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Titus, A. J.

Publications and source records attributed to Titus, A. J..

8 recordsLinked to original sources

tfboot: Bootstrapping and statistical analysis for transcription factor binding site-disrupting variants in gene sets

MotivationGenetic variants in noncoding regions can drive changes in phenotype disrupting transcription factor binding site (TFBS) motifs. Other tools including motifbreakR have been developed to assess the impact of TFBS-disrupting variants. Here we introduce the tfboot package for statistically evaluating the TFBS disruption across a set of variants in upstream promoter regions. ResultsThe tfboot package builds on motifbreakR, plyranges, and GenomicRanges to provide methods for bootstrapping TFBS disruption to statistically quantify the impact across gene sets of interest compared to an empirical null distribution. We demonstrate the analysis here on variants in the elephant genome. The tfboot package readily integrates with Bioconductor and tidyverse-based workflows. AvailabilityThe tfboot package is implemented as an R package and is released under the MIT license at https://github.com/colossal-compsci/tfboot.

bioinformatics↗

FLAG: Find, Label Annotate Genomes, a fully automated tool for genome gene structural and functional annotation of highly fragmented non-model species

Recent advances in long-read sequencing technologies and the efforts of projects aimed at increasing the universe of sequenced reference genomes have led to a growth in the number of whole genomes sequenced for non-model organisms. Still, 81% of the over 36,000 unique publicly available eukaryotic genomes in the NCBI database lack gene structure annotations (1). While there are many open-source tools available for each step in the annotation process, many of these tools are designed for chromosomal assemblies with available transcript data from the same or very closely related organisms. Here we present "Find, Label, Annotate Genomes" (FLAG), a fully automated genome annotation workflow. FLAG (i) works on any computing environment, (ii) runs automatically without initial training data, (iii) generates structural and functional annotations, (iv) performs accurately with fragmented genomes, (v) does not require species-specific extrinsic evidence (transcript sequences) and (vi) includes quality control steps to evaluate annotation completeness. We compared the gene annotations generated by FLAG and publicly available annotations from 12 eukaryotic organisms, including 1 plant, 8 living animals, and 1 extinct animal. In fragmented genomes, FLAG annotations provided an average of 18% increase in complete BUSCO scores and 15x lower error rate for the predicted number of protein-coding genes when compared to published BRAKER2 annotations. With FLAG-Refiner further improved results by decreasing the error rate to 17x lower when compared to published BRAKER2 annotations. In high-quality model organisms, FLAG demonstrates comparable results to those of the NCBI EGAP pipeline, underscoring its robustness and accuracy in gene prediction across diverse taxa and assembly qualities.

bioinformatics↗

Bioacoustic Event Detection with Self-SupervisedContrastive Learning

While deep learning has revolutionized ecological data analysis, existing strategies often rely on supervised learning, which is subject to limitations on real-world applicability. In this paper, we apply self-supervised deep learning methods to bioacoustic data to enable unsupervised detection of bioacoustic event boundaries. We propose a convolutional deep neural network that operates on the raw waveform directly and is trained in accordance with the Noise Contrastive Estimation principle, which enables the system to detect spectral changes in the input acoustic stream. The model learns a representation of the input audio sampled at low frequency that encodes information regarding dissimilarity between sequential acoustic windows. During inference, we use a peak finding algorithm to search for regions of high dissimilarity in order to identify temporal boundaries of bioacoustic events. We report results using these techniques to detect sperm whale (Physeter macrocephalus) coda clicks in real-world recordings, and we demonstrate the viability of analyzing the vocalizations of other species (e.g. Bengalese finch syllable segmentation) in addition to other data modalities (e.g. animal behavioral dynamics, embryo development and tracking). We find that the self-supervised deep representation learning-based technique outperforms established threshold-based baseline methods without requiring manual annotation of acoustic datasets. Quantitatively, our approach yields a maximal R-value and F1-score of 0.887 and 0.876, respectively, and an area under the Precision-Recall curve (PR-AUC) of 0.917, while a baseline threshold detector acting on signal energy amplitude returns a maximal R-value and F1-score of 0.620 and 0.576, respectively, and a PR-AUC of 0.571. We also compare with a threshold detector using preprocessed (e.g. denoised) acoustic input. The findings of this paper establish the validity of unsupervised bioacoustic event detection using deep neural networks and self-supervised contrastive learning as an effective alternative to conventional techniques that leverage supervised methods for signal presence indication. Providing a means for highly accurate unsupervised detection, this paper serves as an important step towards developing a fully automated system for real-time acoustic monitoring of bioacoustic signals in real-world acoustic data. All code and data used in this study are available online.

