Searching and scoring method.
(a) Mutual exclusivity of a group of gene alterations is evaluated by comparing each gene with the union of the other genes. The initial score is the least significant P value. To correct for multiple hypothesis testing, we estimate the significance of the initial P values during a search with permuted alterations. The least significant of these second P values is the multiple hypothesis testing corrected group score. (b) At each step of the greedy search, we expand the group with the next best candidate gene from the surrounding genes that have a common downstream target with the group members, or they are a common downstream target themselves. In this illustration, four sample steps of the search are shown for a sample network. Thick-bordered genes are current group members and genes with a gray background are candidates for the next expansion. The best-scoring candidate gene is added to the group if it increases the score, and the candidates are re-assessed for the next phase. The search will stop if the group cannot expand anymore or a threshold group size is reached.