Spectral methods for the detection and characterization of Topologically Associated Domains

The three-dimensional (3D) structure of the genome plays a crucial role in gene expression regulation. Chromatin conformation capture technologies (Hi-C) have revealed that the genome is organized in a hierarchy of topologically associated domains (TADs), sub-TADs, and chromatin loops which is relatively stable across cell-lines and even across species. These TADs dynamically reorganize during development of disease, and exhibit cell- and conditionspecific differences. Identifying such hierarchical structures and how they change between conditions is a critical step in understanding genome regulation and disease development. Despite their importance, there are relatively few tools for identification of TADs and even fewer for identification of hierarchies. Additionally, there are no publicly available tools for comparison of TADs across datasets. These tools are necessary to conduct large-scale genome-wide analysis and comparison of 3D structure. To address the challenge of TAD identification, we developed a novel sliding window-based spectral clustering framework that uses gaps between consecutive eigenvectors for TAD boundary identification. Our method, implemented in an R package, SpectralTAD, has automatic parameter selection, is robust to sequencing depth, resolution and sparsity of Hi-C data, and detects hierarchical, biologically relevant TADs. SpectralTAD outperforms four state-of-the-art TAD callers in simulated and experimental settings. We demonstrate that TAD boundaries shared among multiple levels of the TAD hierarchy were more enriched in classical boundary marks and more conserved across cell lines and tissues. SpectralTAD is available at http://bioconductor.org/packages/SpectralTAD/. To address the problem of TAD comparison, we developed TADCompare. TADCompare is based on a spectral clustering-derived measure called the eigenvector gap, which enables a loci-by-loci comparison of TAD boundary differences between datasets. Using this measure, we introduce methods for identifying differential and consensus TAD boundaries and tracking TAD boundary changes over time. We further propose a novel framework for the systematic classification of TAD boundary changes. Colocalization- and gene enrichment analysis of different types of TAD boundary changes revealed distinct biological functionality associated with them. TADCompare is available on https://github.com/dozmorovlab/TADCompare

Quantifying Variation in Gait Features from Wearable Inertial Sensors Using Mixed Effects Models

The emerging technology of wearable inertial sensors has shown its advantages in collecting continuous longitudinal gait data outside laboratories. This freedom also presents challenges in collecting high-fidelity gait data. In the free-living environment, without constant supervision from researchers, sensor-based gait features are susceptible to variation from confounding factors such as gait speed and mounting uncertainty, which are challenging to control or estimate. This paper is one of the first attempts in the field to tackle such challenges using statistical modeling. By accepting the uncertainties and variation associated with wearable sensor-based gait data, we shift our efforts from detecting and correcting those variations to modeling them statistically. From gait data collected on one healthy, non-elderly subject during 48 full-factorial trials, we identified four major sources of variation, and quantified their impact on one gait outcome—range per cycle—using a random effects model and a fixed effects model. The methodology developed in this paper lays the groundwork for a statistical framework to account for sources of variation in wearable gait data, thus facilitating informative statistical inference for free-living gait analysis