Fast and accurate exhaustive higher-order epistasis search with BitEpi.

Complex genetic diseases may be modulated by a large number of epistatic interactions affecting a polygenic phenotype. Identifying these interactions is difficult due to computational complexity, especially in the case of higher-order interactions where more than two genomic variants are involved. In this paper, we present BitEpi, a fast and accurate method to test all possible combinations of up to four bi-allelic variants (i.e. Single Nucleotide Variant or SNV for short). BitEpi introduces a novel bitwise algorithm that is 1.7 and 56 times faster for 3-SNV and 4-SNV search, than established software. The novel entropy statistic used in BitEpi is 44% more accurate to identify interactive SNVs, incorporating a p-value-based significance testing. We demonstrate BitEpi on real world data of 4900 samples and 87,000 SNPs. We also present EpiExplorer to visualize the potentially large number of individual and interacting SNVs in an interactive Cytoscape graph. EpiExplorer uses various visual elements to facilitate the discovery of true biological events in a complex polygenic environment.

INSIDER: alignment-free detection of foreign DNA sequences.

External DNA sequences can be inserted into an organism's genome either through natural processes such as gene transfer, or through targeted genome engineering strategies. Being able to robustly identify such foreign DNA is a crucial capability for health and biosecurity applications, such as anti-microbial resistance (AMR) detection or monitoring gene drives. This capability does not exist for poorly characterised host genomes or with limited information about the integrated sequence. To address this, we developed the INserted Sequence Information DEtectoR (INSIDER). INSIDER analyses whole genome sequencing data and identifies segments of potentially foreign origin by their significant shift in k-mer signatures. We demonstrate the power of INSIDER to separate integrated DNA sequences from normal genomic sequences on a synthetic dataset simulating the insertion of a CRISPR-Cas gene drive into wild-type yeast. As a proof-of-concept, we use INSIDER to detect the exact AMR plasmid in whole genome sequencing data from a Citrobacter freundii patient isolate. INSIDER streamlines the process of identifying integrated DNA in poorly characterised wild species or when the insert is of unknown origin, thus enhancing the monitoring of emerging biosecurity threats.

Using wearable cameras to monitor eating and drinking behaviours during transport journeys.

PURPOSE: Young adults are vulnerable to weight gain and dietary behaviours such as 'eating on the run' are likely contributors. The objective of this study was to examine eating and drinking behaviours during transport journeys in a sample of young adults using wearable cameras that take continuous images every 30 s. METHODS: Seventy-eight 18-30 year olds wore an Autographer wearable camera for three consecutive days. Image coding schedules were designed to assess physical activity (included transportation) and diet. For the general description of data, frequency analysis was calculated as image number (percentage) and mean (± SD) or median (IQR) when appropriate. RESULTS: A total of 281,041 images were coded and 32,529 (14%) of images involved transport. The median (IQR) camera wear time was 8 h per day (7-9 h). The camera images identified 52 participants (67%) either eating or drinking during transport (excluding water). A total of 143 eating and drinking occasions were identified, averaging 3 occasions per person over the three study days. Fifty five (38%) eating episodes were identified by the camera images of which 27 (49%) were discretionary and 88 (62%) drinking episodes were identified of which (45%) were discretionary. CONCLUSION: This study confirms that transport is a potential setting for intervention. Young adults are consuming discretionary food and beverages during transport which may contribute to energy-dense diets and compromise diet quality. Substituting unhealthy with healthy food advertising and potentially prohibiting eating and drinking whilst on public transport is suggested.

Feasibility Study Comparing Physical Activity Classifications from Accelerometers with Wearable Camera Data.

