Identifying Drug Sensitivity Subnetworks with NETPHIX.

Phenotypic heterogeneity in cancer is often caused by different patterns of genetic alterations. Understanding such phenotype-genotype relationships is fundamental for the advance of personalized medicine. We develop a computational method, named NETPHIX (NETwork-to-PHenotype association with eXclusivity) to identify subnetworks of genes whose genetic alterations are associated with drug response or other continuous cancer phenotypes. Leveraging interaction information among genes and properties of cancer mutations such as mutual exclusivity, we formulate the problem as an integer linear program and solve it optimally to obtain a subnetwork of associated genes. Applied to a large-scale drug screening dataset, NETPHIX uncovered gene modules significantly associated with drug responses. Utilizing interaction information, NETPHIX modules are functionally coherent and can thus provide important insights into drug action. In addition, we show that modules identified by NETPHIX together with their association patterns can be leveraged to suggest drug combinations.

Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer.

BACKGROUND: Studies of cancer mutations have typically focused on identifying cancer driving mutations that confer growth advantage to cancer cells. However, cancer genomes accumulate a large number of passenger somatic mutations resulting from various endogenous and exogenous causes, including normal DNA damage and repair processes or cancer-related aberrations of DNA maintenance machinery as well as mutations triggered by carcinogenic exposures. Different mutagenic processes often produce characteristic mutational patterns called mutational signatures. Identifying mutagenic processes underlying mutational signatures shaping a cancer genome is an important step towards understanding tumorigenesis. METHODS: To investigate the genetic aberrations associated with mutational signatures, we took a network-based approach considering mutational signatures as cancer phenotypes. Specifically, our analysis aims to answer the following two complementary questions: (i) what are functional pathways whose gene expression activities correlate with the strengths of mutational signatures, and (ii) are there pathways whose genetic alterations might have led to specific mutational signatures? To identify mutated pathways, we adopted a recently developed optimization method based on integer linear programming. RESULTS: Analyzing a breast cancer dataset, we identified pathways associated with mutational signatures on both expression and mutation levels. Our analysis captured important differences in the etiology of the APOBEC-related signatures and the two clock-like signatures. In particular, it revealed that clustered and dispersed APOBEC mutations may be caused by different mutagenic processes. In addition, our analysis elucidated differences between two age-related signatures-one of the signatures is correlated with the expression of cell cycle genes while the other has no such correlation but shows patterns consistent with the exposure to environmental/external processes. CONCLUSIONS: This work investigated, for the first time, a network-level association of mutational signatures and dysregulated pathways. The identified pathways and subnetworks provide novel insights into mutagenic processes that the cancer genomes might have undergone and important clues for developing personalized drug therapies.

Efficient algorithms to discover alterations with complementary functional association in cancer.

Recent large cancer studies have measured somatic alterations in an unprecedented number of tumours. These large datasets allow the identification of cancer-related sets of genetic alterations by identifying relevant combinatorial patterns. Among such patterns, mutual exclusivity has been employed by several recent methods that have shown its effectiveness in characterizing gene sets associated to cancer. Mutual exclusivity arises because of the complementarity, at the functional level, of alterations in genes which are part of a group (e.g., a pathway) performing a given function. The availability of quantitative target profiles, from genetic perturbations or from clinical phenotypes, provides additional information that can be leveraged to improve the identification of cancer related gene sets by discovering groups with complementary functional associations with such targets. In this work we study the problem of finding groups of mutually exclusive alterations associated with a quantitative (functional) target. We propose a combinatorial formulation for the problem, and prove that the associated computational problem is computationally hard. We design two algorithms to solve the problem and implement them in our tool UNCOVER. We provide analytic evidence of the effectiveness of UNCOVER in finding high-quality solutions and show experimentally that UNCOVER finds sets of alterations significantly associated with functional targets in a variety of scenarios. In particular, we show that our algorithms find sets which are better than the ones obtained by the state-of-the-art method, even when sets are evaluated using the statistical score employed by the latter. In addition, our algorithms are much faster than the state-of-the-art, allowing the analysis of large datasets of thousands of target profiles from cancer cell lines. We show that on two such datasets, one from project Achilles and one from the Genomics of Drug Sensitivity in Cancer project, UNCOVER identifies several significant gene sets with complementary functional associations with targets. Software available at: https://github.com/VandinLab/UNCOVER.

