A disadvantage is that while the global test identifies biomarker groupings that are significant, it does not provide information on which PF-2341066 c-Met inhibitor markers are driving the statistical significance. Also, it is not an optimal test procedure if the association of some markers with disease outcome is positive and that of some other markers is negative. Thus, we also carried out a likelihood ratio test that tested the significance of adding all the markers in a functional category to a base model that only included age, duration of symptoms and geographic region. In an influenza challenge study reported in 1998 in which normal human volunteers were experimentally infected with a seasonal influenza A virus, Hayden et al. found that both IL-6 and IFN-alpha levels in nasal lavage fluids peaked early in the course of infection and correlated directly with viral titers, temperature, mucus production, and symptom Nilotinib scores. Several other clinical studies in adults or children have been reported by investigators in which the addition of various serum or nasal biomarker level measurements to the standard clinical evaluation appeared to add to the diagnostic certainty of respiratory virus infection with seasonal influenza. In a number of generally cross-sectional studies focusing either partially or exclusively upon confirmed cases of Apdm09 virus infection in specific geographic areas, potential correlations between various cytokine levels and disease severity have been reported. Investigators from Mexico reported that Apdm09 virus infection resulted in stronger in vitro upregulation of IL-6, CCL3, and CXCL8 in 72-hour cell cultures as well as elevated serum levels of 
IL-6, CXCL8, and certain other cytokines in individuals infected with this subtype compared to those with seasonal influenza virus infection. In separate publications a group in Hong Kong reported that elevated levels of IL-6, CXCL8, CCL2, and sTNFR-1 correlated with severe cases of Apdm09 virus infection overall and, in particular, with the extent and severity of influenza-associated pneumonia. Similar findings concerning elevated IP-10 and IL-6 levels in cases of pediatric pneumonia were reported from Korea. At least two groups from mainland China have described similar relationships for several of the pro-inflammatory cytokines withApdm09 virus infection, and separate groups from Spain, Italy, and Romania have also described correlations between elevated levels of various cytokines such as IL-6, IL-15, and TNF-a and the severity of disease outcomes in patients with confirmed Apdm09 virus infection. Most recently, a group from Canada has found IL-6 to be an important feature of the host response in both humans and mice infected with Apdm09 virus and, in the former case, found elevated IL-6 levels to be an important predictor of severe disease. Biomarker analyses from our two large ongoing international studies of influenza described here have strengthened and extended these observations in important ways. A major virtue of the present studies is that these data were collected prospectively according to a common data-set and with defined periods of follow-up to assess disease progression, samples have been garnered from a relatively large number of patients living in geographically disparate regions of the world and analyzed through common central laboratory systems using standardized methodologies.