Highlights d Genomic data linked to health records capture demography in health systems d Genetic networks reveal recent common ancestry in diverse populations d Evidence of many founder populations in New York City d Fine-scale population structure impacts genetic risk predictions

Whole transcriptome studies typically yield large amounts of data, with expression values for all genes or transcripts of the genome. The search for genes of interest in a particular study setting can thus be a daunting task, usually relying on automated computational methods. Moreover, most biological questions imply that such a search should be performed in a multivariate setting, to take into account the inter-genes relationships. Differential expression analysis commonly yields large lists of genes deemed significant, even after adjustment for multiple testing, making the subsequent study possibilities extensive. Here, we explore the use of supervised learning methods to rank large ensembles of genes defined by their expression values measured with RNA-Seq in a typical 2 classes sample set. First, we use one of the variable importance measures generated by the random forests classification algorithm as a metric to rank genes. Second, we define the EPS (extreme pseudo-samples) pipeline, making use of VAEs (Variational Autoencoders) and regressors to extract a ranking of genes while leveraging the feature space of both virtual and comparable samples. We show that, on 12 cancer RNA-Seq data sets ranging from 323 to 1,210 samples, using either a random forests-based gene selection method or the EPS pipeline outperforms differential expression analysis for 9 and 8 out of the 12 datasets respectively, in terms of identifying subsets of genes associated with survival. These results demonstrate the potential of supervised learning-based gene selection methods in RNA-Seq studies and highlight the need to use such multivariate gene selection methods alongside the widely used differential expression analysis.

The ability to identify segments of genomes identical-by-descent (IBD) is a part of standard workflows in both statistical and population genetics. However, traditional methods for finding local IBD across all pairs of individuals scale poorly leading to a lack of adoption in very large-scale datasets. Here, we present iLASH, an algorithm based on similarity detection techniques that shows equal or improved accuracy in simulations compared to current leading methods and speeds up analysis by several orders of magnitude on genomic datasets, making IBD estimation tractable for millions of individuals. We apply iLASH to the PAGE dataset of ~52,000 multi-ethnic participants, including several founder populations with elevated IBD sharing, identifying IBD segments in ~3 minutes per chromosome compared to over 6 days for a state-of-the-art algorithm. iLASH enables efficient analysis of very large-scale datasets, as we demonstrate by computing IBD across the UK Biobank (~500,000 individuals), detecting 12.9 billion pairwise connections.

Understanding population health disparities is an essential component of equitable precision health efforts. Epidemiology research often relies on definitions of race and ethnicity, but these population labels may not adequately capture disease burdens specific to sub-populations. Here we propose a framework for repurposing data from Electronic Health Records (EHRs) in concert with genomic data to explore enrichment of disease within sub-populations. Using data from a diverse biobank in New York City, we genetically identified 17 sub-populations, and noted the presence of genetic founder effects in 7. By then linking community membership to the EHR, we were able to identify over 600 health outcomes that were statistically enriched within a specific population, with many representing known associations, and many others being novel. This work reinforces the utility of linking genomic data to EHRs, and provides a framework towards fine-scale monitoring of population health.

