Tag: Unger

Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study

Abstract:

BACKGROUND: Complaints of unrefreshing sleep are a prominent component of chronic fatigue syndrome (CFS); yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS.

METHODS: We examined the relationship between perceived sleep quality and polysomnographic measures of nighttime and daytime sleep in 35 people with CFS and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing.

RESULTS: Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects.

CONCLUSION: People with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perception of sleep problems.

 

Source: Majer M, Jones JF, Unger ER, Youngblood LS, Decker MJ, Gurbaxani B, Heim C, Reeves WC. Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study. BMC Neurol. 2007 Dec 5;7:40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2231384/ (Full article)

 

Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study

Abstract:

BACKGROUND: The etiology and pathophysiology of chronic fatigue syndrome (CFS) remain inchoate. Attempts to elucidate the pathophysiology must consider sleep physiology, as unrefreshing sleep is the most commonly reported of the 8 case-defining symptoms of CFS. Although published studies have consistently reported inefficient sleep and documented a variable occurrence of previously undiagnosed primary sleep disorders, they have not identified characteristic disturbances in sleep architecture or a distinctive pattern of polysomnographic abnormalities associated with CFS.

METHODS: This study recruited CFS cases and non-fatigued controls from a population based study of CFS in Wichita, Kansas. Participants spent two nights in the research unit of a local hospital and underwent overnight polysomnographic and daytime multiple sleep latency testing in order to characterize sleep architecture.

RESULTS: Approximately 18% of persons with CFS and 7% of asymptomatic controls were diagnosed with severe primary sleep disorders and were excluded from further analysis. These rates were not significantly different. Persons with CFS had a significantly higher mean frequency of obstructive apnea per hour (p = .003); however, the difference was not clinically meaningful. Other characteristics of sleep architecture did not differ between persons with CFS and controls.

CONCLUSION: Although disordered breathing during sleep may be associated with CFS, this study generally did not provide evidence that altered sleep architecture is a critical factor in CFS. Future studies should further scrutinize the relationship between subjective sleep quality relative to objective polysomnographic measures.

 

Source: Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study. BMC Neurol. 2006 Nov 16;6:41. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1660569/ (Full article)

 

Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study

Abstract:

CONTEXT: Chronic fatigue syndrome (CFS) is an important public health problem. The causes of CFS are unknown and effective prevention strategies remain elusive. A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention.

OBJECTIVE: To examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and nonfatigued control subjects.

DESIGN, SETTING, AND PARTICIPANTS: A case-control study of 43 cases with current CFS and 60 nonfatigued controls identified from a general population sample of 56 146 adult residents from Wichita, Kan.

MAIN OUTCOME MEASURES: Self-reported childhood trauma (sexual, physical, and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety, and posttraumatic stress disorder) by CFS status.

RESULTS: The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety, and posttraumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology.

CONCLUSIONS: This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS.

 

Source: Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Arch Gen Psychiatry. 2006 Nov;63(11):1258-66. https://www.ncbi.nlm.nih.gov/pubmed/17088506

 

Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome

Abstract:

Chronic fatigue syndrome (CFS) is a significant public health problem of unknown etiology, the pathophysiology has not been elucidated, and there are no characteristic physical signs or laboratory abnormalities. Some studies have indicated an association of CFS with deregulation of immune functions and hypothalamic-pituitary-adrenal (HPA) axis activity.

In this study, we examined the association of sequence variations in the glucocorticoid receptor gene (NR3C1) with CFS because NR3C1 is a major effector of the HPA axis. There were 137 study participants (40 with CFS, 55 with insufficient symptoms or fatigue, termed as ISF, and 42 non-fatigued controls) who were clinically evaluated and identified from the general population of Wichita, KS. Nine single nucleotide polymorphisms (SNPs) in NR3C1 were tested for association of polymorphisms and haplotypes with CFS.

We observed an association of multiple SNPs with chronic fatigue compared to non-fatigued (NF) subjects (P < 0.05) and found similar associations with quantitative assessments of functional impairment (by the SF-36), with fatigue (by the Multidimensional Fatigue Inventory) and with symptoms (assessed by the Centers for Disease Control Symptom Inventory).

Subjects homozygous for the major allele of all associated SNPs were at increased risk for CFS with odds ratios ranging from 2.61 (CI 1.05-6.45) to 3.00 (CI 1.12-8.05). Five SNPs, covering a region of approximately 80 kb, demonstrated high linkage disequilibrium (LD) in CFS, but LD gradually declined in ISF to NF subjects. Furthermore, haplotype analysis of the region in LD identified two associated haplotypes with opposite alleles: one protective and the other conferring risk of CFS.

