A Bayesian approach to gene-gene and gene-environment interactions in chronic fatigue syndrome

Abstract:

INTRODUCTION: In the study of genomics, it is essential to address gene-gene and gene-environment interactions for describing the complex traits that involves disease-related mechanisms. In this work, our goal is to detect gene-gene and gene-environment interactions resulting from the analysis of chronic fatigue syndrome patients’ genetic and demographic factors including SNPs, age, gender and BMI.

MATERIALS & METHODS: We employed the dataset that was original to the previous study by the Centers for Disease Control and Prevention Chronic Fatigue Syndrome Research Group. To investigate gene-gene and gene-environment interactions, we implemented a Bayesian based method for identifying significant interactions between factors. Here, we employed a two-stage Bayesian variable selection methodology based on Markov Chain Monte Carlo approaches.

RESULTS: By applying our Bayesian based approach, NR3C1 was found in the significant two-locus gene-gene effect model, as well as in the significant two-factor gene-environment effect model. Furthermore, a significant gene-environment interaction was identified between NR3C1 and gender. These results support the hypothesis that NR3C1 and gender may play a role in biological mechanisms associated with chronic fatigue syndrome.

CONCLUSION: We demonstrated that our Bayesian based approach is a promising method to assess the gene-gene and gene-environment interactions in chronic fatigue syndrome patients by using genetic factors, such as SNPs, and demographic factors such as age, gender and BMI.

 

Source: Lin E, Hsu SY. A Bayesian approach to gene-gene and gene-environment interactions in chronic fatigue syndrome. Pharmacogenomics. 2009 Jan;10(1):35-42. Doi: 10.2217/14622416.10.1.35. https://www.ncbi.nlm.nih.gov/pubmed/19102713

 

Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal

Abstract:

The purpose of this 2-year prospective study was to compare standard self-report and ecologically-based outcome measures in patients with chronic fatigue syndrome (CFS). Standard measures assessed physical function, fatigue impact, psychological variables, and global impression of change ratings. Ecological measures included actigraphy, a structured activity record, and an electronic fatigue/energy diary.

Results for this high functioning sample (N = 75) revealed that self-report global improvement was significantly associated with lower momentary fatigue and fatigue impact, and a higher frequency of standing up (at home), but not with actigraphy or psychological variables. However, actigraphy change was significantly correlated with change in self-report physical function. At follow-up, only a small minority (<20%) scored in the healthy adult range for fatigue impact and physical function.

The findings suggest that home-based measures of symptom severity and physical functioning may provide evidence of change (or lack of change) that is important for interpreting standard self-report outcomes in CFS.

 

Source: Friedberg F, Sohl SJ. Longitudinal change in chronic fatigue syndrome: what home-based assessments reveal. J Behav Med. 2009 Apr;32(2):209-18. doi: 10.1007/s10865-008-9189-9. Epub 2008 Dec 20. https://www.ncbi.nlm.nih.gov/pubmed/19101789

 

Exercise performance and chronic pain in chronic fatigue syndrome: the role of pain catastrophizing

Abstract:

OBJECTIVES: This study aimed to examine the associations between bodily pain, pain catastrophizing, depression, activity limitations/participation restrictions, employment status, and exercise performance in female patients with chronic fatigue syndrome (CFS) who experience widespread pain.

DESIGN: Cross-sectional observational study.

SETTING: A university-based clinic.

PATIENTS: Thirty-six female CFS patients who experienced widespread pain.

OUTCOME MEASURES: Patients filled in the Medical Outcomes Short-Form 36 Health Status Survey, the Chronic Fatigue Syndrome Activities and Participation Questionnaire, the Beck Depression Inventory, and the Pain Catastrophizing Scale, and underwent a maximal exercise stress test with continuous monitoring of electrocardiographic and ventilatory parameters.

RESULTS: Pain catastrophizing was related to bodily pain (r = -0.70), depression (r = 0.55), activity limitations/participation restrictions (r = 0.68), various aspects of quality of life ( r varied between -0.51 and -0.64), and exercise capacity (r varied between -0.41 and -0.61). Based on hierarchical multiple regression analysis, pain catastrophizing accounted for 41% of the variance in bodily pain in female CFS patients who experience chronic widespread musculoskeletal pain. Among the three subscale scores of the Pain Catastrophizing Scale, helplessness and rumination rather than magnification were strongly related to bodily pain. Neither pain catastrophizing nor depression was related to employment status.

CONCLUSIONS: These data provide evidence favoring a significant association between pain catastrophizing, bodily pain, exercise performance, and self-reported disability in female patients with CFS who experience widespread pain. Further prospective longitudinal studying of these variables is required.

