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Jordan, I. K.

Publications and source records attributed to Jordan, I. K..

10 recordsLinked to original sources

The Consortium for Genomic Diversity, Ancestry, and Health in Colombia (CODIGO): building local capacity in genomics, bioinformatics, and precision medicine

The Consortium for Genomic Diversity, Ancestry, and Health in Colombia (CODIGO) aims to build a community of Colombian researchers in support of local capacity in genomics, bioinformatics, and precision health. Here, we present the first CODIGO data release and the consortium web platform, including annotations for more than 95 million genetic variants from 1,441 samples representing 14 populations from across the country. CODIGO samples show a wide range of African (16.7%), European (50.6%), and Indigenous American (32.8%) genetic ancestry components, with five distinct ancestry clusters. Thousands of ancestry-enriched variants, with divergent allele frequencies across clusters, show pharmacogenomic and clinical genetic associations. Examples include African ancestry-enriched variants associated with fast metabolism of the immunosuppressive drug tacrolimus and malaria resistance and European ancestry-enriched variants associated with nicotine dependence and hereditary hemochromatosis. CODIGO reveals the nexus between ancestry and health in Colombia and underscores the utility of collaborative genome sequence analysis efforts.

genomics↗

Explainable machine learning for health disparities: type 2 diabetes in the All of Us research program

Type 2 diabetes (T2D) is a disease with high morbidity and mortality and a disproportionate impact on minority groups. Machine learning (ML) is increasingly used to characterize T2D risk factors; however, it has not been used to study T2D health disparities. Our objective was to use explainable ML methods to discover and characterize T2D health disparity risk factors. We applied SHapley Additive exPlanations (SHAP), a new class of explainable ML methods that provide interpretability to ML classifiers, to this end. ML classifiers were used to model T2D risk within and between self-identified race and ethnicity (SIRE) groups, and SHAP values were calculated to quantify the effect of T2D risk factors. We then stratified SHAP values by SIRE to quantify the effect of T2D risk factors on prevalence differences between groups. We found that ML classifiers (random forest, lightGBM, and XGBoost) accurately modeled T2D risk and recaptured the observed prevalence differences between SIRE groups. SHAP analysis showed the top seven most important T2D risk factors for all SIRE groups were the same, with the order of importance for features differing between groups. SHAP values stratified by SIRE showed that income, waist circumference, and education best explain the higher prevalence of T2D in the Black or African American group, compared to the White group, whereas income, education and triglycerides best explain the higher prevalence of T2D in the Hispanic or Latino group. This study demonstrates that explainable ML can be used to elucidate health disparity risk factors and quantify their group-specific effects. Author SummaryWhile machine learning (ML) methods hold great promise for epidemiological studies, their practical utility is limited by interpretability. Increasingly complex ML models are great at predicting disease risk, but how they arrive at a given prediction is often obscured by model complexity. Explainable ML is an emerging discipline that seeks to render ML models more transparent by elucidating how and why input features contribute to output predictions. This study reports a novel application of explainable ML to epidemiology, focusing on type 2 diabetes (T2D) as a paradigm of health disparities. We found that ML classifiers were able to accurately model T2D disparities, for a large cohort of Black, Hispanic, and White Americans, and explainable ML revealed which risk factors contributed to the observed disparities and how. The results demonstrate that explainable ML can be a powerful tool for the discovery and characterization of health disparity risk factors.

bioinformatics↗

Genetic ancestry and population structure in the All of Us Research Program cohort

The NIH All of Us Research Program (All of Us) aims to build one of the worlds most diverse population biomedical datasets in support of equitable precision medicine. For this study, we analyzed participant genomic variant data to assess the extent of population structure and to characterize patterns of genetic ancestry for the All of Us cohort (n=297,549). Unsupervised clustering of genomic principal component analysis (PCA) data revealed a non-uniform distribution of genetic diversity and substantial population structure in the All of Us cohort, with dense clusters of closely related participants interspersed among less dense regions of genomic PC space. Supervised genetic ancestry inference was performed using genetic similarity between All of Us participants and global reference population samples. Participants show diverse genetic ancestry, with major contributions from European (66.4%), African (19.5%), Asian (7.6%), and American (6.3%) continental ancestry components. Participant genetic similarity clusters show group-specific genetic ancestry patterns, with distinct patterns of continental and subcontinental ancestry among groups. We also explored how genetic ancestry changes over space and time in the United States (US). African and American ancestry are enriched in the southeast and southwest regions of the country, respectively, whereas European ancestry is more evenly distributed across the US. The diversity of All of Us participants genetic ancestry is negatively correlated with age; younger participants show higher levels of genetic admixture compared to older participants. Our results underscore the ancestral genetic diversity of the All of Us cohort, a crucial prerequisite for genomic health equity.

