From Human Genomics, 11 June 2015 [Epub ahead of print]
Prediction of complex human diseases from pathway-focused candidate markers by joint estimation of marker effects: case of chronic fatigue syndrome.
Bhattacharjee M(1), Rajeevan MS(2), Sillanpää MJ(3).
1) School of Mathematics and Statistics, University of Hyderabad, Hyderabad, 500046, India. firstname.lastname@example.org.
2) Division of High-Consequence Pathogens & Pathology, Centers for Disease Control and Prevention, Atlanta, 30333, USA. email@example.com.
3) Departments of Mathematical Sciences, Biocenter Oulu, University of Oulu, Oulu, FIN-90014, Finland. Mikko.Sillanpaa@oulu.fi.
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.
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.
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.
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.
This proof-of-principle study provides a powerfulapproach 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.
From the Journal of Health Psychology, 10 June 2015 [Epub ahead of print]
Caring for people with severe myalgic encephalomyelitis: An interpretative phenomenological analysis of parents’ experiences.
Martina Mihelicova, Zachary Siegel, Meredyth Evans, Abigail Brown, Leonard Jason
DePaul University, USA
Correspondent: Martina Mihelicova, DePaul University, 2219 North Kenmore Avenue, Chicago, IL 60614, USA. Email: firstname.lastname@example.org
Experiences of parents who care for sons or daughters with severe myalgic encephalomyelitis are rarely discussed within the literature.
Narratives of parent-carers in Lost Voices from a Hidden Illness were analyzed using interpretative phenomenological analysis. This study aimed to give voices to those who care for individuals with myalgic encephalomyelitis and are often stigmatized and inform future research supporting parent-carers.
Results included themes of identity change, guilt, feeling like outsiders, uncertainty, changing perceptions of time, coping mechanisms, and improvement/symptom management.
Findings could inform the development of carer-focused interventions and provide vital information to health professionals about parent-carers’ lived experience.
From Journal of Rehabilitation Research & Development, June 2015
Timed loaded standing in female chronic fatigue syndrome compared with other populations
Jan B Eyskens(1,*) Jo Nijs(2) Kristiaan D’Aout(3) Alain Sand(4), Kristien Wouters(5,6), Greta Moorkens(6)
1) Department of Internal Medicine, Antwerp University Hospital, Antwerp, Belgium;
2) Pain in Motion Research Group; Departments of Human Physiology and Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; and Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium;
3) Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; Department of Biology, University of Antwerp, Antwerp, Belgium;
4) Nuclear Medicine, AZ Jan Palfijn, Ghent, Belgium;
5) Department of Scientific Coordination and Biostatistics, Antwerp University Hospital, Antwerp, Belgium; 6Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium
* Address all correspondence to Jan B Eyskens, MSc PT, DO, Pr Ph; Rijsenbergstraat 31, 9000 Ghent, Belgium; +32 486 50 70 01. Email: email@example.com
Patients with chronic fatigue syndrome (CFS), like patients with osteoporosis, have similar difficulties in standing and sitting. The aim of the study was to compare combined trunk and arm endurance among women with CFS (n=72), women with osteoporosis (n=30), nondisabled women (n=55), and women from non-industrialized countries (n=58) using the timed loaded standing (TLS) test.
TLS measures how long a person can hold a 1 kg dumbbell in each hand in front of him or her with straight arms. TLS was higher in the industrialized nondisabled population than in the non-industrialized study population (p<0.001) and in patients with osteoporosis (p=0.002). TLS was lower in patients with CFS than in nondisabled controls (p<0.001). After adjusting for age, body height, and weight, combined trunk and arm endurance was even lower in CFS than in osteoporotic patients more than 25 yr old (p<0.001). In CFS, TLS was lower than in the non-industrialized group (p=0.02). Since only women were studied, external validity of the results is limited to adult female patients with CFS. TLS revealed a specific biomechanical weakness in CFS patients that can be taken into account from the onset of a rehabilitation program. We propose that influencing the quality, rather than the quantity, of movement could be used in the rehabilitation.
FROM ANNALS OF INTERNAL MEDICINE | 16 JUNE 2015 | EDITION FOCUSES ON ME/CFS
Elizabeth Haney, MD; M.E. Beth Smith, DO; Marian McDonagh, PharmD; Miranda Pappas, MA; Monica Daeges, BA; Ngoc Wasson, MPH; and Heidi D. Nelson, MD, MPH
Oregon Health & Science University and Providence Cancer Center, Providence Health and Services Oregon, Portland, Oregon.
The diagnosis of myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is based on clinical criteria, yet there has been no consensus regarding which set of criteria best identifies patients with the condition. The Institute of Medicine has recently proposed a new case definition and diagnostic algorithm.
