A kernelisation approach for multiple d-hitting set and its application in optimal multi-drug therapeutic combinations

Abstract

Therapies consisting of a combination of agents are an attractive proposition, especially in the context of diseases such as cancer, which can manifest with a variety of tumor types in a single case. However uncovering usable drug combinations is expensive both financially and temporally. By employing computational methods to identify candidate combinations with a greater likelihood of success we can avoid these problems, even when the amount of data is prohibitively large. HITTING SET is a combinatorial problem that has useful application across many fields, however as it is NP-complete it is traditionally considered hard to solve exactly. We introduce a more general version of the problem (α,β,d)-HITTING SET, which allows more precise control over how and what the hitting set targets. Employing the framework of Parameterized Complexity we show that despite being NP-complete, the ((α,β,d)-HITTING SET problem is fixed-parameter tractable with a kernel of size O(αdkd) when we parameterize by the size k of the hitting set and the maximum number a of the minimum number of hits, and taking the maximum degree d of the target sets as a constant. We demonstrate the application of this problem to multiple drug selection for cancer therapy, showing the flexibility of the problem in tailoring such drug sets. The fixed-parameter tractability result indicates that for low values of the parameters the problem can be solved quickly using exact methods. We also demonstrate that the problem is indeed practical, with computation times on the order of 5 seconds, as compared to previous Hitting Set applications using the same dataset which exhibited times on the order of 1 day, even with relatively relaxed notions for what constitutes a low value for the parameters. Furthermore the existence of a kernelization for ((α,β,d)-HITTING SET indicates that the problem is readily scalable to large datasets. © 2010 Mellor et al.