MIP source proteins are very different in the 2 sibships, but are implicated in similar biologic pathways and are interconnected functionally. (A) Venn diagram showing the minimal overlap between MIP source proteins from sibships 1 versus 2. Protein numbers and percentages are depicted for each category. Total numbers of MIP source proteins for each sibship are shown in colors. (B) The Ingenuity Pathway Analysis resource was used to identify overrepresented biologic pathways for MIPs source proteins in sibships 1 and 2. Pathways are sorted by their statistical significance as follows: −log(P value calculated with the right-tailed Fisher exact test). Higher scores indicate an increased association between the MIP source proteins and a given pathway. The dotted line represents the threshold for statistical significance (P < .05). Immune-associated pathways are highlighted in red. (C) MIP source proteins from HLA-disparate sibships are interconnected functionally. An all-pairs-shortest-path matrix was used to calculate the functional association between MIP source proteins of sibship 1 and MIPs source proteins of sibship 2 (see “Functional connectivity score” for details). The functional association was measured as a connectivity score, which corresponds to the mean of the shortest path distance between every pair of proteins (1 protein from each sibship) in an interaction network. Lower scores indicate increased connectivity. The red line represents the connectivity score between the MIP source proteins of sibship 1 and the MIP source proteins of sibship 2. A bootstrap procedure, represented by the Gaussian distribution, was used to calculate control connectivity scores between MIP source proteins (of sibships 1 or 2) and random sets of proteins from the human proteome (*P < .0001, calculated as the number of times that the score of the bootstrap is smaller than the score of the sample/number of bootstraps).