To review methods to diagnose ME/CFS in adults and identify research gaps and needs for future research.
MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; and reference lists.
English-language studies describing methods of diagnosis of ME/CFS and their accuracy.
Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria, and discrepancies were resolved through consensus.
Forty-four studies met inclusion criteria. Eight case definitions have been used to define ME/CFS; a ninth, recently proposed by the Institute of Medicine, includes principal elements of previous definitions. Patients meeting criteria for ME represent a more symptomatic subset of the broader ME/CFS population. Scales rating self-reported symptoms differentiate patients with ME/CFS from healthy controls under study conditions but have not been evaluated in clinically undiagnosed patients to determine validity and generalizability.
Studies were heterogeneous and were limited by size, number, applicability, and methodological quality. Most methods were tested in highly selected patient populations.
Nine sets of clinical criteria are available to define ME/CFS, yet none of the current diagnostic methods have been adequately tested to identify patients with ME/CFS when diagnostic uncertainty exists. More definitive studies in broader populations are needed to address these research gaps.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality. (PROSPERO: CRD42014009779)
M.E. Beth Smith, DO; Elizabeth Haney, MD; Marian McDonagh, PharmD; Miranda Pappas, MA; Monica Daeges, BA; Ngoc Wasson, MPH; Rongwei Fu,PhD; and Heidi D. Nelson, MD, MPH
From Pacific Northwest Evidence-based Practice Center, Oregon Health & Science University, and Providence Cancer Center, Providence Health and Services Oregon, Portland, Oregon.
Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a debilitating multisystem condition affecting more than 1 million adults in the United States.
To determine benefits and harms of treatments for adults with ME/CFS and identify future research needs.
MEDLINE, PsycINFO, and Cochrane databases (January 1988 to September 2014); clinical trial registries; reference lists; and manufacturer information.
STUDY SELECTION E
English-language randomized trials of the effectiveness and adverse effects of ME/CFS treatments.
Data on participants, study design, analysis, follow-up, and results were extracted and confirmed. Study quality was dual-rated by using prespecified criteria; discrepancies were resolved through consensus.
Among 35 treatment trials enrolling participants primarily meeting the 1994 Centers for Disease Control and Prevention and Oxford case definitions of CFS, the immune modulator rintatolimod improved some measures of exercise performance compared with placebo in 2 trials (low strength of evidence).
Trials of galantamine, hydrocortisone, IgG, valganciclovir, isoprinosine, fluoxetine, and various complementary medicines were inconclusive (insufficient evidence).
Counseling therapies and graded exercise therapy compared with no treatment, relaxation, or support improved fatigue, function, global improvement, and work impairment in some trials; counseling
therapies also improved quality of life (low to moderate strength of evidence). Harms were rarely reported across studies (insufficient evidence).
Trials were heterogeneous and were limited by size, number, duration, applicability, and methodological quality.
Trials of rintatolimod, counseling therapies, and graded exercise therapy suggest benefit for some patients meeting case definitions for CFS, whereas evidence for other treatments and harms is insufficient. More definitive studies comparing participants meeting different case definitions, including ME, and providing subgroup analysis are needed to fill research gaps.
PRIMARY FUNDING SOURCE
Agency for Healthcare Research and Quality. (PROSPERO: CRD42014009779)
Carmen R. Green, MD; Penney Cowan; Ronit Elk, PhD; Kathleen M. O’Neil, MD; and Angela L. Rasmussen, PhD
From University of Michigan Health System, Ann Arbor, Michigan; American Chronic Pain Association, Rocklin, California; College of Nursing, University of South Carolina, Columbia, South Carolina; Indiana University School of Medicine and Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana; and Katze Lab, University of Washington, Seattle, Washington.
Note: The independent panel was charged with providing guidance to the NIH on research gaps and research priorities for ME/CFS. While this manuscript was being developed, the Institute of Medicine developed a report titled “Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness” and released their findings in February 2015. Although many would like the panel to consider and incorporate the Institute of Medicine’s recommendations within this report, it is beyond the scope and charge. Nonetheless, the panel believes that it is important for federal agencies, clinicians, patients with ME/CFS, and ME/CFS advocates to consider both reports to move the science forward. Furthermore, the panel believes that its recommendations provide many opportunities to incorporate both reports and new knowledge during the deliberations of the other proposed meetings and, more specifically, if and when the panel is reconvened in 5 years.