Comment in: Response to: exercise performance and chronic pain in chronic fatigue syndrome: the role of pain catastrophizing. [Pain Med. 2009]

 

Source: Nijs J, Van de Putte K, Louckx F, Truijen S, De Meirleir K. Exercise performance and chronic pain in chronic fatigue syndrome: the role of pain catastrophizing. Pain Med. 2008 Nov;9(8):1164-72. Epub 2007 Oct 3. http://painmedicine.oxfordjournals.org/content/9/8/1164.long (Full article)

 

Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and health-care settings?

Abstract:

OBJECTIVE: The validity of the diagnosis of chronic fatigue syndrome and related chronic fatigue states remains controversial, particularly in psychiatry. This project utilized international epidemiological and clinical research data to test construct validity across diagnostic categories, health-care settings and countries. Relevant demographic, symptom and diagnostic data were obtained from 33 studies in 21 countries. The subjects had fatigue lasting 1-6 months (prolonged fatigue), or >6 months (chronic fatigue), or met diagnostic criteria for chronic fatigue syndrome.

METHOD: Common symptom domains were derived by factor analytic techniques. Mean scores on each symptom factor were compared across diagnostic categories, health-care settings and countries.

RESULTS: Data were obtained on 37,724 subjects (n = 20,845 female, 57%), including from population-based studies (n = 15,749, 42%), studies in primary care (n = 19 472, 52%), and secondary or specialist tertiary referral clinics (n = 2503, 7%). The sample included 2013 subjects with chronic fatigue, and 1958 with chronic fatigue syndrome. A five-factor model of the key symptom domains was preferred (‘musculoskeletal pain/fatigue’, ‘neurocognitive difficulties’, ‘inflammation’, ‘sleep disturbance/fatigue’ and ‘mood disturbance’) and was comparable across subject groups and settings. Although the core symptom profiles were similar, some differences in symptoms were observed across diagnostic categories, health-care settings and between countries.

CONCLUSIONS: The construct validity of chronic fatigue and chronic fatigue syndrome is supported by an empirically derived factor structure from existing international datasets.

 

 

Source: Hickie I, Davenport T, Vernon SD, Nisenbaum R, Reeves WC, Hadzi-Pavlovic D, Lloyd A; International Chronic Fatigue Syndrome Study Group. Collaborators (28) Are chronic fatigue and chronic fatigue syndrome valid clinical entities across countries and health-care settings? Aust N Z J Psychiatry. 2009 Jan;43(1):25-35. Doi: 10.1080/00048670802534432. https://www.ncbi.nlm.nih.gov/pubmed/19085525

 

Power spectral analysis of sleep EEG in twins discordant for chronic fatigue syndrome

Abstract:

OBJECTIVE: The purpose of the study was to evaluate quantitative sleep electroencephalogram (EEG) frequencies in monozygotic twins discordant for chronic fatigue syndrome.

METHODS: Thirteen pairs of female twins underwent polysomnography. During the first night, they adapted to the sleep laboratory, and during the second night, their baseline sleep was assessed. Visual stage scoring was conducted on sleep electroencephalographic records according to standard criteria, and power spectral analysis was used to quantify delta through beta frequency bands, processed in 6-s blocks. Data were averaged across sleep stage within each twin and coded for sleep stage and the presence or absence of chronic fatigue syndrome (CFS). A completely within-subjects repeated measure multivariate analysis of variance evaluated twin pairs by frequency band by sleep stage interactions and simple effects. The relationship between alpha and delta EEG was also assessed across twin pairs.

RESULTS: No significant differences in spectral power in any frequency band were found between those with CFS and their nonfatigued cotwins. Phasic alpha activity, coupled with delta was noted in five subjects with CFS but was also present in 4/5 healthy twins, indicating this finding likely reflects genetic influences on the sleep electroencephalogram rather than disease-specific sleep pathology.

CONCLUSIONS: The genetic influences on sleep polysomnography and microarchitecture appear to be stronger than the disease influence of chronic fatigue syndrome, despite greater subjective sleep complaint among the CFS twins. EEG techniques that focus on short duration events or paradigms that probe sleep regulation may provide a better description of sleep abnormalities in CFS.

 

Source: Armitage R, Landis C, Hoffmann R, Lentz M, Watson N, Goldberg J, Buchwald D. Power spectral analysis of sleep EEG in twins discordant for chronic fatigue syndrome. J Psychosom Res. 2009 Jan;66(1):51-7. doi: 10.1016/j.jpsychores.2008.08.004. Epub 2008 Nov 25. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2634600/ (Full article)

 

Does depression mediate the relation between fatigue severity and disability in chronic fatigue syndrome sufferers?

