Deep learning with Convolutional Neural Networks has shown great promise in image-based classification and enhancement but is often unsuitable for predictive modeling using features without spatial correlations. We present a feature representation approach termed REFINED (REpresentation of Features as Images with NEighborhood Dependencies) to arrange highdimensional vectors in a compact image form conducible for CNN-based deep learning. We consider the similarities between features to generate a concise feature map in the form of a two-dimensional image by minimizing the pairwise distance values following a Bayesian Metric Multidimensional Scaling Approach. We hypothesize that this approach enables embedded feature extraction and, integrated with CNN-based deep learning, can boost the predictive accuracy. We illustrate the superior predictive capabilities of the proposed framework as compared to state-of-the-art methodologies in drug sensitivity prediction scenarios using synthetic datasets, drug chemical descriptors as predictors from NCI60, and both transcriptomic information and drug descriptors as predictors from GDSC.

Drug sensitivity prediction for individual tumors is a significant challenge in personalized medicine. Current modeling approaches consider prediction of a single metric of the drug response curve such as AUC or IC50. However, the single summary metric of a dose-response curve fails to provide the entire drug sensitivity profile which can be used to design the optimal dose for a patient. In this article, we assess the problem of predicting the complete dose-response curve based on genetic characterizations. We propose an enhancement to the popular ensemble-based Random Forests approach that can directly predict the entire functional profile of a dose-response curve rather than a single summary metric. We design functional regression trees with node costs modified based on dose/response region dependence methodologies and response distribution based approaches. Our results relative to large pharmacological databases such as CCLE and GDSC show a higher accuracy in predicting dose-response curves of the proposed functional framework in contrast to univariate or multivariate Random Forest predicting sensitivities at different dose levels. Furthermore, we also considered the problem of predicting functional responses from functional predictors i.e., estimating the dose-response curves with a model built on dose-dependent expression data. The superior performance of Functional Random Forest using functional data as compared to existing approaches have been shown using the HMS-LINCS dataset. In summary, Functional Random Forest presents an enhanced predictive modeling framework to predict the entire functional response profile considering both static and functional predictors instead of predicting the summary metrics of the response curves.

Ammonia is a cytotoxic molecule generated during normal cellular functions. Dysregulated ammonia metabolism, which is evident in many chronic diseases such as liver cirrhosis, heart failure, and chronic obstructive pulmonary disease, initiates a hyperammonemic stress response in tissues including skeletal muscle and in myotubes. Perturbations in levels of specific regulatory molecules have been reported, but the global responses to hyperammonemia are unclear. In this study, we used a multiomics approach to vertically integrate unbiased data generated using an assay for transposase-accessible chromatin with high-throughput sequencing, RNA-Seq, and proteomics. We then horizontally integrated these data across different models of hyperammonemia, including myotubes and mouse and human muscle tissues. Changes in chromatin accessibility and/or expression of genes resulted in distinct clusters of temporal molecular changes including transient, persistent, and delayed responses during hyperammonemia in myotubes. Known responses to hyperammonemia, including mitochondrial and oxidative dysfunction, protein homeostasis disruption, and oxidative stress pathway activation, were enriched in our datasets. During hyperammonemia, pathways that impact skeletal muscle structure and function that were consistently enriched were those that contribute to mitochondrial dysfunction, oxidative stress, and senescence. We made several novel observations, including an enrichment in antiapoptotic B-cell leukemia/lymphoma 2 family protein expression, increased calcium flux, and increased protein glycosylation in myotubes and muscle tissue upon hyperammonemia. Critical molecules in these pathways were validated experimentally. Human skeletal muscle from patients with cirrhosis displayed similar responses, establishing translational relevance. These data demonstrate complex molecular interactions during adaptive and maladaptive responses during the cellular stress response to hyperammonemia.

BackgroundIn precision medicine, scarcity of suitable biological data often hinders the design of an appropriate predictive model. In this regard, large scale pharmacogenomics studies, like CCLE and GDSC hold the promise to mitigate the issue. However, one cannot directly employ data from multiple sources together due to the existing distribution shift in data. One way to solve this problem is to utilize the transfer learning methodologies tailored to fit in this specific context.ResultsIn this paper, we present two novel approaches for incorporating information from a secondary database for improving the prediction in a target database. The first approach is based on latent variable cost optimization and the second approach considers polynomial mapping between the two databases. Utilizing CCLE and GDSC databases, we illustrate that the proposed approaches accomplish a better prediction of drug sensitivities for different scenarios as compared to the existing approaches.ConclusionWe have compared the performance of the proposed predictive models with database-specific individual models as well as existing transfer learning approaches. We note that our proposed approaches exhibit superior performance compared to the abovementioned alternative techniques for predicting sensitivity for different anti-cancer compounds, particularly the nonlinear mapping model shows the best overall performance.Electronic supplementary materialThe online version of this article (10.1186/s12859-018-2465-y) contains supplementary material, which is available to authorized users.

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