Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships

Rare and common genetic determinants of metabolic individuality and their effects on human health

Garrod’s concept of ‘chemical individuality’ has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant–metabolite associations (P < 1.25 × 10−11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant–metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships

Availability of Advance Care Planning Documentation for Older Emergency Department Patients: A Cross-Sectional Study

Introduction: Increasing advance care planning (ACP) among older adults is a national priority. Documentation of ACP in the electronic health record (EHR) is particularly important during emergency care. Objective: We sought to characterize completion and availability of ACP among a subset of older patients at an academic emergency department (ED) with an integrated EHR. Methods: In this cross-sectional study, patients were eligible if aged ≥80 years or aged 65–79 with ≥1 indicator of high risk for short-term mortality. Patient-reported completion of ACP and availability of ACP documentation in the EHR were assessed. Results: Among study patients (n = 104), 59% reported completing some form of ACP: living will 52%, heathcare power of attorney 54%, do not resuscitate 38%, and medical orders for scope of treatment or physician orders for life-sustaining treatment 6%. Whites were more likely to report having some form of ACP than minorities (66% vs. 37%, p < 0.01), as were patients aged ≥80 years than those aged 65–79 (79% vs. 44%, p < 0.01). Only 13% of all patients had either a current code status or any other current ACP documentation in the EHR. Among patients whose primary care provider uses the same EHR system as the study ED, only 19% had a current code status or any other ACP documentation in the EHR. Conclusion: In a sample of older ED patients likely to benefit from ACP, few patients had documented end-of-life care preferences in the EHR

Identifying a Proxy for Health Care as Part of Routine Medical Inquiry

BACKGROUND: Physician-initiated advance care planning is desirable, effective, and routinely indicated for competent adult patients, but doctors are often reluctant to begin the necessary conversations. OBJECTIVE: To determine whether patients are willing and able to designate a surrogate for medical decision making, when asked to do so as part of routine medical inquiry. DESIGN, PATIENTS, MEASUREMENTS: A survey asking patients to name a health care agent was designed and administered in the context of routine clinical care. Participants were drawn from a consecutive sample of 309 competent adult outpatients. Data were analyzed using ordinary descriptive statistics. RESULTS: Two hundred ninety-eight of 309 patients (response rate, 96%) completed the survey and were willing and able to specify a proxy for health care. One third of married participants did not choose their spouse as proxy. CONCLUSIONS: Asking patients to identify a surrogate for medical decision making opens the door for ongoing individualized medical care planning in the context of ordinary patient-physician interaction. This approach is applicable to all competent adults. Documenting proxy choice protects a patient's wishes and preferences until more definitive planning is accomplished