INTRODUCTION Diverse phenotypes, including large brains relative to body size, group living, and vocal learning ability, have evolved multiple times throughout mammalian history. These shared phenotypes may have arisen repeatedly by means of common mechanisms discernible through genome comparisons. RATIONALE Protein-coding sequence differences have failed to fully explain the evolution of multiple mammalian phenotypes. This suggests that these phenotypes have evolved at least in part through changes in gene expression, meaning that their differences across species may be caused by differences in genome sequence at enhancer regions that control gene expression in specific tissues and cell types. Yet the enhancers involved in phenotype evolution are largely unknown. Sequence conservation–based approaches for identifying such enhancers are limited because enhancer activity can be conserved even when the individual nucleotides within the sequence are poorly conserved. This is due to an overwhelming number of cases where nucleotides turn over at a high rate, but a similar combination of transcription factor binding sites and other sequence features can be maintained across millions of years of evolution, allowing the function of the enhancer to be conserved in a particular cell type or tissue. Experimentally measuring the function of orthologous enhancers across dozens of species is currently infeasible, but new machine learning methods make it possible to make reliable sequence-based predictions of enhancer function across species in specific tissues and cell types. RESULTS To overcome the limits of studying individual nucleotides, we developed the Tissue-Aware Conservation Inference Toolkit (TACIT). Rather than measuring the extent to which individual nucleotides are conserved across a region, TACIT uses machine learning to test whether the function of a given part of the genome is likely to be conserved. More specifically, convolutional neural networks learn the tissue- or cell type–specific regulatory code connecting genome sequence to enhancer activity using candidate enhancers identified from only a few species. This approach allows us to accurately associate differences between species in tissue or cell type–specific enhancer activity with genome sequence differences at enhancer orthologs. We then connect these predictions of enhancer function to phenotypes across hundreds of mammals in a way that accounts for species’ phylogenetic relatedness. We applied TACIT to identify candidate enhancers from motor cortex and parvalbumin neuron open chromatin data that are associated with brain size relative to body size, solitary living, and vocal learning across 222 mammals. Our results include the identification of multiple candidate enhancers associated with brain size relative to body size, several of which are located in linear or three-dimensional proximity to genes whose protein-coding mutations have been implicated in microcephaly or macrocephaly in humans. We also identified candidate enhancers associated with the evolution of solitary living near a gene implicated in separation anxiety and other enhancers associated with the evolution of vocal learning ability. We obtained distinct results for bulk motor cortex and parvalbumin neurons, demonstrating the value in applying TACIT to both bulk tissue and specific minority cell type populations. To facilitate future analyses of our results and applications of TACIT, we released predicted enhancer activity of >400,000 candidate enhancers in each of 222 mammals and their associations with the phenotypes we investigated. CONCLUSION TACIT leverages predicted enhancer activity conservation rather than nucleotide-level conservation to connect genetic sequence differences between species to phenotypes across large numbers of mammals. TACIT can be applied to any phenotype with enhancer activity data available from at least a few species in a relevant tissue or cell type and a whole-genome alignment available across dozens of species with substantial phenotypic variation. Although we developed TACIT for transcriptional enhancers, it could also be applied to genomic regions involved in other components of gene regulation, such as promoters and splicing enhancers and silencers. As the number of sequenced genomes grows, machine learning approaches such as TACIT have the potential to help make sense of how conservation of, or changes in, subtle genome patterns can help explain phenotype evolution. Tissue-Aware Conservation Inference Toolkit (TACIT) associates genetic differences between species with phenotypes. TACIT works by generating open chromatin data from a few species in a tissue related to a phenotype, using the sequences underlying open and closed chromatin regions to train a machine learning model for predicting tissue-specific open chromatin and associating open chromatin predictions across dozens of mammals with the phenotype. [Species silhouettes are from PhyloPic]
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Optimized CNN-based Diagnosis System to Detect the Pneumonia from Chest Radiographs
Pneumonia is a high mortality disease that kills 50, 000 people in the United States each year. Children under the age of 5 and older population over the age of 65 are susceptible to serious cases of pneumonia. The United States spend billions of dollars fighting pneumonia-related infections every year. Early detection and intervention are crucial in treating pneumonia related infections. Since chest x-ray is one of the simplest and cheapest methods to diagnose pneumonia, we propose a deep learning algorithm based on convolutional neural networks to identify and classify pneumonia cases from these images. For all three models implemented, we obtained varying classification results and accuracy. Based on the results, we obtained better prediction with average accuracy of (68%) and average specificity of (69%) in contrast to the current state-of-the-art accuracy that is (51%) using the Visual Geometry Group (VGG16 also called OxfordNet), which is a convolutional neural network architecture developed by the Visual Geometry Group of Oxford. By implementing more novel lung segmentation techniques, reducing over fitting, and adding more learning layers, the proposed model has the potential to predict at higher accuracy than human specialists and will help subsidies and reduce the cost of diagnosis across the globe.
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- Award ID(s):
- 1925960
- NSF-PAR ID:
- 10140313
- Date Published:
- Journal Name:
- Proceedings of IEEE International Conference on Bioinformatics and Biomedicine (BIBM)
- Page Range / eLocation ID:
- 2405 to 2412
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objective . Understanding neural activity patterns in the developing brain remains one of the grand challenges in neuroscience. Developing neural networks are likely to be endowed with functionally important variability associated with the environmental context, age, gender, and other variables. Therefore, we conducted experiments with typically developing children in a stimulating museum setting and tested the feasibility of using deep learning techniques to help identify patterns of brain activity associated with different conditions.Approach . A four-channel dry EEG-based Mobile brain-body imaging data of children at rest and during videogame play (VGP) was acquired at the Children’s Museum of Houston. A data-driven approach based on convolutional neural networks (CNN) was used to describe underlying feature representations in the EEG and their ability to discern task and gender. The variability of the spectral features of EEG during the rest condition as a function of age was also analyzed.Main results . Alpha power (7–13 Hz) was higher during rest whereas theta power (4–7 Hz) was higher during VGP. Beta (13–18 Hz) power was the most significant feature, higher in females, when differentiating between males and females. Using data from both temporoparietal channels to classify between VGP and rest condition, leave-one-subject-out cross-validation accuracy of 67% was obtained. Age-related changes in EEG spectral content during rest were consistent with previous developmental studies conducted in laboratory settings showing an inverse relationship between age and EEG power.Significance . These findings are the first to acquire, quantify and explain brain patterns observed during VGP and rest in freely behaving children in a museum setting using a deep learning framework. The study shows how deep learning can be used as a data driven approach to identify patterns in the data and explores the issues and the potential of conducting experiments involving children in a natural and engaging environment.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Conference Paper:
- https://doi.org/10.1109/BIBM47256.2019.8983114
