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Register a new userA cross-study analysis of drug response prediction in cancer cell lines
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To enable personalized cancer treatment, machine learning models have been developed to predict drug response as a function of tumor and drug features. However, most algorithm development efforts have relied on cross validation within a single study to assess model accuracy. While an essential first step, cross validation within a biological data set typically provides an overly optimistic estimate of the prediction performance on independent test sets. To provide a more rigorous assessment of model generalizability between different studies, we use machine learning to analyze five publicly available cell line-based data sets: NCI60, CTRP, GDSC, CCLE and gCSI. Based on observed experimental variability across studies, we explore estimates of prediction upper bounds. We report performance results of a variety of machine learning models, with a multitasking deep neural network achieving the best cross-study generalizability. By multiple measures, models trained on CTRP yield the most accurate predictions on the remaining testing data, and gCSI is the most predictable among the cell line data sets included in this study. With these experiments and further simulations on partial data, two lessons emerge: (1) differences in viability assays can limit model generalizability across studies, and (2) drug diversity, more than tumor diversity, is crucial for raising model generalizability in preclinical screening.
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Motivated by the size of cell line drug sensitivity data, researchers have been developing machine learning (ML) models for predicting drug response to advance cancer treatment. As drug sensitivity studies continue generating data, a common question is whether the proposed predictors can further improve the generalization performance with more training data. We utilize empirical learning curves for evaluating and comparing the data scaling properties of two neural networks (NNs) and two gradient boosting decision tree (GBDT) models trained on four drug screening datasets. The learning curves are accurately fitted to a power law model, providing a framework for assessing the data scaling behavior of these predictors. The curves demonstrate that no single model dominates in terms of prediction performance across all datasets and training sizes, suggesting that the shape of these curves depends on the unique model-dataset pair. The multi-input NN (mNN), in which gene expressions and molecular drug descriptors are input into separate subnetworks, outperforms a single-input NN (sNN), where the cell and drug features are concatenated for the input layer. In contrast, a GBDT with hyperparameter tuning exhibits superior performance as compared with both NNs at the lower range of training sizes for two of the datasets, whereas the mNN performs better at the higher range of training sizes. Moreover, the trajectory of the curves suggests that increasing the sample size is expected to further improve prediction scores of both NNs. These observations demonstrate the benefit of using learning curves to evaluate predictors, providing a broader perspective on the overall data scaling characteristics. The fitted power law curves provide a forward-looking performance metric and can serve as a co-design tool to guide experimental biologists and computational scientists in the design of future experiments.
Sensitivity analysis is an effective tool for systematically identifying specific perturbations in parameters that have significant effects on the behavior of a given biosystem, at the scale investigated. In this work, using a two-dimensional, multiscale non-small cell lung cancer (NSCLC) model, we examine the effects of perturbations in system parameters which span both molecular and cellular levels, i.e. across scales of interest. This is achieved by first linking molecular and cellular activities and then assessing the influence of parameters at the molecular level on the tumors spatio-temporal expansion rate, which serves as the output behavior at the cellular level. Overall, the algorithm operated reliably over relatively large variations of most parameters, hence confirming the robustness of the model. However, three pathway components (proteins PKC, MEK, and ERK) and eleven reaction steps were determined to be of critical importance by employing a sensitivity coefficient as an evaluation index. Each of these sensitive parameters exhibited a similar changing pattern in that a relatively larger increase or decrease in its value resulted in a lesser influence on the systems cellular performance. This study provides a novel cross-scaled approach to analyzing sensitivities of computational model parameters and proposes its application to interdisciplinary biomarker studies.
Cancer is a primary cause of human death, but discovering drugs and tailoring cancer therapies are expensive and time-consuming. We seek to facilitate the discovery of new drugs and treatment strategies for cancer using variational autoencoders (VAEs) and multi-layer perceptrons (MLPs) to predict anti-cancer drug responses. Our model takes as input gene expression data of cancer cell lines and anti-cancer drug molecular data and encodes these data with our {sc {GeneVae}} model, which is an ordinary VAE model, and a rectified junction tree variational autoencoder ({sc JTVae}) model, respectively. A multi-layer perceptron processes these encoded features to produce a final prediction. Our tests show our system attains a high average coefficient of determination ($R^{2} = 0.83$) in predicting drug responses for breast cancer cell lines and an average $R^{2} = 0.845$ for pan-cancer cell lines. Additionally, we show that our model can generates effective drug compounds not previously used for specific cancer cell lines.
Prediction of Overall Survival (OS) of brain cancer patients from multi-modal MRI is a challenging field of research. Most of the existing literature on survival prediction is based on Radiomic features, which does not consider either non-biological factors or the functional neurological status of the patient(s). Besides, the selection of an appropriate cut-off for survival and the presence of censored data create further problems. Application of deep learning models for OS prediction is also limited due to the lack of large annotated publicly available datasets. In this scenario we analyse the potential of two novel neuroimaging feature families, extracted from brain parcellation atlases and spatial habitats, along with classical radiomic and geometric features; to study their combined predictive power for analysing overall survival. A cross validation strategy with grid search is proposed to simultaneously select and evaluate the most predictive feature subset based on its predictive power. A Cox Proportional Hazard (CoxPH) model is employed for univariate feature selection, followed by the prediction of patient-specific survival functions by three multivariate parsimonious models viz. Coxnet, Random survival forests (RSF) and Survival SVM (SSVM). The brain cancer MRI data used for this research was taken from two open-access collections TCGA-GBM and TCGA-LGG available from The Cancer Imaging Archive (TCIA). Corresponding survival data for each patient was downloaded from The Cancer Genome Atlas (TCGA). A high cross validation $C-index$ score of $0.82pm.10$ was achieved using RSF with the best $24$ selected features. Age was found to be the most important biological predictor. There were $9$, $6$, $6$ and $2$ features selected from the parcellation, habitat, radiomic and region-based feature groups respectively.
Characterization of breast parenchyma on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a challenging task owing to the complexity of underlying tissue structures. Current quantitative approaches, including radiomics and deep learning models, do not explicitly capture the complex and subtle parenchymal structures, such as fibroglandular tissue. In this paper, we propose a novel method to direct a neural networks attention to a dedicated set of voxels surrounding biologically relevant tissue structures. By extracting multi-dimensional topological structures with high saliency, we build a topology-derived biomarker, TopoTxR. We demonstrate the efficacy of TopoTxR in predicting response to neoadjuvant chemotherapy in breast cancer. Our qualitative and quantitative results suggest differential topological behavior of breast tissue on treatment-naive imaging, in patients who respond favorably to therapy versus those who do not.
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