TY - JOUR
T1 - A weighted exact test for mutually exclusive mutations in cancer
AU - Leiserson, Mark D.M.
AU - Reyna, Matthew A.
AU - Raphael, Benjamin J.
N1 - Funding Information:
This study was supported by the US National Institutes of Health (NIH) grants (R01HG005690, R01HG007069 and R01CA180776 to B.J.R.), NSF fellowship (GRFP DGE 0228243 to M.D.M.L.) and a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, an Alfred P. Sloan Research Fellowship and an NSF CAREER Award (CCF-1053753 to B.J.R.).
Publisher Copyright:
© 2016 The Author 2016. Published by Oxford University Press.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - Motivation: The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision. Results: We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches.
AB - Motivation: The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision. Results: We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches.
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U2 - 10.1093/bioinformatics/btw462
DO - 10.1093/bioinformatics/btw462
M3 - Article
C2 - 27587696
AN - SCOPUS:84990923850
SN - 1367-4803
VL - 32
SP - i736-i745
JO - Bioinformatics
JF - Bioinformatics
IS - 17
ER -