Device-based assessments are frequently used to measure physical activity (PA) but contextual measures are often lacking. There is a need for new methods, and one under-explored option is the use of wearable cameras. This study tested the use of wearable cameras in PA measurement by comparing intensity classifications from accelerometers with wearable camera data. Seventy-eight 18-30-year-olds wore an Actigraph GT9X link accelerometer and Autographer wearable camera for three consecutive days. An image coding schedule was designed to assess activity categories and activity sub-categories defined by the 2011 Compendium of Physical Activities (Compendium). Accelerometer hourly detailed files processed using the Montoye (2020) cut-points were linked to camera data using date and time stamps. Agreement was examined using equivalence testing, intraclass correlation coefficient (ICC) and Spearman's correlation coefficient (rho). Fifty-three participants contributing 636 person-hours were included. Reliability was moderate to good for sedentary behavior (rho = 0.77), light intensity activities (rho = 0.59) and moderate-to-vigorous physical activity (MVPA) (rho = 0.51). The estimates of sedentary behavior, light activity and MVPA from the two methods were similar, but not equivalent. Wearable cameras are a potential complementary tool for PA measurement, but practical challenges and limitations exist. While wearable cameras may not be feasible for use in large scale studies, they may be feasible in small scale studies where context is important.

VariantSpark: Cloud-based machine learning for association study of complex phenotype and large-scale genomic data.

BACKGROUND: Many traits and diseases are thought to be driven by >1 gene (polygenic). Polygenic risk scores (PRS) hence expand on genome-wide association studies by taking multiple genes into account when risk models are built. However, PRS only considers the additive effect of individual genes but not epistatic interactions or the combination of individual and interacting drivers. While evidence of epistatic interactions ais found in small datasets, large datasets have not been processed yet owing to the high computational complexity of the search for epistatic interactions. FINDINGS: We have developed VariantSpark, a distributed machine learning framework able to perform association analysis for complex phenotypes that are polygenic and potentially involve a large number of epistatic interactions. Efficient multi-layer parallelization allows VariantSpark to scale to the whole genome of population-scale datasets with 100,000,000 genomic variants and 100,000 samples. CONCLUSIONS: Compared with traditional monogenic genome-wide association studies, VariantSpark better identifies genomic variants associated with complex phenotypes. VariantSpark is 3.6 times faster than ReForeSt and the only method able to scale to ultra-high-dimensional genomic data in a manageable time.

Supporting pandemic response using genomics and bioinformatics: A case study on the emergent SARS-CoV-2 outbreak.

Pre-clinical responses to fast-moving infectious disease outbreaks heavily depend on choosing the best isolates for animal models that inform diagnostics, vaccines and treatments. Current approaches are driven by practical considerations (e.g. first available virus isolate) rather than a detailed analysis of the characteristics of the virus strain chosen, which can lead to animal models that are not representative of the circulating or emerging clusters. Here, we suggest a combination of epidemiological, experimental and bioinformatic considerations when choosing virus strains for animal model generation. We discuss the currently chosen SARS-CoV-2 strains for international coronavirus disease (COVID-19) models in the context of their phylogeny as well as in a novel alignment-free bioinformatic approach. Unlike phylogenetic trees, which focus on individual shared mutations, this new approach assesses genome-wide co-developing functionalities and hence offers a more fluid view of the 'cloud of variances' that RNA viruses are prone to accumulate. This joint approach concludes that while the current animal models cover the existing viral strains adequately, there is substantial evolutionary activity that is likely not considered by the current models. Based on insights from the non-discrete alignment-free approach and experimental observations, we suggest isolates for future animal models.

Macronutrient intakes and the lifespan-fecundity trade-off: a geometric framework agent-based model.

Lifespan and fecundity, the main components in evolutionary fitness, are both strongly affected by nutritional state. Geometric framework of nutrition (GFN) experiments has shown that lifespan and fecundity are separated in nutrient space leading to a functional trade-off between the two traits. Here we develop a spatially explicit agent-based model (ABM) using the GFN to explore how ecological factors may cause selection on macronutrient appetites to optimally balance these life-history traits. We show that increasing the risk of extrinsic mortality favours intake of a mixture of nutrients that is associated with maximal fecundity at the expense of reduced longevity and that this result is robust across spatial and nutritional environments. These model behaviours are consistent with what has been observed in studies that quantify changes in life history in response to environmental manipulations. Previous GFN-derived ABMs have treated fitness as a single value. This is the first such model to instead decompose fitness into its primary component traits, longevity and fecundity, allowing evolutionary fitness to be an emergent property of the two. Our model demonstrates that selection on macronutrient appetites may affect life-history trade-offs and makes predictions that can be directly tested in artificial selection experiments.