In general, a 2-week public comment period is provided. The panel’s initial report was completed in December 2014. The public comment period was extended to 4 weeks to allow for maximum participation of persons with ME/CFS who may have significant physical, social, and emotional disabilities and to accommodate the 2014 holidays. Unfortunately and inadvertently, some of the comments from the final day were not included and considered by the panel during the review period. Once this oversight was identified, publication was paused to consider these comments as individual panel members and then as a panel via conference call. An opportunity was provided to consider all public comments. The panel believes that this process allowed for a rigorous and inclusive review and a final product that moves the science forward.
The National Institutes of Health (NIH) Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was cosponsored by the NIH Office of Disease Prevention and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group.
A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion.
During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities.
The report was posted on the NIH Office of Disease Prevention Web site for 4 weeks for public comment.
Anthony L. Komaroff, MD
Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
Chronic fatigue syndrome (named by some as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS]) frustrates many physicians. That is understandable because there are no diagnostic tests or proven treatments. Some physicians even insist that the illness has no biological basis. Patients who seek help from such physicians are unlikely to have a satisfying therapeutic experience.
Fortunately, ME/CFS has recently received some welcome attention from the Institute of Medicine (IOM), Agency for Healthcare Research and Quality (AHRQ), and National Institutes of Health (NIH). Four articles in Annals address their findings (1–4). I will recap their answers to important questions.
How Prevalent and Important Is the Illness?
The IOM estimates that 836 000 to 2.5 million Americans have ME/CFS (5). The direct and indirect economic costs of the illness to society are estimated to be between $17 billion and $24 billion annually.
Is ME/CFS Real?
According to the most widely used case definition (6), the illness is characterized exclusively by symptoms; therefore, physicians have understandably wondered whether there are “real” underlying biological abnormalities. The IOM, AHRQ, and NIH panels concluded that there are such biological abnormalities. After evaluating thousands of published articles, the IOM committee stated that “ME/CFS is a serious, chronic, complex systemic disease that often can profoundly affect the lives of patients” (5). Summarizing the committee’s deliberations, Ganiats (1) said that the illness “is not, as many clinicians believe, a psychological problem,” while emphasizing that psychiatric comorbid conditions occur in some patients with ME/CFS and need to be diagnosed and treated.
The IOM committee concluded that there is evidence of various neurologic abnormalities in patients with ME/CFS (5). Formal studies of cognition show slowed information processing, potentially related to problems with white matter integrity. A positron emission tomography study demonstrated neuroinflammation (activated microglia or astrocytes) (6), functional magnetic resonance imaging studies found distinctive abnormalities when patients were challenged with working memory tasks, and the NIH report found “strong evidence of neurotransmitter signaling disruption.” Studies summarized in the IOM report showed that some patients had reduced overnight cortisol, 24-hour urinary cortisol, and adrenocorticotropic hormone levels compared with healthy control participants, suggesting a secondary (brain) rather than a primary (adrenal) cause of reduced cortisol production. Many patients have orthostatic intolerance, manifested by objective heart rate and blood pressure abnormalities during standing or head-up tilt testing.
The IOM report also concluded that several immunologic abnormalities have been demonstrated in ME/CFS. Patients may have poor natural killer cell cytotoxicity that correlates with illness severity, although the IOM report noted that this abnormality was not specific to ME/CFS. There may be increased cytokine levels in the blood (or increased production of cytokines by leukocytes in the culture), suggesting a state of immune activation, although not all studies agreed on this point. A recently published study—the largest of its type (298 case participants, 348 healthy control participants, and 51 cytokines measured in each blood sample)—found strikingly increased cytokine levels in the first 3 years of illness, which decreased thereafter (7). This suggests that heterogeneity in illness duration across studies may explain discrepant results.
Finally, the IOM assessed the possible role of infection in ME/CFS. It found “sufficient evidence suggesting that ME/CFS follows infection with EBV [Epstein–Barr virus] and possibly other specific infections—viral, bacterial and possibly protozoal.” The NIH report called especially for research on herpesviruses.
Is There a Biological Diagnostic Test?
As summarized previously, the IOM and NIH reports cited several objective biological abnormalities that help distinguish persons with ME/CFS from healthy control participants and, in some instances, from control participants with other fatiguing diseases, such as depression and multiple sclerosis. However, neither report found conclusive evidence that any particular biomarker was sufficiently sensitive or specific to serve as a diagnostic test.
Are There Proven Treatments?
The AHRQ-commissioned review of treatment trials, published in this issue (2), finds that counseling therapies and graded exercise therapy might help improve fatigue and function in some, but not all, patients; that not all trials show a benefit for the average patient; and that neither treatment is curative. Authors of the review warn that exercise therapy must be pursued very cautiously because several trials show that exercise leads to more adverse events and withdrawals. This is not surprising, given that postexertional malaise is a cardinal feature of the illness (1, 5, 8). The review notes that trials of drug treatments typically are of fair or poor quality, that no drug treatments are of proven value, and that some treatments – particularly corticosteroids and galantine – cause important adverse events.
