In Figure Sorafenib Tosylate FDA Figure3B3B a strong separation was observed between all ‘controls’ (GEO and HC) when compared with the sepsis cohort, thus generating a specificity of greater than 99% using ROC curve analyses.Figure 3Principal Component Analysis for preliminary HGU133 Plus 2.0 array studies. A strong separation between HC (referred to as “Control”) and MI groups and a moderate separation between PS and sepsis participants was noted (A), where all but one sepsis sample …The objective of the GEO data exploration was to investigate whether or not the diagnostic signature is robust to inter-laboratory variation. There is limited evidence that the signature is robust, but inter-laboratory variation in positive sepsis samples would have to be evaluated before this can be proven.
Importantly, the high specificity for the GEO data must be interpreted with caution given that no sepsis data from the GEO database were included. Whilst the GEO database does contain gene expression information from sepsis trials, the clinical status of the participant cohorts appeared to be ambiguous based on Inclusion and Exclusion Criteria and for this reason, it was not included in these analyses. At this stage it may be the case that the very high specificity is adversely affecting sensitivity. However, it is encouraging that a classifier developed in one laboratory does not result in a large number of false positives when applied to samples from a large number of laboratories. This provides some evidence that the difference between sepsis and control patients from this trial is greater than the inter-laboratory variation in the gene expression data.
Had the difference between control and sepsis patients from the current trial been small with respect to between laboratory variations in ‘control’ gene expression, it is likely to have resulted in the GEO data decreasing the sensitivity. In this sense, the GEO data provide preliminary evidence that the sensitivity of the test is robust to inter-laboratory variation.It is routine practice in research and development that microarray studies be employed in preliminary investigations, particularly in molecular oncology, in order to identify statistically relevant panels in which to re-evaluate and further refine in the clinical setting [23-25]. Given that these analyses were not restricted to inflammatory biomarkers, these results provided a strong rationale for further clinical research.
When the a priori set of 145 biomarkers was compared with all gene expression change from the Affymetrix Genechip data they were strongly representative of widespread change and, had the greatest capacity to differentiate Anacetrapib within the MI cohort. Thus, based on preliminary outcomes, a further subset of 42 biomarkers including three control/normalisation genes were tested in a larger cohort of critical care patients, to ascertain the clinical utility of this sepsis test using the more efficient quantitative real time PCR platform.
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