With regard to the cohort under study, I note that the authors write that their analysis sample: "...consisted of 44 pairs of rigorously discordant and genetically proven monozygotic twins. Discordance was defined as one twin meeting criteria for either idiopathic chronic fatigue (ICF, 12 pairs) or CFS (32 pairs)". (1) They then reference both the Fukuda et al criteria (2), and Reeves et al criteria (3), though I believe the latter in error, as the actual Reeves et al criteria were apprently produced in 2005 (4). Perhaps the authors could clarify whether this is the case.

Both criteria have been critiqued for their inclusion of non-neurological and psychological symptoms and exclusion of neurological symptoms (5), in opposition to the 'Canadian' clinical criteria (6) for ME/CFS, which has recently been produced as research criteria (7) . The Reeves et al criteria have come under particular criticism for their methodology in defining 'CFS' patients as suffering fatigue and psychological symptoms only, and excluding patients with neurological symptoms (5). The Canadian Criteria have also been demonstrated in a further study to identify ME/CFS patients with significant differences from Fukuda defined 'CFS' patients (8) . That idiopathic chronic fatigue is a different illness entity to chronic fatigue syndrome (which is used as a synonym for the WHO ICD-10 stated neurological condition Myalgic Encephalomyelitis (at G93.3) has been acknowledged, by the WHO themselves (9), and by the American Medical Association (10).

With this in mind, I ask these questions of the authors:

1. Of the 12 patients defined as 'idiopathic chronic fatigue' sufferers, how many were defined as such by Fukuda criteria, and how many by Reeves criteria, as such?

2. Of the 32 patients defined as 'chronic fatigue syndrome' sufferers, how many were defined as such by Fukuda criteria, and how many by Reeves criteria, as such?

3. Why did the authors not acknowledge, as part of their discussion, the problem of the differences in criteria identification of chronic fatigue syndrome patients, including the issue of neurological symptoms identified by the 'Canadian' criteria, and how these may differ to patients identified as 'CFS' under other criteria? Since the Canadian criteria have been available since 2003, and further validation work has been produced, it is problematic that these criteria, and the methodological problems thrown up by the discordancy of the different criteria, were not even mentioned. At the very least this should have been discussed in a 'limitations' of study' section, for example, to acknowledge that 'Canadian' defined patients were not part of this cohort.

REFERENCES

(1) Byrnes, A. et al (2009) 'Gene Expression in Peripheral Blood Leukocytes in Monozygotic Twins Discordant for Chronic Fatigue: No Evidence of a Biomarker' PLos ONE, 4(6): e5805. doi:10.1371/journal.pone.0005805

(2) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. 'The chronic fatigue syndrome: a comprehensive approach to its definition and study' Ann Intern Med. 1994 Dec 15;121(12):953-9.

(3) Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, et al. (2003) Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res 3: 25.

(4) Reeves, W. C. Wagner, D. Nisenbaum, R. Jones, J. F. Gurbaxani, B. Solomon, L. Papanicolaou, D. A. Unger, E. R. Vernon, S. D. Heim, C. 'Chronic Fatigue Syndrome - a clinically empirical approach to its definition and study' BMC medicine 2005 3: 19. Also available via open access: http://www.biomedcentral....

(5)Jason, L. A. Najar, N. Porter, N. Reh, C. 'Evaluating the Centers for Disease Control's Empirical Chronic Fatigue Syndrome Case Definition' Journal of Disability Policy Studies (2009) 20: 93.

(6) Carruthers, B. et al (2003) “Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols” Journal of Chronic Fatigue Syndrome, Vol. 11(1), pp 7 - 115.

(7) Jason, L. A. Evans, M. Porter, N. Brown, M. Brown, A. Hunnell, J. Anderson, V. Lerch, A. de Meirleir, K. Friedberg, F. (2010) 'The Development of a Revised Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome Case Definition' American Journal of Biochemistry and Biotechnology 6 (2): 120-135.

(8) Jason LA, Torres-Harding SR, Jurgens A, Helgerson J. “Comparing the Fukuda et al. Criteria and the Canadian Case Definition for chronic Fatigue Syndrome”. Journal of Chronic Fatigue Syndrome 12(1):37-52, 2004

(9) WHO classification details cited in CFIDS Chronicle: Summer 1990:144

(10) JAMA issues correction. Journal of the American Medical Association 1990 (referring to the issue dated 4th July 1990 and article entitled Chronic fatigue: A prospective clinical and virologic study by Deborah Gold et al:264:1:48-53).