Predicting drug response of tumors from integrated genomic profiles by deep neural networks

The study of high-throughput genomic profiles from a pharmacogenomics viewpoint has provided unprecedented insights into the oncogenic features modulating drug response. A recent screening of ~1,000 cancer cell lines to a collection of anti-cancer drugs illuminated the link between genotypes and vulnerability. However, due to essential differences between cell lines and tumors, the translation into predicting drug response in tumors remains challenging. Here we proposed a DNN model to predict drug response based on mutation and expression profiles of a cancer cell or a tumor. The model contains a mutation and an expression encoders pre-trained using a large pan-cancer dataset to abstract core representations of high-dimension data, followed by a drug response predictor network. Given a pair of mutation and expression profiles, the model predicts IC50 values of 265 drugs. We trained and tested the model on a dataset of 622 cancer cell lines and achieved an overall prediction performance of mean squared error at 1.96 (log-scale IC50 values). The performance was superior in prediction error or stability than two classical methods and four analog DNNs of our model. We then applied the model to predict drug response of 9,059 tumors of 33 cancer types. The model predicted both known, including EGFR inhibitors in non-small cell lung cancer and tamoxifen in ER+ breast cancer, and novel drug targets. The comprehensive analysis further revealed the molecular mechanisms underlying the resistance to a chemotherapeutic drug docetaxel in a pan-cancer setting and the anti-cancer potential of a novel agent, CX-5461, in treating gliomas and hematopoietic malignancies. Overall, our model and findings improve the prediction of drug response and the identification of novel therapeutic options.Comment: Accepted for presentation in the International Conference on Intelligent Biology and Medicine (ICIBM 2018) at Los Angeles, CA, USA. Currently under consideration for publication in a Supplement Issue of BMC Genomic

Measles Rash Identification Using Residual Deep Convolutional Neural Network

Measles is extremely contagious and is one of the leading causes of vaccine-preventable illness and death in developing countries, claiming more than 100,000 lives each year. Measles was declared eliminated in the US in 2000 due to decades of successful vaccination for the measles. As a result, an increasing number of US healthcare professionals and the public have never seen the disease. Unfortunately, the Measles resurged in the US in 2019 with 1,282 confirmed cases. To assist in diagnosing measles, we collected more than 1300 images of a variety of skin conditions, with which we employed residual deep convolutional neural network to distinguish measles rash from other skin conditions, in an aim to create a phone application in the future. On our image dataset, our model reaches a classification accuracy of 95.2%, sensitivity of 81.7%, and specificity of 97.1%, indicating the model is effective in facilitating an accurate detection of measles to help contain measles outbreaks

A Predictive Model for Assessment of Successful Outcome in Posterior Spinal Fusion Surgery

Background: Low back pain is a common problem in many people. Neurosurgeons recommend posterior spinal fusion (PSF) surgery as one of the therapeutic strategies to the patients with low back pain. Due to the high risk of this type of surgery and the critical importance of making the right decision, accurate prediction of the surgical outcome is one of the main concerns for the neurosurgeons.Methods: In this study, 12 types of multi-layer perceptron (MLP) networks and 66 radial basis function (RBF) networks as the types of artificial neural network methods and a logistic regression (LR) model created and compared to predict the satisfaction with PSF surgery as one of the most well-known spinal surgeries.Results: The most important clinical and radiologic features as twenty-seven factors for 480 patients (150 males, 330 females; mean age 52.32 ± 8.39 years) were considered as the model inputs that included: age, sex, type of disorder, duration of symptoms, job, walking distance without pain (WDP), walking distance without sensory (WDS) disorders, visual analog scale (VAS) scores, Japanese Orthopaedic Association (JOA) score, diabetes, smoking, knee pain (KP), pelvic pain (PP), osteoporosis, spinal deformity and etc. The indexes such as receiver operating characteristic–area under curve (ROC-AUC), positive predictive value, negative predictive value and accuracy calculated to determine the best model. Postsurgical satisfaction was 77.5% at 6 months follow-up. The patients divided into the training, testing, and validation data sets.Conclusion: The findings showed that the MLP model performed better in comparison with RBF and LR models for prediction of PSF surgery.Keywords: Posterior spinal fusion surgery (PSF); Prediction, Surgical satisfaction; Multi-layer perceptron (MLP); Logistic regression (LR) (PDF) A Predictive Model for Assessment of Successful Outcome in Posterior Spinal Fusion Surgery. Available from: https://www.researchgate.net/publication/325679954_A_Predictive_Model_for_Assessment_of_Successful_Outcome_in_Posterior_Spinal_Fusion_Surgery [accessed Jul 11 2019].Peer reviewe