bioinformatics↗

Rye: genetic ancestry inference at biobank scale

Biobank projects around the world are generating genomic data for many thousands and even millions of individuals. Computational methods are needed to handle these massive data sets, including tools for genetic ancestry (GA) inference. Current methods for GA inference are generally accurate, but they are slow and do not scale to biobank-size genomic datasets. Here we present Rye - a new algorithm for GA inference at biobank scale. We compare the accuracy and runtime performance of Rye to the widely used RFMix and ADMIXTURE programs, and we apply it to a dataset of 488,221 genome-wide variant samples from the UK Biobank. Rye infers GA based on principal component analysis (PCA) of genomic variant samples from ancestral reference populations and query individuals. The algorithms accuracy is powered by Metropolis-Hastings optimization and its speed is provided by non-negative least squares (NNLS) regression. Rye produces highly accurate GA estimates for three-way admixed populations - African, European, and Native American - compared to RFMix and ADMIXTURE (R2 = 0.998 - 1.00), and shows 50x runtime improvement compared to ADMIXTURE on the UK Biobank dataset. Rye analysis of UK Biobank samples demonstrates how it can be used to infer GA at different levels of relatedness. We discuss user consideration and options for the use of Rye; the program and its documentation are distributed on the GitHub repository: https://github.com/healthdisparities/rye.

bioinformatics↗

Population structure and pharmacogenomic risk stratification in the United States

Pharmacogenomic (PGx) variants mediate how individuals respond to medication, and response differences among racial/ethnic groups have been attributed to patterns of PGx diversity. We hypothesized that genetic ancestry (GA) would provide higher resolution for stratifying PGx risk, since it serves as a more reliable surrogate for genetic diversity than self-identified race/ethnicity (SIRE), which includes a substantial social component. We analyzed a cohort of 8,628 individuals from the United States (US), for whom we had both SIRE information and whole genome genotypes, with a focus on the three largest SIRE groups in the US: White, Black, and Hispanic. Whole genome genotypes were used to characterize individuals continental ancestry fractions - European, African, and Native American - and individuals were grouped according to their GA profiles. SIRE and GA groups were found to be highly concordant. Continental ancestry predicts individuals SIRE with >96% accuracy, and accordingly GA provides only a marginal increase in resolution for PGx risk stratification. PGx variants are highly diverged compared to the genomic background; 82 variants show significant frequency differences among SIRE groups, and genome-wide patterns of PGx variation are almost entirely concordant with SIRE. Nevertheless, 97% of PGx variation is found within rather than between groups. Examples of highly differentiated PGx variants illustrate how SIRE partitions PGx variation based on group-specific ancestry patterns and contains valuable information for risk stratification. Finally, we show that individuals who identify as Black or Hispanic benefit more when SIRE is considered for treatment decisions than individuals from the majority White population.

genomics↗

STing: accurate and ultrafast genomic profiling with exact sequence matches

Genome-enabled approaches to molecular epidemiology have become essential to public health agencies and the microbial research community. We developed the algorithm STing to provide turn-key solutions for molecular typing and gene detection directly from next-generation sequence data of microbial pathogens. Our implementation of STing uses an innovative k-mer search strategy that eliminates the computational overhead associated with the time consuming steps of quality control, assembly, and alignment required by more traditional methods. We compared STing to six of the most widely used programs for genome-based molecular typing and demonstrate its ease of use, accuracy, speed, and efficiency. STing shows superior accuracy and performance for standard multilocus sequence typing schemes, along with larger genome-scale typing schemes, and it enables rapid automated detection of antimicrobial resistance and virulence factor genes. We hope that the adoption of STing will help to democratize microbial genomics and thereby maximize its benefit for public health.

bioinformatics↗

Admixture-enabled selection for rapid adaptive evolution in the Americas

BackgroundAdmixture occurs when previously isolated populations come together and exchange genetic material. We hypothesized that admixture can enable rapid adaptive evolution in human populations by introducing novel genetic variants (haplotypes) at intermediate frequencies, and we tested this hypothesis via the analysis of whole genome sequences sampled from admixed Latin American populations in Colombia, Mexico, Peru, and Puerto Rico.\n\nResultsOur screen for admixture-enabled selection relies on the identification of loci that contain more or less ancestry from a given source population than would be expected given the genome-wide ancestry frequencies. We employed a combined evidence approach to evaluate levels of ancestry enrichment at (1) single loci across multiple populations and (2) multiple loci that function together to encode polygenic traits. We found cross-population signals of African ancestry enrichment at the major histocompatibility locus on chromosome 6, consistent with admixture-enabled selection for enhanced adaptive immune response. Several of the human leukocyte antigen genes at this locus (HLA-A, HLA-DRB51 and HLA-DRB5) showed independent evidence of positive selection prior to admixture, based on extended haplotype homozygosity in African populations. A number of traits related to inflammation, blood metabolites, and both the innate and adaptive immune system showed evidence of admixture-enabled polygenic selection in Latin American populations.\n\nConclusionsThe results reported here, considered together with the ubiquity of admixture in human evolution, suggest that admixture serves as a fundamental mechanism that drives rapid adaptive evolution in human populations.

genomics↗

Genomic characterization and computational phenotyping of nitrogen-fixing bacteria isolated from Colombian sugarcane fields