What Should Be the Case Definition?
The IOM committee proposes a new clinical case definition that is simpler than the most widely used research case definition (8). It will likely encompass a more homogeneous and sicker group of persons than the past case definitions and may help discriminate persons with this illness from those with other illnesses associated with fatigue, such as depression (9). However, as Haney and colleagues (4) caution in their AHRQ-commissioned review of diagnostic methods, the proposed new case definition needs thorough testing in many patients with other fatiguing illnesses to ascertain its specificity.
What Should the Illness Be Named?
The IOM committee also proposes a new name for ME/CFS: systemic exertional intolerance syndrome (5). The reason to consider a new name is clear: The name “chronic fatigue syndrome” trivializes this often devastating illness. The U.S. Department of Health and Human Services commissioned the IOM report, and its agencies and advisory bodies will consider the proposed new name and case definition. This includes the Centers for Disease Control and Prevention, which sponsored the IOM’s effort as well as earlier efforts that had resulted in 2 previous case definitions.
These reports from the IOM, AHRQ, and NIH demonstrate how much we have learned about ME/CFS and how much we still do not know. We do not understand its pathogenesis, and we do not have a diagnostic test or a cure. However, these recent reports, summarizing information from more than 9000 articles, should put the question of whether ME/CFS is a “real” illness to rest. When skeptical physicians, many of whom are unaware of this literature, tell patients with ME/CFS that “there is nothing wrong”, they not only commit a diagnostic error: They also compound the patients’ suffering.
1. Ganiats TG. Redefining the chronic fatigue syndrome. Ann Intern Med. 2015; 162:653-4.
2. Smith MEB, Haney E, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Treatment of myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:841-50.
3. Green CR, Cowan P, Elk R, O’Neil KM, Rasmussen AL. National Institutes of Health Pathways to Prevention Workshop: advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Ann Intern Med. 2015; 162:860-5.
4. Haney E, Smith MEB, McDonagh M, Pappas M, Daeges M, Wasson N, et al. Diagnostic methods for myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review for a National Institutes of Health Pathways to Prevention Workshop. Ann Intern Med. 2015; 162:834-40.
5. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Pr; 2015.
6. Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an 11C-(R)-PK11195 PET study. J Nucl Med. 2014; 55:945-950.
7. Hornig M, Montoya JG, Klimas NG, Levine S, Felsenstein D, Bateman L, et al. Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Science Advances. 2015; 1:e1400121.
8. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, International Chronic Fatigue Syndrome Study Group. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994; 121:953-9.
9. Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. Int J Behav Med. 2006; 13:244-51.
From Fatigue: Biomedicine, Health and Behavior, 15 June 2015
Chronic fatigue syndrome versus systemic exertion intolerance disease
Leonard A. Jason(a*), Madison Sunnquist(a), Abigail Brown(a), Julia L. Newton(b), Elin Bolle Strand(c) & Suzanne D. Vernon(d)
a) Center for Community Research, DePaul University, 990 W. Fullerton Avenue, Suite 3100, Chicago, IL 60614, USA
b) Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK
c) Oslo University Hospital, Oslo, Norway
d) Solve ME/CFS Initiative, Los Angeles, CA, USA
The Institute of Medicine has recommended a change in the name and criteria for chronic fatigue syndrome (CFS), renaming the illness systemic exertion intolerance disease (SEID). The new SEID case definition requires substantial reductions or impairments in the ability to engage in pre-illness activities, unrefreshing sleep, post-exertional malaise, and either cognitive impairment or orthostatic intolerance.
In the current study, samples were generated through several different methods and were used to compare
this new case definition to previous case definitions for CFS, the International Consensus Criteria for myalgic encephalomyelitis (ME-ICC), the Canadian myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) definition, as well as a case definition developed through empirical methods.
We used a cross-sectional design with samples from tertiary care settings, a BioBank sample, and other
forums. Seven hundred and ninety-six patients from the USA, Great Britain, and Norway completed the DePaul Symptom Questionnaire.
Findings indicated that the SEID criteria identified 88% of participants in the samples analyzed, which is comparable to the 92% that met the Fukuda criteria. The SEID case definition was compared to a four-item empiric criteria, and findings indicated that the four-item empiric criteria identified a smaller, more functionally limited and symptomatic group of patients.
The recently developed SEID criteria appears to identify a group comparable in size to the Fukuda et al. criteria, but a larger group of patients than the Canadian ME/CFS and ME criteria, and selects more patients who have less impairment and fewer symptoms than a four-item empiric criteria.