These results demonstrate NR3C1 as a potential mediator of chronic fatigue, and implicate variations in the 5′ region of NR3C1 as a possible mechanism through which the alterations in HPA axis regulation and behavioural characteristics of CFS may manifest.

 

Source: Rajeevan MS, Smith AK, Dimulescu I, Unger ER, Vernon SD, Heim C, Reeves WC. Glucocorticoid receptor polymorphisms and haplotypes associated with chronic fatigue syndrome. Genes Brain Behav. 2007 Mar;6(2):167-76. http://onlinelibrary.wiley.com/doi/10.1111/j.1601-183X.2006.00244.x/full (Full article)

 

Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS

Abstract:

OBJECTIVE: Studies of primary and tertiary care patients suggest that maladaptive coping styles contribute to the pathogenesis and maintenance of chronic fatigue syndrome (CFS). We assessed coping styles in persons with unexplained fatigue and nonfatigued controls in a population-based study.

METHODS: We enrolled 43 subjects meeting the 1994 Research Case Definition of CFS, matching them with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [we term them insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using standard rating scales.

RESULTS: Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability.

CONCLUSIONS: We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls.

 

Source: Nater UM, Wagner D, Solomon L, Jones JF, Unger ER, Papanicolaou DA, Reeves WC, Heim C. Coping styles in people with chronic fatigue syndrome identified from the general population of Wichita, KS. J Psychosom Res. 2006 Jun;60(6):567-73. https://www.ncbi.nlm.nih.gov/pubmed/16731231

 

Exploration of statistical dependence between illness parameters using the entropy correlation coefficient

Abstract:

The entropy correlation coefficient (ECC) is a useful tool for measuring statistical dependence between variables. We employed this tool to search for pairs of variables that correlated in the chronic fatigue syndrome (CFS) Computational Challenge dataset. Highly related variables are candidates for data reduction, and novel relationships could lead to hypotheses regarding the pathogenesis of CFS.

METHODS: Data for 130 female participants in the Wichita (KS, USA) clinical study [1] was coded into numerical values. Metric data was grouped using Gaussian mixture models; the number of groups was chosen using Bayesian information content. The pair-wise correlation between all variables was computed using the ECC. Significance was estimated from 1000 iterations of a permutation test and a threshold of 0.01 was used to identify significantly correlated variables.

RESULTS: The five dimensions of multidimensional fatigue inventory (MFI) were all highly correlated with each other. Seven Short Form (SF)-36 measures, four CFS case-defining symptoms and the Zung self-rating depression scale all correlated with all MFI dimensions. No physiological variables correlate with more than one MFI dimension. MFI, SF-36, CDC symptom inventory, the Zung self-rating depression scale and three Cambridge Neuropsychological Test Automated Battery (CANTAB) measures are highly correlated with CFS disease status.

DISCUSSION: Correlations between the five dimensions of MFI are expected since they are measured from the same instrument. The relationship between MFI and Zung depression index has been previously reported. MFI, SF-36, and Centers for Disease Control and Prevention (CDC) symptom inventory are used to classify CFS; it is not surprising that they are correlated with disease status. Only one of the three CANTAB measures that correlate with disease status has been previously found, indicating the ECC identifies relationships not found with other statistical tools.

CONCLUSION: The ECC is a useful tool for measuring statistical dependence between variables in clinical and laboratory datasets. The ECC needs to be further studied to gain a better understanding of its meaning for clinical data.

 

Source: Craddock RC, Taylor R, Broderick G, Whistler T, Klimas N, Unger ER. Exploration of statistical dependence between illness parameters using the entropy correlation coefficient. Pharmacogenomics. 2006 Apr;7(3):421-8. https://www.ncbi.nlm.nih.gov/pubmed/16610952

 

Identifying illness parameters in fatiguing syndromes using classical projection methods

Abstract:

OBJECTIVES: To examine the potential of multivariate projection methods in identifying common patterns of change in clinical and gene expression data that capture the illness state of subjects with unexplained fatigue and nonfatigued control participants.

METHODS: Data for 111 female subjects was examined. A total of 59 indicators, including multidimensional fatigue inventory (MFI), medical outcome Short Form 36 (SF-36), Centers for Disease Control and Prevention (CDC) symptom inventory and cognitive response described illness. Partial least squares (PLS) was used to construct two feature spaces: one describing the symptom space from gene expression in peripheral blood mononuclear cells (PBMC) and one based on 117 clinical variables. Multiplicative scatter correction followed by quantile normalization was applied for trend removal and range adjustment of microarray data. Microarray quality was assessed using mean Pearson correlation between samples. Benjamini-Hochberg multiple testing criteria served to identify significantly expressed probes.