Previous studies have shown that the sugarcane microbiome harbors diverse plant growth promoting (PGP) microorganisms, including nitrogen-fixing bacteria, and the objective of this study was to design a genome-enabled approach to prioritize sugarcane associated nitrogen-fixing bacteria according to their potential as biofertilizers. Using a systematic high throughput approach, 22 pure cultures of nitrogen-fixing bacteria were isolated and tested for diazotrophic potential by PCR amplification of nitrogenase (nifH) genes, common molecular markers for nitrogen fixation capacity. Genome sequencing confirmed the presence of intact nitrogenase nifH genes and operons in the genomes of 18 of the isolates. Isolate genomes also encoded operons for phosphate solubilization, siderophore production operons, and other PGP phenotypes. Klebsiella pneumoniae strains comprised 14 of the 22 nitrogen-fixing isolates, and four others were members of closely related genera to Klebsiella. A computational phenotyping approach was developed to rapidly screen for strains that have high potential for nitrogen fixation and other PGP phenotypes while showing low risk for virulence and antibiotic resistance. The majority of sugarcane isolates were below a genotypic and phenotypic threshold, showing uniformly low predicted virulence and antibiotic resistance compared to clinical isolates. Six prioritized strains were experimentally evaluated for PGP phenotypes: nitrogen fixation, phosphate solubilization, and the production of siderophores, gibberellic acid and indole acetic acid. Results from the biochemical assays were consistent with the computational phenotype predictions for these isolates. Our results indicate that computational phenotyping is a promising tool for the assessment of benefits and risks associated with bacteria commonly detected in agricultural ecosystems.\n\nIMPORTANCEA genome-enabled approach was developed for the prioritization of native bacterial isolates with the potential to serve as biofertilizers for sugarcane fields in Colombias Cauca Valley. The approach is based on computational phenotyping, which entails predictions related to traits of interest based on bioinformatic analysis of whole genome sequences. Bioinformatic predictions of the presence of plant growth promoting traits were validated with experimental assays and more extensive genome comparisons, thereby demonstrating the utility of computational phenotyping for assessing the benefits and risks posed by bacterial isolates that can be used as biofertilizers. The quantitative approach to computational phenotyping developed here for the discovery of biofertilizers has the potential for use with a broad range of applications in environmental and industrial microbiology, food safety, water quality, and antibiotic resistance studies.

microbiology↗

Cryptic Native American ancestry recapitulates population-specific migration and settlement of the continental United States

European and African descendants settled the continental US during the 17th-19th centuries, coming into contact with established Native American populations. The resulting admixture among these groups yielded a significant reservoir of cryptic Native American ancestry in the modern US population. We analyzed the patterns of Native American admixture seen for the three largest genetic ancestry groups in the US population: African American, European American, and Hispanic/Latino. The three groups show distinct Native American ancestry profiles, which are indicative of their historical patterns of migration and settlement across the country. Native American ancestry in the modern African American population does not coincide with local geography, instead forming a monophyletic group with origins in the southeastern US, consistent with the Great Migration of the early 20th century. European Americans show Native American ancestry that tracks their geographic origins across the US, indicative of ongoing contact during westward expansion, and Native American ancestry can resolve Hispanic/Latino individuals into distinct local groups formed by more recent migration from Mexico and Puerto Rico. We found an anomalous pattern of Native American ancestry from the US southwest, which most likely corresponds to the Nuevomexicano descendants of early Spanish settlers to the region. We addressed a number of controversies surrounding this population, including the extent of Sephardic Jewish ancestry. Nuevomexicanos are less admixed than nearby Mexican-American individuals, with more European and less Native American and African ancestry, and while they do show demonstrable Sephardic Jewish ancestry, the fraction is no greater than seen for other Hispanic/Latino populations.

genetics↗

Assortative mating on ancestry-variant traits in admixed Latin American populations

BackgroundAssortative mating is a universal feature of human societies, and individuals from ethnically diverse populations are known to mate assortatively based on similarities in genetic ancestry. However, little is currently known regarding the exact phenotypic cues, or their underlying genetic architecture, which inform ancestry-based assortative mating.\n\nResultsWe developed a novel approach, using genome-wide analysis of ancestry-specific haplotypes, to evaluate ancestry-based assortative mating on traits whose expression varies among the three continental population groups - African, European, and Native American - that admixed to form modern Latin American populations. Application of this method to genome sequences sampled from Colombia, Mexico, Peru, and Puerto Rico revealed widespread ancestry-based assortative mating. We discovered a number of anthropometric traits (body mass, height, facial development and waist-hip ratio) and neurological attributes (educational attainment and schizophrenia) that serve as phenotypic cues for ancestry-based assortative mating. Major histocompatibility complex (MHC) loci show population-specific patterns of both assortative and disassortative mating in Latin America. Ancestry-based assortative mating in the populations analyzed here appears to be driven primarily by African ancestry.\n\nConclusionsThis study serves as an example of how population genomic analyses can yield novel insights into human behavior.

genomics↗