HNCcorr: A Novel Combinatorial Approach for Cell Identification in Calcium-Imaging Movies.

Calcium imaging is a key method in neuroscience for investigating patterns of neuronal activity in vivo. Still, existing algorithms to detect and extract activity signals from calcium-imaging movies have major shortcomings. We introduce the HNCcorr algorithm for cell identification in calcium-imaging datasets that addresses these shortcomings. HNCcorr relies on the combinatorial clustering problem HNC (Hochbaum's Normalized Cut), which is similar to the Normalized Cut problem of Shi and Malik, a well known problem in image segmentation. HNC identifies cells as coherent clusters of pixels that are highly distinct from the remaining pixels. HNCcorr guarantees a globally optimal solution to the underlying optimization problem as well as minimal dependence on initialization techniques. HNCcorr also uses a new method, called "similarity squared", for measuring similarity between pixels in calcium-imaging movies. The effectiveness of HNCcorr is demonstrated by its top performance on the Neurofinder cell identification benchmark. We believe HNCcorr is an important addition to the toolbox for analysis of calcium-imaging movies.

Ranking of multidimensional drug profiling data by fractional-adjusted bi-partitional scores.

MOTIVATION: The recent development of high-throughput drug profiling (high content screening or HCS) provides a large amount of quantitative multidimensional data. Despite its potentials, it poses several challenges for academia and industry analysts alike. This is especially true for ranking the effectiveness of several drugs from many thousands of images directly. This paper introduces, for the first time, a new framework for automatically ordering the performance of drugs, called fractional adjusted bi-partitional score (FABS). This general strategy takes advantage of graph-based formulations and solutions and avoids many shortfalls of traditionally used methods in practice. We experimented with FABS framework by implementing it with a specific algorithm, a variant of normalized cut-normalized cut prime (FABS-NC(')), producing a ranking of drugs. This algorithm is known to run in polynomial time and therefore can scale well in high-throughput applications. RESULTS: We compare the performance of FABS-NC(') to other methods that could be used for drugs ranking. We devise two variants of the FABS algorithm: FABS-SVM that utilizes support vector machine (SVM) as black box, and FABS-Spectral that utilizes the eigenvector technique (spectral) as black box. We compare the performance of FABS-NC(') also to three other methods that have been previously considered: center ranking (Center), PCA ranking (PCA), and graph transition energy method (GTEM). The conclusion is encouraging: FABS-NC(') consistently outperforms all these five alternatives. FABS-SVM has the second best performance among these six methods, but is far behind FABS-NC('): In some cases FABS-NC(') produces over half correctly predicted ranking experiment trials than FABS-SVM. AVAILABILITY: The system and data for the evaluation reported here will be made available upon request to the authors after this manuscript is accepted for publication.

Polynomial time algorithms for ratio regions and a variant of normalized cut.

In partitioning, clustering, and grouping problems, a typical goal is to group together similar objects, or pixels in the case of image processing. At the same time, another goal is to have each group distinctly dissimilar from the rest and possibly to have the group size fairly large. These goals are often combined as a ratio optimization problem. One example of such a problem is a variant of the normalized cut problem, another is the ratio regions problem. We devise here the first polynomial time algorithms solving optimally the ratio region problem and the variant of normalized cut, as well as a few other ratio problems. The algorithms are efficient and combinatorial, in contrast with nonlinear continuous approaches used in the image segmentation literature, which often employ spectral techniques. Such techniques deliver solutions in real numbers which are not feasible to the discrete partitioning problem. Furthermore, these continuous approaches are computationally expensive compared to the algorithms proposed here. The algorithms presented here use as a subroutine a minimum s,t-cut procedure on a related graph which is of polynomial size. The output consists of the optimal solution to the respective ratio problem, as well as a sequence of nested solutions with respect to any relative weighting of the objectives of the numerator and denominator.