RESULTS: A single common trend in 59 symptom constructs isolates of nonfatigued subjects from the overall group. This segregation is supported by two co-regulation patterns representing 10% of the overall microarray variation. Of the 39 principal contributors, the 17 probes annotated related to basic cellular processes involved in cell signaling, ion transport and immune system function. The single most influential gene was sestrin 1 (SESN1), supporting recent evidence of oxidative stress involvement in chronic fatigue syndrome (CFS). Dominant variables in the clinical feature space described heart rate variability (HRV) during sleep. Potassium and free thyroxine (T4) also figure prominently.

CONCLUSION: Combining multiple symptom, gene or clinical variables into composite features provides better discrimination of the illness state than even the most influential variable used alone. Although the exact mechanism is unclear, results suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired sympatho-vagal balance strongly reflected in abnormal HRV.

 

Source: Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER. Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics. 2006 Apr;7(3):407-19. https://www.ncbi.nlm.nih.gov/pubmed/16610951

 

Gene expression correlates of unexplained fatigue

Abstract:

Quantitative trait analysis (QTA) can be used to test whether the expression of a particular gene significantly correlates with some ordinal variable. To limit the number of false discoveries in the gene list, a multivariate permutation test can also be performed. The purpose of this study is to identify peripheral blood gene expression correlates of fatigue using quantitative trait analysis on gene expression data from 20,000 genes and fatigue traits measured using the multidimensional fatigue inventory (MFI).

A total of 839 genes were statistically associated with fatigue measures. These mapped to biological pathways such as oxidative phosphorylation, gluconeogenesis, lipid metabolism, and several signal transduction pathways. However, more than 50% are not functionally annotated or associated with identified pathways. There is some overlap with genes implicated in other studies using differential gene expression. However, QTA allows detection of alterations that may not reach statistical significance in class comparison analyses, but which could contribute to disease pathophysiology.

This study supports the use of phenotypic measures of chronic fatigue syndrome (CFS) and QTA as important for additional studies of this complex illness. Gene expression correlates of other phenotypic measures in the CFS Computational Challenge (C3) data set could be useful. Future studies of CFS should include as many precise measures of disease phenotype as is practical.

 

Source: Whistler T, Taylor R, Craddock RC, Broderick G, Klimas N, Unger ER. Gene expression correlates of unexplained fatigue. Pharmacogenomics. 2006 Apr;7(3):395-405. https://www.ncbi.nlm.nih.gov/pubmed/16610950

 

Chronic fatigue syndrome–a clinically empirical approach to its definition and study

Abstract:

BACKGROUND: The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria.

METHODS: This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms).

RESULTS: One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm.

CONCLUSION: The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.

 

Source: Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome–a clinically empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1334212/ (Full article)

 

Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome

Abstract:

OBJECTIVES: Validated or standardized self-report questionnaires used in research studies and clinical evaluation of chronic fatigue syndrome(CFS) generally focus on the assessment of fatigue. There are relatively few published questionnaires that evaluate case defining and other accompanying symptoms in CFS. This paper introduces the self-report CDC CFS Symptom Inventory and analyzes its psychometric properties.

METHODS: One hundred sixty-four subjects (with CFS, other fatiguing illnesses and non fatigued controls) identified from the general population of Wichita, Kansas were enrolled. Evaluation included a physical examination, a standardized psychiatric interview, three previously validated self-report questionnaires measuring fatigue and illness impact (Medical Outcomes Survey Short-Form-36 [MOS SF-36], Multidimensional Fatigue Inventory [MFI], Chalder Fatigue Scale), and the CDC CFS Symptom Inventory. Based on theoretical assumptions and statistical analyses, we developed several different Symptom Inventory scores and evaluated them on their ability to differentiate between participants with CFS and non-fatigued controls.

RESULTS: The Symptom Inventory had good internal consistency and excellent convergent validity. A Total score (all symptoms), Case Definition score (CFS case defining symptoms) and Short Form score (6 symptoms with minimal correlation) differentiated CFS cases from controls. Furthermore, both the Case Definition and Short Form scores distinguished people with CFS from fatigued subjects who did not meet criteria for CFS.

CONCLUSION: The Symptom Inventory appears to be a reliable and valid instrument to assess symptoms that accompany CFS. It is a positive addition to existing instruments measuring fatigue because it allows other dimensions of the illness to be assessed. Further research is needed to confirm and replicate the current findings in a normative population.

 

Source: Wagner D, Nisenbaum R, Heim C, Jones JF, Unger ER, Reeves WC. Psychometric properties of the CDC Symptom Inventory for assessment of chronic fatigue syndrome. Popul Health Metr. 2005 Jul 22;3:8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1183246/ (Full article)