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Register a new userMachine Learning Applications for Therapeutic Tasks with Genomics Data
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Thanks to the increasing availability of genomics and other biomedical data, many machine learning approaches have been proposed for a wide range of therapeutic discovery and development tasks. In this survey, we review the literature on machine learning applications for genomics through the lens of therapeutic development. We investigate the interplay among genomics, compounds, proteins, electronic health records (EHR), cellular images, and clinical texts. We identify twenty-two machine learning in genomics applications across the entire therapeutics pipeline, from discovering novel targets, personalized medicine, developing gene-editing tools all the way to clinical trials and post-market studies. We also pinpoint seven important challenges in this field with opportunities for expansion and impact. This survey overviews recent research at the intersection of machine learning, genomics, and therapeutic development.
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By combining various cancer cell line (CCL) drug screening panels, the size of the data has grown significantly to begin understanding how advances in deep learning can advance drug response predictions. In this paper we train >35,000 neural network models, sweeping over common featurization techniques. We found the RNA-seq to be highly redundant and informative even with subsets larger than 128 features. We found the inclusion of single nucleotide polymorphisms (SNPs) coded as count matrices improved model performance significantly, and no substantial difference in model performance with respect to molecular featurization between the common open source MOrdred descriptors and Dragon7 descriptors. Alongside this analysis, we outline data integration between CCL screening datasets and present evidence that new metrics and imbalanced data techniques, as well as advances in data standardization, need to be developed.
$textbf{Background:}$ At the onset of a pandemic, such as COVID-19, data with proper labeling/attributes corresponding to the new disease might be unavailable or sparse. Machine Learning (ML) models trained with the available data, which is limited in quantity and poor in diversity, will often be biased and inaccurate. At the same time, ML algorithms designed to fight pandemics must have good performance and be developed in a time-sensitive manner. To tackle the challenges of limited data, and label scarcity in the available data, we propose generating conditional synthetic data, to be used alongside real data for developing robust ML models. $textbf{Methods:}$ We present a hybrid model consisting of a conditional generative flow and a classifier for conditional synthetic data generation. The classifier decouples the feature representation for the condition, which is fed to the flow to extract the local noise. We generate synthetic data by manipulating the local noise with fixed conditional feature representation. We also propose a semi-supervised approach to generate synthetic samples in the absence of labels for a majority of the available data. $textbf{Results:}$ We performed conditional synthetic generation for chest computed tomography (CT) scans corresponding to normal, COVID-19, and pneumonia afflicted patients. We show that our method significantly outperforms existing models both on qualitative and quantitative performance, and our semi-supervised approach can efficiently synthesize conditional samples under label scarcity. As an example of downstream use of synthetic data, we show improvement in COVID-19 detection from CT scans with conditional synthetic data augmentation.
One of the outstanding challenges in comparative genomics is to interpret the evolutionary importance of regulatory variation between species. Rigorous molecular evolution-based methods to infer evidence for natural selection from expression data are at a premium in the field, and to date, phylogenetic approaches have not been well-suited to address the question in the small sets of taxa profiled in standard surveys of gene expression. We have developed a strategy to infer evolutionary histories from expression profiles by analyzing suites of genes of common function. In a manner conceptually similar to molecular evolution models in which the evolutionary rates of DNA sequence at multiple loci follow a gamma distribution, we modeled expression of the genes of an emph{a priori}-defined pathway with rates drawn from an inverse gamma distribution. We then developed a fitting strategy to infer the parameters of this distribution from expression measurements, and to identify gene groups whose expression patterns were consistent with evolutionary constraint or rapid evolution in particular species. Simulations confirmed the power and accuracy of our inference method. As an experimental testbed for our approach, we generated and analyzed transcriptional profiles of four emph{Saccharomyces} yeasts. The results revealed pathways with signatures of constrained and accelerated regulatory evolution in individual yeasts and across the phylogeny, highlighting the prevalence of pathway-level expression change during the divergence of yeast species. We anticipate that our pathway-based phylogenetic approach will be of broad utility in the search to understand the evolutionary relevance of regulatory change.
Exploring the genetic basis of heritable traits remains one of the central challenges in biomedical research. In simple cases, single polymorphic loci explain a significant fraction of the phenotype variability. However, many traits of interest appear to be subject to multifactorial control by groups of genetic loci instead. Accurate detection of such multivariate associations is nontrivial and often hindered by limited power. At the same time, confounding influences such as population structure cause spurious association signals that result in false positive findings if they are not accounted for in the model. Here, we propose LMM-Lasso, a mixed model that allows for both, multi-locus mapping and correction for confounding effects. Our approach is simple and free of tuning parameters, effectively controls for population structure and scales to genome-wide datasets. We show practical use in genome-wide association studies and linkage mapping through retrospective analyses. In data from Arabidopsis thaliana and mouse, our method is able to find a genetic cause for significantly greater fractions of phenotype variation in 91% of the phenotypes considered. At the same time, our model dissects this variability into components that result from individual SNP effects and population structure. In addition to this increase of genetic heritability, enrichment of known candidate genes suggests that the associations retrieved by LMM-Lasso are more likely to be genuine.
The study of biological processes can greatly benefit from tools that automatically predict gene functions or directly cluster genes based on shared functionality. Existing data mining methods predict protein functionality by exploiting data obtained from high-throughput experiments or meta-scale information from public databases. Most existing prediction tools are targeted at predicting protein functions that are described in the gene ontology (GO). However, in many cases biologists wish to discover functionally related genes for which GO terms are inadequate. In this paper, we introduce a rich set of features and use them in conjunction with semisupervised learning approaches in order to expand an initial set of seed genes to a larger cluster of functionally related genes. Among all the semi-supervised methods that were evaluated, the framework of learning with positive and unlabeled examples (LPU) is shown to be especially appropriate for mining functionally related genes. When evaluated on experimentally validated benchmark data, the LPU approaches1 significantly outperform a standard supervised learning algorithm as well as an established state-of-the-art method. Given an initial set of seed genes, our best performing approach could be used to mine functionally related genes in a wide range of organisms.
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