Motivation: Proteomics profiling is increasingly being used for molecular stratification of cancer patients and cell-line panels. However, systematic assessment of the predictive power of large-scale proteomic technologies across various drug classes and cancer types is currently lacking. To that end, we carried out the first pan-cancer, multi-omics comparative analysis of the relative performance of two proteomic technologies, targeted reverse phase protein array (RPPA) and global mass spectrometry (MS), in terms of their accuracy for predicting the sensitivity of cancer cells to both cytotoxic chemotherapeutics and molecularly targeted anticancer compounds. Results: Our results in two cell-line panels demonstrate how MS profiling improves drug response predictions beyond that of the RPPA or the other omics profiles when used alone. However, frequent missing MS data values complicate its use in predictive modeling and required additional filtering, such as focusing on completely measured or known oncoproteins, to obtain maximal predictive performance. Rather strikingly, the two proteomics profiles provided complementary predictive signal both for the cytotoxic and targeted compounds. Further, information about the cellular-abundance of primary target proteins was found critical for predicting the response of targeted compounds, although the non-target features also contributed significantly to the predictive power. The clinical relevance of the selected protein markers was confirmed in cancer patient data. These results provide novel insights into the relative performance and optimal use of the widely applied proteomic technologies, MS and RPPA, which should prove useful in translational applications, such as defining the best combination of omics technologies and marker panels for understanding and predicting drug sensitivities in cancer patients. Availability and implementation: Processed datasets, R as well as Matlab implementations of the methods are available at https://github.com/mehr-een/bemkl-rbps. Contact: [email protected] or [email protected]. Supplementary information: Supplementary data are available at Bioinformatics online.

We introduce the convex factorization machine (CFM), which is a convex variant of the widely used Factorization Machines (FMs). Specifically, we employ a linear+quadratic model and regularize the linear term with the ℓ2-regularizer and the quadratic term with the trace norm regularizer. Then, we formulate the CFM optimization as a semidefinite programming problem and propose an efficient optimization procedure with Hazan's algorithm. A key advantage of CFM over existing FMs is that it can find a globally optimal solution, while FMs may get a poor locally optimal solution since the objective function of FMs is non-convex. In addition, the proposed algorithm is simple yet effective and can be implemented easily. Finally, CFM is a general factorization method and can also be used for other factorization problems, including multi-view matrix factorization and tensor completion problems, in various domains including toxicogenomics and bioinformatics. Through synthetic and traditionally used movielens datasets, we first show that the proposed CFM achieves results competitive to FMs. We then show in a toxicogenomics prediction task that CFM predicts the toxic outcomes of a collection of drugs better than a state-of-the-art tensor factorization method.

MOTIVATION: A prime challenge in precision cancer medicine is to identify genomic and molecular features that are predictive of drug treatment responses in cancer cells. Although there are several computational models for accurate drug response prediction, these often lack the ability to infer which feature combinations are the most predictive, particularly for high-dimensional molecular datasets. As increasing amounts of diverse genome-wide data sources are becoming available, there is a need to build new computational models that can effectively combine these data sources and identify maximally predictive feature combinations. RESULTS: We present a novel approach that leverages on systematic integration of data sources to identify response predictive features of multiple drugs. To solve the modeling task we implement a Bayesian linear regression method. To further improve the usefulness of the proposed model, we exploit the known human cancer kinome for identifying biologically relevant feature combinations. In case studies with a synthetic dataset and two publicly available cancer cell line datasets, we demonstrate the improved accuracy of our method compared to the widely used approaches in drug response analysis. As key examples, our model identifies meaningful combinations of features for the well known EGFR, ALK, PLK and PDGFR inhibitors. AVAILABILITY AND IMPLEMENTATION: The source code of the method is available at https://github.com/suleimank/mvlr . CONTACT: [email protected] or [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: A key goal of computational personalized medicine is to systematically utilize genomic and other molecular features of samples to predict drug responses for a previously unseen sample. Such predictions are valuable for developing hypotheses for selecting therapies tailored for individual patients. This is especially valuable in oncology, where molecular and genetic heterogeneity of the cells has a major impact on the response. However, the prediction task is extremely challenging, raising the need for methods that can effectively model and predict drug responses. RESULTS: In this study, we propose a novel formulation of multi-task matrix factorization that allows selective data integration for predicting drug responses. To solve the modeling task, we extend the state-of-the-art kernelized Bayesian matrix factorization (KBMF) method with component-wise multiple kernel learning. In addition, our approach exploits the known pathway information in a novel and biologically meaningful fashion to learn the drug response associations. Our method quantitatively outperforms the state of the art on predicting drug responses in two publicly available cancer datasets as well as on a synthetic dataset. In addition, we validated our model predictions with lab experiments using an in-house cancer cell line panel. We finally show the practical applicability of the proposed method by utilizing prior knowledge to infer pathway-drug response associations, opening up the opportunity for elucidating drug action mechanisms. We demonstrate that pathway-response associations can be learned by the proposed model for the well-known EGFR and MEK inhibitors. AVAILABILITY AND IMPLEMENTATION: The source code implementing the method is available at http://research.cs.aalto.fi/pml/software/cwkbmf/ CONTACTS: [email protected] or [email protected] SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

