We describe a new signature definition and analysis method to be used as biomarker for blood-based diagnosis of tuberculosis. Our new approach is based on the construction of a reference map of transcriptional signatures of both healthy and affected individuals using circulating miRNA from a large number of subjects. Once such a map is available, the diagnosis for a new patient can be performed by observing the relative position on the map of his/her transcriptional signature. To demonstrate its efficacy for this specific application we report the results of the application of our method to published data sets of circulating miRNA. Two crucial features make this method an ideal candidate for large scale applications such as a mass screening tool, or for point-of-care diagnostics. Specifically, our method is minimally invasive because it works well with profiles of circulating miRNA. More importantly, it is robust with respect to lab-to-lab protocol variability, measurement errors and batch effects because it requires that only the relative ranking of miRNA species in a profile be accurate, not their absolute values.