The ability to identify segments of genomes identical-by-descent (IBD) is a part of standard workflows in both statistical and population genetics. However, traditional methods for finding local IBD across all pairs of individuals scale poorly leading to a lack of adoption in very large-scale datasets. Here, we present iLASH, IBD by LocAlity-Sensitive Hashing, an algorithm based on similarity detection techniques that shows equal or improved accuracy in simulations compared to the current leading method and speeds up analysis by several orders of magnitude on genomic datasets, making IBD estimation tractable for hundreds of thousands to millions of individuals. We applied iLASH to the Population Architecture using Genomics and Epidemiology (PAGE) dataset of ~52,000 multi-ethnic participants, including several founder populations with elevated IBD sharing, which identified IBD segments on a single machine in an hour (~3 minutes per chromosome compared to over 6 days per chromosome for a state-of-the-art algorithm). iLASH is able to efficiently estimate IBD tracts in very large-scale datasets, as demonstrated via IBD estimation across the entire UK Biobank (~500,000 individuals), detecting nearly 13 billion pairwise IBD tracts shared between ~11% of participants. In summary, iLASH enables fast and accurate detection of IBD, an upstream step in applications of IBD for population genetics and trait mapping.Inferring segments of the genome inherited Identical-By-Descent (IBD) is a standard method in modern genomics pipelines to understand population structure and infer relatedness across datasets 1-6 . Furthermore, it can be leveraged for alternative mapping strategies such as populationbased linkage 7 , capturing rare variation from array datasets 8 , and improving long-range phasing. However, the ability to scale this process to mega-scale datasets while comparing individuals along the genome has been limited. While approximate methods have been developed to improve

Groups of distantly related individuals who share a short segment of their genome identical-by-descent (IBD) can provide insights about rare traits and diseases in massive biobanks using IBD mapping. Clustering algorithms play an important role in finding these groups accurately and at scale. We set out to analyze the fitness of commonly used, fast and scalable clustering algorithms for IBD mapping applications. We designed a realistic benchmark for local IBD graphs and utilized it to compare the statistical power of clustering algorithms via simulating 2.3 million clusters across 850 experiments. We found Infomap and Markov Clustering (MCL) community detection methods to have high statistical power in most of the scenarios. They yield a 30% increase in power compared to the current state-of-art approach, with a 3 orders of magnitude lower runtime. We also found that standard clustering metrics, such as modularity, cannot predict statistical power of algorithms in IBD mapping applications. We extend our findings to real datasets by analyzing the Population Architecture using Genomics and Epidemiology (PAGE) Study dataset with 51,000 samples and 2 million shared segments on Chromosome 1, resulting in the extraction of 39 million local IBD clusters. We demonstrate the power of our approach by recovering signals of rare genetic variation in the Whole-Exome Sequence data of 200,000 individuals in the UK Biobank. We provide an efficient implementation to enable clustering at scale for IBD mapping for various populations and scenarios.

Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have a significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors; however, recent work suggests prevalence may differ between sub-groups. Here, we examined a large cohort of diverse adults in the BioMe biobank in New York City. We observed the prevalence of PAD at 1.7% in EAs vs. 8.5% and 9.4% in AAs and HLs, respectively, and among HL sub-groups, the prevalence was found at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs [OR = 3.15 (95% CI 2.33–4.25), p < 6.44 × 10−14]. To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry and PAD in Dominican BioMe participants (N = 1,813) separately from European, African, and Native American (NAT) continental ancestry tracts. The top association with PAD was an NAT ancestry tract at chromosome 2q35 [OR = 1.96 (SE = 0.16), p < 2.75 × 10−05) with 22.6% vs. 12.9% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA) LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. Efforts to reproduce the signal in other Hispanic cohorts were unsuccessful. In summary, we showed how leveraging health system data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a putative risk locus in a Dominican population.

An individual's disease risk is affected by the populations that they belong to, due to shared genetics and shared environment. The study of fine-scale populations in clinical care will be important for reducing health disparities and for developing personalized treatments. In this work, we developed a novel health monitoring system, which leverages biobank data and electronic medical records from over 40,000 UCLA patients. Using identity by descent (IBD), we analyzed one type of fine-scale population, an IBD cluster. In total, we identified 376 IBD clusters, including clusters characterized by the presence of many significantly understudied communities, such as Lebanese Christians, Iranian Jews, Armenians, and Gujaratis. Our analyses identified thousands of novel associations between IBD clusters and clinical diagnoses, physician offices, utilization of specific medical specialties, pathogenic allele frequencies, and changes in diagnosis frequency over time. To enhance the impact of the research and engage the broader community, we provide a web portal to query our results: www.ibd.la