MOTIVATION: Analysis of relationships of drug structure to biological response is key to understanding off-target and unexpected drug effects, and for developing hypotheses on how to tailor drug therapies. New methods are required for integrated analyses of a large number of chemical features of drugs against the corresponding genome-wide responses of multiple cell models. RESULTS: In this article, we present the first comprehensive multi-set analysis on how the chemical structure of drugs impacts on genome-wide gene expression across several cancer cell lines [Connectivity Map (CMap) database]. The task is formulated as searching for drug response components across multiple cancers to reveal shared effects of drugs and the chemical features that may be responsible. The components can be computed with an extension of a recent approach called Group Factor Analysis. We identify 11 components that link the structural descriptors of drugs with specific gene expression responses observed in the three cell lines and identify structural groups that may be responsible for the responses. Our method quantitatively outperforms the limited earlier methods on CMap and identifies both the previously reported associations and several interesting novel findings, by taking into account multiple cell lines and advanced 3D structural descriptors. The novel observations include: previously unknown similarities in the effects induced by 15-delta prostaglandin J2 and HSP90 inhibitors, which are linked to the 3D descriptors of the drugs; and the induction by simvastatin of leukemia-specific response, resembling the effects of corticosteroids. AVAILABILITY AND IMPLEMENTATION: Source Code implementing the method is available at: http://research.ics.aalto.fi/mi/software/GFAsparse. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

We extend kernelized matrix factorization with a fully Bayesian treatment and with an ability to work with multiple side information sources expressed as different kernels. Kernel functions have been introduced to matrix factorization to integrate side information about the rows and columns (e.g., objects and users in recommender systems), which is necessary for making out-of-matrix (i.e., cold start) predictions. We discuss specifically bipartite graph inference, where the output matrix is binary, but extensions to more general matrices are straightforward. We extend the state of the art in two key aspects: (i) A fully conjugate probabilistic formulation of the kernelized matrix factorization problem enables an efficient variational approximation, whereas fully Bayesian treatments are not computationally feasible in the earlier approaches. (ii) Multiple side information sources are included, treated as different kernels in multiple kernel learning that additionally reveals which side information sources are informative. Our method outperforms alternatives in predicting drug-protein interactions on two data sets. We then show that our framework can also be used for solving multilabel learning problems by considering samples and labels as the two domains where matrix factorization operates on. Our algorithm obtains the lowest Hamming loss values on 10 out of 14 multilabel classification data sets compared to five state-of-the-art multilabel learning algorithms.

BACKGROUND: Detailed and systematic understanding of the biological effects of millions of available compounds on living cells is a significant challenge. As most compounds impact multiple targets and pathways, traditional methods for analyzing structure-function relationships are not comprehensive enough. Therefore more advanced integrative models are needed for predicting biological effects elicited by specific chemical features. As a step towards creating such computational links we developed a data-driven chemical systems biology approach to comprehensively study the relationship of 76 structural 3D-descriptors (VolSurf, chemical space) of 1159 drugs with the microarray gene expression responses (biological space) they elicited in three cancer cell lines. The analysis covering 11350 genes was based on data from the Connectivity Map. We decomposed the biological response profiles into components, each linked to a characteristic chemical descriptor profile. RESULTS: Integrated analysis of both the chemical and biological space was more informative than either dataset alone in predicting drug similarity as measured by shared protein targets. We identified ten major components that link distinct VolSurf chemical features across multiple compounds to specific cellular responses. For example, component 2 (hydrophobic properties) strongly linked to DNA damage response, while component 3 (hydrogen bonding) was associated with metabolic stress. Individual structural and biological features were often linked to one cell line only, such as leukemia cells (HL-60) specifically responding to cardiac glycosides. CONCLUSIONS: In summary, our approach identified several novel links between specific chemical structure properties and distinct biological responses in cells incubated with these drugs. Importantly, the analysis focused on chemical-biological properties that emerge across multiple drugs. The decoding of such systematic relationships is necessary to build better models of drug effects, including unanticipated types of molecular properties having strong biological effects.