Abstract:

OBJECTIVE: Chronic fatigue syndrome (CFS) is often associated with significant levels of disability. Although fatigue and depression have been found to be independently related to severity of disability, it is not clear how these three factors are mutually related. The present study sought to address this issue by specifically testing a model of mediation whereby depression was hypothesized to influence relations between fatigue and disability.

METHODS: Participants included 90 individuals seeking treatment for CFS at a tertiary care facility. Each provided demographic information and completed standardized measures of depression and fatigue severity, as well as a measure of disability, which assessed difficulties in physical, psychosocial, and independence domains.

RESULTS: Analyses indicated that depression and fatigue were positively correlated with one another, as well as all three disability domains. Analyses of mediation indicated that depression completely mediated the relation between fatigue and psychosocial disability and partially mediated the relation between fatigue and the other two disability domains. Indirect effects tests indicated that the inclusion of depression in the statistical models was statistically meaningful.

CONCLUSIONS: These results replicate previous findings that fatigue and depression are independently related to disability in those with CFS. A more complex statistical model, however, suggested that depression severity substantially influenced the strength of the relation between fatigue and disability levels across a range of domains, including complete mediation in areas involving psychosocial functioning. These results may aid in clarifying contemporary conceptualizations of CFS and provide guidance in the identification of appropriate treatment targets.

 

Source: Hadlandsmyth K, Vowles KE. Does depression mediate the relation between fatigue severity and disability in chronic fatigue syndrome sufferers? J Psychosom Res. 2009 Jan;66(1):31-5. doi: 10.1016/j.jpsychores.2008.08.002. Epub 2008 Nov 22. https://www.ncbi.nlm.nih.gov/pubmed/19073290

 

Chronic fatigue syndrome and DSM-IV personality disorders

Abstract:

OBJECTIVE: Personality is an important factor in the research of the chronic fatigue syndrome (CFS). Although some studies report a high rate of personality disorders–around the 40% level–in samples of patients with CFS, the generalizability of these findings can be questioned. The present study evaluates the prevalence of Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) personality disorders in a sample of female CFS patients and in two control groups.

METHOD: The ADP-IV questionnaire (Assessment of DSM Personality Disorders IV) was used to assess the DSM-IV-TR personality disorders at a dimensional and categorical level in a sample of 50 female CFS patients and in two matched control samples of Flemish civilians (n=50) and psychiatric patients (n=50).

RESULTS: The results indicate a striking lack of statistical significant differences between the CFS sample and the Flemish control group at the level of dimensional Trait scores, number of criteria, and prevalence rates of personality disorder diagnoses. Unsurprisingly, higher scores at these levels were obtained within the psychiatric sample. The prevalence of an Axis II disorder was 12% in the Flemish and CFS samples, whereas the psychiatric sample obtained a prevalence of 54%.

CONCLUSION: The prominent absence of any significant difference in personality disorder characteristics between the female Flemish general population and the CFS samples seems to suggest only a minor etiological role for personality pathology, as defined by the DSM-IV Axis II, within CFS.

 

Source: Courjaret J, Schotte CK, Wijnants H, Moorkens G, Cosyns P. Chronic fatigue syndrome and DSM-IV personality disorders. J Psychosom Res. 2009 Jan;66(1):13-20. doi: 10.1016/j.jpsychores.2008.07.001. Epub 2008 Nov 22. https://www.ncbi.nlm.nih.gov/pubmed/19073288

 

Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome

Abstract:

The present study was conducted with the aim of elucidating the possible role of nitric oxide (NO) in the neuroprotective effects of trazodone used to treat chronic fatigue syndrome (CFS) in mice.

Male albino mice were forced to swim for a six minute session each day for 7 days and the immobility period was recorded every other day. Trazodone (5 mg/kg and 10 mg/kg) was administered each day 30 min before the forced swim test. In addition, L-arginine (100 mg/kg) and L-NAME (5 mg/kg) were administered 15 min before administration of trazodone (5 mg/kg).

Various behavioral tests, including locomotor (actophotometer) and anxiety (mirror chamber and plus maze) tests, as well as biochemical parameters (lipid peroxidation, reduced glutathione, catalase, and nitrites) were evaluated on the 8th day.

Forced swimming for 7 days caused a chronic fatigue-like condition, anxiety-like behavior, impairments in locomotor activity, and oxidative damage (increased lipid peroxidation and nitrite levels, and depletions in the reduced forms of glutathione and catalase activity) in animals. Pretreatment with L-NAME (5 mg/kg) potentiated the antioxidant effect of trazodone (5 mg/kg). However, L-arginine (100 mg/kg) pretreatment reversed the protective effect of trazodone (5 mg/kg) (p<0.05). The present study suggests the possible involvement of NO signaling in the protective effect of trazodone.

