20,762 research outputs found
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
Machine Learning and Integrative Analysis of Biomedical Big Data.
Recent developments in high-throughput technologies have accelerated the accumulation of massive amounts of omics data from multiple sources: genome, epigenome, transcriptome, proteome, metabolome, etc. Traditionally, data from each source (e.g., genome) is analyzed in isolation using statistical and machine learning (ML) methods. Integrative analysis of multi-omics and clinical data is key to new biomedical discoveries and advancements in precision medicine. However, data integration poses new computational challenges as well as exacerbates the ones associated with single-omics studies. Specialized computational approaches are required to effectively and efficiently perform integrative analysis of biomedical data acquired from diverse modalities. In this review, we discuss state-of-the-art ML-based approaches for tackling five specific computational challenges associated with integrative analysis: curse of dimensionality, data heterogeneity, missing data, class imbalance and scalability issues
A systematic evaluation of deep learning methods for the prediction of drug synergy in cancer
One of the main obstacles to the successful treatment of cancer is the phenomenon of drug resistance. A common strategy to overcome resistance is the use of combination therapies. However, the space of possibilities is huge and efficient search strategies are required. Machine Learning (ML) can be a useful tool for the discovery of novel, clinically relevant anti-cancer drug combinations. In particular, deep learning (DL) has become a popular choice for modeling drug combination effects. Here, we set out to examine the impact of different methodological choices on the performance of multimodal DL-based drug synergy prediction methods, including the use of different input data types, preprocessing steps and model architectures. Focusing on the NCI ALMANAC dataset, we found that feature selection based on prior biological knowledge has a positive impact on performance. Drug features appeared to be more predictive of drug response. Molecular fingerprint-based drug representations performed slightly better than learned representations, and gene expression data of cancer or drug response-specific genes also improved performance. In general, fully connected feature-encoding subnetworks outperformed other architectures, with DL outperforming other ML methods. Using a state-of-the-art interpretability method, we showed that DL models can learn to associate drug and cell line features with drug response in a biologically meaningful way. The strategies explored in this study will help to improve the development of computational methods for the rational design of effective drug combinations for cancer therapy.Author summary Cancer therapies often fail because tumor cells become resistant to treatment. One way to overcome resistance is by treating patients with a combination of two or more drugs. Some combinations may be more effective than when considering individual drug effects, a phenomenon called drug synergy. Computational drug synergy prediction methods can help to identify new, clinically relevant drug combinations. In this study, we developed several deep learning models for drug synergy prediction. We examined the effect of using different types of deep learning architectures, and different ways of representing drugs and cancer cell lines. We explored the use of biological prior knowledge to select relevant cell line features, and also tested data-driven feature reduction methods. We tested both precomputed drug features and deep learning methods that can directly learn features from raw representations of molecules. We also evaluated whether including genomic features, in addition to gene expression data, improves the predictive performance of the models. Through these experiments, we were able to identify strategies that will help guide the development of new deep learning models for drug synergy prediction in the future.Competing Interest StatementThe authors have declared no competing interest.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit and through a PhD scholarship (SFRH/BD/130913/2017) awarded to Delora Baptista.info:eu-repo/semantics/publishedVersio
Personalised Drug Identifier for Cancer Treatment with Transformers using Auxiliary Information
Cancer remains a global challenge due to its growing clinical and economic
burden. Its uniquely personal manifestation, which makes treatment difficult,
has fuelled the quest for personalized treatment strategies. Thus, genomic
profiling is increasingly becoming part of clinical diagnostic panels.
Effective use of such panels requires accurate drug response prediction (DRP)
models, which are challenging to build due to limited labelled patient data.
Previous methods to address this problem have used various forms of transfer
learning. However, they do not explicitly model the variable length sequential
structure of the list of mutations in such diagnostic panels. Further, they do
not utilize auxiliary information (like patient survival) for model training.
We address these limitations through a novel transformer based method, which
surpasses the performance of state-of-the-art DRP models on benchmark data. We
also present the design of a treatment recommendation system (TRS), which is
currently deployed at the National University Hospital, Singapore and is being
evaluated in a clinical trial
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