTS: Patients with myalgic encephalomyelitis/chronic fatigue syndrome who participated in a 6-month outpatient rehabilitation programme were included in the study. Eleven patients who showed signs of working memory deficit were recruited for additional memory training and 12 patients with no working memory deficit served as controls.

METHODS: Cognitive training with computerized working memory tasks of increasing difficulty was performed 30-45 min/day, 5 days/week over a 5-week period. Short-term and working memory tests (Digit Span – forward, backward, total) were used as primary outcome measures. Nine of the 11 patients were able to complete the training.

RESULTS: Cognitive training increased working memory (p = 0.003) and general attention (p = 0.004) to the mean level. Short-term memory was also improved, but the difference was not statistically significant (p = 0.052) vs prior training. The control group did not show any significant improvement in primary outcome measures.

CONCLUSION: Cognitive training may be a new treatment for patients with myalgic encephalomyelitis/chronic fatigue syndrome.

 

Source: Maroti D, Westerberg AF, Saury JM, Bileviciute-Ljungar I. Computerized training improves verbal working memory in patients with myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. J Rehabil Med. 2015 Aug 18;47(7):665-8. doi: 10.2340/16501977-1976. https://www.medicaljournals.se/jrm/content/abstract/10.2340/16501977-1976 (Full article)

 

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors.

RESULTS: CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells.

CONCLUSIONS: This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

 

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Wong N, Ramos S, Staines D, Marshall-Gradisnik S. Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC Immunol. 2015 Jun 2;16:35. doi: 10.1186/s12865-015-0101-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450981/ (Full article)

 

Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition

Abstract:

Current case definitions of Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have been based on consensus methods, but empirical methods could be used to identify core symptoms and thereby improve the reliability. In the present study, several methods (i.e., continuous scores of symptoms, theoretically and empirically derived cut off scores of symptoms) were used to identify core symptoms best differentiating patients from controls. In addition, data mining with decision trees was conducted. Our study found a small number of core symptoms that have good sensitivity and specificity, and these included fatigue, post-exertional malaise, a neurocognitive symptom, and unrefreshing sleep. Outcomes from these analyses suggest that using empirically selected symptoms can help guide the creation of a more reliable case definition.

 

Source: Jason LA, Kot B, Sunnquist M, Brown A, Evans M, Jantke R, Williams Y, Furst J, Vernon SD. Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition. Health Psychol Behav Med. 2015;3(1):82-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443921/ (Full article)

 

Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case-control study

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness. Symptoms include profound fatigue and distinctive post-exertional malaise (PEM). We asked whether a submaximal exercise test would prove useful for identifying different patterns of tissue oxygen utilization in individuals with ME/CFS versus healthy subjects. Such a test has potential to aid with ME/CFS diagnosis, or to characterize patients’ illness.

METHODS: A case-control study of 16 patients with ME/CFS compared to 16 healthy controls completing a 3-min handgrip protocol was performed. Response was measured using near-infrared spectroscopy, resulting in measurements of oxygenated (O2Hb) and deoxygenated hemoglobin (HHb) over wrist extensors and flexors. Changes in O2Hb (delta (d)O2Hb) and HHb (dHHb) absorbance between the first and last contraction were calculated, as were the force-time product of all contractions, measured as tension-time index (TTI), and ratings of perceived exertion (RPE).

RESULTS: Individuals with ME/CFS demonstrated smaller dO2Hb and dHHb than controls. However, after adjusting for TTI and change in total hemoglobin (delta (d)tHb), differences in dO2Hb and dHHb were reduced, with large overlapping variances. RPE was significantly higher for cases than controls, particularly at rest.

CONCLUSIONS: Relative to controls, participants with ME/CFS demonstrated higher RPE, lower TTI, and reduced dO2Hb and dHHb during repetitive handgrip exercise, although considerable variance was observed. With further study, submaximal exercise testing may prove useful for stratifying patients with a lower propensity for inducing PEM, and have the ability to establish baseline intensities for exercise prescription.

 

Source: Miller RR, Reid WD, Mattman A, Yamabayashi C, Steiner T, Parker S, Gardy J, Tang P, Patrick DM. Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case-control study. J Transl Med. 2015 May 20;13:159. doi: 10.1186/s12967-015-0527-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438583/ (Full article)

 

Working with uncertainty: A grounded theory study of health-care professionals’ experiences of working with children and adolescents with chronic fatigue syndrome

Abstract:

This grounded theory study explores conceptualisations of chronic fatigue syndrome/myalgic encephalomyelitis from semi-structured interviews with 10 health-care professionals working with children and adolescents. The findings suggest that a lack of a clear empirical understanding of chronic fatigue syndrome/myalgic encephalomyelitis leads to ‘working with uncertainty’, whereby health-care professionals utilise previous experiences to make sense of the condition and inform their clinical practice. How health-care professionals make sense of chronic fatigue syndrome/myalgic encephalomyelitis may influence the labels given to young people and the interventions they receive. The findings provide insight into a currently understudied area, and highlight potential avenues for further research and clinical practice.

© The Author(s) 2015.

 

Source: Marks MR, Huws JC, Whitehead L. Working with uncertainty: A grounded theory study of health-care professionals’ experiences of working with children and adolescents with chronic fatigue syndrome. J Health Psychol. 2015 May 8. pii: 1359105315583367. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/25957226

 

A critical analysis of the proposal of the Institute of Medicine to replace myalgic encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion intolerance disease

Abstract:

The Institute of Medicine (IOM) recently published their report in response to an assignment “to define diagnostic criteria for Myalgic Encephalomyelitis (ME)/chronic fatigue syndrome (CFS), to propose a process for reevaluation of these criteria in the future, and to consider whether a new name for this disease is warranted”.

