Tag: heterogeneity

Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue

Abstract:

Persons with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often complain of fatigue states (eg, postexertional malaise, brain fog) that are qualitatively different than normal, daily fatigue. Given the heterogeneous nature of ME/CFS, it is likely that individuals with this illness experience these fatigue types differently in terms of severity and frequency. It is also possible that meaningful subgroups of patients exist that exhibit different patterns of the fatigue experience. The purpose of this study was to investigate whether individuals with ME/CFS can be classified in a meaningful way according to the different types of fatigue they experience.

One hundred individuals with ME/CFS participated in the study. Individuals that met inclusion criteria were administered the Multiple Fatigue Types Questionnaire (MFTQ), a 5-factor instrument that distinguishes between different types of fatigue. A cluster analysis was used to classify patients into various clusters based on factor subscale scores. Using a 3-factor solution, individuals were classified according to illness severity (low, moderate, severe) across the different fatigue factors.

However, a 5-cluster solution enabled participants with moderate to severe fatigue levels to fall into more differentiated clusters and demonstrate distinct fatigue state patterns. These results suggest that fatigue patterns of individuals with ME/CFS are heterogeneous, and that patients may be classified into meaningful subgroups.

 

Source: Jason LA, Boulton A, Porter NS, Jessen T, Njoku MG, Friedberg F. Classification of myalgic encephalomyelitis/chronic fatigue syndrome by types of fatigue. Behav Med. 2010 Jan-Mar;36(1):24-31. Doi: 10.1080/08964280903521370. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852700/ (Full article)

 

Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome

Abstract:

CONTEXT: Patients with chronic fatigue syndrome and those with orthostatic intolerance share many symptoms, yet questions exist as to whether CFS patients have physiological evidence of orthostatic intolerance.

OBJECTIVE: To determine if some CFS patients have increased rates of orthostatic hypotension, hypertension, tachycardia, or hypocapnia relative to age-matched controls.

DESIGN: Assess blood pressure, heart rate, respiratory rate, end tidal CO2 and visual analog scales for orthostatic symptoms when supine and when standing for 8 minutes without moving legs.

SETTING: Referral practice and research center.

PARTICIPANTS: 60 women and 15 men with CFS and 36 women and 4 men serving as age matched controls with analyses confined to 62 patients and 35 controls showing either normal orthostatic testing or a physiological abnormal test.

MAIN OUTCOME MEASURES: Orthostatic tachycardia; orthostatic hypotension; orthostatic hypertension; orthostatic hypocapnia or combinations thereof.

RESULTS: CFS patients had higher rates of abnormal tests than controls (53% vs 20%, p < .002), but rates of orthostatic tachycardia, orthostatic hypotension, and orthostatic hypertension did not differ significantly between patients and controls (11.3% vs 5.7%, 6.5% vs 2.9%, 19.4% vs 11.4%, respectively). In contrast, rates of orthostatic hypocapnia were significantly higher in CFS than in controls (20.6% vs 2.9%, p < .02). This CFS group reported significantly more feelings of illness and shortness of breath than either controls or CFS patients with normal physiological tests.

CONCLUSION: A substantial number of CFS patients have orthostatic intolerance in the form of orthostatic hypocapnia. This allows subgrouping of patients with CFS and thus reduces patient pool heterogeneity engendered by use of a clinical case definition.

 

Source: Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM. Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome. Dyn Med. 2007 Jan 30;6:2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1796865/ (Full article)

 

The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue

Abstract:

OBJECTIVES: To validate a latent class structure derived empirically from a clinical data set obtained from persons with chronic medically unexplained fatigue.

METHODS: The strategies utilized in this validation study included: recalculating latent class analysis (LCA) results varying random seeds and the number of initial random starting sets; recalculating LCA results by substituting alternate variables to demonstrate a robust solution; determining the statistical significance of between-class differences on disability, fatigue and demographic measures omitted from the data set used for LCA; cross-classifying class membership using established Centers for Disease Control and Prevention (CDC) research criteria for chronic fatigue syndrome (CFS) to compare the relative proportions of subjects designated CFS, chronic fatigue (not CFS) or healthy controls captured by the latent classes.

