Running time of UNCOVER on simulated data.

The running time (expectation and standard deviation) of the greedy algorithm and of the ILP approach are shown for different number of samples and the difference p − n between the fraction p of samples with positive target and the fraction n of samples with negative target covered by the the correct solution.</p

Impact of the target on the results.

UNCOVER results for target Palbociclib considering or ignoring target values. (a) Solution found by UNCOVER looking for an association with samples with high target values. (b) Solution found by UNCOVER looking for association with low target values. (c) Solution found by UNCOVER when the target values are ignored. Each panel shows the value of the target (top row) for various samples (columns), with yellow being negative and blue being positive values. For each gene in the solution, alterations in each sample are shown in dark blue, while samples not altered are in yellow. The last row shows the alteration profile of the entire solution.</p

Quality of solutions of UNCOVER on simulated data.

The fraction of genes in the planted (i.e., correct) solution found by the greedy algorithm and by the ILP approach are shown for different number of samples and the difference p − n between the fraction p of samples with positive target and the fraction n of samples with negative target covered by the the correct solution.</p

Identification of mutually exclusive alterations associated with a target profile.

Alterations in the green set have high mutual exclusivity but no association with the target profile (e.g., a molecular mechanism commonly altered in cancer). Alterations in the orange set have lower mutual exclusivity but strong association with the target profile (e.g., genes in the same pathway of the drug target). Methods that find mutually exclusive sets of alterations without considering the target profile will identify the green set as the most important gene set.</p

Solution by UNCOVER on GDSC drug sensitivity data data.

The alteration matrix of genes in some solutions identified by UNCOVER as associated to drug sensitivity for different targets. (a) Solution for reduced sensitivity to Sunitinib. (b) Solution for increased sensitivity to PLX-4720-2. (c) Solution for increased sensitivity to VX-11e. Each panel shows the value of the target (top row) for various samples (columns), with yellow being negative and blue being positive values. For each gene in the solution, alterations in each sample are shown in dark blue, while samples not altered are in yellow. The last row shows the alteration profile of the entire solution.</p

Comparison of UNCOVER with REVEALER on REVEALER’s datasets.

Comparison of UNCOVER with REVEALER on REVEALER’s datasets.</p

UNCOVER: Functional complementarity of alterations discovery.

UNCOVER takes in input the alterations information and a target profile for a set of samples, and identifies the set of complementary alterations with the highest association to the target by solving the Target Associated k-Set problem and performing a permutation test.</p

Comparison of UNCOVER with REVEALER on GDSC dataset.

Comparison of UNCOVER with REVEALER on GDSC dataset.</p

Results of UNCOVER on four cancer datasets from [33].

(a) Solution found by ILP and greedy for KRAS essentiality target. (b) Solution found by ILP and greedy for β-catenin activation target. (c) Solution found by ILP for MEK inhibitor target. (d) Solution found by greedy for MEK inhibitor target. (e) Solution found by ILP and greedy for NFE2L2 activation target. Each panel shows the value of the target (top row) for various samples (columns), with yellow being negative and blue being positive values. For each gene in the solution, alterations in each sample are shown in dark blue, while samples not altered are in yellow. The last row shows the alteration profile of the entire solution.</p

Solution by UNCOVER for silencing of TSG101 (data from Achilles project).

The alteration matrix of genes in the solution identified by UNCOVER as associated to reduced cell viability is reported. The value of the target (top row) for various samples (columns) is shown, with yellow being negative and blue being positive values. For each gene in the solution, alterations in each sample are shown in dark blue, while samples not altered are in yellow. The last row shows the alteration profile of the entire solution.</p