Development of Integrated Machine Learning and Data Science Approaches for the Prediction of Cancer Mutation and Autonomous Drug Discovery of Anti-Cancer Therapeutic Agents

Few technological ideas have captivated the minds of biochemical researchers to the degree that machine learning (ML) and artificial intelligence (AI) have. Over the last few years, advances in the ML field have driven the design of new computational systems that improve with experience and are able to model increasingly complex chemical and biological phenomena. In this dissertation, we capitalize on these achievements and use machine learning to study drug receptor sites and design drugs to target these sites. First, we analyze the significance of various single nucleotide variations and assess their rate of contribution to cancer. Following that, we used a portfolio of machine learning and data science approaches to design new drugs to target protein kinase inhibitors. We show that these techniques exhibit strong promise in aiding cancer research and drug discovery

Unmasking Clever Hans Predictors and Assessing What Machines Really Learn

Current learning machines have successfully solved hard application problems, reaching high accuracy and displaying seemingly "intelligent" behavior. Here we apply recent techniques for explaining decisions of state-of-the-art learning machines and analyze various tasks from computer vision and arcade games. This showcases a spectrum of problem-solving behaviors ranging from naive and short-sighted, to well-informed and strategic. We observe that standard performance evaluation metrics can be oblivious to distinguishing these diverse problem solving behaviors. Furthermore, we propose our semi-automated Spectral Relevance Analysis that provides a practically effective way of characterizing and validating the behavior of nonlinear learning machines. This helps to assess whether a learned model indeed delivers reliably for the problem that it was conceived for. Furthermore, our work intends to add a voice of caution to the ongoing excitement about machine intelligence and pledges to evaluate and judge some of these recent successes in a more nuanced manner.Comment: Accepted for publication in Nature Communication

Artificial Intelligence-Based Drug Design and Discovery

The drug discovery process from hit-to-lead has been a challenging task that requires simultaneously optimizing numerous factors from maximizing compound activity, efficacy to minimizing toxicity and adverse reactions. Recently, the advance of artificial intelligence technique enables drugs to be efficiently purposed in silico prior to chemical synthesis and experimental evaluation. In this chapter, we present fundamental concepts of artificial intelligence and their application in drug design and discovery. The emphasis will be on machine learning and deep learning, which demonstrated extensive utility in many branches of computer-aided drug discovery including de novo drug design, QSAR (Quantitative Structure–Activity Relationship) analysis, drug repurposing and chemical space visualization. We will demonstrate how artificial intelligence techniques can be leveraged for developing chemoinformatics pipelines and presented with real-world case studies and practical applications in drug design and discovery. Finally, we will discuss limitations and future direction to guide this rapidly evolving field

Development of Machine Learning Models for Generation and Activity Prediction of the Protein Tyrosine Kinase Inhibitors

The field of computational drug discovery and development continues to grow at a rapid pace, using generative machine learning approaches to present us with solutions to high dimensional and complex problems in drug discovery and design. In this work, we present a platform of Machine Learning based approaches for generation and scoring of novel kinase inhibitor molecules. We utilized a binary Random Forest classification model to develop a Machine Learning based scoring function to evaluate the generated molecules on Kinase Inhibition Likelihood. By training the model on several chemical features of each known kinase inhibitor, we were able to create a metric that captures the differences between a SRC Kinase Inhibitor and a non-SRC Kinase Inhibitor. We implemented the scoring function into a Biased and Unbiased Bayesian Optimization framework to generate molecules based on features of SRC Kinase Inhibitors. We then used similarity metrics such as Tanimoto Similarity to assess their closeness to that of known SRC Kinase Inhibitors. The molecules generated from this experiment demonstrated potential for belonging to the SRC Kinase Inhibitor family though chemical synthesis would be needed to confirm the results. The top molecules generated from the Unbiased and Biased Bayesian Optimization experiments were calculated to respectively have Tanimoto Similarity scores of 0.711 and 0.709 to known SRC Kinase Inhibitors. With calculated Kinase Inhibition Likelihood scores of 0.586 and 0.575, the top molecules generated from the Bayesian Optimization demonstrate a disconnect between the similarity scores to known SRC Kinase Inhibitors and the calculated Kinase Inhibition Likelihood score. It was found that implementing a bias into the Bayesian Optimization process had little effect on the quality of generated molecules. In addition, several molecules generated from the Bayesian Optimization process were sent to the School of Pharmacy for chemical synthesis which gives the experiment more concrete results. The results of this study demonstrated that generating molecules throughBayesian Optimization techniques could aid in the generation of molecules for a specific kinase family, but further expansions of the techniques would be needed for substantial results