RESULTS: Recalculation of results and substitution of variables for low-loading variables demonstrated a robust LCA result. Highly significant between-class differences were confirmed between Class 2 (well) and those interpreted as ill/fatigued. Analysis of between-class differences for the fatigue groups revealed significant differences for all disability and fatigue variables, but with equivalent levels of reported activity and reduction in motivation. Cross-classification against established CDC criteria demonstrated that 89% of subjects constituting Class 2 (well) were indeed nonfatigued controls. A general tendency for grouping CFS cases in the multiple symptomatic classes was noted.

CONCLUSION: This study established reasonably good validity for an empirically-derived latent class solution reflecting considerable heterogeneity among subjects with medically unexplained chronic fatigue. This work strengthens the growing understanding of CFS as a heterogeneous entity comprised of several conditions with different underlying pathophysiological mechanisms.

 

Source: Aslakson E, Vollmer-Conna U, White PD. The validity of an empirical delineation of heterogeneity in chronic unexplained fatigue. Pharmacogenomics. 2006 Apr;7(3):365-73. https://www.ncbi.nlm.nih.gov/pubmed/16610947

 

An empirical delineation of the heterogeneity of chronic unexplained fatigue in women

Abstract:

OBJECTIVES: To test the hypothesis that medically unexplained chronic fatigue and chronic fatigue syndrome (CFS) are heterogeneous conditions, and to define the different conditions using both symptom and laboratory data.

METHODS: We studied 159 women from KS, USA. A total of 51 of these suffered from fatigue consistent with established criteria for CFS, 55 had chronic fatigue of insufficient symptoms/severity for a CFS diagnosis and 53 were healthy controls matched by age and body mass index (BMI) against those with CFS. We used principal components analyses to define factors that best described the variable space and to reduce the number of variables. The 38 most explanatory variables were then used in latent class analyses to define discrete subject groups.

RESULTS: Principal components analyses defined six discrete factors that explained 40% of the variance. Latent class analyses provided several interpretable solutions with four, five and six classes. The four-class solution was statistically most convincing, but the six-class solution was more interpretable. Class 1 defined 41 (26%) subjects with obesity and relative sleep hypnoea. Class 2 were 38 (24%) healthy subjects. Class 3 captured 24 (15%) obese relatively hypnoeic subjects, but with low heart rate variability and cortisol. Class 4 were 23 (14%) sleep-disturbed and myalgic subjects without obesity or significant depression. The two remaining classes with 22 (14%) and 11 (7%) subjects consisted of the most symptomatic and depressed, but without obesity or hypnoea. Class 5 had normal sleep indices. Class 6 was characterized by disturbed sleep, with low sleep heart rate variability, cortisol, and sex hormones.

CONCLUSION: Chronic medically unexplained fatigue is heterogeneous. The putative syndromes were differentiated by obesity, sleep hypnoea, depression, physiological stress response, sleep disturbance, interoception and menopausal status. If these syndromes are externally validated and replicated, they may prove useful in determining the causes, pathophysiology and treatments of CFS.

 

Source: Vollmer-Conna U, Aslakson E, White PD. An empirical delineation of the heterogeneity of chronic unexplained fatigue in women. Pharmacogenomics. 2006 Apr;7(3):355-64. https://www.ncbi.nlm.nih.gov/pubmed/16610946

 

The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a debilitating illness characterized by multiple unexplained symptoms including fatigue, cognitive impairment and pain. People with CFS have no characteristic physical signs or diagnostic laboratory abnormalities, and the etiology and pathophysiology remain unknown. CFS represents a complex illness that includes alterations in homeostatic systems, involves multiple body systems and results from the combined action of many genes, environmental factors and risk-conferring behavior. In order to achieve understanding of complex illnesses, such as CFS, studies must collect relevant epidemiological, clinical and laboratory data and then integrate, analyze and interpret the information so as to obtain meaningful clinical and biological insight. This issue of Pharmacogenomics represents such an approach to CFS.