 

Source: Kumar A, Garg R, Kumar P. Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome. Pharmacol Rep. 2008 Sep-Oct;60(5):664-72. http://www.if-pan.krakow.pl/pjp/pdf/2008/5_664.pdf (Full article)

 

Assessment of fibromyalgia & chronic fatigue syndrome: a new protocol designed to determine work capability–chronic pain abilities determination (CPAD)

Abstract:

The objective was to design a protocol to assess work ability in people suffering ill-defined painful and disabling disorders, the outstanding prototype of which is fibromyalgia/chronic fatigue syndrome (FM/CSF).Following an extensive literature search, the mos appropriate components of current methods of assessment of physical and cognitive abilities were incorporated into the protocol, occasionally with appropriate modification to suit the specific requirements of the individual.

The initial part of the assessment consists of a standard history taking, principally focusing on the patient’s self-reported physical and cognitive abilities and disabilities, as well as the completion of established pain and fatigue scales, and relevant disability questionnaires.

Following this, physical and cognitive abilities are objectively assessed on two separate occasions, utilizing computerized hand-held dynamometers, inclinometers, algometers, and force dynamometers. Specific work simulation tests using the industrial standards Methods-Time-Measurement testing are availed of, as is aerobic testing using the Canadian Aerobic Fitness Test (CAFT). Objective computerised neuro-cognitive testing are also utilised as an integral component of the assessment. All results are then subject to specific computerized analysis and compared to normative and standardised work-based databases.

The designed system produces reliable, consistent and reproducible results. It also proves capable of detecting any inconsistencies in patient input and results, in addition to being independent of any possible assessor bias. A new protocol has been designed to determine the working capability of individuals who suffer from various chronic disabling conditions, and represents a significant step forward in a difficult but rapidly expanding area of medical practice.

 

Source: Kelly M, Gagne R, Newman JD, Olney C, Gualtieri C, Trail D. Assessment of fibromyalgia & chronic fatigue syndrome: a new protocol designed to determine work capability–chronic pain abilities determination (CPAD). Ir Med J. 2008 Oct;101(9):277-8. https://www.ncbi.nlm.nih.gov/pubmed/19051616

 

Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls

Abstract:

PURPOSE: Since physical exertion is known to exacerbate the symptoms of chronic fatigue syndrome (CFS) and metabolic changes and including oxidative stress can modulate heat shock protein (HSP) expression responses, we sought to determine whether HSP expression is altered in CFS patients before and after exercise. Heat shock proteins (HSPs) in peripheral blood mononuclear cells (PBMC) were examined from 6 chronic fatigue syndrome (CFS) patients and 7 controls before and after a standardized treadmill exercise. Basal hsp27 was significantly higher among CFS patients compared to controls, and decreased immediately post-exercise, remaining below basal levels even at 7 days. A similar pattern was observed for HSP60, which gradually decreased in CFS patients but increased in controls post-exercise. These findings suggest an abnormal adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness.

METHODS: HSP27, HSP60, HSP70 and HSP90 expression from 6 CFS patients and 7 age- and sex-matched controls were examined by western blot analysis of peripheral blood mononuclear cells immediately before, after, and at 1 day and 7 days following a standardized treadmill exercise.

RESULTS: Basal HSP27 was higher among CFS patients than in controls (0.54 +/- 0.13 vs. 0.19 +/- 0.06, mean +/- SEM; P < 0.01). In addition, these levels in CFS patients decreased immediately post-exercise (0.25 +/- 0.09; P < 0.05) and remained below basal levels at day 1 post-exercises (0.18 +/- 0.05; P < 0.05). P < 0.05). This declining expression of HSP27 during the post-exercise period among CFS patients was confirmed by one-way ANOVA analysis with repeated measures (P < 0.05). In contrast, HSP27 levels remained relatively constant following exercise among control subjects. Similar patterns of declining HSP levels in CFS patients were also observed for HSP60 (0.94 +/- 0.40 vs. 1.32 +/- 0.46; P < 0.05), and for HSP90 (0.34 +/- 0.09 vs. 0.49 +/- 0.10; P < 0.05) at day 7 post-exercise compared with basal levels, respectively. In contrast, HSP60 levels in control subjects increased at day 1 (1.09 +/- 0.27) and day 7 (1.24 +/- 0.50) post-exercise compared to corresponding levels immediately post-exercise (0.55 +/- 0.06) (P < 0.05, respectively).

CONCLUSION: These preliminary findings suggest an abnormal or defective adaptive response to oxidative stress in CFS, and raise the possibility that HSP profiling may provide a more objective biologic marker for this illness.

 

Source: Thambirajah AA, Sleigh K, Stiver HG, Chow AW. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Clin Invest Med. 2008 Dec 1;31(6):E319-27. https://www.ncbi.nlm.nih.gov/pubmed/19032901