Anticancer drug synergy prediction in understudied tissues using transfer learning

ocaa212Objective: Drug combination screening has advantages in identifying cancer treatment options with higher efficacy without degradation in terms of safety. A key challenge is that the accumulated number of observations in in-vitro drug responses varies greatly among different cancer types, where some tissues are more understudied than the others. Thus, we aim to develop a drug synergy prediction model for understudied tissues as a way of overcoming data scarcity problems. Materials and Methods: We collected a comprehensive set of genetic, molecular, phenotypic features for cancer cell lines. We developed a drug synergy prediction model based on multitask deep neural networks to integrate multimodal input and multiple output. We also utilized transfer learning from data-rich tissues to data-poor tissues. Results: We showed improved accuracy in predicting synergy in both data-rich tissues and understudied tissues. In data-rich tissue, the prediction model accuracy was 0.9577 AUROC for binarized classification task and 174.3 mean squared error for regression task. We observed that an adequate transfer learning strategy significantly increases accuracy in the understudied tissues. Conclusions: Our synergy prediction model can be used to rank synergistic drug combinations in understudied tissues and thus help to prioritize future in-vitro experiments. Code is available at https://github.com/yejinjkim/synergy-transfer.Peer reviewe

Addendum to Informatics for Health 2017: Advancing both science and practice

This article presents presentation and poster abstracts that were mistakenly omitted from the original publication

Deep transfer learning for drug response prediction

The goal of precision oncology is to make accurate predictions for cancer patients via some omics data types of individual patients. Major challenges of computational methods for drug response prediction are that labeled clinical data is very limited, not publicly available, or has drug response for one or two drugs. These challenges have been addressed by generating large-scale pre-clinical datasets such as cancer cell lines or patient-derived xenografts (PDX). These pre-clinical datasets have multi-omics characterization of samples and are often screened with hundreds of drugs which makes them viable resources for precision oncology. However, they raise new questions: how can we integrate different data types? how can we handle data discrepancy between pre-clinical and clinical datasets that exist due to basic biological differences? and how can we make the best use of unlabeled samples in drug response prediction where labeling is extra challenging? In this thesis, we propose methods based on deep neural networks to answer these questions. First, we propose a method of multi-omics integration. Second, we propose a transfer learning method to address data discrepancy between cell lines, patients, and PDX models in the input and output space. Finally, we proposed a semi-supervised method of out-of-distribution generalization to predict drug response using labeled and unlabeled samples. The proposed methods have promising performance when compared to the state-of-the-art and may guide precision oncology more accurately

Personalized Medicine: Studies of Pharmacogenomics in Yeast and Cancer

Advances in microarray and sequencing technology enable the era of personalized medicine. With increasing availability of genomic assays, clinicians have started to utilize genetics and gene expression of patients to guide clinical care. Signatures of gene expression and genetic variation in genes have been associated with disease risks and response to clinical treatment. It is therefore not difficult to envision a future where each patient will have clinical care that is optimized based on his or her genetic background and genomic profiles. However, many challenges exist towards the full realization of the potential personalized medicine. The human genome is complex and we have yet to gain a better understanding of how to associate genomic data with phenotype. First, the human genome is very complex: more than 50 million sequence variants and more than 20,000 genes have been reported. Many efforts have been devoted to genome-wide association studies (GWAS) in the last decade, associating common genetic variants with common complex traits and diseases. While many associations have been identified by genome-wide association studies, most of our phenotypic variation remains unexplained, both at the level of the variants involved and the underlying mechanism. Finally, interaction between genetics and environment presents additional layer of complexity governing phenotypic variation. Currently, there is much research developing computational methods to help associate genomic features with phenotypic variation. Modeling techniques such as machine learning have been very useful in uncovering the intricate relationships between genomics and phenotype. Despite some early successes, the performance of most models is disappointing. Many models lack robustness and predictions do not replicate. In addition, many successful models work as a black box, giving good predictions of phenotypic variation but unable to reveal the underlying mechanism. In this thesis I propose two methods addressing this challenge. First, I describe an algorithm that focuses on identifying causal genomic features of phenotype. My approach assumes genomic features predictive of phenotype are more likely to be causal. The algorithm builds models that not only accurately predict the traits, but also uncover molecular mechanisms that are responsible for these traits. . The algorithm gains its power by combining regularized linear regression, causality testing and Bayesian statistics. I demonstrate the application of the algorithm on a yeast dataset, where genotype and gene expression are used to predict drug sensitivity and elucidate the underlying mechanisms. The accuracy and robustness of the algorithm are both evaluated statistically and experimentally validated. The second part of the thesis takes on a much more complicated system: cancer. The availability of genomic and drug sensitivity data of cancer cell lines has recently been made available. The challenge here is not only the increasing complexity of the system (e.g. size of genome), but also the fundamental differences between cancers and tissues. Different cancers or tissues provide different contexts influencing regulatory networks and signaling pathways. In order to account for this, I propose a method to associate contextual genomic features with drug sensitivity. The algorithm is based on information theory, Bayesian statistics, and transfer learning. The algorithm demonstrates the importance of context specificity in predictive modeling of cancer pharmacogenomics. The two complementary algorithms highlight the challenges faced in personalized medicine and the potential solutions. This thesis detailed the results and analysis that demonstrate the importance of causality and context specificity in predictive modeling of drug response, which will be crucial for us towards bringing personalized medicine in practice