A review on machine learning approaches and trends in drug discovery

Abstract: Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search presents an important component in computer science with the skyrocketing of machine learning techniques due to its democratization. With the objectives set by the Precision Medicine initiative and the new challenges generated, it is necessary to establish robust, standard and reproducible computational methodologies to achieve the objectives set. Currently, predictive models based on Machine Learning have gained great importance in the step prior to preclinical studies. This stage manages to drastically reduce costs and research times in the discovery of new drugs. This review article focuses on how these new methodologies are being used in recent years of research. Analyzing the state of the art in this field will give us an idea of where cheminformatics will be developed in the short term, the limitations it presents and the positive results it has achieved. This review will focus mainly on the methods used to model the molecular data, as well as the biological problems addressed and the Machine Learning algorithms used for drug discovery in recent years.Instituto de Salud Carlos III; PI17/01826Instituto de Salud Carlos III; PI17/01561Xunta de Galicia; Ref. ED431D 2017/16Xunta de Galicia; Ref. ED431D 2017/23Xunta de Galicia; Ref. ED431C 2018/4

Psychobiological factors of resilience and depression in late life.

In contrast to traditional perspectives of resilience as a stable, trait-like characteristic, resilience is now recognized as a multidimentional, dynamic capacity influenced by life-long interactions between internal and environmental resources. We review psychosocial and neurobiological factors associated with resilience to late-life depression (LLD). Recent research has identified both psychosocial characteristics associated with elevated LLD risk (e.g., insecure attachment, neuroticism) and psychosocial processes that may be useful intervention targets (e.g., self-efficacy, sense of purpose, coping behaviors, social support). Psychobiological factors include a variety of endocrine, genetic, inflammatory, metabolic, neural, and cardiovascular processes that bidirectionally interact to affect risk for LLD onset and course of illness. Several resilience-enhancing intervention modalities show promise for the prevention and treatment of LLD, including cognitive/psychological or mind-body (positive psychology; psychotherapy; heart rate variability biofeedback; meditation), movement-based (aerobic exercise; yoga; tai chi), and biological approaches (pharmacotherapy, electroconvulsive therapy). Additional research is needed to further elucidate psychosocial and biological factors that affect risk and course of LLD. In addition, research to identify psychobiological factors predicting differential treatment response to various interventions will be essential to the development of more individualized and effective approaches to the prevention and treatment of LLD

Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis

Simple Summary Metastatic colorectal cancer (mCRC) has high incidence and mortality. Nevertheless, innovative biomarkers have been developed for predicting the response to therapy. We have examined the ability of learning methods to build prognostic and predictive models to predict response to chemotherapy, alone or combined with targeted therapy in mCRC patients, by targeting specific narrative publications. After a literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. We showed that all investigations conducted in this field provided generally promising results in predicting the response to therapy or toxic side-effects, using a meta-analytic approach. We found that radiomics and molecular biomarker signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Our study supports the use of computer science for developing personalized treatment decision processes for mCRC patients. Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set

EGFR and KRAS mutation prediction on lung cancer through medical image processing and artificial intelligence

Lung cancer causes more deaths globally than any other type of cancer. To determine the best treatment, detecting EGFR and KRAS mutations is of interest. However, non-invasive ways to obtain this information are not available. In this study, an ensemble approach is applied to increase the performance of EGFR and KRAS mutation prediction from CT images using a small dataset. A new voting scheme, Selective Class Average Voting (SCAV) is proposed and its performance is assessed both for machine learning models and Convolutional Neural Networks (CNNs). For the EGFR mutation, in the machine learning approach, there was an increase in the Sensitivity from 0.66 to 0.75, and an increase in AUC from 0.68 to 0.70. With the deep learning approach an AUC of 0.846 was obtained with custom CNNs, and with SCAV the Accuracy of the model was increased from 0.80 to 0.857. Finally, when combining the best Custom and Pre-trained CNNs using SCAV an AUC of 0.914 was obtained. For the KRAS mutation both in the machine learning models (0.65 to 0.71 AUC) and the deep learning models (0.739 to 0.778 AUC) a significant increase in performance was found. This increase was even greater with Ensembles of Pre-trained CNNs (0.809 AUC). The results obtained in this work show how to effectively learn from small image datasets to predict EGFR and KRAS mutations, and that using ensembles with SCAV increases the performance of machine learning classifiers and CNNs.DoctoradoDoctor en Ingeniería de Sistemas y Computació