Data was collected during a 2-day in-hospital study of persons with CFS, other medically and psychiatrically unexplained fatiguing illnesses and nonfatigued controls identified from the general population of Wichita, KS, USA. While in the hospital, the participants’ psychiatric status, sleep characteristics and cognitive functioning was evaluated, and biological samples were collected to measure neuroendocrine status, autonomic nervous system function, systemic cytokines and peripheral blood gene expression. The data generated from these assessments was made available to a multidisciplinary group of 20 investigators from around the world who were challenged with revealing new insight and algorithms for integration of this complex, high-content data and, if possible, identifying molecular markers and elucidating pathophysiology of chronic fatigue. The group was divided into four teams with representation from the disciplines of medicine, mathematics, biology, engineering and computer science. The papers in this issue are the culmination of this 6-month challenge, and demonstrate that data integration and multidisciplinary collaboration can indeed yield novel approaches for handling large, complex datasets, and reveal new insight and relevance to a complex illness such as CFS.

Comment in: The postgenomic era and complex disease. [Pharmacogenomics. 2006]

 

Source: Vernon SD, Reeves WC. The challenge of integrating disparate high-content data: epidemiological, clinical and laboratory data collected during an in-hospital study of chronic fatigue syndrome. Pharmacogenomics. 2006 Apr;7(3):345-54. https://www.ncbi.nlm.nih.gov/pubmed/16610945

 

Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness.

RESULTS: CFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.

CONCLUSION: These results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.

 

Source: Whistler T, Unger ER, Nisenbaum R, Vernon SD. Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome. J Transl Med. 2003 Dec 1;1(1):10. http://www.ncbi.nlm.nih.gov/pubmed/14641939

 

Cognitive functioning in chronic fatigue syndrome and the role of depression, anxiety, and fatigue

Abstract:

OBJECTIVE: This study was designed to investigate the role of depression, anxiety, and fatigue in Chronic Fatigue Syndrome (CFS) sufferers’ objective and subjective cognitive performance.

METHODS: Twenty-three CFS sufferers and 23 healthy control participants were compared on objective and subjective assessments of cognitive performance. Depression, anxiety, and fatigue were also evaluated.

RESULTS: CFS sufferers did not demonstrate any impairment in objective cognitive functioning compared to the control group, and objective performance was not related to their higher levels of depression or their level of fatigue. Depression scores only accounted for a small amount of the variance in CFS sufferers’ lower subjective assessment of their cognitive performance compared to control participants. There were no differences between the groups on anxiety scores.

CONCLUSION: The results are discussed in terms of the heterogeneity of the CFS population and the complex interaction of symptomatological factors that characterise CFS.

 

Source: Short K, McCabe M, Tooley G. Cognitive functioning in chronic fatigue syndrome and the role of depression, anxiety, and fatigue. J Psychosom Res. 2002 Jun;52(6):475-83. http://www.ncbi.nlm.nih.gov/pubmed/12069872

 

A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: The Holmes and Fukuda criteria are widely used criteria all over the world, yet a specific European study regarding chronic fatigue syndrome (CFS) patient symptomatology has not been conducted so far. This study was performed to answer the need to assess the homogeneity of a large CFS population in relationship to the Fukuda or Holmes definitions and to assess the importance of a symptom severity scale.

DESIGN: Multivariate analyses were performed to assess the symptom presentation within a fatigued population and the differences between the Fukuda and Holmes definitions compared with an excluded chronic fatigued group in a large cohort of fatigued patients.

SETTING: An outpatient tertiary care setting fatigue clinic in Brussels.

MAIN OUTCOME MEASURES: Prevalence and severity of symptoms and signs in a CFS population and in a chronic fatigued population.

SUBJECTS AND METHODS: A total of 2073 consecutive patients with major complaints of prolonged fatigue participated in this study. Multivariate analyses were performed to assess the symptom presentation and severity and the differences between the Fukuda and Holmes definitions.

RESULTS: Of the 2073 patients complaining of chronic fatigue (CF), 1578 CFS patients fulfilled the Fukuda criteria (100% of CFS group) and 951 (60.3% of the CFS group) fulfilled the Holmes criteria. Discriminant function analysis revealed that the Fukuda and Holmes definitions can be differentiated by symptom severity and prevalence. The Holmes definition was more strongly associated than the Fukuda definition with the symptoms that differentiated the CFS patients from the patients that did not comply with the CFS definitions. The inclusion of 10 additional symptoms was found to improve the sensitivity/specificity and accuracy for selection of CFS patients.

