Fig. 2

Knowledge model template of the fundamental CICD derived relationships. The fundamental CICD derived relationship is a Modulator biomarker modulates a Source biomarker that stimulates or suppresses a Target biomarker. Modulator is a biomarker that modulates a Source biomarker. Source is a biomarker that stimulates or suppresses a Target biomarker. Target is a biomarker that is stimulated or suppressed by either a modulated Source biomarker or a non-modulated Source biomarker. The Knowledge Model for the current study is a template of 7 relationship criteria to reduce number of relationships analyzed to a total of 28,605 unique relationships. Each type of CICD derived relationships is shown with the total number of combinations included in the current Knowledge Model. For each relationship, a cell is required to be either a Target or a Source component. Bi-linear relationships are those in which the Modulator affects the Source, then this Source affects the Target. Bi-linear relationships with more than one cellular component requires it is the same cell unless it acts as a Modulator for a cytokine Target; that is, autocrine signaling is included and for simplicity purposes paracrine signaling is currently excluded. Linear relationships are a non-modulated Source biomarker acting directly on a Target biomarker. *Relationship requires the same cell used for each cellular component. **An additional modulator has been included to model possible non-biomarker modulations