ecology↗

Investigation of Capsule-Inspired Neural Network Approaches for DNA Methylation

DNA methylation (DNAm) alterations have been heavily implicated in carcinogenesis and the pathophysiology of diseases through upstream regulation of gene expression. DNAm deep-learning approaches are able to capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. Here, we present modular, user-friendly deep learning methodology and software, MethylCapsNet and MethylSPWNet, that group CpGs into biologically relevant capsules - such as gene promoter context, CpG island relationship, or user-defined groupings - and relate them to diagnostic and prognostic outcomes. We demonstrate these models utility on 3,897 individuals in the classification of central nervous system (CNS) tumors. MethylCapsNet and MethylSPWNet provide an opportunity to increase DNAm deep learning analyses interpretability by enabling a flexible organization of DNAm data into biologically relevant capsules.

bioinformatics↗

MethylNet: A Modular Deep Learning Approach to Methylation Prediction

BackgroundDNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have not yet been formalized into user-friendly frameworks for execution, training, and interpreting models. Here, we describe MethylNet, a DNAm deep learning method that can construct embeddings, make predictions, generate new data, and uncover unknown heterogeneity with minimal user supervision. ResultsThe results of our experiments indicate that MethylNet can study cellular differences, grasp higher order information of cancer sub-types, estimate age and capture factors associated with smoking in concordance with known differences. ConclusionThe ability of MethylNet to capture nonlinear interactions presents an opportunity for further study of unknown disease, cellular heterogeneity and aging processes.

bioinformatics↗

PyMethylProcess - highly parallelized preprocessing for DNA methylation array data

SummaryThe ability to perform high-throughput preprocessing of methylation array data is essential in large scale methylation studies. While R is a convenient language for methylation analyses, performing highly parallelized preprocessing using Python can accelerate data preparation for downstream methylation analyses, including large scale production-ready machine learning pipelines. Here, we present a methylation data preprocessing pipeline called PyMethylProcess that is highly reproducible, scalable, and that can be quickly set-up and deployed through Docker and PIP.\n\nAvailability and ImplementationProject Name: PyMethylProcess\n\nProject Home Page: https://github.com/Christensen-Lab-Dartmouth/PyMethylProcess. Available on PyPI as pymethylprocess.\n\nAvailable on DockerHub via joshualevy44/pymethylprocess.\n\nHelp Documentation: https://christensen-lab-dartmouth.github.io/PyMethylProcess/\n\nOperating Systems: Linux, MacOS, Windows (Docker)\n\nProgramming Language: Python, R\n\nOther Requirements: Python 3.6, R 3.5.1, Docker (optional) License: MIT\n\nContactjoshua.j.levy.gr@dartmouth.edu

epidemiology↗

An unsupervised deep learning framework with variational autoencoders for genome-wide DNA methylation analysis and biologic feature extraction applied to breast cancer

Recent advances in deep learning, particularly unsupervised approaches, have shown promise for furthering our biological knowledge through their application to gene expression datasets, though applications to epigenomic data are lacking. Here, we employ an unsupervised deep learning framework with variational autoencoders (VAEs) to learn latent representations of the DNA methylation landscape from three independent breast tumor datasets. Through interrogation of methylation-based learned latent dimension activation values, we demonstrate the feasibility of VAEs to track representative differential methylation patterns among clinical subtypes of tumors. CpGs whose methylation was most correlated VAE latent dimension activation values were significantly enriched for CpG sparse regulatory regions of the genome including enhancer regions. In addition, through comparison with LASSO, we show the utility of the VAE approach for revealing novel information about CpG DNA methylation patterns in breast cancer.

bioinformatics↗

Reference-free deconvolution of DNA methylation signatures identifies common differentially methylated gene regions on 1p36 across breast cancer subtypes

Breast cancer is a complex disease and studying DNA methylation (DNAm) in tumors is complicated by disease heterogeneity. We compared DNAm in breast tumors with normal-adjacent breast samples from The Cancer Genome Atlas (TCGA). We constructed models stratified by tumor stage and PAM50 molecular subtype and performed cell-type reference-free deconvolution on each model. We identified nineteen differentially methylated gene regions (DMGRs) in early stage tumors across eleven genes (AGRN, C1orf170, FAM41C, FLJ39609, HES4, ISG15, KLHL17, NOC2L, PLEKHN1, SAMD11, WASH5P). These regions were consistently differentially methylated in every subtype and all implicated genes are localized on chromosome 1p36.3. We also validated seventeen DMGRs in an independent data set. Identification and validation of shared DNAm alterations across tumor subtypes in early stage tumors advances our understanding of common biology underlying breast carcinogenesis and may contribute to biomarker development. We also provide evidence on the importance and potential function of 1p36 in cancer.

genomics↗