CONCLUSIONS: The CFS patients fulfilling the Holmes criteria have an increased symptom prevalence and severity of many symptoms. Patients fulfilling the Fukuda criteria were less severely affected patients which leads to an increase in clinical heterogeneity. Addition of certain symptoms and removal of others would strengthen the ability to select CFS patients.

 

Source: De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med. 2001 Sep;250(3):234-40. http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2001.00890.x/full (Full article)

 

What is chronic fatigue syndrome? Heterogeneity within an international multicentre study

Abstract:

OBJECTIVE: We sought to compare the characteristics of patients presenting with chronic fatigue (CF) and related syndromes in eight international centres and to subclassify these subjects based on symptom profiles. The validity of the subclasses was then tested against clinical data.

METHOD: Subjects with a clinical diagnosis of CF completed a 119-item self-report questionnaire to provide clinical symptom data and other information such as illness course and functional impairment. Subclasses were generated using a principal components-like analysis followed by latent profile analysis (LPA).

RESULTS: 744 subjects returned complete data sets (mean age 40.8 years, mean length of illness 7.9 years, female to male ratio 3:1). Overall, the subjects had a high rate of reporting typical CF symptoms (fatigue, neuropsychological dysfunction, sleep disturbance). Using LPA, two subclasses were generated. Class one (68% sample) was characterized by: younger age, lower female to male ratio; shorter episode duration; less premorbid, current and familial psychiatric morbidity; and, less functional disability. Class two subjects (32%) had features more consistent with a somatoform illness. There was substantial variation in subclass prevalences between the study centres (Class two range 6-48%).

CONCLUSIONS: Criteria-based approaches to the diagnosis of CF and related syndromes do not select a homogeneous patient group. While substratification of patients is essential for further aetiological and treatment research, the basis for allocating such subcategories remains controversial.

 

Source: Wilson A, Hickie I, Hadzi-Pavlovic D, Wakefield D, Parker G, Straus SE, Dale J, McCluskey D, Hinds G, Brickman A, Goldenberg D, Demitrack M, Blakely T,Wessely S, Sharpe M, Lloyd A. What is chronic fatigue syndrome? Heterogeneity within an international multicentre study. Aust N Z J Psychiatry. 2001 Aug;35(4):520-7. http://www.ncbi.nlm.nih.gov/pubmed/11531735

 

Graded exercise in chronic fatigue syndrome. Chronic fatigue syndrome is heterogeneous condition

Comment on: Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. [BMJ. 1997]

 

Editor—The study reported by Kathy Y Fulcher and Peter D White will provide new hope to many patients diagnosed as having the chronic fatigue syndrome.1 Before exercise regimens become the treatment of choice, however, it is worth noting that over two fifths of the patients in the study reported no or little improvement. It is a pity that the researchers did not compare those who were “very much better” with those who were not, in terms of variables such as the onset of illness (acute or gradual, history of infection) 2 and the presence of additional symptoms frequently associated with the syndrome—for example, cognitive difficulties, nausea, and malaise after exercise. This might have shown whether one particular subgroup fared better than another, allowing doctors to tailor their advice and further improve patients’ care.3

The possibility that subgroups may have different prognoses also deserves consideration. For instance, a recent study found that 70% of patients diagnosed as having epidemic neuromyasthenia recovered within two years.4 If two thirds of the subjects studied by Fulcher and White also had disease of acute onset linked to infection, one could argue that the exercise regimen reflected the natural course of the illness while the flexibility training made patients worse.

A final point concerns the 20 subjects taking full dose antidepressants. The authors do not specify why these drugs were being taken by people who did not have clinical depression or sleep disorders. Moreover, since many patients with the chronic fatigue syndrome cannot tolerate therapeutic doses of antidepressants,5 some of the reported fatigue and malaise may have been drug induced.

You can read the rest of this comment here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2127599/pdf/9361552.pdf

 

Source: Goudsmit EM. Graded exercise in chronic fatigue syndrome. Chronic fatigue syndrome is heterogeneous condition. BMJ. 1997 Oct 11;315(7113):948. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2127599/