The basic pre-assumption of the IOM committee for the development of evidence-based diagnostic criteria for ME/CFS was that ME and CFS denote conditions with similar symptoms, hence ME/CFS. The IOM committee recommends: (1) that ME/CFS will be renamed ‘systemic exertion intolerance disease’ (SEID); and that a new code should be assigned to SEID in the International Classification of Diseases (ICD), replacing the existing codes for ME (a neurological disease: G93.3) and CFS (‘signs, symptoms, and abnormal clinical and laboratory findings, not elsewhere classified’: R53.82); (2) that a diagnosis of SEID should be made if the new diagnostic criteria are met; (3) that the Department of Health and Human Services develops a toolkit appropriate for screening and diagnosing patients; and (4) that a multidisciplinary group re-examines the new diagnostic criteria when necessary.

This editorial reviews the working procedure of the IOM and two of the outcomes: the recommendation to introduce a new clinical entity (SEID) and new diagnostic criteria. Based upon the contents of the report, and the arguments of the IOM, a search of PubMed and the archive of the Journal of Chronic Fatigue Syndrome using the search terms ME (and old synonyms) and CFS, and a search of PubMed related to the five core symptoms of SEID was conducted.

Reviewing the working method and the recommendations, it is concluded that the new diagnostic criteria for SEID are based upon important methodological shortcomings and that the introduction of SEID to replace both ME and CFS has several profound negative consequences outweighing the advantages.

 

Source: Twisk FN. A critical analysis of the proposal of the Institute of Medicine to replace myalgic encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion intolerance disease. Curr Med Res Opin. 2015;31(7):1333-47. doi: 10.1185/03007995.2015.1045472. Epub 2015 May 29. https://www.ncbi.nlm.nih.gov/pubmed/25912615 (Full article)

 

Medical constructions of long-term exhaustion, past and present

Abstract:

Culture and history affect the ways in which medical knowledge is shaped, sustained and changed. The less knowledge we have, the larger the space for the cultural imprint becomes. Based on these assumptions, we ask: how have medical constructions of long-term exhaustion changed over time, and how are changing constructions related to societal change? To discuss these questions we conducted a comparative study of medical texts from two historical periods: 1860-1930 and 1970-2013.

Our data are limited to two diagnoses: neurasthenia and encephalomyelitis. After comparing the two periods by identifying diverging and converging aspects, we interpreted observed continuities and interruptions in relation to historical developments. We found that in the medical literature, long-term exhaustion became transformed from a somatic ailment bred by modern civilisation to a self-inflicted psychiatric ailment. At the same time, it changed from being a male-connoted high-status condition to a female-connoted low-status condition. We interpret these changes as contingent upon culturally available modes of interpretations. Medical knowledge thereby becomes infused with cultural norms and values which give them a distinct cultural bias. The historical controversies surrounding this medically contested condition neatly display the socially contingent factors that govern the social construction of medical knowledge.

© 2015 The Authors. Sociology of Health & Illness published by John Wiley & Sons Ltd on behalf of Foundation for SHIL.

 

Source: Lian OS, Bondevik H. Medical constructions of long-term exhaustion, past and present. Sociol Health Illn. 2015 Jul;37(6):920-35. doi: 10.1111/1467-9566.12249. Epub 2015 Apr 24. https://www.ncbi.nlm.nih.gov/pubmed/25912053

 

Chronic Fatigue Syndrome

Excerpt:

Fatigue is a universal symptom, occurring in all individuals after prolonged exertion or lack of sleep. However, when fatigue is persistently present, without adequate environmental or medical explanation, fatigue has been recognised as the hallmark of a frequent and enigmatic clinical syndrome. Although difficult to precisely define and measure, fatigue is a pervasive sense of tiredness or lack of energy, that is not related exclusively to exertion. Fatigue may be appreciated centrally in terms of concentration, memory and motivation, or appreciated peripherally, where symptoms are often referred to the muscles. Chronic Fatigue Syndrome (CFS) is a term that was chosen and defined by Holmes et al., in 1988 to describe a combination of non-specific symptoms including profound fatigue, weakness, malaise and cognitive impairment with a remarkable lack of objective physical or laboratory abnormalities (1).

This syndrome had previously been known as “Chronic Epstein-Barr Virus Syndrome” and “Chronic Mononucleosis”. The terminology “CFS” was widely accepted because it implies no aetiology or specific pathological process. Several definitions of CFS have been developed, primarily to standardise research (2,3). It was not intended that they be used for clinical diagnosis. The Canadian Clinical Working Case Definition of Chronic Fatigue Syndrome was developed in response to an increasing need for such a definition for practising clinicians (4). It is the first definition that was created primarily to aid in clinical diagnosis, by encompassing many of the positive signs and symptoms of CFS, in order that it can be recognised as a distinct entity and distinguished from other clinical syndromes that have overlapping symptoms.

Copyright © 2000-2017, MDText.com, Inc.

 

Source: Torpy BDJ, Saranapala M. Chronic Fatigue Syndrome. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R,Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. 2014 Nov 20. https://www.ncbi.nlm.nih.gov/books/NBK279099/ (Full article)