Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed ...in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.
Background Atherosclerosis in >1 vascular bed (ie, polyvascular disease), often a feature of peripheral artery disease (PAD), is associated with high morbidity and mortality. We sought to identify ...risk factors for polyvascular involvement in patients with PAD. Methods and Results We performed 2-sample Mendelian randomization using an inverse-variance-weighted approach, to assess 60 exposures including size and lipid content of atherogenic lipoproteins, blood pressure, glycated hemoglobin, and smoking as causal mediators for polyvascular disease in patients with PAD. Genetic instruments for these exposures were obtained from prior genome-wide association studies. Patients with PAD were from the Mayo Vascular Disease Biorepository, and polyvascular disease (ie, concomitant coronary heart disease, cerebrovascular disease, and/or abdominal aortic aneurysm) was ascertained by validated phenotyping algorithms. Of 3279 patients with PAD, 61% had polyvascular disease. Genetically predicted levels of the lipid content and/or particle measures of very small and small size very low-density lipoprotein, intermediate-density lipoprotein, and large low-density lipoprotein were associated with polyvascular disease: odds ratios (OR) of 1.80 (95% CI, 1.23-2.61), 1.70 (95% CI, 1.17-2.61), and 1.40 (95% CI, 1.09-1.80) per 1 SD increase in genetically determined levels, respectively. Both genetically predicted diastolic and systolic blood pressure were associated with polyvascular disease; OR per 10 mm Hg genetic increase in diastolic and systolic blood pressure were 1.66 (95% CI, 1.19-2.33) and 1.31 (95% CI, 1.07-1.60), respectively. Conclusions Lifetime exposure to increased lipid content and levels of very small and small very low-density lipoprotein, intermediate-density lipoprotein, and large low-density lipoprotein particles as well as elevated blood pressure are associated with polyvascular involvement in patients with PAD. Reduction in levels of such exposures may limit progression of atherosclerosis in patients with PAD.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the ...results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.
•Critical limb ischemia (CLI) is a complication of advanced peripheral artery disease.•Automated identification of cases is challenging due to absence of a single International Classification of ...Diseases code for CLI.•A natural language processing (NLP)-based algorithm for ascertainment of CLI from narrative clinical notes was developed.•The CLI-NLP algorithm for identification of CLI had excellent positive predictive value with potential for translation to patient care.
Critical limb ischemia (CLI) is a complication of advanced peripheral artery disease (PAD) with diagnosis based on the presence of clinical signs and symptoms. However, automated identification of cases from electronic health records (EHRs) is challenging due to absence of a single definitive International Classification of Diseases (ICD-9 or ICD-10) code for CLI.
In this study, we extend a previously validated natural language processing (NLP) algorithm for PAD identification to develop and validate a subphenotyping NLP algorithm (CLI-NLP) for identification of CLI cases from clinical notes. We compared performance of the CLI-NLP algorithm with CLI-related ICD-9 billing codes. The gold standard for validation was human abstraction of clinical notes from EHRs. Compared to billing codes the CLI-NLP algorithm had higher positive predictive value (PPV) (CLI-NLP 96%, billing codes 67%, p < 0.001), specificity (CLI-NLP 98%, billing codes 74%, p < 0.001) and F1-score (CLI-NLP 90%, billing codes 76%, p < 0.001). The sensitivity of these two methods was similar (CLI-NLP 84%; billing codes 88%; p < 0.12).
The CLI-NLP algorithm for identification of CLI from narrative clinical notes in an EHR had excellent PPV and has potential for translation to patient care as it will enable automated identification of CLI cases for quality projects, clinical decision support tools and support a learning healthcare system.
Abstract
Pharmacogenomics (PGx) clinical decision support integrated into the electronic health record (EHR) has the potential to provide relevant knowledge to clinicians to enable individualized ...care. However, past experience implementing PGx clinical decision support into multiple EHR platforms has identified important clinical, procedural, and technical challenges. Commercial EHRs have been widely criticized for the lack of readiness to implement precision medicine. Herein, we share our experiences and lessons learned implementing new EHR functionality charting PGx phenotypes in a unique repository, genomic indicators, instead of using the problem or allergy list. The Gen-Ind has additional features including a brief description of the clinical impact, a hyperlink to the original laboratory report, and links to additional educational resources. The automatic generation of genomic indicators from interfaced PGx test results facilitates implementation and long-term maintenance of PGx data in the EHR and can be used as criteria for synchronous and asynchronous CDS.
A significant proportion of patients with elevated LDL and a clinical presentation of familial hypercholesterolemia do not carry known genetic mutations associated with hypercholesterolemia, such as ...defects in the LDL receptor. To identify new genes involved in the cellular uptake of LDL, we developed a novel whole-genome clustered regularly interspaced short palindromic repeat-Cas9 KO screen in HepG2 cells. We identified transgelin (TAGLN), an actin-binding protein, as a potentially new gene involved in LDL endocytosis. In silico validation demonstrated that genetically predicted differences in expression of TAGLN in human populations were significantly associated with elevated plasma lipids (triglycerides, total cholesterol, and LDL-C) in the Global Lipids Genetics Consortium and lipid-related phenotypes in the UK Biobank. In biochemical studies, TAGLN-KO HepG2 cells showed a reduction in cellular LDL uptake, as measured by flow cytometry. In confocal microscopy imaging, TAGLN-KO cells had disrupted actin filaments as well as an accumulation of LDL receptor on their surface because of decreased receptor internalization. Furthermore, TAGLN-KO cells exhibited a reduction in total and free cholesterol content, activation of SREBP2, and a compensatory increase in cholesterol biosynthesis. TAGLN deficiency also disrupted the uptake of VLDL and transferrin, other known cargoes for receptors that depend upon clathrin-mediated endocytosis. Our data suggest that TAGLN is a novel factor involved in the actin-dependent phase of clathrin-mediated endocytosis of LDL. The identification of novel genes involved in the endocytic uptake of LDL may improve the diagnosis of hypercholesterolemia and provide future therapeutic targets for the prevention of cardiovascular disease.
Despite potential clinical benefits, implementation of pharmacogenomics (PGx) faces many technical and clinical challenges. These challenges can be overcome with a comprehensive and systematic ...implementation model.
The development and implementation of PGx were organized into eight interdependent components addressing resources, governance, clinical practice, education, testing, knowledge translation, clinical decision support (CDS), and maintenance. Several aspects of implementation were assessed, including adherence to the model, production of PGx-CDS interventions, and access to educational resources.
Between August 2012 and June 2015, 21 specific drug–gene interactions were reviewed and 18 of them were implemented in the electronic medical record as PGx-CDS interventions. There was complete adherence to the model with variable production time (98–392 days) and delay time (0–148 days). The implementation impacted approximately 1,247 unique providers and 3,788 unique patients. A total of 11 educational resources complementary to the drug–gene interactions and 5 modules specific for pharmacists were developed and implemented.
A comprehensive operational model can support PGx implementation in routine prescribing. Institutions can use this model as a roadmap to support similar efforts. However, we also identified challenges that will require major multidisciplinary and multi-institutional efforts to make PGx a universal reality.
Genet Med19 4, 421–429.
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